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5 Human by organ site

Malignant tumours can develop in any organ from cell types still actively engaged in replication. The nomenclature refers to the tissue of origin: (derived from epithelial tis- sues), (soft tissues and bone), glioma (brain), leukaemia and (haematopoietic and lymphatic tis- sues), being by far the most frequent type. Irrespective of the site, malignant transformation is a multi- step process involving the sequential accumulation of genet- ic alterations. However, the types of or suppressor involved and the sequence of amplification or varies greatly in different organs and target cells. Susceptibility to carcinogenic factors may depend on the capacity to metabolize chemical , to effectively repair DNA damage or to harbour chronic . There are also marked variations in response to therapy and overall clin- ical outcome. WCR-S5.Q (composition) 27/01/03 10:27 Page 182

LUNG

SUMMARY

> is the most common tumour worldwide, with 900,000 new cases each year in men and 330,000 in women It is the leading cause of death from can- cer.

> In men, more than 80% of lung cancer cases are caused by ; in women, the attributable risk is less (about 70% in Northern Europe; 45% worldwide).

> Some occupational exposures and air (including environmental smoke) make a minor contribu- tion to incidence.

> No population-based screening proce- dures have been established. <5.7 <16.7 < 27.8 < 48.4 < 95.5 Age-standardized incidence/100,000 population > No effective treatment is available; the five-year survival rate for lung cancer Fig. 5.1 The global incidence of lung cancer in men. Incidence is highest in Europe, especially Eastern patients is less than 15%. Europe, and in North America and Australia.

USA and Maoris from New Zealand and are The association between lung cancer and followed by those in the United Kingdom smoking is probably the most intensively and the Netherlands. The lowest incidence investigated relationship in epidemiology. rates are reported from Africa and Smoking causes lung cancer. An increase Definition Southern Asia [2] (Fig. 5.1). Rates in in tobacco consumption is paralleled some Lung cancer almost exclusively involves car- women are high in the USA, Canada, 20 years later by an increase in the inci- cinomas, these tumours arising from Denmark and the UK, but are lower in dence of lung cancer, and a decrease in epithelia of the trachea, bronchi or lungs. countries such as France, Japan and Spain, consumption (e.g. a large proportion of There are several histological types, the in which the prevalence of smoking in smokers who quit) is followed by a most common being squamous cell carci- women has increased only recently. The decrease in incidence. In both men and noma, and small (oat) cell lowest rates (<3 cases per 100,000 popu- women, the incidence of lung cancer is low carcinoma. lation) are recorded in Africa and India. In before age 40, and increases up to at least most countries, lung cancer incidence is age 70. The situation in China appears to Epidemiology greater in lower socioeconomic classes; to be different, given the relatively high rates Lung cancer is the most common malignant a large extent, this pattern is explained by of lung cancer (particularly adenocarcino- disease worldwide, and is the major cause differences in the prevalence of smoking. ma) recorded among Chinese women, of death from cancer, particularly amongst Having risen dramatically since the turn of despite a low prevalence of smoking. men. It was a rare disease until the begin- the century, lung cancer mortality The association between lung cancer and ning of the 20th century. Since then, the amongst males is now abating in several smoking was demonstrated in the 1950s occurrence of lung cancer has increased countries, including the USA, the UK and and has been recognized by public health rapidly and it now accounts for an estimat- Finland (Fig. 5.4). and regulatory authorities since the mid- ed 901,746 new cases each year among 1960s. The risk of lung cancer among men and 337,115 among women [1]. Etiology smokers relative to the risk among never- The highest incidence rates (>100 cases The geographical and temporal patterns of smokers is in the order of 8-15 in men and per 100,000 population) are recorded lung cancer incidence are overwhelmingly 2-10 in women. This overall risk reflects among Afro-Americans from New Orleans, determined by consumption of tobacco. the contribution of the different aspects of

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: age at start, average An association between exposure to pas- consumption, duration of smoking, time sive smoke and lung cancer risk in non- since quitting, type of tobacco product and smokers has been shown in a number of inhalation pattern, with duration being the case-control and cohort studies (Fig. 5.9). dominant factor. While lung cancer risks In general, such studies involve exposure rise sharply with increasing numbers of to environmental tobacco smoke in the cigarettes per day, the trends have been home or the workplace or both. In many reported to be even stronger with duration instances, the increased risk recorded is at of smoking. Such findings are essentially the margin of statistical significance, and consistent in men from diverse communi- in some cases less than that. However, a ties, including those of the USA, UK and causal relationship has been recognized Fig. 5.2 The incidence of smoking-induced lung China. In populations with a long duration on the basis of consistent findings and tak- cancer in women is increasing in many countries and heavy intensity of cigarette usage, the ing account of biological plausibility (that at an alarming rate. proportion of lung cancer attributable to is, the established carcinogenic activity of smoking is of the order of 90% [3]. tobacco smoke). The magnitude of the risk As compared to continuous smokers, the is in the order of 15-20% [4]. excess risk sharply decreases in ex-smok- Occupational exposures have been associ- ers approximately five years after quitting, ated with increased risk of lung cancer but a small excess risk persists in long- more than of any other tumour type term quitters throughout life. The risk of (Occupational exposures, p33). For many lung cancer is slightly lower among smok- workplace exposures associated with a ers of low-tar and low-nicotine cigarettes high risk of lung cancer, the specific than among other smokers, although “low- agent(s) responsible for the increased risk tar smokers” tend to compensate for lower has been identified. Risk of lung cancer yields of nicotine by deeper inhalation or and (a malignant tumour of greater consumption. A relative reduction the pleura) is increased in a variety of in risk has also been observed among occupations involving exposure to long-term smokers of filtered cigarettes of various types. A characteristic compared to smokers of unfiltered ciga- of asbestos-related lung cancer is its syn- rettes. Smokers of black (air-cured) tobac- ergistic relationship to cigarette smoking: co cigarettes are at a two to three-fold risk is increased multiplicatively amongst higher risk of lung cancer than smokers of persons who both smoke and are exposed blond (flue-cured) tobacco cigarettes. A to asbestos. Such a phenomenon has been causal association with lung cancer has recorded in relation to other occupational also been shown for consumption of lung cancers. Fig. 5.3 Smoking is the primary cause of lung can- cigars, cigarillos, pipe, bidis and water Atomic bomb survivors and patients treat- cer. “Every cigarette is doing you damage” com- pipe. ed with radiotherapy are at increased risk paign, Australia.

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1960197019801990 2000 1960197019801990 2000 1960197019801990 2000 1960197019801990 2000 1960197019801990 2000 1960197019801990 2000 Fig. 5.4 Trends in mortality from lung cancer in men and women. Countries in which the smoking habit was first established are also the first to show decreas- es in mortality following reduction in the prevalence of smoking. D.M. Parkin et al. (2001) Eur J Cancer 37 Suppl. 8: S4 - 66.

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Detection Sputum cytology and radiology (chest X-ray and computed tomography (CT)) scans are the only non-invasive methods of detecting early lung cancer. Sensitivity can be variable dependent on histological type (greater for small cell and squamous cell carcinomas), tumour size and location [10]. Sputum cytotology may be appropri- ate for certain clearly defined groups or individuals at risk of lung cancer. Currently, however, there are no practica- Fig. 5.5 The relative risk of lung cancer is markedly lower five years after quitting, and decreases further ble and effective procedures available to with time (by comparison with those who continue to smoke). provide population-based screening for lung cancer. The signs and symptoms of lung cancer depend on the location of the tumour, the spread and the effects of metastatic growth. Many patients are diagnosed on the basis of an asymptomatic lesion dis- covered incidentally on X-ray. Symptoms indicative of the primary tumour include fatigue, decreased activity, persistent cough, laboured breathing, chest pain, decreased appetite and weight loss. Hoarseness as a result of recurrent laryn- geal nerve injury may be provoked by left- sided lesions, and superior vena cava syn- drome by right-sided lesions. Wheeze or stridor may also develop in advanced stages. Continuous tumour growth may result in collapsed lung, pneumonia and abscess formation. Fig. 5.6 The relative risk of major histological types of cancer by average cigarette consumption. In some patients with lung cancer, metastatic deposits lead to the first symp- toms; the majority of patients with lung of lung cancer. Although the magnitude of burning heaters without proper exhaust cancer already have locally advanced dis- the increased risk is moderate (relative risk, emission (e.g. kang in North-Eastern China) ease or distant metastases at diagnosis; 1.5 to 2 for cumulative exposure in excess and high-temperature cooking using unre- common metastatic sites are mediastinal of 100 rads), the number of extra cases of fined vegetable oils, such as rapeseed oil and supraclavicular lymph nodes, liver, lung cancer exceeds that of other neo- (common in several parts of China). Indoor adrenal glands, brain, lungs, pleura and plasms. Underground miners exposed to levels of benzo[a]pyrene have been report- pericardium. Less commonly, a patient radioactive and its decay pro- ed to be very high in such circumstances may be diagnosed on the basis of a para- ducts have been found to be at an increased [8]. Indoor air pollution is a major cause of neoplastic syndrome (signs and symp- risk of lung cancer [5,6]. Indoor exposure to lung cancer in Chinese women, who experi- toms not produced by the direct effect of radon has been associated with a marginal ence very high lung cancer rates despite a a tumour or its ), such as the increase in risk of lung cancer. low prevalence of smoking. syndrome of inappropriate secretion of There is abundant evidence that lung can- There is convincing evidence that a diet antidiuretic in small cell lung cer rates are higher in cities than in rural rich in vegetables and fruits exerts a pro- cancers. Diagnostic procedures involve settings [7]. Urban air pollution is a risk tective effect against lung cancer [9]. chest X-ray, bronchoscopy and sputum factor for lung cancer and the excess risk Subjects in the categories of highest con- analysis, as well as CT and magnetic may be in the order of 50% (Environmental sumption experience about 50% of the risk nuclear resonance. CT imaging is used for pollution, p39). Two particular sources of of lung cancer compared with subjects in the detection of liver and adrenal gland indoor air pollution are the use of coal- the categories of lowest consumption. metastases. Clinical and image-based

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diagnosis is usually confirmed by histolog- of lung cancer in many populations. It ical examination of obtained by tends to grow slowly, three to four years fibre-optic endoscopy or surgical speci- being required for development from an in T mens. Percutaneous fine needle aspira- situ lesion to a clinically apparent tumour. tion may be used to diagnose peripheral Adenocarcinoma is less strongly associat- tumours, or in the event of inconclusive ed with smoking. This tumour is often bronchoscopy results. The complementa- peripheral in origin and may present as a ry use of spiral CT in screening may solitary peripheral nodule, multifocal dis- M improve the robustness with which lung ease, or a rapidly progressive pneumonic cancer of any cell type can be detected form, spreading from lobe to lobe. These early [11]. However, many cases of lung tumours form glands and produce mucin. Fig. 5.7 A lung tumour viewed by computed cancer, especially at older ages and in low Early metastasis is common, particularly to tomography. T= tumour, M= mediastinum. resource countries, are diagnosed only on the brain, pleura and adrenal glands. Large the basis of clinical and X-ray evidence. cell carcinoma often appears in the distal bronchi and is generally undifferentiated. and genetics Small cell carcinoma typically arises in the Principal histological types of lung cancer central endobronchial location and is com- are , adenocarci- monly aggressive and invasive; frequently noma, large cell carcinoma and small cell metastases are present at diagnosis. carcinoma. The first three are also referred Although the histogenesis and the putative to as “non-small cell” lung carcinomas. In precursor lesions of lung cancer are large- North America and Europe over the last 20 ly unknown for the different histological years, the proportion of squamous cell types, the presence of putative precursor Fig. 5.8 of a small cell lung carcinoma, carcinoma, previously the predominant lesions (, metaplasia and carcino- showing a monomorphic proliferation of small type, has been decreasing, while an ma in situ) are commonly reported in tumour cells with dense nuclei and poorly-defined increase of adenocarcinoma has been resection specimens and/or cytology for cytoplasm, invading the deep parts of the recorded in both genders. Squamous cell squamous cell carcinoma [12]. bronchial wall. carcinoma arises most frequently in proxi- A positive familial history of lung cancer mal segmental bronchi and is associated has been identified as a risk factor. with squamous metaplasia. This tumour Increased risk of lung cancer has been ciencies in DNA repair capacity [13]. type is very strongly associated with smok- associated with certain polymorphisms of Genetic changes associated with progres- ing and represents the most common type the cytochrome P450 genes and with defi- sion of premalignant lesions to malignant tumours have been identified [14] (Table 5.1). in the are fre- quent events in lung cancer, although ade- nocarcinoma shows a lower prevalence of p53 mutations than other histological types. Among lung cancer cases, the pro- portion of p53 mutations increases with duration and amount of tobacco smoking. A wide distribution and a variety of types of p53 mutation have been observed follow- ing different environmental exposures; their analysis is likely to elucidate different mechanisms involved in lung carcinogene- sis [15]. Activating point mutations in the KRAS oncogene (mainly at codon 12) occur in adenocarcinoma, with a prevalence rang- ing from 15% to 60%. This alteration, which is more prevalent in tumours from smok- Fig. 5.9 Relative risk of lung cancer (odds ratio) among non-smokers by cumulative exposure to envi- ers than from non-smokers, may be a rel- ronmental tobacco smoke from the spouse and workplace. Pooled analysis of data from two studies in atively early event in lung . the USA and in Europe. Frequent loss of heterozygosity and aber-

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women), serum concentration of lactate dehydrogenase and the detection of bone and liver metastases. Non-small cell carcinomas are grouped T together because of similarity in the response of the different subtypes to treatment. Early stage tumours are treat- ed by surgical resection, if possible, with patients who refuse or who are deemed medically unfit for surgery being treated with radiotherapy. More advanced stage disease may be treated with a combina- tion of surgery and radiotherapy. Radio- Fig. 5.11 A smoking-induced lung cancer. Autopsy therapy can be effective for palliation of specimen of a large-cell carcinoma of the left lung (T) with nearby metastases (arrow). superior vena cava obstruction, haemopt- ysis (expectoration of blood), pain, dys- pnoea (shortness of breath), brain metas- lung cancer is , with con- Fig. 5.10 Five-year relative survival rates of lung tases and atelectasis (partial or complete comitant radiotherapy being used at an cancer patients after diagnosis. lung collapse) [17]. The introduction of early point for patients with limited dis- cisplatin-containing drug combinations ease. Surgery may be considered in the rant transcripts of the Fragile Histidine Triad improves the rate of response to therapy, case of a patient with a small isolated (FHIT) gene, located at with accompanying moderate to severe lesion [17]. Combinations of drugs, as a 3p14.2, occur in pre-neoplastic and neo- toxicity. Combination chemotherapy general rule, yield better results than the plastic lesions and such changes have (using cisplatin and etoposide, or mito- respective agents used alone and those been linked to smoking and asbestos mycin, vinblastine and cisplatin) with commonly used include cisplatin and exposure. Homozygous deletions and radiotherapy also seems to convey a sur- etoposide, cyclophosphamide, doxoru- transcriptional silencing due to methyla- vival advantage in patients with stage III bicin and vincristine, and cyclophos- tion in the locus of the cyclin-dependent disease. More recently, paclitaxel has phamide, doxorubicin and etoposide. kinase inhibitor p16INK4A on chromosome shown significant activity when used as a More recently, the taxanes paclitaxel and 9p have been found in about 40% of lung single agent. Other drugs credited with docetaxel and the camptothecins irinote- cancer cases. Other have also response rates of at least 15% include can and topotecan have shown promise as been implicated in lung carcinogenesis: in gemcitabine, docetaxel and vinorelbine. single agents and in combination. Despite particular, ERBB1 and ERBB2; C-MYC, N- The mainstay of treatment for small cell good initial responses to therapy, relapse MYC and L-MYC, and BCL2 [16]. No clear correlations have been established as yet between particular genetic changes and Gene Locus Alteration Frequency (% of tumours) histological type of tumour. Small cell Adeno- Squamous cell carcinoma carcinoma carcinoma Management p53 17p13 Deletion, 70-90 30 50 Staging of lung cancer is based on an mutation (G:C>T:A), assessment of the presence of distant (overexpression) metastases and the condition of the chest KRAS 12p21 Mutation (GGT>TGT) <1 15-60 8-9 and mediastinum (the tissues and organs separating the lungs), in accordance with CDKN2A/ 9p21 Deletion, mutation, <1 27-59 33-40 the universally used TNM system (Box: p16 INK4 hypermethylation TNM, p124). Although treatment protocols are subject to refinement and improve- LOH 3p 3p Deletion (loss of 100 50-85 ment, the outlook for patients diagnosed heterozygosity) with lung cancer is poor by comparison FHIT 3p14.2 Deletion (loss of 76 40-76 with many other cancers. The main prog- heterozygosity), nostic factors are stage of the tumour and transcriptional performance status; other important fac- dysregulation tors include amount of weight loss, gender (men having a poorer prognosis than Table 5.1 Genetic alterations in lung tumours.

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is frequent and survival rates are poor based series from high-income countries, most patients will die of disease progres- (two-year survival of 20-30% for limited the five-year relative survival barely sion and current treatments can be highly stage disease) although limited stage exceeds 10%. However, survival is better toxic. Trials of vaccination against tumour small cell cancer has a cure rate of about among patients aged less than 55 at diag- specific antigens such as carcinoembry- 10-15%. Treatment should be considered nosis (five-year relative survival in the onic antigen (CEA) and Fuc-GM1 are since good symptom control can be order of 15%). There is evidence of a very underway [18]. A further strategy under attained. Prophylactic cranial irradiation modest improvement in survival during the investigation is that of vaccination with may reduce the risk of brain metastases, last 20 years. In developing countries, sur- tumour cells designed to have enhanced and has recently been shown in meta- vival rates are comparable to those in immunogenicity due to the expression of, analysis to prolong survival in limited industrialized countries. for example, cytokine granulocyte- small cell cancer. In the light of poor survival rates, preven- macrophage colony-stimulating factor Although survival for stage I cancers may tion of lung cancer is a priority. However, (GM-CSF). reach about 65%, overall survival from lung the development of novel therapies cancer is poor (Fig. 5.10). In population- remains important in view of the fact that

REFERENCES WEBSITE 1. Ferlay J, Bray F, Parkin DM, Pisani P (2001) Globocan Fund/American Institute of Cancer NCI Lung Cancer Homepage: 2000: Cancer Incidence and Mortality Worldwide (IARC Research, 130-147. http://www.cancer.gov/cancer_information/cancer_type/ lung/ Cancer Bases No. 5), Lyon, IARCPress. 10. Lam S, Shibuya H (1999) Early diagnosis of lung can- 2. Parkin DM, Whelan SL, Ferlay J, Raymond L, Young J, cer. Clin Chest Med, 20: 53-61. eds (1997) Cancer Incidence in Five Continents, Vol. VII 11. Mulshine JL, Henschke CI (2000) Prospects for lung- (IARC Scientific Publication No. 143 and IARC Cancerbase cancer screening. Lancet, 355: 592-593. No. 2), Lyon, IARCPress. 12. Montuenga LM, Mulshine JL (2000) New molecular 3. IARC (1986) Tobacco Smoking (IARC Monographs on strategies for early lung cancer detection. Cancer Invest, the Evaluation of the Carcinogenic Risk of Chemicals to 18: 555-563. Humans, Vol. 38), Lyon, IARCPress. 13. Wright GS, Gruidl ME (2000) Early detection and pre- 4. Hackshaw AK, Law MR, Wald NJ (1997) The accumu- vention of lung cancer. Curr Opin Oncol, 12 : 143-148. lated evidence on lung cancer and environmental tobacco smoke. BMJ, 315: 980-988. 14. Bunn PA, Jr., Soriano A, Johnson G, Heasley L (2000) New therapeutic strategies for lung cancer: biology and 5. Samet JM (1989) Radon and lung cancer. J Natl Cancer molecular biology come of age. Chest, 117: 163S-168S. Inst, 81: 745-757. 15. Bennett WP, Hussain SP, Vahakangas KH, Khan MA, 6. Lubin JH, Boice JD, Edling C, Hornung RW, Howe G, Shields PG, Harris CC (1999) Molecular epidemiology of Kunz E (1994) Radon and lung cancer risk: a joint analysis human cancer risk: gene-environment interactions and p53 of 11 underground miners studies. In: Public Health mutation spectrum in human lung cancer. J Pathol, 187: 8- Service, National Institute of Health eds, NIH Publication 18. No. 94-3644, Washington D.C., US Department of Health and Human Services. 16. Minna JD, Sekido Y, Fong KM, Gazdar AF (1997) Molecular biology of lung cancer. In: DeVita VT, Hellman S, 7. Speizer FE, Samet JM (1994) Air pollution and lung can- Rosenberg, SA eds, Cancer: Principles and Practice of cer. In: Samet JM ed., Epidemiology of Lung Cancer (Lung , Philadelphia, Lippincott-Raven Publishers, 849- Biology in Health and Disease, Vol. 74), New York, Marcel 857. Dekker, 131-150. 17. Williams C (1998) Lung cancer. In: Morris D, Kearsley J, 8. Smith KR, Liu Y (1994) Indoor air pollution in develop- Williams C eds, Cancer: a comprehensive clinical guide, ing countries. In: Samet JM ed., Epidemiology of Lung Harwood Academic Publishers, 141-152. Cancer (Lung Biology in Health and Disease, Vol. 74), New York, Marcel Dekker, 151-184. 18. Antonia SJ, Sotomayor E (2000) Gene therapy for lung cancer. Curr Opin Oncol, 12: 138-142. 9. World Cancer Research Fund (1997) Lung. In: WCRF/AICR ed, Food, Nutrition and the Prevention of Cancer: a Global Perspective, Washington, DC, World

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BREAST CANCER

SUMMARY

> is the most common affecting women, with more than one million cases occurring world- wide annually. Affluent societies carry the greatest risk, with incidence rates of >80 per100,000 population per year.

> The worldwide breast cancer epidemic has many etiological factors, including reproductive history (early menarche, late or no pregnancy), and Western lifestyle (high caloric diet, lack of physi- cal activity).

>In some regions, including North America, Western Europe and Australia, breast cancer mortality rates have start- ed to decline, mainly due to improve- < 19.3 < 26.1 < 36.0 < 54.2 < 91.6 ments in early detection and treatment Age-standardized rate/100,000 population (chemotherapy and ). Five- year survival rates are higher than 70% Fig. 5.12 The global burden of breast cancer in women; incidence is high in developed countries such as the USA, UK and Australia. in most developed countries.

> Breast cancer screening trials of mam- In 1998, there were 412,000 deaths attrib- mography have shown that mortality can be reduced by up to 30%. However, uted to breast cancer for women in the there is limited evidence that this can be world, representing 1.6% of all female achieved in population-based country- deaths. In terms of absolute numbers, the wide screening programmes. greatest contribution is now from develop- ing countries, where 250,000 such deaths occurred, as compared to developed countries, which account for 160,000 deaths. However, the proportion of deaths Definition due to breast cancer in women remains Breast cancer generally refers to a malig- higher in the latter countries at 2.0% in nancy in women that arises from the ter- comparison to 0.5% in the developing minal ductal-lobular units of epithelial tis- countries. Male breast cancer is about sue, which in the mature breast represent 100 times less frequent than the disease 10% of the total volume. in women. The Netherlands exemplifies the high inci- Epidemiology dence of breast cancer in developed coun- Latest estimates suggest that more than tries, with an age-standardized incidence 1,050,000 new breast cancer cases occur rate of 91.6 new cases per 100,000 worldwide annually, with nearly 580,000 woman-years, but there are sub-popula- cases occurring in developed countries and tions, such as white women in California, the remainder in developing countries [1]. which exhibit age-adjusted incidence Thus breast cancer now ranks first among rates of 100 or more. Overall, the inci- cancers affecting women throughout the dence rate in the USA is estimated at Fig. 5.13 Risk of breast cancer is decreased in world and its marked impact is not restricted 91.4. Such high rates are also observed in women who have children early and who have to Western industrialized societies (Fig. 5.12). Europe, Australia and New Zealand, and in breast-fed.

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dences for breast cancer vary from 0.76% for women in Kangwha, Korea to 11.9% for non-Hispanic whites in San Francisco, USA [2]. The absolute number of new breast can- cer cases worldwide increased from 572,100 in 1980 to 1,050,346 for the most recent period [3]. Comparison of rates rather than absolute figures excludes change attributable to ageing of the population as well as differences in Fig. 5.15 Fine needle aspirate of cells from a Fig. 5.14 Physician reading digital images of the age structures across countries. Even so, breast tumour. breast in preparation for a computer-guided mini- mally invasive biopsy. most cancer registries of the world have recorded an increase in the incidence of breast cancer over the past 20 years some parts of South America, especially (Screening for breast cancer, p156). In the Uruguay and Argentina. In contrast, low period 1975-1990, the largest increases, rates are found among African and Asian greater than 1% and sometimes 5% per populations. Amongst population-based year, are exhibited by registries previously cancer registries (as distinct from nation- having low rates of disease, mostly in Asia al estimates), the 30 recording the highest and Africa, as well as in some parts of rates include 20 registries from North Europe. In contrast, the smallest increas- America, one from South America (Monte- es, in general inferior to 0.5% per year, are Fig. 5.16 An example of lobular , video), two from Israel and five from usually seen in places previously having comprising a well-differentiated malignant prolif- Europe. Amongst this group, the only one high rates, mostly in North America and eration without signs of invasion. from Africa is for Europeans in Harare. By Europe. These changes are particularly contrast, among population-based reg- obvious in relation to disease in younger istries with the 30 lowest rates, five are women, that is below 45 years of age from Africa, 18 from Asia and Israel, three [2,4]. However, mortality rates are falling, from South America, two from Eastern probably due to better treatment (Fig. Europe and two from the United States of 5.19). America (American Indians in New Mexico and Koreans in Los Angeles, California) Etiology [2]. Risk factors for breast cancer (Fig. 5.18) These large geographical differences are specifically concern the reproductive life potentially explicable on the basis of of women. Increased risk is correlated genetics or the influences of lifestyle and with early menarche, nulliparity or late age Fig. 5.17 Infiltrating . This is a environment. Studies of migrant popula- at first birth, late menopause, as well as poorly-differentiated adenocarcinoma infiltrating the adipose tissue. tions have revealed that when women hormonal factors, be they endogenous or migrate from low-risk to high-risk regions, exogenous (e.g. long term use of oral con- particular at times of breast development, the migrant populations acquire the rates traceptives or menopausal hormonal causes breast cancer. Women with epithe- of the host country after two or three gen- replacement, Reproductive factors and lial proliferative lesions, particularly with erations, indicating lifestyle as primarily , p76). Genetic risk factors are atypical ductal or lobular by determining the geographic variations in discussed later (Pathology and genetics). comparison with normal , have a risk. Other risk factors that may also be medi- four to five times increase in the risk of “Cumulative incidence” represents the ated through a hormonal pathway include developing breast cancer [7]. probability of developing a particular dis- and diet, characterized by a high ease over a life span. Given the uncertain- caloric intake, not counterbalanced by suf- Detection ties of breast cancer diagnosis in older ficient physical activity, high total and sat- The commonest presentation of breast women and the high likelihood of the dis- urated animal fat, as well as a diet poor in cancer is of a painless lump; other symp- ease not being reported in the oldest age fruits and vegetables and rich in meat and toms may include dimpling of the overly- groups, it is common practice to present alcohol [5,6]. The role of contaminants, ing skin, nipple inversion, oedema or peau cumulative incidence for the age span 0- such as xenoestrogens and certain pesti- d’orange and blood-stained nipple dis- 74 years. In the world, cumulative inci- cides, remains controversial. , in charge. In countries where no mammo-

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A woman may be considered to be at a potentially high risk of breast cancer if DIET AND DIET-RELATED FACTORS IONIZING HORMONES AND RADIATION REPRODUCTIVE FACTORS there are three or more first or second Increased weight (postmenopause) ↑ degree relatives on the same side of the Increased height ↑ at times of Young age at menarche ↑ family with breast or , or Western diet ↑ breast Regular, ovular menstrual cycle ↑ High intake of fibre? ↓ development ↑ Older age at first full-term birth ↑ two or more first or second degree rela- Alcohol ↑ Nulliparity ↑ tives on the same side of the family with High intake of fresh fruit Older age at menopause ↑ breast or ovarian cancer which has been and vegetables ↓ Oral contraceptives ↑ diagnosed at age 40 or younger, bilateral Infertility ↑ Lack of breast feeding ↑ disease, both breast and ovarian cancer in the same individual or breast cancer in a male [11]. The currently available appro- aches to the management of the high-risk woman are close surveillance (involving FEMALE BREAST CANCER regular self and clinical breast examina- tion and annual mammography), genetic counselling or prophylactic mastectomy (a procedure which does not, however, guar- FAMILY HISTORY OF BREAST CANCER ↑ BENIGN BREAST DISEASE ↑ including BRCA1, BRCA2, and p53 including atypical ductal antee complete prevention of subsequent germline mutations hyperplasia breast cancer).

Pathology and genetics Fig. 5.18 Risk and protective factors for breast cancer. Factors associated with an increased (↑) or decreased (↓) risk of breast cancer. Ductal carcinoma in situ is a proliferation of presumably malignant epithelial cells and is confined to the mammary ducts and lobules. It carries a 30% chance of graphic screening exists, and in fact for mortality. Mammography is associated developing into invasive disease, although women generally, health education should with a reduction of up to 30% in breast the natural history of this progression include recognition of breast cancer cancer mortality in the context of well- remains uncertain. The rate of detection symptoms. Diagnosis of breast cancer is conducted trials [9]. Where adopted, pop- of ductal carcinoma in situ has increased currently made by triple assessment of ulation-based screening is commonly significantly with the introduction of breast lumps – clinical history and exami- based on biennial examination from the mammography and questions have been nation, complemented by mammography age of 50 onwards. To realize the benefit raised regarding the possible overtreat- and/or breast ultrasound plus fine needle of screening, prompt and adequate follow- ment of this condition. It can be classified aspiration cytology or biopsy [8]. Breast up must be available to all women with a into comedo and non-comedo subtypes screening can have an impact on disease suspected malignancy [10]. based on growth pattern, the comedo

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Fig. 5.19 Trends in mortality from breast cancer. In some countries, such the USA and UK mortality is decreasing; in almost all developing countries, mortali- ty is increasing. D.M. Parkin et al. (2001) Eur J Cancer 37 Suppl 8: S4-66

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Markers of prognosis in breast cancer

Commonly assessed markers: Number of positive axillary lymph nodes Tumour size Tumour TNM stage Lymphatic and vascular invasion Histological tumour type Steroid hormone receptors ( receptors ER-α, ER-β; receptor) Growth factor receptor genes (epidermal growth factor gene, EGFR) DNA ploidy (DNA histogram) Proliferative indices (fraction of cells in S-phase; thymidine labelling index; mitotic index) Fig. 5.20 Physician performing a biopsy. With this state-of-the-art radio-guid- Less commonly assessed markers: ed surgical equipment, the patient avoids com- Proliferative indices (Ki67, PCNA, cyclins, thymidylate synthetase, MIB1) plete resection of the axillary lymphatic nodes and Topoisomerase II the complications of lymphoedema. Histone H3 Transforming growth factors (TGF-α, TGF-β) Epidermal growth factor (EGF) Insulin-like growth factors and their binding proteins (IGF-I, IGF-II) Oncogene products (c-erbB2, ras, c-myc, int2) Markers of (mutations of p53, Bcl-2 proteins, caspases, survirin, p21, R6 ) Markers of proteolysis (activation of urokinase-type plasminogen, cathepsin D, matrix metalloproteases) Markers of cell adhesion (integrins, cadherins, CD-44 variants) Markers of (endothelial markers: Factor VII, CD-31, CD34; angiogenic peptides e.g. VEGF) Markers of cell mobility (cytokines) Steroid hormones (, glucocorticoids, prolactin, progestins) Tumour-associated antigens (carcinoembryogenic antigen, CEA; tissue polypeptide antigen, TPA; gross cystic disease fluid protein, GCDP; mucin-like molecules, CA 15.3, MAM-6, MSA, MC) pS2 NM23 Heat shock proteins MDR1

Table 5.2 Prognostic indicators in breast cancer.

type, having a higher rate of prolifera- being lobular, tubular, medullary or other tion, being more aggressive and more special types (Fig. 5.17). likely to be associated with areas of The most important genes identified in the Fig. 5.21 Five-year relative survival rates after microinvasion and with expression of context of familial breast cancer are diagnosis of breast cancer. markers such as and overex- BRCA1 and BRCA2 [12]. Inherited muta- pression of p53, c-erbB2 and Bcl-2. tions in these genes account for a very Lobular carcinoma in situ (Fig. 5.16), high relative risk of breast and sometimes genes, p96). Loss of heterogeneity on 13q unlike ductal carcinoma in situ, is not ovarian cancer among carrier women [13], and 17p may involve the RB or p53 genes readily detected clinically or mammo- although such instances of breast cancer respectively. Gene amplification is also graphically, is frequently multicentric account for less than 5% of all cases observed, the most studied gene in this and bilateral, and occurs more common- (Genetic susceptibility, p71). Other genetic context being that encoding the growth ly in younger women. It is associated conditions suspected of playing a role factor receptor c-erbB2. Although the with an increased risk for development include heterozygosity of the ataxia telang- estrogen receptor cannot be clearly clas- of cancer, but is not a precursor lesion. iectasia gene (Box: ATM and breast can- sified as the product of an oncogene or Lobular carcinoma in situ is character- cer, p192) and germline mutations of p53 tumour suppressor, expression of this ized by a solid proliferation of small cells (the Li-Fraumeni syndrome) [14]. gene mediates progression of breast can- with small uniform, round or oval nuclei, The most common genetic abnormality in cer, and the responsiveness of tumours to which grow slowly, are usually estrogen breast carcinoma tissue appears to be a hormone-based therapy. receptor positive and rarely overexpress loss of heterogeneity at multiple loci. Such c-erbB2. The most frequent malignant change may determine the influence of a Management lesion (80%) is invasive ductal carcinoma mutated allele of a tumour suppressor Successful management of a breast can- of no special type, with 20% of cancers gene (Oncogenes and tumour suppressor cer implies a multidisciplinary approach to

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ATM AND BREAST CANCER NORMAL Whilst mutations in the BRCA1 and BRCA2 genes contribute to familial breast cancer risk, their contribution to sporadic breast cancer is relatively minor. In the latter disease category, genes frequently altered in the general population, such as the gene mutated in ataxia telangiectasia, ATM, may be important risk factors. Studies of ataxia telangiectasia families initially revealed that ataxia telangiecta- sia heterozygotic women hadan increased risk of breast cancer. Taken together with the estimation that 1% of the general pop- ulation are ATM heterozygotes, up to 8% of breast cancer patients could thus be ATM heterozygotes. One of the identifying characteristics of ataxia telangiectasia INVASIVE DUCTAL CARCINOMA patients is that they are extremely sensi- tive to . Radiosensitivity, Fig. 5.22 Normal tissue showing a brown nuclear ATM staining in the inner epithelial cells of the breast ducts seen as exaggerated acute or late tissue and no staining in the outer myoepithelial cells. Invasive ductal carcinoma shows no ATM staining in the tumour area, in contrast to lymphocytes in the same section. reactions after radiotherapy, has been reported in a significant proportion of revealed the magnitude of involvement of a second group comprises those who are breast cancer patients. This suggests that the ATM gene expected, based on the heterozygous for a missense mutation; ataxia telangiectasia heterozygosity plays increased relative risk and mutation profile the latter group might predominantly a role in such radiosensitivity and in found in family studies (in terms of truncat- include those individuals who are predis- breast cancer development. Loss of het- ing mutations). However, the molecular posed to developing sporadic cancers. erozygosity in the region of the ATM gene approaches used in these studies have Further research, in particular on the role on chromosome 11 has been found in shown clearly that, in the general popula- and phenotype associated with these rare about 40% of sporadic breast tumours. tion, there are two groups of heterozygotes ATM sequence variants, is needed to clar- Screening for ATM mutations in sporadic (Gatti RA et al., Mol Genet Metab, 68: 419- ify the understanding of ATM heterozy- breast cancer cases, regardless of 422, 1999). One group includes those who gosity as a risk factor for breast cancer. adverse response to radiotherapy, has not are heterozygous for a truncating allele and

achieve local disease control (surgery and followed by radiotherapy will allow for complete local resection plus radiothera- radiotherapy) and treat metastatic spread breast conservation. For larger tumours, a py to reduce the incidence of local recur- (chemotherapy) [15]. Optimal surgery primary mastectomy may be necessary. rence. In addition to local therapy, sys- may comprise a lumpectomy for a tumour Immediate or delayed breast reconstruc- temic adjuvant therapy, which may involve of <4 cm, or mastectomy and excision of tion will allow for an acceptable cosmetic hormonal manipulation, including ovarian axillary lymph nodes for more advanced result, many techniques for which exist, ablation and cytotoxic agents, is employed disease and depending on pathological including insertion of subpectoral silicone to treat undetectable remaining malignant findings [16]. Biopsy of the first lymph implants or tissue expanders and myocu- cells. Ovarian ablation, whether achieved node to which a tumour drains (“sentinel taneous latissimus dorsi or rectus surgically or pharmacologically, is appro- node biopsy”) is currently being investi- abdominous flaps (Rehabilitation, p292). priate only for premenopausal women. gated as an alternative to complete axil- There is no evidence that immediate The non-steroidal anti-estrogen drug lary lymph node dissection (which may be reconstructive surgery prevents the detec- tamoxifen is probably the single mostly associated with post-surgical complica- tion of local recurrence or affects survival. widely-used agent for all stages of breast tions such as lymphœdema, numbness, a Surgical removal of a breast tumour cancer, though it is more effective in persistent burning sensation, , should be followed by radiotherapy to the women whose tumours exhibit estrogen and limited movement of the shoulder) breast. There is no difference in long-term receptors. Tamoxifen also substantially [17]. In early stage disease, lumpectomy disease control between mastectomy and reduces the risk of a new primary breast can-

192 Human cancers by organ site 181 A 214 WORLD CANCER 17/06/03 15:13 Page 193

cer in the contralateral breast (Chemopre- (Box: TNM, p124). If the tumour is large, dif- within the last five years. In Europe for exam- vention, p151), a property not seen with cyto- fuse or multicentric, mastectomy may be ple, survival is an average of 72.5% at five toxic adjuvant therapy. In postmenopausal appropriate. Involvement of axillary lymph years (Fig. 5.21). women who have had breast cancer, tamox- nodes is an indicator of high risk of relapse Patient follow-up involves the diagnosis and ifen can reduce the annual rate of death by from metastatic disease. An increasing num- treatment of recurrent disease, evaluation of 17%. However, long-term use has been asso- ber of molecular markers of prognosis are treatment effectiveness, monitoring for long- ciated with endometrial thickening and also becoming commonly assessed (Table term complications, patient rehabilitation endometrial carcinoma. A new-generation 5.2) [14]. Metastatic disease is incurable; and psychological support. The combination hormonal drug, anastrozole, has recently once detected, average survival time is two of various treatment modalities has led to an been reported to be just as, if not more, years. However, at least half the patients with improvement in survival for the last 20 years. effective than tamoxifen in treating advanced breast cancer will survive for five years, The challenge remains of also providing ade- breast cancer and as adjuvant therapy. including those living in the developing world. quate treatment in the developing world. The strongest predictive factor for survival Because of this relatively good prognosis, after diagnosis of breast cancer is the extent there are an estimated 3.46 million women of cancer as defined in the TNM classification alive who have had breast cancer diagnosed

CLASSIFYING CANCERS: EPIDEMIOLOGICAL indicate the prognosis and appropriate treat- use this terminology. The existence of a AND CLINICAL NEEDS ment, reference to organ site alone is inade- standardized classification system is of key quate. For clinical purposes, tumours are importance (WHO Classification of To monitor the impact of cancer within identified by a naming system based on the Tumours). populations, epidemiological records are tissue or cell of origin. All organs involve mul- In practice, particularly in the context of based on organ site (topography), liver tiple tissue types including glandular or broad generalizations about cancer, the cancer, breast cancer, colon cancer secretory tissue, of various complexity implicit in comprehensive etc, using established codes (Inter- types (muscle, fat), blood and immunological tumour nomenclature is greatly reduced by national Classification of Disease, see elements and nervous tissue. “Carcinoma” the practical consideration that over 90% of http://www.cdc.gov/nchs/about/otheract/ indicates a malignant tumour of surface or the tumours afflicting humans are carcino- icd9/abticd10.htm). Accordingly, this ter- glandular tissue, “sarcoma” indicates con- mas. As a result, for many purposes (and minology applies to Chapters 1 and 2 of nective tissue, “” indicates embry- often in common practice) “lung cancer” this Report. onic tissue, “leukaemia” involves elements of may be equated with “carcinoma of the To describe the type of cancer (or tumour) blood and there are other specialist terms. Of lung”. affecting an individual in terms which will necessity, Chapters 5 and 6 of this Report

REFERENCES 1. Ferlay J, Bray F, Parkin DM, Pisani P, eds (2001) 7. Harris J, Morrow M, Norton L (1997) Malignant tumors 13. Bishop DT (1999) BRCA1 and BRCA2 and breast can- Globocan 2000: Cancer Incidence and Mortality Worldwide of the breast. In: DeVita VTJ, Hellman,S, Rosenberg, SA cer incidence: a review. Ann Oncol, 10 Suppl 6: 113-119. (IARC Cancer Bases No. 5), Lyon, IARCPress. eds, Cancer Principles and Practice of Oncology, 14. Tavassoli FA, Stratton MR, eds (2003) World Health 2. Parkin DM, Whelan SL, Ferlay J, Raymond L, Young J, Philadelphia, Lippincott-Raven Publishers, 1557-1616. Organization Classification of Tumours. Pathology and eds (1997) Cancer Incidence in Five Continents, Vol. VII 8. Marsden J, Baum M (1998) Breast cancer. In: Morris D, Genetics of Tumours of the Breast and Female Genital (IARC Scientific Publication No. 143 and IARC Cancerbase Kearsley J, Williams C eds, Cancer: a comprehensive clini- Organs, Lyon, IARC Press. In preparation. No. 2), Lyon, IARCPress. cal guide, Harwood Academic Publishers, 131-139. 15. Reviews (2001) Breast cancer. Curr Opin Oncol, 13: 3. Parkin DM, Pisani P, Ferlay J (1999) Estimates of the 9. Kerlikowske K, Grady D, Rubin SM, Sandrock C, Ernster 415-449. worldwide incidence of 25 major cancers in 1990. Int J VL (1995) Efficacy of screening mammography. A meta- 16. Early Breast Cancer Trialists' Collaborative Group Cancer, 80: 827-841. analysis. JAMA, 273: 149-154. (2000) Favourable and unfavourable effects on long-term 4. Peto R, Boreham J, Clarke M, Davies C, Beral V (2000) 10. Fletcher SW, Black W, Harris R, Rimer BK, Shapiro S survival of radiotherapy for early breast cancer: an overview UK and USA breast cancer deaths down 25% in year 2000 (1993) Report of the International Workshop on Screening of the randomised trials. Lancet, 355: 1757-1770. at ages 20-69 years. Lancet, 355: 1822. for Breast Cancer. J Natl Cancer Inst, 85: 1644-1656. 17. Mansel RE, Khonji NI, Clarke D (2000) History, pres- 5. COMA Working Group on (1998) 11. South East Health Public Health Unit. (2000) ent status and future of sentinel node biopsy in breast can- Nutritional Aspects of the Development of Cancer (UK Information for GPs: Risk of Breast Cancer. cer. The Mary Beves Lecture. Acta Oncol, 39: 265-268. Department of Health Report on Health and Social www.sesahs.nsw.gov.au/cancerbulletins/. NSW Cancer Subjects No. 48), Norwich, HMSO. Control Program, Australia. 6. Potter JD. (1997) Food, nutrition and the prevention of 12. Eeles RA (1999) Screening for hereditary cancer and cancer: a global perspective. Washington DC, American , epitomized by breast cancer. Eur J Cancer, Institute for Cancer Research. 35: 1954-1962.

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STOMACH CANCER

SUMMARY

> Cancer of the is amongst the most common worldwide, with some 870,000 new cases every year. Mortality from is second only to lung cancer.

> Incidence is declining worldwide. In most European countries it has fallen by more than 60% during the past 50 years. This trend is mainly due to markedly decreased consumption of -pre- served food, increasing avoidance of a high-salt diet and availability, in many countries, of fresh fruit and vegetables throughout the year.

> Infection with caus- es chronic atrophic gastritis and is con- < 5.9 < 9.6 < 14.6 < 22.0 < 70.0 sidered a factor in the development of Age-standardized rate/100,000 population stomach cancer. Fig. 5.23 Global incidence of stomach cancer in men; the highest rates occur in Eastern Asia, South > Patients are often diagnosed with America and Eastern Europe. advanced disease and five-year survival rates are poor, usually less than 30%. between countries and among different ticular in North America and Western ethnic groups within the same locale. Europe (Fig. 5.24 and Stomach cancer pre- Migration studies show that the risk of vention and screening, p175). However, cancer changes within two generations the absolute number of new cases per year when people move from high-incidence to is increasing mainly because of ageing of Definition low-incidence areas. For example, Japan- the population. Gastric carcinoma is The vast majority of stomach cancer cases ese immigrants to the USA retain their extremely rare below age 30; thereafter are gastric carcinomas. Non-epithelial original risk of stomach cancer, whereas incidence increases rapidly and steadily to tumours predominantly include lym- subsequent generations show the inci- reach the highest rates in the oldest age phomas and mesenchymal tumours. dence of the host country. Incidence in groups in both sexes. men is twice that in women in both high- Epidemiology and low-risk countries. Etiology Stomach cancer was the fourth most com- The well-differentiated type of adenocarci- Dietary risk factors include inadequate mon malignancy in the world in 2000, with noma (which is showing the greatest intake of fresh fruits and vegetables, high an estimated 870,000 new cases and decrease in incidence) occurs more pre- salt intake and consumption of smoked or 650,000 deaths per year [1]. Approxi- dominantly in high-risk areas, while the dif- cured meats or fish. There is good evi- mately 60% of all stomach cancers occur in fuse poorly-differentiated type is relatively dence that refrigeration of food also pro- developing countries (Fig. 5.23). The areas more frequent in low-risk areas [2]. In con- tects against this cancer by facilitating with the highest incidence rates trast to the overall decreasing trend, there year-round consumption of fruit and veg- (>40/100,000 in males) are in Eastern has been an increase of cancers localized etables and probably by reducing the need Asia, the Andean regions of South America to the cardia, documented by data from for salt as a preservative. Vitamin C, con- and Eastern Europe. Low rates (< the UK and USA. The reasons for this tained in vegetables and fruits and other 15/100,000) occur in North America, increase are not known. Over the last few foods of plant origin, is probably protec- Northern Europe and most countries in decades, a steady decline in the incidence tive, and so too are diets high in whole- Africa and in South Eastern Asia. There is and mortality rates of gastric carcinoma grain cereals, carotenoids and allium com- marked geographical variation in incidence has been observed worldwide and in par- pounds, and also green tea. Conversely,

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ach cancer. Endoscopic detection of early Japan Chile Poland Denmark lesions may be improved with dye- 100 100 100 100 endoscopy using indigo carmine, congo- red, truigine or methylene blue. Diagnosis 50 50 50 50 Males Males may also be obtained by double-contrast 25 25 Males Females 25 25 barium X-ray. Screening for early disease Females by X-ray (photofluoroscopy), followed by 10 10 10 Females 10 Males gastroscopy and biopsy of suspicious find- ings, has been widely used in Japan since 5 5 5 5 Females the 1960s. It is a costly approach to pre- 2.5 2.5 2.5 2.5 vention, and the results have been contro- versial. Serum pepsinogen screening is a 1 1 1 1 new and potentially useful method for 1960197019801990 2000 1960197019801990 2000 1960197019801990 2000 1960197019801990 2000 detection of stomach cancer [4]. Fig. 5.24 The mortality from stomach cancer is decreasing worldwide, including in countries with a high Tumour staging prior to treatment decision disease burden. D.M. Parkin et al. (2001) Eur J Cancer, 37 Suppl. 8: S4-66. involves percutaneous ultrasound or com- puted tomography to detect liver metas- monotonous diets which are rich in starchy alter gastric acid secretion, elevating gas- tases and distant lymph node metastases food pose an increased risk, probably tric pH, changing the gastric flora and and laparoscopy (with or without laparo- because they are deficient in the protec- allowing anaerobic to colonize the scopic ultrasound) to seek evidence for tive dietary constituents. Many studies stomach. peritoneal spread or serosal involvement. suggest a small increase in risk (about two-fold) in smokers, but alcohol does not Detection Pathology and genetics affect risk, other than at the gastric cardia. Early stomach cancer is an adenocarcino- Chronic atrophic gastritis, in particular H. Conditions which cause an excessive rate ma limited to the mucosa, or the mucosa pylori-associated chronic active gastritis, of cell proliferation in the gastric epitheli- and submucosa. It often does not cause um, thus increasing the chance of fixation symptoms, although up to 50% of patients of replication errors induced by dietary and may have non-specific gastrointestinal endogenous carcinogens, include Helico- complaints, such as dyspepsia. This often bacter pylori infection (Chronic infections, delays the diagnosis of stomach cancer. p56), gastric ulcer, atrophic gastritis and Approximately 80% of Western patients autoimmune gastritis associated with per- with stomach cancer present to the physi- nicious anaemia. Gastritis is associated cian with advanced tumours, symptoms of with increased production of oxidants and which may include nausea, weight loss, reactive nitrogen intermediates, including back pain, epigastric pain, gastrointestinal nitric oxide. There is increased expression bleeding or perforation [3]. Endoscopy and of the inducible isoform of nitric oxide syn- biopsy is considered to be the most sensi- Fig. 5.25 Severe atrophic gastritis with intestinal thase in gastritis. Gastritis and atrophy tive and specific diagnostic test for stom- metaplasia, a risk factor for gastric carcinoma.

A B Fig. 5.26 (A) Endoscopy showing advanced gastric carcinoma in an 80-year-old male patient (ulcerated Fig. 5.27 Invasive gastric carcinoma: a well-differen- tumour without definite limits, infiltrating into the surrounding stomach wall). (B) Corresponding gross tiated trabecular invasive tubular adenocarcinoma. feature of the resected stomach with advanced cancer located in the lesser curvature of the angulus.

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component [10]. Case-control studies also Histologic type suggest a small but consistent increased Gene alterations Poorly-differentiated (%) Well-differentiated (%) risk in first-degree relatives of gastric carci- noma patients [11]. Germline E-cadherin (CDH1) mutations lead to an autosomal KRAS mutation 0 10-20 dominant predisposition to diffuse gastric c-met carcinoma [12]. Gastric carcinomas may Amplification ≈ 40 ≈20 also develop as part of the hereditary non- 6.0 kb mRNA ≈ 80 ≈ 50 polyposis colon cancer (HNPCC) syndrome K-sam amplification 20-30 0 [13] (, p198). They exhibit intestinal type cancers and microsatellite c-erbB2 amplification 0 20-40 instability. Cyclin E amplification 10 10 Loss of heterozygosity studies and com- parative genomic hybridization (CGH) p53 LOH/mutation ≈ 80 ≈ 60 studies have shown that frequent loss or APC LOH/mutation - 40-60 gain occurs at chromosomal regions 1p, 1q, 3p, 4, 5q (APC locus), 6q, 7q, 9p, 17p DCC LOH - 50 (p53 locus), 18q (DCC locus), and 20q [14]. Well- and poorly-differentiated ade- Cadherin, catenin deletion 50 - nocarcinomas frequently show different CD44 abnormal transcript 100 100 genetic alterations (Table 5.3), as do dif- fuse and intestinal types [15,16]. Genetic instability ≈ 40 ≈10

Table 5.3 Genetic alterations in gastric carcinomas, (≈ = approximately), [15, 16]. Management Most patients diagnosed with stomach cancer have advanced disease and the prognosis is extremely poor with survival and intestinal metaplasia (Fig. 5.25), fre- well-differentiated adenocarcinoma (com- rates rarely exceeding 15%. Differences in quently precede and/or accompany intes- posed of well-formed glands, often resem- classification of cancer lead to apparently tinal type adenocarcinoma, especially in bling metaplastic intestinal epithelium) much higher survival rates in Japan (Fig. high incidence areas. Premalignant condi- and poorly-differentiated adenocarcinoma 5.28). Management of stomach cancer tions include gastric polyps, Menetrier dis- (composed of highly irregular glands or ease, gastric ulcer, pernicious anaemia single cells that remain isolated). (achlorydia) and previous gastric surgery Moderately-differentiated adenocarcino- to reduce acid output [3]. H. pylori strains mas show intermediate features between containing a group of genes named cag the two. induce a great degree of , Gastric carcinomas may also be classified as and there is an association between infec- diffuse and intestinal types (Laurén classifi- tion with a cag positive H. pylori strain and cation) [8]. Intestinal type carcinoma is com- the development of gastric carcinoma [5]. posed of distinct glandular elements with Gastric carcinomas are morphologically well-defined lumina, sometimes accompa- heterogeneous, resulting in various classi- nied by papillary structures or solid compo- fications based on histological appear- nents. Diffuse gastric carcinoma is charac- ance, degree of differentiation, growth terized by the lack of cell cohesion, and pattern, and histogenesis [6]. The major malignant cells infiltrate the surrounding tis- histological types include tubular adeno- sue as single cells or small clusters of cells carcinoma (Fig. 5.27), papillary adenocar- without glandular lumina [8]. Other classifi- cinoma, mucinous adenocarcinoma and cation systems are also in use. signet-ring cell carcinoma. When more Clinical and pathological staging of stomach than one histological type is observed cancer is based on the TNM system (Box: within the tumour, the diagnosis is based TNM, p124) in Western countries and the on the predominant histological pattern Japanese classification system in Japan [9]. [7]. Based on their differentiation status, Most gastric carcinomas occur sporadical- Fig. 5.28 Five-year relative survival after diagnosis gastric carcinomas are also classified as ly, but up to 10% have an inherited familial of gastric carcinoma.

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depends on staging. Small intramucosal Corynebacterium parvum is practised in reaction, lymphatic and vascular invasion cancers can be treated endoscopically by Korea, but is still subject to scepticism in all have prognostic value. Patients with endoscopic mucosal resection [17]. For Western practice [3]. cancers limited to the mucosa and sub- invasive cancer, standard treatment is Annual surveillance endoscopy, post-gas- mucosa have a five-year survival of with regional lymph node dis- trectomy, has been associated with a approximately 95%. Tumours that invade section [18]. For patients with advanced small beneficial outcome in terms of gain the muscularis propria have a 60% to 80% stage stomach cancer, neo-adjuvant (pre- of life-years, but this may be inflated by five-year survival, whereas tumours invad- operative) or adjuvant (post-operative) the exaggerated assumptions of a high ing the subserosa and serosa have a less chemotherapy is currently being investi- incidence rate of gastric stump cancer than 50% five-year survival on average gated in research protocols. Drugs most and a cure rate of 80% achieved by timely [19]. There is recent evidence that the often employed are 5-fluorouracil, doxoru- surgery after cancer detection. type of mucin and polymorphism of the bicin and cisplatin, and greatest success In advanced stomach cancer, tumour gene encoding mucin may be an impor- has been achieved on the basis of combi- stage, tumour size, histological tumour tant factor determining susceptibility to nation regimens rather than single agent type, growth pattern, degree of cytological stomach cancer [20]. treatments. Immunochemosurgery using atypia, DNA-nuclear content, stromal

REFERENCES WEBSITE 1. Ferlay J, Bray F, Parkin DM, Pisani P, eds (2001) 11. Zanghieri G, Di Gregorio C, Sacchetti C, Fante R, NCI Stomach (Gastric) Cancer Homepage: Globocan 2000: Cancer Incidence and Mortality Sassatelli R, Cannizzo G, Carriero A, Ponz dL (1990) http://www.cancer.gov/cancer_information/cancer_type/ Worldwide (IARC Cancer Bases No. 5), Lyon, IARCPress. Familial occurrence of gastric cancer in the 2-year experi- stomach/ 2. Muñoz N (1988) Descriptive epidemiology of stomach ence of a population-based registry. Cancer, 66: 2047- cancer. In: Reed PI, Hill, MJ eds, Gastric Carcinogenesis, 2051. Amsterdam, Excerpta Medica, 51-69. 12. Guilford PJ, Hopkins JB, Grady WM, Markowitz SD, 3. Branicki FJ, Gotley DG (1998) Gastric cancer. In: Morris Willis J, Lynch H, Rajput A, Wiesner GL, Lindor NM, Burgart D, Kearsley J, Williams C, eds, Cancer: a comprehensive LJ, Toro TT, Lee D, Limacher JM, Shaw DW, Findlay MP, clinical guide, Harwood Academic Publishers, 165-169. Reeve AE (1999) E-cadherin germline mutations define an inherited dominated by diffuse gastric 4. Miki K, Ichinose M, Ishikawa KB, Yahagi N, Matsushima cancer. Hum Mutat, 14: 249-255. M, Kakei N, Tsukada S, Kido M, Ishihama S, Shimizu Y (1993) Clinical application of serum pepsinogen I and II lev- 13. Watson P, Lynch HT (1993) Extracolonic cancer in els for mass screening to detect gastric cancer. Jpn J hereditary nonpolyposis colorectal cancer. Cancer, 71: Cancer Res, 84: 1086-1090. 677-685. 5. Queiroz DM, Mendes EN, Rocha GA, Oliveira AM, 14. Becker KF, Keller G, Hoefler H (2000) The use of Oliveira CA, Cabral MM, Nogueira AM, Souza AF (1999) molecular biology in diagnosis and prognosis of gastric Serological and direct diagnosis of Helicobacter pylori in cancer. Surg Oncol, 9: 5-11. gastric carcinoma: a case-control study. J Med Microbiol, 15. Tahara E (1995) Molecular biology of gastric cancer. 48: 501-506. World J Surg, 19: 484-488. 6. Hamilton SR and Aaltonen LA, eds (2000) World 16. Hirohashi S, Sugimura T (1991) Genetic alterations in Health Organization Classification of Tumours. Pathology human gastric cancer. Cancer Cells, 3: 49-52. and Genetics of Tumours of the Digestive System, Lyon, 17. Hiki Y, Sakakibara Y, Mieno H, Shimao H, Kobayashi IARCPress. N, Katada N (1991) Endoscopic treatment of gastric can- 7. Watanabe H, Jass JR, Sobin LH, eds (1990) Histological cer. Surg Endosc, 5: 11-13. Typing of Oesophageal and Gastric Tumours (International 18. Maruyama K, Sasako M, Kinoshita T, Okajima K (1993) Histological Classification of Tumours, 2nd Ed.), Berlin, Effectiveness of systemic lymph node dissection in gastric Springer-Verlag. cancer surgery. In: Nishi M, Ichikawa H, Nakajima T, 8. Laurén PA (1965) The two histological main types of Maruyama K, Tahara E eds, Gastric Cancer, Tokyo, gastric carcinoma: diffuse and so-called intestinal-type car- Springer-Verlag, 293-305. cinoma. Acta Pathol Microbiol Scand, 64: 31-49. 19. Yoshikawa K, Maruyama K (1985) Characteristics of 9. Ichikura T, Tomimatsu S, Uefuji K, Kimura M, Uchida T, gastric cancer invading to the proper muscle layer--with Morita D, Mochizuki H (1999) Evaluation of the New special reference to mortality and cause of death. Jpn J Clin American Joint Committee on Cancer/International Union Oncol, 15: 499-503. against cancer classification of lymph node metastasis 20. Utsunomiya T, Yonezawa S, Sakamoto H, Kitamura H, from gastric carcinoma in comparison with the Japanese Hokita S, Aiko T, Tanaka S, Irimura T, Kim YS, Sato E (1998) classification. Cancer, 86: 553-558. Expression of MUC1 and MUC2 mucins in gastric carcino- 10. La Vecchia C, Negri E, Franceschi S, Gentile A (1992) mas: its relationship with the prognosis of the patients. Clin Family history and the risk of stomach and colorectal can- Cancer Res, 4: 2605-2614. cer. Cancer, 70: 50-55.

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COLORECTAL CANCER

SUMMARY

> Cancers of the colon and rectum are rare in developing countries, but are the second most frequent malignancy in affluent societies; over 940,000 cases occur annually worldwide.

> A major etiological factor is lifestyle involving a diet rich in fat, refined carbo- hydrates and animal protein, combined with low physical activity.

>Studies suggest that risk can be reduced by decreasing meat consumption and increasing intake of vegetables and fruit.

>Sequential genetic alterations mediate development of colon cancer, the earli- est such change being mutation of the < 3.8 < 7.7 < 12 < 21.2 < 43.4 APC gene. Age-standardized incidence/100,000 population

>Familial clustering has usually a genetic Fig. 5.29 Global incidence of colorectal cancer in women. Incidence rates are highest in North America, Western Europe and Australia/New Zealand. basis. Typical syndromes include famil- ial adenomatosis polyposis (FAP) and hereditary non-polyposis colon cancer high rates occurring in countries of ing and protective factors have been (HNPCC). Europe, North America, in Australia and, identified in cohort and case-control > Colonoscopy is the most reliable means more recently, in Japan (Fig. 5.29, Table studies [3]. There is convincing evidence for early detection. Progressively 5.4). Migrant groups rapidly reach the that a diet high in calories and rich in ani- improved treatment has resulted in a higher level of risk of the adopted country, mal fats, most often as red meat, and five-year survival rate of about 50%. indicating that environmental factors play an important role in etiology. In North America, the trend towards increased inci- Cumulative dence is now reversed [1] and a possible incidence (%) beneficial influence of dietary change Definition and/or endoscopic polypectomy has been Country Male Female The majority of cancers occurring in the suggested. In Western Europe, this recent colon and rectum are , downward trend has not yet been Black, USA 5.60 4.22 which account for more than 90% of all observed. Most cases occur after the age White, USA 4.98 3.38 large bowel tumours. of 60, except in individuals who carry a Denmark 4.48 3.53 genetic predisposition. Netherlands 4.25 3.25 Epidemiology Colorectal cancer ranks second in terms Etiology Osaka, Japan 4.03 2.28 of both incidence and mortality in more Colorectal cancer most commonly Qidong China 1.13 0.29 developed countries. Nearly 945,000 new occurs sporadically and is inherited in Khon Kaen,Thailand 1.06 0.64 colorectal cancer cases are diagnosed only 5% of cases. Diet is by far the most worldwide each year and colorectal can- important exogenous factor so far identi- cer is responsible for some 492,000 fied in the etiology of colorectal cancer Table 5.4 Cumulative incidence of colorectal can- cer. The sum of incidence rates for all ages 0-74 deaths. There is significant geographical [2]. It has been estimated that 70% of provides a measure of the risk of developing col- variation in age-standardized incidence as colorectal cancers could be prevented by orectal cancer over a life span, in the absence of well as in cumulative 0-74 year incidence, nutritional intervention; various promot- any other cause of death.

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poor in vegetables and fibre is associated Detection with an increased risk of colorectal can- Bleeding is a common symptom of cer. Alcohol intake and smoking (for advanced cancer. Diarrhoea suggests a polyps only) have also been suggested to right-sided tumour and constipation or increase risk. Conversely, a low fat, high occlusion suggests a left-sided tumour. vegetable and possibly high fibre diet has However, premalignant lesions (- a protective effect. Persons with an tous polyps) and cancer limited to the increased intake of vitamin D and calcium mucosa and submucosa are asymptomatic have a reduced risk of colon cancer [4]. as a rule. Thus screening is now proposed Physical activity is also protective. The for healthy people, with a view to cancer chronic use of non-steroidal anti-inflam- prevention (Screening for colorectal can- matory drugs (NSAIDs) and aspirin is cer, p163). Appropriate populations for associated with a significant risk reduc- screening may be those at an average risk tion in certain groups [5] (Chemopreven- who are above the age of 50, or individuals tion, p151). It has also been suggested selected by a risk factor questionnaire that use of hormone replacement therapy (which may also be used to search for other in postmenopausal women may decrease cases in the family of the person exam- the risk of colon cancer. ined). Should the questionnaire findings be Conditions that predispose to the devel- positive, the risk is increased 2.5 fold for opment of colorectal cancer include that individual. The questionnaire is includ- inflammatory bowel disease and Crohn ed in the assessment of patients with spo- disease [4]. Patients who have had previ- radic colorectal cancer. It also aims to ous malignant disease are also at a detect genetic syndromes, transmitted in a Fig. 5.30 A diet rich in fresh fruit and vegetables greater risk of developing a second col- dominant autosomal fashion, which are is associated with a lower risk of colorectal cancer. orectal tumour. much less frequent than sporadic cancer.

TGFBR2 PEUTZ-JEGHER SYNDROME LKB1 LATE RER+ Hypermethylation IGFIIR RER+ JUVENILE POLYPOSIS SYNDROME Familial ADENOMA BAX CANCER DPC 4 HEREDITARY MIXED POLYPOSIS SYNDROME PMS2 E2F4 ? COWDEN SYNDROME PTEN PMS1 p15 MLH1 p16 MSH2 Hypomethylation GTBP Bub1 δ polymerase Sporadic 1p cyclin D1

NORMAL EARLY INTERMEDIATE SMAD 4 LATE SPORADIC 7q EPITHELIUM APC ADENOMA KRAS ADENOMA SMAD 2 ADENOMA p53 CANCER 17q DCC CTNNB1 14q BCL 2 p53 C MYC 22q Aneuploidy 8p ULCERATIVE COLITIS- LOW GRADE HIGH GRADE tPa DYSPLASIA DYSPLASIA ASSOCIATED COLORECTAL CARCINOMA CEA nm23 EARLY MHAP/ METAPLASTIC ? INTERMEDIATE LATE SPORADIC MMP POLYP SERRATED ADENOMA ADENOMA CANCER ADENOMA E-cadherin CD44 FLAT ? progression FLAT ADENOMA CANCER

Fig. 5.31 Putative genetic pathways in colorectal cancer. It is thought that the majority of tumours develop according to the original Vogelstein model (bold arrows). See Multistage carcinogenesis, p 84. MHAP=Mixed hyperplastic adenomatous polyps.

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Diagnostic criteria for hereditary nonpolyposis colorectal cancer

There should be at least three relatives with colorectal cancer:

•One should be a first degree relative of the other two •At least two successive generations should be affected •At least one colorectal cancer should be diagnosed before age 50 •Familial adenomatous polyposis should be excluded •Tumours should be verified by pathological examination

Table 5.5 Criteria for hereditary nonpolyposis colorectal cancer syndrome. Fig. 5.32 Surgical specimen of the colon from a patient suffering from polyposis coli.

The occurrence of colorectal cancer in ing, p163). The depressed IIc type is a three successive generations and at a precursor of advanced cancer. Flexible young age in at least one person is among sigmoidoscopy explores the distal colon; the so-called Amsterdam criteria, which colonoscopy explores the whole of the suggest the possibility of hereditary non- colon. Another advantage of endoscopy is polyposis colorectal cancer syndrome, the potential for interventional proce- and justifies colorectal exploration and dures and the resection of adenomatous genetic testing (Table 5.5). The detection of polyps. diffuse polyposis in the colon (Fig. 5.32) justifies genetic testing for familial adeno- Pathology and genetics matous polyposis syndrome. Abnormalities of the colonic epithelium, Fig. 5.33 A polypoid tubulovillus adenoma of the Occult bleeding in the stools of asympto- cell atypia and architectural disorders colon; the adenomatous proliferation (arrow) matic persons can be explored by the fae- have been classified as premalignant (low- forms the head of the polyp, the stalk of which is cal occult blood test (FOBT). However, grade and high-grade dysplasia) or malig- lined by normal colonic mucosa. this test is reserved for mass screening nant (cancer). The current trend is to interventions with assessment of its sen- adopt a classification of tissue samples sitivity and specificity. In other situations, based upon the term “neoplasia” [6]. The endoscopy is the gold standard method of following grades are considered: absence detection and should be preferred to the of neoplasia, indeterminate for neoplasia, barium enema (Fig. 5.35), which while certain for neoplasia with the two grades detecting large tumours is less reliable for of light and severe cell atypia and intra- the detection of small and flat lesions. mucosal cancer. However, there is no T Helical CT scan is proposed in most cases invasion of lymph nodes when the lesion is T as a complementary investigation, help- limited to the mucosa. Therefore there is a ing to assess local tumour invasion and tendency to use the term “cancer” only regional and distant metastases. In elder- when there is a submucosal extension of Fig. 5.34 Moderately differentiated adenocarcino- ly persons with a poor health status, a the lesion. Epithelial abnormalities in poly- ma of the colon (T), infiltrating the submucosa. colo-scanner with a water enema is a less poid neoplasia are usually called “adeno- aggressive procedure than colonoscopy. ma” (Fig. 5.33). Only a small fraction of or the nonpolyposis syndromes. The major A major advantage of endoscopy is the polypoid or flat lesions progress to carci- polyposis syndrome is familial adenoma- ease with which tissue can be sampled by noma. tous polyposis, caused by a germline forceps biopsy and the ability to detect The major malignant histological type is mutation in the adenomatous polyposis small or flat neoplastic lesions, such as adenocarcinoma (Fig. 5.34). Other less coli (APC) gene. Familial adenomatous described by the Japanese school and common epithelial tumour types include polyposis can be associated with nervous classified as II type (IIa or elevated, IIb or mucinous adenocarcinoma, signet-ring system tumours (Turcot syndrome) or with completely flush, IIc or depressed). tumours, squamous cell carcinomas, desmoid tumours (Gardner syndrome). Detection of such lesions requires a high adenosquamous carcinomas and undiffer- The APC gene, on chromosome 5q21-22, definition fibroscope with a contrast entiated carcinomas. produces the APC protein, a negative reg- enhancement system and the use of chro- Genetic susceptibility to colorectal cancer ulator that controls β-catenin concentra- moendoscopy (Colorectal cancer screen- may be attributable to either the polyposis tion and interacts with E-cadherin, a mem-

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brane protein involved in cell adhesion. show mutations similar to those observed The following genotypic/phenotypic rela- in classical hereditary nonpolyposis col- tionships have been demonstrated: APC orectal cancer. mutations in the first or last third of the Colon cancer has been the archetype for gene and attenuated polyposis; mutation the correlation of tumour pathology and after codon 1444 and desmoid tumours; genetics since the publication of the first mutations in the central region of the gene such correlative statement by Vogelstein and a severe phenotype. Commercial et al. in 1988 (Multistage carcinogenesis, genetic tests involve identification of the p84). As a result of extensive analysis of mutant APC allele by in vitro detection of genetic alterations occurring during truncated APC protein. Sigmoidoscopy is tumorigenesis [7-12], understanding of Fig. 5.35 Double contrast barium enema revealing used to screen gene carriers from the age the complex and comprehensive nature of an adenocarcinoma of the colon. Between the prox- imal (top) and distal (bottom) segment of the colon, of10-12 years. these relationships has since expanded the lumen is narrowed with an irregular surface Hereditary nonpolyposis colorectal cancer (Fig. 5.31). Sporadic colorectal cancer (arrow), due to tumour infiltration. (often referred to as HNPCC) syndrome is arises mainly through two distinct path- associated with germline mutations in six ways. In the first, chromosome instability, valuable information regarding prognosis DNA mismatch repair genes: MSH2 and the initial mutation is inactivation of the and response to treatment. For example, MSH3, MLH1, PMS1, PMS2, and MSH6. APC tumour suppressor gene (Oncogenes microarray technology is based on the The protein products of these genes cor- and tumour suppressor genes, p96) (all simultaneous assay showing either dele- rect mismatches that arise during DNA tumours) followed by clonal accumulation tion or overexpression of multiple gene replication ( activation and of alterations in additional oncogenes fragments (around 20,000) and gives a DNA repair, p89). Mismatch repair defi- (KRAS, 50% of tumours) and suppressor characteristic “fingerprint” of the tumour ciency gives rise to instability in micro- genes on 18 and 17 (DCC; [14]. satellite DNA and may aid in the diagnosis p53 gene, found in 70% of tumours and of this syndrome via the Replication Error associated with a shift to a malignant Management positive (RER+) test. Surveillance of female tumour). The second, associated with The management of familial colorectal hereditary nonpolyposis colorectal cancer microsatellite instability, occurs in 15-20% cancer requires the systematic genetic syndrome patients includes exploration of of sporadic colorectal cancers. Alterations and endoscopic screening of the pro- endometrium and and other poten- have been found to cluster in genes band (the person presenting with a disor- tial tumour sites by ultrasound. Kindreds encoding enzymes involved in the repair of der, whose case serves as a stimulus for a with the Muir-Torre phenotype, as well as a DNA mismatches (in particular MLH1 and genetic/familial study). Total colo-proc- subset of those with Turcot syndrome, MSH2). tectomy with ileo-anal anastomosis is per- Histopathology related to poor prognosis formed when adenomatous polyps are includes deep infiltration of the layers of detected in patients with familial adeno- the bowel wall, poor differentiation, high matous polyposis. With hereditary non- levels of angiogenesis in the tumour and polyposis colorectal cancer syndrome, metastasis to numerous or distant lymph total colectomy is the treatment for con- nodes. Evidence of host response such as firmed cancer, with a tendency to prophy- intense inflammatory infiltrate is a lactic colectomy in presence of multiple favourable prognostic feature. Predictive polyps. It has recently been shown that in factors relate to response to therapy [13]. probands of hereditary nonpolyposis col- The presence of wildtype p53 is associat- orectal cancer syndrome families carrying ed in vitro with a good response to many the mutation, surveillance colonoscopy at agents. In contrast, mutant p53 is associ- short (less than two years) intervals is a ated with lack of response to postopera- safe method to detect the first neoplastic tive adjuvant chemotherapy with 5-FU-lev- lesions and prevents death from cancer. amisole. In sporadic colorectal cancer, as Precursor adenomatous polyps are usual- well as in hereditary nonpolyposis col- ly resected at endoscopy by snare orectal cancer syndrome, microsatellite polypectomy, when pedunculated, or by instability is a favourable indicator [12] strip resection combined with saline sub- and the tumour may respond to 5-FU- mucosal injection, when sessile or flat. based chemotherapy. In the future, it is Endoscopic treatment is safe for flat or Fig. 5.36 Five-year relative survival rates after expected that information regarding the elevated lesions with intramucosal cancer diagnosis of colorectal cancer. molecular biology of the tumour will give up to 2 cm in diameter; however this

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applies to depressed, flat neoplastic oxaliplatin, are beginning to become aggressive management of operable lesions (type IIc) only when the diameter established in treatment regimes [15]. patients is based on initial segmental liver does not exceed 1 cm. Advanced cancer located in the rectum is or lung resection followed by first line Sporadic advanced colonic cancer is treated by neo-adjuvant radiotherapy if chemotherapy. In inoperable patients, treated by segmental colectomy with a the tumour is either T3 (showing local first and second line chemotherapy proto- tendency to large resection. Adjuvant invasion) or N+ (positive lymph nodes). cols are proposed and a delayed surgical chemotherapy (5 FU-levamisole or 5 FU- Colorectal cancer is nowadays considered resection may be considered in some leucovorine) is recommended if lymph to be a chemosensitive tumour; in some cases. The five-year survival following node invasion is confirmed and some patients, the occurrence of liver or pul- detection and treatment of colorectal can- advocate a similar indication in B2 (sub- monary metastases does not exclude a cer is around 50% (Fig. 5.36). serosal) tumours. Recently introduced curative management based upon com- cytotoxic drugs, such as irinotecan and bined resection and chemotherapy. The

REFERENCES WEBSITES 1. Troisi RJ, Freedman AN, Devesa SS (1999) Incidence of 9. Potter JD (1999) Colorectal cancer: molecules and Johns Hopkins Hereditary Colorectal Cancer Website: colorectal carcinoma in the U.S.: an update of trends by populations. J Natl Cancer Inst, 91: 916-932. http://www.hopkins coloncancer.org/subspecialties/ gender, race, age, subsite, and stage, 1975-1994. Cancer, 10. Fujiwara T, Stolker JM, Watanabe T, Rashid A, Longo P, heredicolor_cancer/overview.htm 85: 1670-1676. Eshleman JR, Booker S, Lynch HT, Jass JR, Green JS, Kim H, APC gene mutation database: 2. Tomatis L, Aitio A, Day NE, Heseltine E, Kaldor J, Miller Jen J, Vogelstein B, Hamilton SR (1998) Accumulated clon- http://perso.curie.fr/Thierry.Soussi/APC.html AB, Parkin DM, Riboli E, eds (1990) Cancer: Causes, al genetic alterations in familial and sporadic colorectal Occurrence and Control (IARC Scientific Publications, No. carcinomas with widespread instability in microsatellite 100), Lyon, IARCPress. sequences. Am J Pathol, 153: 1063-1078. 3. Honda T, Kai I, Ohi G (1999) Fat and dietary fiber intake 11. Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, and colon cancer mortality: a chronological comparison Eshleman JR, Burt RW, Meltzer SJ, Rodriguez-Bigas MA, between Japan and the United States. Nutr Cancer, 33: 95- Fodde R, Ranzani GN, Srivastava S (1998) A National 99. Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development 4. Cohen AM, Minsky BD, Schilsky RL (1997) Cancers of of international criteria for the determination of microsatel- the Colon. In: DeVita VTJ, Hellman,S, Rosenberg,SA eds, lite instability in colorectal cancer. Cancer Res, 58: 5248- Cancer: Principles and Practice of Oncology, Philadelphia- 5257. New York, Lippincott-Raven, 1144-1197. 12. Gryfe R, Kim H, Hsieh ET, Aronson MD, Holowaty EJ, 5. Clapper ML, Chang WC, Meropol NJ (2001) Bull SB, Redston M, Gallinger S (2000) Tumor microsatellite Chemoprevention of colorectal cancer. Curr Opin Oncol, instability and clinical outcome in young patients with col- 13: 307-313. orectal cancer. N Engl J Med, 342: 69-77. 6. Hamilton SR and Aaltonen LA, eds (2000) World Health 13. McLeod HL, Murray GI (1999) Tumour markers of Organization Classification of Tumours. Pathology and prognosis in colorectal cancer. Br J Cancer, 79: 191-203. Genetics of Tumours of the Digestive System, Lyon, 14. Hegde P, Qi R, Gaspard R, Abernathy K, Dharap S, IARCPress. Earle-Hughes J, Gay C, Nwokekeh NU, Chen T, Saeed AI, 7. Ilyas M, Straub J, Tomlinson IP, Bodmer WF (1999) Sharov V, Lee NH, Yeatman TJ, Quackenbush J (2001) Genetic pathways in colorectal and other cancers. Eur J Identification of tumor markers in models of human col- Cancer, 35: 335-351. orectal cancer using a 19,200-element complementary 8. Gryfe R, Swallow C, Bapat B, Redston M, Gallinger S, DNA microarray. Cancer Res, 61: 7792-7797. Couture J (1997) Molecular biology of colorectal cancer. 15. Grothey A, Schmoll HJ (2001) New chemotherapy Curr Probl Cancer, 21: 233-300. approaches in colorectal cancer. Curr Opin Oncol, 13: 275-286.

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LIVER CANCER

SUMMARY

> About 560,000 new cases of liver can- cer, usually , occur annually, and contribute signifi- cantly to cancer mortality worldwide. More than 80% of cases occur in Asia and Africa and irrespective of etiology, the incidence rate is more than twice as high in men as in women.

> In Africa and Asia, hepatocellular carci- noma is most frequently caused by hep- atitis B infection; concomitant dietary exposure to aflatoxins multiplies the risk. In Japan, this cancer is predom- inantly caused by virus infec- tion. < 3.3 < 5.6 < 9.0 < 15.0 < 98.9 > In Western countries, liver due Age-standardized incidence/100,000 population to chronic alcohol abuse is the major etiological factor. Fig. 5.37 Global burden of in men. Note the high incidence rates in some African and Asian regions.

> Hepatocellular carcinoma is almost always lethal, survival from time of diag- worldwide, but is the eighth in women. regions, including France. Some of these nosis often being less than six months; Liver cancer is a major health problem in increases may be the result of improved only 10% of patients survive five years or developing countries where more than detection. more. 80% of the world total (457,000 new annu- al cases) occur. The highest incidence Etiology rates are recorded in China (55% of the Experimental evidence in a variety of in world total), Japan, South East Asia and vitro and animal models has demonstrat- Definition sub-Saharan Africa (Fig. 5.37). In both ed the carcinogenic effects of Hepatocellular carcinoma arises from high and low incidence areas, there is virus (HBV) on hepatocytes through both hepatocytes and accounts for 80% of all great variability in incidence among ethnic direct and indirect mechanisms [5]. HBV primary cancers of the liver. Other tumour groups [2]. viral DNA has been found to integrate into types include intrahepatic cholangiocarci- Age-specific rates of incidence show hepatocyte DNA and may serve as an noma (tumours of that part of the bile marked geographical variation (Fig. 5.38). insertional mutagen. Viral replication in duct epithelium located within the liver), In the Gambia, age-specific rates peak in infected cells and the concurrent host (a malignant embryomal the 45-55 years age range, whereas in immune response results in persistent tumour of childhood) and angiosarcoma Europe and the USA, high risk is associat- inflammation that may eventually (arising from blood vessels) and are rela- ed with old age. progress to cirrhosis and also may dis- tively rare. Time trends in liver cancer are difficult to pose toward carcinogenesis; this is the interpret due to changes in classification mechanism most commonly exhibited by Epidemiology and variable inclusion of metastatic (HCV) (Chronic infec- Liver cancer ranks third amongst the tumours [3]. However, the incidence of tions, p56). Consistent epidemiological organ-specific -related hepatocellular carcinoma in Japan, the UK, data have associated a significant risk of deaths in men worldwide and accounts for the USA and several Nordic countries has hepatocellular carcinoma with chronic almost 4% of all human cancers [1]. increased noticeably over the past two HBV infection, which accordingly has been Globally, men are three times as likely as decades and has become progressively categorized as causing cancer in the con- women to be afflicted; liver cancer is the associated with younger age groups [4]. text of IARC Monograph evaluations [6]. fifth most common cancer among men Mortality rates have increased in several Prevalence of carriers in developing coun-

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tries is high (10-15%) and it can be esti- which may carry an increased risk of Risk factors and predisposing mated that two-thirds of liver cancer hepatocellular carcinoma or other liver conditions cases in developing countries are attribut- cancers include alpha-1-trypsin deficien- able to this virus [7]. HBV is particularly cy, hypercitrullinaemia and glycogen stor- Hepatocellular carcinoma Chronic infection with implicated in hepatocellular carcinoma in age disease (Table 5.6). Infection with hepatitis C virus Africa and Asia, and HCV in Japan and the Hepatic is rare in Chronic liver cirrhosis USA [4]. most populations, the exception being in Untreated haemochromatosis In developing countries, dietary ingestion the population of Northern Thailand where Tyrosinaemia of aflatoxins (produced by the mould it is associated with chronic infection by Alcohol abuse Aspergillus flavus, which under hot and the , which Aflatoxins Long-term use of oral contraceptives humid conditions contaminates stored is contracted through consumption of High dose anabolic steroids grain), and specifically , is infected raw fish. Agents causing peroxisome proliferation causally associated with development of hepatocellular carcinoma, and exposure Detection Cholangiocarcinoma to aflatoxins may be synergistic with HBV Screening programmes by ultrasound Liver fluke (Opisthorchis viverrini and infection (Food contaminants, p43). In examination with or without pre-selection ) infection (esp. certain developed countries, principal known risk on the basis of raised levels of alpha-feto- areas of China and South East Asia) Hepatolithiasis factors are smoking and chronic alcohol protein have not proved effective in reduc- Thorotrast (no-longerused X-raycontrast medium) abuse. The major clinical hepatocellular ing mortality. Recent observations indicate Inflammatory bowel disease carcinoma risk factor is cirrhosis; 70-90% that free DNA originating from tumour cells of hepatocellular carcinomas develop in is detectable in the plasma of liver cancer patients with macronodular cirrhosis. patients at an early stage. Detection of rel- Angiosarcoma Iron overload caused by untreated haema- evant genetic changes in the plasma (such Vinyl chloride (polymer industry) tochromatosis may provoke in some as p53 mutation at codon 249 in the inhab- Table 5.6 Risk factors and predisposing condi- patient series a risk of death of as much itants of high incidence areas and aberrant tions for liver cancer. as 45% from hepatocellular carcinoma methylation of CDKN2A in most parts of [8]. Hepatocellular carcinoma may occur the world) may soon become useful aids in in 37% of patients with tyrosinaemia who screening tests for hepatocellular carcino- Common symptoms of hepatocellular survive to two years old and may occur in ma. The availability of simple, genetic tests carcinoma are abdominal pain, weight patients who have successfully undergone would be an important contribution to loss, fatigue, abdominal swelling and liver transplant. Other metabolic disorders screening programmes. anorexia. Most patients, particularly in sub-Saharan Africa, present with hepatomegaly; other common signs are ascites and jaundice. Hepatocellular carcinoma which infiltrates a cirrhotic liver often compromises the already impaired hepatic function and thus causes death before becoming very large, as is the case in most Japanese and American patients [8]. Intrahepatic cholangiocarcinoma is characterized by general malaise, mild abdominal pain and weight loss, and by jaundice and cholangitis at later stages [9]. The majority of cases can be diagnosed by computed tomography (CT) (Fig. 5.40) and ultrasonography. A definitive diag- nosis may depend on histological analy- sis via fine needle biopsy. Endoscopic retrograde, transhepatic or magnetic resonance cholangiography can identify the level of biliary obstruction in the Fig. 5.38 Age-specific incidence of liver cancer in men; rates are higher in young men in areas where viral case of intrahepatic cholangiocarcino- hepatitis is endemic. ma.

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Genetic change in hepatocellular carcino- ma may be directly related to relevant environmental factors. In areas with high exposure to aflatoxin B1, mutation of the third nucleotide in codon 249 of p53 is frequent, compatible with mis-coding due to the binding of aflatoxin (adduct forma- tion) to relevant nucleotides in DNA. There is evidence that mutation of p53 is an early event in hepatocellular carcinomas in high-incidence areas, whereas it occurs as a late event in progression in industri- Fig. 5.40 CT image of a multifocal hepatocellular alized countries. In hepatocellular carcino- carcinoma (arrows). mas associated with low aflatoxin expo- sure, mutation of various other sites in p53 may be detected. Sections of the HBV genome are frequently integrated into tumour DNA and expressed. Mutational activation of known oncogenes is rare [10]. Point mutations of KRAS and co-amplification of the cyclin D1 gene are detected in only a minority of hepatocellu- β Fig. 5.39 A woman in the Gambia preparing food lar carcinomas. Mutations of the -catenin which is potentially contaminated by aflatoxin. The gene are evident in about a third of combination of aflatoxin ingestion and chronic tumours examined. Accordingly, the Fig. 5.41 Macroscopic appearance of hepatocellu- hepatitis B poses a high risk of hepatocellular car- sequence of genetic events (Table 5.7) lar carcinoma. cinoma (Chronic infections, p56). that leads to hepatocellular carcinoma is poorly known and may vary from one tumour to another. Pathology and genetics Intrahepatic cholangiocarcinoma (Fig. Hepatocellular carcinoma is a malignant 5.43) comprises cells resembling those of epithelial tumour derived from hepato- bile ducts, which is the site parasitized by cytes, and thus resembles normal liver liver flukes [9]. Most intrahepatic cholan- both structurally and cytologically. Small giocarcinomas are adenocarcinomas early-stage hepatocellular carcinomas (<2 showing tubular and/or papillary struc- cm) are well-differentiated histologically tures with a variable fibrous stroma. and arranged in a thin trabecular pattern Mutations of the KRAS and p53 genes are without a capsule (Fig. 5.42) [8]. Tumour the most common genetic abnormalities Fig. 5.42 Histological appearance of hepatocellu- cells grow in cords of variable thickness identified. lar carcinoma: a well-differentiated, trabecular that are separated by sinusoid-like blood carcinoma containing numerous sinusoid-like cap- spaces. Hepatocellular carcinoma is Management illary vessels. believed to progress from adenomatous The treatment of primary and malignant hyperplasia (or dysplastic nodules) liver tumours depends on the extent of the through atypical hyperplasia to early disease and the underlying liver function hepatocellular carcinoma. Trabeculae [11]. The most frequently used staging become thicker with de-differentiation. system is that in which the patient is eval- Larger cancer nodules may consist of uated according to the adverse criteria of more than two types of tissue of different ascites, serum albumin and bilirubin con- F histological grade [10]. Invasion into the centration and tumour size. The TNM sys- blood vessels, especially the portal vein, is tem (Box: TNM, p124) is less useful as it a characteristic of hepatocellular carcino- does not take into account underlying liver ma. The malignant cells produce alpha- disease. Liver cancer follows a rapid, pro- Fig. 5.43 Infection with the liver fluke fetoprotein which may be detected in the gressive course: only about 10% of Opisthorchis viverrini (arrow) is typically associat- serum of most patients. patients survive at least five years in the ed with cholangiocarcinoma in parts of Asia.

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USA and the percentage is much lower in developing countries (Fig. 5.44). Hepatocellular carcinoma In the absence of extrahepatic disease, Familial resection with negative pathologic mar- CDKN 2A, APC and BRCA2 gins is the mainstay of treatment for Sporadic malignant liver . In patients in HBV genome integration p53 whom a small liver remnant is anticipated, CDKN2A portal vein embolization is used to M6P/IGF2R increase the size of the future liver rem- SMAD gene family members nant [11]. The fact that most hepatocellu- Cyclin D and Cyclin A lar carcinomas occur in a cirrhotic liver Altered MET function? excludes many patients from considera- tion for surgical resection, due to the risk Intrahepatic cholangiocarcinoma of liver failure. Other techniques used KRAS alone or as an adjuvant to resection p53 include radiofrequency ablation and c-erbB2 cryoablation. Liver transplantation has MET oncogene α β been performed in non-resectable E-cadherin, -cadherin, -cadherin BCL2 patients, although use of this procedure Telomerase has declined due to a number of factors, including the frequency of death from Fig. 5.44 Five-year relative survival after diagnosis Table 5.7 Genes involved in the development of tumour recurrence, especially in the of liver cancer. liver cancer. transplanted liver, and organ shortages. Hepatocellular carcinoma is largely radio- therapy resistant [10]. Nonsurgical treat- ments include hepatic artery infusion of apy regimen combining cisplatin, doxoru- apy and local regional therapy is poor [12]. drugs or thrombotic agents (port or bicin, interferon and 5-fluorouracil may The liver is also a frequent site of metas- pump), chemoembolization and percuta- elicit a response, although previously no tases from cancers at other sites, of which neous alcohol or acetic acid injection, agent, either singly or in combination, has the most common is colorectal cancer. although side-effects are many and bene- been found to improve survival. Hormone The poor prognosis and lack of effective fit to the unresectable patient is doubtful therapy is also disappointing, although therapies for hepatocellular cancer sug- [4,11]. Hepatic intra-arterial iodine 131- results with octreotide are more hopeful gest that the development of prevention labelled lipiodol (iodized poppy seed oil) than with tamoxifen. Metastatic hepato- programmes is of critical importance shows promise for the future [4,12]. cellular cancer commonly spreads to the (Hepatitis B vaccination, p144). Recent results suggest that a chemother- lungs and bones. Response to chemother-

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REFERENCES WEBSITES 1. Ferlay J, Bray F, Parkin DM, Pisani P, eds (2001) 8. Schafer DF, Sorrell MF (1999) Hepatocellular carcino- NCI Liver Cancer Homepage: Globocan 2000: Cancer Incidence and Mortality Worldwide ma. Lancet, 353: 1253-1257. http://www.cancer.gov/cancer_information/cancer_type /liver/ (IARC Cancer Bases No. 5), Lyon, IARCPress. 9. Nakanuma Y, Sripa B, Vatanasapt V, Leong AS-Y, Ponchon 2. Engstrom PF, McGlynn K, Hoffman JP (1997) Primary T, Ishak KG (2000) Intrahepatic cholangiocarcinoma. In: American Association for the Study of Liver Diseases: http://www.aasld.org/ neoplasms of the liver. In: Holland JF, Bast RC, Morton DL, Hamilton SR, Aaltonen, LA eds, World Health Organization Frei E, Kufe DW, Weichselbaum RR eds, Cancer Medicine, Classification of Tumours. Pathology and Genetics of Tumours Williams and Wilkins, 1923-1938. of the Digestive System, Lyon, IARCPress, 173-180. 3. Parkin DM, Bray FI, Devesa SS (2001) Cancer burden 10. Hirohashi S, Ishak KG, Kojiro M, Wanless IR, Theise ND, Tsukuma H, Blum HE, Deugnier Y, Laurent Puig P, in the year 2000. The global picture. Eur J Cancer, 37 Suppl Fischer HP, Sakamoto M (2000) Hepatocellular carcinoma. 8: S4-66. In: Hamilton SR, Aaltonen, LA eds, World Health 4. Bergsland EK, Venook AP (2000) Hepatocellular carci- Organization Classification of Tumours. Pathology and noma. Curr Opin Oncol, 12: 357-361. Genetics of Tumours of the Digestive System, Lyon, IARCPress, 159-172. 5. Okuda K (2000) Hepatocellular carcinoma. J Hepatol, 32: 225-237. 11. Vauthey NJ (1999) Multidisciplinary approaches to pri- mary and metastatic liver cancer, 2nd UICC Cancer 6. IARC (1994) Hepatitis (IARC Monographs on Management Meeting: The Team Approach to Cancer the Evaluation of Carcinogenic Risks to Humans, Vol. 59), Management, 14-18 April 1999, Antwerp, Belgium. Lyon, IARCPress. http://www.uicc.org/publ/antwerp/landmarks4.htm 7. Pisani P, Parkin DM, Muñoz N, Ferlay J (1997) Cancer 12. Clingan PR (1998) Hepatobiliary carcinoma. In: Morris and infection: estimates of the attributable fraction in D, Kearsley J, Williams C eds, Cancer: a comprehensive 1990. Cancer Epidemiol Biomarkers Prev, 6: 387-400. clinical guide, Harwood Academic Publishers.

Liver cancer 207 WCR-S5.Q (composition) 27/01/03 10:27 Page *208

CANCERS OF THE MALE REPRODUCTIVE TRACT

SUMMARY

> accounts for about 200,000 deaths annually worldwide, predominantly afflicting older men in developed countries.

> Risk factors include high caloric intake and low physical activity. Black men have the highest, white men an interme- diate, and Asian men a lower risk. Recorded incidence is increasing in many countries, partly as a result of screening for elevated serum levels of prostate-specific antigen.

> mainly affects young men, with close to 50,000 new cases each year worldwide. Incidence is increasing in many developed countries; < 7.6 < 14.5 < 23.7 < 34.7 < 104.3 its etiology is largely unknown. Age-standardized incidence/100,000 population

> The mean five-year survival rate is high- Fig. 5.45 The global incidence of prostate cancer. Rates are highest in developed countries and in some er than 95% mainly due to the efficacy of parts of Africa. chemotherapy using cisplatin; long-term disease-free survival can even be ence has been suggested by screening of The prevalence of latent prostate cancer achieved in cases of metastatic testicu- lar cancer. asymptomatic individuals) and also by shows much less geographic and ethno- detection of latent cancer in tissue removed graphic variation than clinical prostate during prostatectomy operations, or at cancer, where the ethnicity-specific rank- autopsy. Thus, especially where screening ings are much the same as for incidence examinations are prevalent, recorded inci- [1]. The lifetime risk for microfocal cancer dence may be very high by comparison with is estimated to be at least 30% of the PROSTATE CANCER earlier levels. In the USA, for example, the male population, with progression to clin- introduction of screening using prostate- ical cancer occurring in about 10%, while Definition specific antigen (PSA) testing has led to an the lifetime risk of dying from prostate The majority of prostate cancers are ade- enormous increase in the diagnosis of cancer is approximately 3%. nocarcinomas of a heterogeneous nature, prostate cancer, recorded incidence now Incidence and mortality increase with which develop primarily in the peripheral reaching 104 cases per 100,000 popula- ageing, with peaks somewhere within the zone of the prostate gland. tion, making it by far the most commonly seventh decade, depending on the diagnosed cancer in men (Screening for degree of awareness and the establish- Epidemiology prostate cancer, p160). Similar changes ment of population screening pro- Prostate cancer is the third most common have been observed in Australia, Finland grammes in different populations. The cancer in men in the world, with 543,000 and Sweden. However, incidence rates and, low fatality rate means that many men new cases each year. In the majority of to a lesser extent, mortality rates are rising are alive following a diagnosis of prostate more developed and developing countries, in many other countries where a possible cancer – an estimated 1.37 million at five prostate cancer is the most commonly diag- impact of screening may be excluded. There years in 2000 - making this the most nosed affecting men beyond mid- is even a recognized increase in those Asian prevalent form of cancer in men. More dle age. countries where risk is low, e.g. in Japan and than any other, this is a cancer of the In recent times, incidence rates (Fig. 5.45) China, as well as in Africa. Such changes elderly. Thus, about three-quarters of of prostate cancer have been influenced by suggest the influence of lifestyle or environ- cases worldwide occur in men aged 65 or the diagnosis of latent cancers (whose pres- mental factors in etiology. above.

208 Human cancers by organ site WCR-S5.Q (composition) 27/01/03 10:27 Page 209

role for genetic-environmental interactions as determining patterns of disease. Dietary Certain Possible Uncertain patterns suggest that saturated fat is a sig- nificant risk factor, while micronutrients such as the vitamins A, E and D, selenium, Age Body size lycopene and calcium may exercise a pro- High fat diet Race Sexual activity tective effect against cancer. The role of hormones, especially androgens, Family history Estrogens Vasectomy is obviously important, granted the impact Selenium Vitamin A of orchidectomy (excision of the testes) on progression. However, an endocrine basis Vitamin E/D Calcium for carcinogenesis is still not well under- Phyto-estrogens Lycopene stood. Genetic polymorphisms in the andro- gen receptor may be more important than Table 5.8 Risk and protective (in italics) factors for prostate cancer. any imbalance of hormones in the circula- tion. Studies of body size, vasectomy, sexu- al activity and cigarette smoking as risk fac- The distribution of mortality rates is less than in whites, who in turn have rates con- tors have produced inconclusive, equivocal affected than incidence by the effects of siderably higher than populations of Asian results. early diagnosis of asymptomatic cancers origin (Chinese, Japanese, Korean). A diet characteristic of Asian countries such (whether through screening, or by detec- as Japan and China, essentially a low fat tion of latent cancer in tissue removed dur- Etiology intake with consequent low body weight, ing prostatectomy operations). Mortality Age is the strongest risk factor for prostate with an intake of relatively high levels of rates are comparatively high in North cancer. Development of this malignancy is a phyto-estrogens (Box: Phyto-estrogens, America, Northern and Western Europe, multi-step process associated with a long p78) may provide the means of restraining Australia/New Zealand, parts of South natural history [2]. It can be inferred that the growth and progression of prostate can- America (Brazil) and the Caribbean, and in the initiation of preneoplastic lesions and cer. A strategy for prevention would be to much of sub-Saharan Africa and low in microscopic cancer is influenced by envi- increase the intake of phyto-estrogens, Asian populations, and in North Africa (Fig. ronmental factors which, in turn, implies a essentially isoflavonoids, lignans and possi- 5.46). The difference in mortality between case for lifestyle causes and primary pre- bly certain flavonoids [3]. The years of China and the USA is 26-fold (while it is vention. potential life saved by preventive measures almost 90-fold for incidence). Racially Although many of the risk factors for ade- for prostate cancer may be less than for based differences are evident within the nocarcinoma of the prostate (Table 5.8) are cancers occurring earlier in life, but the United States, where the black population weakly linked, the strong association of number of men with the disease worldwide has the highest incidence (and mortality) race, familial and geographic patterns with adequately justifies a focus on this effort rates, those rates being some 35% higher mortality directs attention to a significant (Screening for prostate cancer, p160).

Japan Singapore USA Australia Poland Spain

250 250 250 250 250 250

100 100 100 100 100 100 50 50 50 50 50 50 Black 25 25 25 25 25 25

White 10 10 10 10 10 10

5 5 5 5 5 5 2.5 2.5 2.5 2.5 2.5 2.5

1 1 1 1 1 1

19601970 1980 1990 2000 19601970 1980 1990 2000 19601970 1980 1990 2000 19601970 1980 1990 2000 19601970 1980 1990 2000 19601970 1980 1990 2000 Fig. 5.46 Trends in prostate cancer mortality. Although mortality rates increased generally in the last 30 years, in some places, e.g. the USA, mortality is now falling. D.M. Parkin et al. (2001) Eur J Cancer, 37 Suppl.8: S4-66.

Cancers of the male reproductive tract 209 WCR-S5.Q (composition) 27/01/03 10:27 Page 210

Basal cells Luminal cells

Bladder Secretions Prostate Rectum

PROSTATIC NORMAL INVASIVE INTRAEPITHELIAL METASTASIS EPITHELIUM CARCINOMA NEOPLASIA (PIN)

Fig. 5.47 Diagram describing patient configura- Loss of basal cells Loss of basal lamina -independence tion during transrectal ultrasound imaging of the Loss of 8p21 Loss of 10q Loss of 13q Loss of 17p prostate gland, which is an important technique NKX3.1 PTEN RB p53 used to measure prostate volume and to direct biopsies in prostatic tissue. Fig. 5.50 Stages of prostate cancer progression are correlated with loss of specific chromosome regions and of candidate tumour suppressor genes.

prostate gland, and asymmetry and cer. Microfocal, latent or incidental induration are indicative of prostate can- prostate cancer are terms used to cer. Raised levels of PSA may confirm the describe small histological tumours suspicion and mandate an ultrasound- found at autopsy, or in surgical speci- guided biopsy, after the patient has been mens, the prevalence of which is corre- informed of the consequences of both lated with age. The studies of Sakr [5] medical procedures [4]. Good clinical directed attention to the relatively high practice requires that symptomatic incidence of these microscopic cancers patients need a differential diagnosis before the age of 50. Fig. 5.48 A premalignant lesion of the prostate gland: this biopsy shows prostatic intraepithelial (analysis of clinical data to determine spe- Most instances of prostate cancer are neoplasia (arrow) within a dilated gland. cific nature of disease) whereas asympto- adenocarcinomas (Fig. 5.49), generally matic patients, especially those over 70 heterogeneous, that develop primarily in years of age, must be counselled as to the the peripheral zone of the prostate gland. benefits and disadvantages of further A clinical cancer is recognized as having investigation and treatment. Imaging pro- a volume over 0.5 cm3 and is less well vides no further support to confirm the differentiated than the latent cancers. suspicion of prostate cancer. Transrectal Slow growth with long doubling times, as ultrasound guided biopsies establish the well as de-differentiation over time, even dimensions of the prostate gland and in the advanced stages of the disease, enable effective location of the usual six are the hallmarks of prostate cancer [3]. core biopsies (Fig. 5.47). Radiological The stages of progression are associated examinations such as CT scans, MRI and with specific genetic alterations. Fig. 5.49 A biopsy from the prostate gland show- especially bone scans, are performed only It is estimated that up to 10% of all cases ing a focus (arrow) of moderately differentiated in order to stage a diagnosed cancer. of prostate cancer may be inherited. Two adenocarcinoma with tubular architecture. Radiolabelled immunoproteins may well familial genetic susceptibility loci have offer a potential imaging improvement. thus far been mapped to the X chromo- some and to chromosome 1p [6]. Detection Pathology and genetics Prostate cancer is genetically unstable The presence of lower urinary tract symp- Cancer of the prostate is a slow but con- and its genomic mutations can be divid- toms (e.g. difficulty in urinating, frequent tinuously growing form of neoplasia that ed into five major types: subtle sequence need) above age 50 are mostly due to con- is present in its preclinical form in men changes, alterations in chromosome comitant benign prostatic hypertrophy. from the age of 30, remaining latent for number (aneuploidy), chromosome trans- Latent cancer can progress to adenocarci- up to 20 years before progressing to the locations, gene amplifications and allelic nomas, which can infiltrate local urogeni- aggressive, malignant clinical cancer that deletions. Tumour growth suppressor tal organs and give rise to distant metas- generally attains its peak incidence in proteins such as p53 and bcl-2 are cur- tases, particularly to the bones. Digital the seventh decade. Prostatic intraep- rently being evaluated as prognostic fac- rectal examination is the simplest way to ithelial neoplasia (Fig. 5.48) is thought to tors, together with an associated wide detect anatomical abnormalities of the represent the precursor of prostate can- array of other genetic alterations [7-9].

210 Human cancers by organ site WCR-S5.Q (composition) 27/01/03 10:27 Page 211

Management operation. The TNM staging system (Box: which are classified as seminoma or The dramatic division between localized TNM, p124) is universally recognized. The nonseminoma. Less common testicular curable prostate cancer versus the differentiation or grade of the tumour is a tumours are Leydig cell tumours, Sertoli advanced incurable disease has provoked well-recognized dominant prognostic factor tumours, and, in the heated controversies regarding the impact that predicts the outcome of disease in all elderly, non-Hodgkin lymphoma. of early diagnosis and appropriate manage- stages and independently of the applied ment. For localized disease in patients with therapy. The Gleason grade scoring system Epidemiology a reasonable life expectancy, cure is the is now widely accepted as a means to Cancer of the testis accounts for 1.5 % of all ultimate goal [10]. Radical prostatectomy assess the histological degree of differenti- male cancers in most markedly affected (retropubic, perineal or laparoscopic) is ation. Serum PSA values and tumour size populations and about 0.5% elsewhere. usually recommended for patients with a are valuable indicators; other promising About 49,300 new cases are diagnosed life expectancy of greater than ten years. potential prognostic factors include each year. A rapid increase in incidence has Although the cure rate is very high, side kallikreins, microvessel density, epidermal been observed in most countries, such that effects may include incontinence (2-10%) growth factors and androgen receptors. in some populations testicular cancer is the and impotence (30-90%). Due to subse- Tuning or integrating the different prognos- most common malignancy among young quent incapacity to produce semen, men tic factors into a nomogram, or an analysis men at age 15-34. The reasons for this who wish to father children may be advised by artificial neural net system may provide trend are not well understood, although concerning sperm-banking or retrieval. better probabilities for the individual improved diagnostic procedures may be Radiotherapy is effective and may be re- patient in the future [12]. partially responsible. The highest incidence commended for patients who are not suit- Survival time after diagnosis is significantly is in Central Europe (Denmark, Norway and able for surgery. Proctitis (inflammation of longer in high-risk countries (80% in the Germany) and generally in Caucasian popu- the rectum) is, however, a common side USA compared to 40% in developing coun- lations of developed countries (Fig. 5.51). In effect of conventional external beam thera- tries), although this more favourable prog- the USA and Western Europe, the lifetime py (occurring severely in 3-5% of patients), nosis could well be due to the greater num- incidence of tumours is one in as is erectile dysfunction (6-84%) [11]. bers of latent cancers being detected by 500 or 15-20 per 100,000 males per Alternatives include conformal radiothera- screening procedures in these countries. annum. Incidence is low in Africa and Asia, py or brachytherapy. Locally advanced dis- including Japan, with only Israel having an ease is frequently managed by a combina- intermediate rate. tion of endocrine therapy and radiotherapy, CANCER OF THE TESTIS Cancer of the testis can occur at all ages, while endocrine treatment is the mainstay risk being maximal during the third and for metastatic disease. Such endocrine Definition fourth decades of life and declining after treatment may comprise luteinizing hor- The most common malignant tumours of age 50; the median age at diagnosis for mone-releasing hormone agonists, anti- the testis (>90%) are germ cell tumours, testicular nonseminoma is 24 years and a androgens or orchidectomy. The initial choice of treatment is best done after counselling the patient and with access to a multidisciplinary team. Endocrine treat- ment almost invariably achieves a remis- sion of the disease for a period, followed by a relapse and the development of endocrine unresponsive cancer. This type of disease needs aggressive but compas- sionate management, depending upon the general health status of the patient. More research is, however, essential to establish specific optimal treatment for the individual patient. Stage and grade determine the outcome of the disease in both localized and advanced disease. The limiting factor to cure is the presence of extraprostatic extension of the disease, a frequent companion to surgical < 0.5 < 0.8 < 1.5 < 4.0 < 10.4 Age-standardized incidence/100,000 population treatment due to the uncertainty of detect- ing extracapsular perforation before the Fig. 5.51 Global incidence of testicular cancer. The highest rates are in affluent Caucasian populations.

Cancers of the male reproductive tract 211 WCR-S5.Q (composition) 27/01/03 10:28 Page 212

Fig. 5.53 Histology of a seminoma with uniform cells resembling primitive germ cells, large vesi- cular nuclei and a glycogen-rich clear cytoplasm. Note the scattered lymphocytic infiltrates.

Fig. 5.52 Trends in incidence and mortality of testicular cancer in Norway, 1960-1990. Incidence has increased significantly while mortality has decreased, due to effective chemotherapy.

decade older for testicular seminoma. or a nodule in the testis. Other common Fig. 5.54 consisting of a Mortality has declined markedly since the presentations include back pain, (caused pleiomorphic proliferation containing glandular introduction of cisplatin as the basis of by retroperitoneal metastasis), haemopty- structures. chemotherapy in the mid-1970s. sis (consequent upon pulmonary metas- tases) and gynecomastia (excessive devel- Etiology opment of male mammary glands). (25-30%) and Generally relevant environmental causes Diagnosis is based on physical examina- (1%). Germ cell tumours can also arise of testicular cancer have not been estab- tion, ultrasonography and biopsy. In from extra-gonadal primary sites. lished. There is an increased incidence of patients with nonseminoma, serum Ovarian germ cell tumours of young the disease in individuals with a history of tumour markers alpha-fetoprotein and/or women share clinical features and treat- an undescended , testicular femi- human chorionic gonadotrophin are elevat- ment approaches with male germ cell nization and those with a family history of ed in 80% of patients with disseminated tumours. All germ cell tumours are com- testicular cancer. In utero exposure to disease and in 50% of patients with early monly associated with the presence of exogenous estrogens may increase the stage disease. Patients with testicular isochromosome 12p (an abnormal chro- risk of testicular cancer as a result of seminoma may have modestly elevated mosome 12 with two identical short increased incidence of cryptorchidism and levels of human chorionic gonadotrophin arms), a region which contains the gene dysgenesis. A history of maternal exposure and of lactic dehydrogenase. for cyclin D2 [15]. The initiation of a to has been associated There are no reliable screening tests for germ cell tumour is associated with var- with an increased relative risk of up to 5.3 testicular cancer. Due to low incidence and ious aberrations in the normal develop- [13]. Testicular cancer is more common in a high cure rate, advocacy of testicular mental pathway of the germ cell (Fig. higher socioeconomic groups. Hormonal self-examination and the impact of self- 5.55). and genetic factors seem likely to play an assessment are controversial. important, but currently unclear, role as Management risk factors; other factors may include the Pathology and genetics Current management of germ cell influence of heat [14]. About 90% of testicular malignancies tumours should yield average cure rates in arise from germ cells and these tumours excess of 95%, and even 80% of patients Detection are classified as seminoma (40%) (Fig. with metastatic disease respond to Most patients with testicular germ cell 5.53) or nonseminoma, which includes chemotherapy, radiotherapy and surgery tumours present with a painless swelling embryonal tumours (20-25%) (Fig. 5.54), (Fig. 5.56). However, survival in develop-

212 Human cancers by organ site WCR-S5.Q (composition) 27/01/03 10:28 Page 213

BIRTH PUBERTY FERTILIZATION

Gastrula Foetal gonad Postnatal gonad Maternal host

Mitosis Mitosis Mitosis Mitosis NORMAL

PGC Gonocyte Spermatogonium Spermatogonium Spermatocyte Sperm Zygote Embryo 2n 2n 2n 2n 4n 1n 2n 2n Apoptosis Apoptosis

Imprint Recombination Gamete Embryonal erasure checkpoint imprinting imprinting Body plan Cell fate Cyclin D2 p53 Differentiation

Mitosis

Aberrant chromatid exchange 12p Amplification (↑ Cyclin D2) Transformation Apoptosis rescue CIS GCT 4n ±4n TUMOUR Apoptosis Aberrant Imprinting

Cell fate Differentiation

Fig. 5.55 Normal and neoplastic male germ cell development. The division of a precursor cell, the spermatocyte (4n), produces 4 sperm cells each with one set of chromosomes (1n). The fusion of egg and sperm to form the zygote doubles the number of chromosomes to the normal complement (2n). Aberrant deve- lopment may produce a cell which has twice the normal chromosomal complement (4n). CIS = carcinoma in situ, GCT = germ cell tumour, PGC = primordial germ cell.

ing countries is only 42% to 61%, an indi- ment from seminoma should receive prognostic factors include low levels of cation of limited access to appropriate either (<5 cm bulk dis- alpha-fetoprotein (<1000 ng/ml), human therapy [13]. ease) or primary chemotherapy (>5 cm chorionic gonadotrophin (<5000 iu/L) and bulk disease). lactic dehydrogenase (<1.5 times the Seminoma upper limit of normal). Approximately 30% Stage I disease, confined to the testis, is Nonseminoma of patients under surveillance will relapse managed by post-operative radiotherapy Patients with local nonseminoma confined and are reliably cured with chemotherapy. to the retroperitoneal nodes which to the testis should be offered either Retroperitoneal lymph node dissection is reduces risk of recurrence from about aggressive surveillance or nerve-sparing both diagnostic and therapeutic. It also 20% to 2%. Patients who relapse either retroperitoneal lymph node dissection. eliminates the need for abdominal imaging during surveillance or after radiation are Surveillance requires monthly chest X- in follow-up. reliably cured with chemotherapy or radia- rays and assay of markers and two-month- Patients with abdominal involvement of tion at the time of relapse. Normal levels ly abdominal CT scans for one year. In the nonseminoma should receive retroperi- of alpha-fetoprotein, the presence of any second year following diagnosis, chest X- toneal lymph node dissection (<2 cm dis- human chorionic gonadotrophin or any ray and assay of tumour markers should ease) or primary chemotherapy (>2 cm lactic dehydrogenase are good prognostic be carried out every six months and CT disease). Those who undergo retroperi- factors. Patients with abdominal involve- performed every three months. Good toneal lymph node dissection and are

Cancers of the male reproductive tract 213 181 A 214 WORLD CANCER 27/06/03 12:08 Page 214

found to have positive nodes can consider Patients with nonseminoma who have nor- two cycles of adjuvant chemotherapy malized serum tumour markers and resid- (100% cure rate). ual radiographic abnormalities should be considered for post-chemotherapy resec- Disseminated germ cell tumours tion of residual disease. Teratoma (a Guidelines for treatment of disseminated malignant tumour that contains a variety germ cell tumours (both seminoma and of embryo-derived tissues, such as bone, nonseminoma) are driven by the muscle, cartilage, nerve, tooth buds) and International Germ Cell Consensus persistent cancer are common findings in (IGCC) prognostic index. Patients with this setting. In contrast, patients with low-risk nonseminoma (56% of cases) or seminoma and residual masses after seminoma (90% of cases) should receive chemotherapy should be simply observed, three cycles of bleomycin, etoposide and as teratoma and residual cancer are not cisplatin (BEP). Cure rate is approximate- common findings in this situation. ly 90-95%. Patients with intermediate-risk Patients with recurrent disease after disease or high-risk disease should chemotherapy still have the potential for receive four cycles of BEP, with an expect- cure. Salvage chemotherapy with vinblastine, Fig. 5.56 Five-year relative survival rates after ed cure rate of 75% or 50% of patients ifosamide and cisplatin cures approximately diagnosis of testicular cancer. respectively. 25% of these patients.

REFERENCES WEBSITES 1. Stanford JL, Damber JE, Fair WR, Sancho-Garnier H, selected p53 mutants in the primary site define foci with Information for GPs: Screening for Prostate Cancer: Griffiths K, Gu FL, Kiemeney LA (2000) Epidemiology of metastatic potential. J Urol, 161: 304-308. http://www.sesahs.nsw.gov.au/publichealth/Cancer Control/default.htm prostate cancer. In: Murphy G, Khoury S, Partin A, Denis L 9. Ozen M, Hopwood VL, Balbay MD, Johnston DA, eds, Prostate cancer, Health Publication Ltd, UK, 21-55 . Babaian RJ, Logothetis CJ, von Eschenbach AC, Pathak S The Prostate Cancer Research Institute (USA): 2. von Eschenbach AC (1996) The biologic dilemma of (2000) Correlation of non-random chromosomal aberra- http://www.prostate-cancer.org/ early carcinoma of the prostate. Cancer, 78: 326-329. tions in lymphocytes of prostate cancer patients with spe- NCI Prostate Cancer Homepage : 3. Griffiths K, Denis LJ, Turkes A (2001) Oestrogens, cific clinical parameters. Int J Oncol, 17: 113-117. http ://www.cancer.gov/prostate phyto-oestrogens and the pathogenesis of prostatic dis- 10. Lu-Yao GL, Yao SL (1997) Population-based study of ease. London, Martin Dunitz Publishers. long-term survival in patients with clinically localised 4. Dunn IB, Kirk D (2000) Legal pitfalls in the diagnosis of prostate cancer. Lancet, 349: 906-910. prostate cancer. BJU Int, 86: 304-307. 11. Incrocci L, Slob AK, Levendag PC (2002) Sexual 5. Sakr WA (1999) Prostatic intraepithelial neoplasia: A (dys)function after radiotherapy for prostate cancer: a marker for high-risk groups and a potential target for review. Int J Radiat Oncol Biol Phys, 52: 681-693. chemoprevention. Eur Urol, 35: 474-478. 12. Denis L, Murphy GP (2000) Cancer of the Prostate. In: 6. Abate-Shen C, Shen MM (2000) Molecular genetics of Pollock RE ed., UICC Manual of Clinical Oncology, New prostate cancer. Genes Dev, 14: 2410-2434. York, Wiley-Liss, 563-574. 7. Ozen M, Hopwood VL, Johnston DA, Babaian RJ, 13. Noss M, Klotz L (1998) Male urogenital cancer. In: Logothetis CJ, von Eschenbach AC, Pathak S (1999) Morris D, Kearsley J, Williams C eds, Cancer: a comprehen- Aneuploidy index in blood: a potential marker for early sive clinical guide, Harwood Academic Publishers, 213-222. onset, androgen response, and metastasis in human 14. Oliver RT (2001) Testicular cancer. Curr Opin Oncol, prostate cancer. Urology, 53: 381-385. 13: 191-198. 8. Navone NM, Labate ME, Troncoso P, Pisters LL, Conti 15. Chaganti RS, Houldsworth J (2000) Genetics and biol- CJ, von Eschenbach AC, Logothetis CJ (1999) p53 muta- ogy of adult human male germ cell tumors. Cancer Res, 60: tions in prostate cancer bone metastases suggest that 1475-1482.

214 Human cancers by organ site 215 A 269 WORLD CANCER 17/06/03 15:18 Page 215

CANCERS OF THE FEMALE REPRODUCTIVE TRACT

SUMMARY

> is the second most com- mon cancer of women worldwide with more than 470,000 new cases per year. Of about 230,000 deaths every year, more than 80% occur in developing countries. Five-year survival rates are up to 70%.

> Sexually transmitted infection with human papillomavirus is fundamental to development of carcinoma of the cervix.

> Population-based screening has greatly reduced mortality in developed coun- tries

> mainly affects post- menopausal women in developed coun- < 9.3 < 16.1 < 23.8 < 35.8 < 93.9 tries; 188,000 new cases are diagnosed Age-standardized incidence/100,000 population annually and obesity is a major risk fac- tor. Fig. 5.57 The global burden of cervical cancer. Note the high incidence rates in Central and South America, Southern Africa and India. Today, more than 80% of all cervical cancers occur in developing > About 190,000 cases of ovarian cancer countries. occur each year, predominantly among postmenopausal women in developed countries; five-year survival rates are 470,000 new cases are diagnosed each tive cervical cytology, typically by means of about 40%. year. 80% of cases of cervical cancer occur the Pap smear (Screening for cervical can- in developing countries where, in many cer, p167). Nevertheless, in several coun- regions, it is the most common cancer of tries, notably the UK, Australia, New women. The highest incidence rates are in Zealand, and in central Europe, there have South America and the Caribbean, sub- been increases in risk in younger women, Saharan Africa, and South and South- probably the result of changes in exposure CERVICAL CANCER Eastern Asia (Fig. 5.57). However, very low to risk factors. These changes are most rates are observed in China, and in evident for adenocarcinomas, which share Definition Western Asia. In developed countries, the to some extent the etiological agents of The majority of epithelial tumours of the incidence rates are generally low, with age- squamous cell carcinomas, but for which cervix are squamous cell carcinomas standardized rates of less than 15 per cytological screening is ineffective in coun- (85%). Adenocarcinomas are less com- 100,000, with the exception of Eastern tering the increase in risk. In developing mon. Most cervical carcinomas arise at Europe, where incidence rates range from countries the situation is more mixed, with the junction between the columnar epithe- 18-35 per 100,000. The incidence of can- high rates persisting in some areas (Latin lium of the endocervix and the squamous cer of the cervix begins to rise at ages 20- America, India, Africa), and declines else- epithelium of the ectocervix, a site of con- 29, and then increases rapidly to reach a where, most notably in China. tinuous metaplastic change, especially in peak at around ages 45-49 in European utero, at puberty and during a first preg- populations, but often rather later in devel- Etiology nancy. oping countries. Molecular epidemiological studies have Incidence and mortality have declined shown that certain human papillomavirus Epidemiology markedly in the last 40 years in Western types (HPV) are the central cause of cervi- Cancer of the cervix is the second most Europe, USA, Canada, Australia and New cal cancer and cervical intraepithelial neo- common cancer among women worldwide, Zealand, mainly in relation to extensive plasia (CIN) [1, 2, 3]. It is now clear that second only to breast cancer; about screening programmes based on exfolia- the well-established risk factors associat-

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Phylogenetic Classification Epidemiologic Classification

High risk Low risk High risk 16, 18, 31, 33, 35, 39, 70 45, 51, 52, 56, 58, 59, 68, 82, 26, *53, *66* Low risk 6, 11, 40, 42, 43, 44, 73 54, 61, 72, 81, CP6108 Fig. 5.58 A “Healthy Women” group in a Nigerian village discusses the benefits of condom usage to * The epidemiologic classification of these types as probable high-risk types is based prevent sexually transmitted diseases. on zero controls and one to three positive cases.

Table. 5.2 B. Phylogenetic and Epidemiologic Classification of HPV Types. Munoz et al. N Engl J Med 348:518- 527 (2003).

central and strong effect of HPV is taken Cervical cancer does not tend to produce into account. A review of studies fulfilling any symptoms in the early stages. Only this requirement has revealed that high when invasive disease is established do parity, smoking and long-term use of oral symptoms such as vaginal bleeding, dis- contraceptives are co-factors that increase charge and pain become manifest. the risk of cervical cancer. The role of additional co-factors such as, herpes sim- plex virus type 2 (HSV-2), Chlamydia tra- Fig. 5.59 An invasive cancer of the cervix, seen by chomatis infection, HIV and other causes unaided visual inspection. of immunosuppression, certain nutritional deficiencies and genetic susceptibility, is ed with sexual behaviour, such as multiple being investigated. sexual partners and early age at initiation of sexual activity, simply reflect the proba- Detection bility of being infected with HPV. HPV DNA Early changes in the cervix, specifically cer- has been detected in virtually all cervical vical intraepithelial neoplasia, can be cancer specimens [4, 5]. The association detected years before invasive cancer of HPV with cervical cancer is equally develops, and this is the basis for the effec- strong for the two main histological types: tiveness of cytological screening in second- Fig. 5.60 Histology of cervical intraepithelial neo- squamous cell carcinoma and adenocarci- ary prevention. The diagnosis of cervical plasia stage I (CIN1). Note that dysplastic cells noma. Over 100 HPV types have been cancer is made on examination of cytologi- (arrow) are confined to the lower third of the identified and about 40 can infect the gen- cal samples taken from the endocervix with epithelium. ital tract (Table 5.2 B). Fifteen of these a cytobrush and from the ectocervix with an have been classified as high-risk (HPV Ayre’s spatula (an ectocervical or a 16,18, 31, 33, 35, 39, 45, 51, 52, 56, 58, Papanicolaou smear) [7]. A tissue specimen 59, 68, 73, and 82), three as probably may also be obtained by colposcopy and high-risk (HPV 26, 53, and 66) and twelve biopsy, which may be the loop electrosurgi- as low-risk (HPV 6, 11, 40, 42, 43, 44, 54, cal excision procedure. In the course of EX 61, 70, 72, 81, and CP6108) [1, 4, 6]. screening, false negatives are common so However, since only a small fraction of all suspicious lesions are biopsied. If clinical HPV-infected women will eventually devel- cancer is apparent, a punch biopsy speci- op cervical cancer, there must be other men is evaluated. Patients with abnormal exogenous or endogenous factors which, Pap smear and no visible lesion require col- acting in conjunction with HPV, influence poscopy and biopsy. The diagnosis of Fig. 5.61 A well-differentiated mucinous adeno- the progression from cervical infection to microinvasive carcinoma is made from cone carcinoma (arrow) with a papillary architecture developing from the endocervical mucosa, deep cervical cancer. The assessment of the biopsy or hysterectomy specimen patholo- under the normal squamous epithelium of the exo- role of these co-factors requires that the gy. cervical mucosa (EX).

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ploid, moderate or severe dysplasia or car- do not produce a tissue specimen for his- cinoma in situ) [6]. One of the precursors tology may ablate an undetected adeno- of invasive adenocarcinoma is recognized carcinoma in situ or microinvasive carcino- as adenocarcinoma in situ. This is some- ma [12]. Recurrences or persistent resid- times difficult to diagnose, often not being ual disease may occur. detected by Pap smear [8]. For early stage invasive carcinoma, where Squamous cell carcinomas may be either the cancer is confined to the cervix or large cell non-keratinizing or large cell ker- spread to the upper vagina, surgery and atinizing, or a less common variant, such radiotherapy are the primary treatment as the well-differentiated verrucous carci- options. Radiotherapy is usually employed noma. The worldwide prevalence of adeno- for patients with advanced disease and carcinomas of the cervix has increased external beam therapy is used initially for from 5% in 1950-60 to 20-25% of all cervi- patients with bulky tumours. The use of an cal tumours [6]. The most common type is intracavity source is being replaced mucinous adenocarcinoma, which may be with caesium-137, which is considered intestinal, endocervical or signet-ring, fol- safer. Radiotherapy may be given post- lowed by endometrioid adenocarcinoma. operatively to patients at a high risk of Another epithelial tumour type consists of recurrence (although benefits are not a mixture of squamous cell carcinomas proven) [13]. Fig. 5.62 Five-year relative survival rates after diagnosis of cervical cancer. and adenocarcinomas. Unresectable lymph node metastases are Subsequent to infection, the HPV genome a risk factor for persistent disease. of high-risk types becomes stably integrat- Invasive carcinoma of the cervix may fol- Advanced carcinoma is suggested by back- ed into the host DNA, commonly near cel- low a more rapidly progressive course in pain, oedema of the lower extremity, a non- lular oncogenes such as C-MYC and N- HIV-positive women. Despite initial treat- functioning kidney (due to ureteral obstruc- MYC, or into regulatory sequences, such ment and even hysterectomy, cervical tion), invasion of sacral nerve branches or as the genes encoding transcription fac- intraepithelial neoplasia and even invasive extranodal extension and encroachment of tors Erg and Ets-2 [9]. The observation that cancer may still recur, or residual disease the pelvic wall veins and lymphatics [6]. low frequencies of p53 gene mutations are may persist. Common sites of recurrence In the event of invasive disease, investiga- found in tumours associated with HPV is are the paraortic lymph nodes, liver, lungs, tions are undertaken to determine whether probably a reflection of the fact that the abdomen, bones, the central nervous sys- metastatic disease is present, i.e. chest viral protein E6 is able to functionally inac- tem and supraclavicular lymph nodes. radiography, blood cell count and serum tivate p53 protein. A variety of molecular Recent treatment advances include high chemistry. Intravenous pyelography is used markers for cervical cancer are under pre- dose rate brachytherapy, refinement of to investigate the possibility of uretic liminary investigation, including telom- treatment dose to minimize failure rate, obstruction; abdominal CT and MRI are erase (Box: Telomeres and Telomerase, and addition of chemotherapy concurrent- used to indicate spread and to take tumour p108), which appears to be expressed in ly with radiotherapy to minimize local and measurements, respectively. Cytoscopy most cervical epithelial neoplasias and distant failures. Palliative treatment of and sigmoidoscopy are necessary in the KRAS (mutations having been detected in those with advanced or metastatic disease event of anterior or posterior spread. DNA extracted from cervical aspirates) may consist of combination platinum- [10]. Loss of heterozygosity on chromo- based chemotherapy [14]. Pathology and genetics some 3p has been observed in invasive Survival from cancer of the cervix depends Precursor lesions of the cervix are com- and pre-invasive lesions [11] suggesting on stage of disease, with 70-85% of local- monly classified using terminology for his- the presence of a tumour suppressor gene; ized cancer cases surviving five years com- tological diagnosis, thus mild dysplasia is the FHIT gene (fragile histidine triad) has pared to less than 10% of cases with distant categorized as cervical intraepithelial neo- been mapped to 3p14.2 (a suspected HPV spread. Important differences are present plasia CIN I, moderate dysplasia is CIN II, integration site which is commonly altered in relation to age and ethnic or socioeco- and severe dysplasia, CIN III. However, in cervical cancer). nomic characteristics, probably as a conse- newer terminology for precursor lesions of quence of differential access to medical the cervix classifies them as squamous Management care. Survival rates for all stages also vary intraepithelial lesions, which are graded Cervical intraepithelial neoplasms may be between regions; even in developing coun- from low (mild dysplasia, usually diploid or treated by local excision (wire loop elec- tries, where many cases present at rela- polyploid, associated with various HPV trode, conisation with laser or scalpel) or tively advanced stage, survival rates reach types) to high (associated with intermedi- destruction (laser vapourisation, radical 49% on average (Fig. 5.62). The poorest ate or high-risk HPV type, typically aneu- diathermy or cryocautery). Methods which survival is estimated for Eastern Europe.

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estrogen therapy for menopause or prior oophorectomy, increase the risk of cancer whereas oral contraceptives containing an estrogen-progesterone combination decrease it. Syndromes of increased endogenous estrogen exposure, such as granulosa-theca cell tumours of and polycystic ovary, are also associated with an increased risk. Other risk factors include a history of colon or breast carci- noma. Use of tamoxifen as a therapeutic or chemopreventive agent is a risk factor [15]. The disease is clearly associated with obesity, diabetes and hypertension.

Detection The most common sign is metrorragia (uterine bleeding), especially after menopause. Irregular or postmenopausal < 2.4 < 4.2 < 7.7 < 13.2 < 28.9 Age-standardized incidence/100,000 population bleeding is the presenting symptom in at least 75% of patients. At the time of diag- Fig. 5.63 The global incidence of endometrial cancer. Affluent populations are predominantly affected. nosis, 75% of patients have disease con- fined to the uterus although up to 20% of new cases and 45,000 deaths occurring patients have no symptoms [16, 7]. worldwide each year; about 60% of these Other signs include those linked to a mass Definition occur in more developed countries. The in the lower abdomen, such as dysuria (dif- Tumours of the uterine corpus are predom- highest incidence rates are in the USA and ficult urination), constipation or bloating. inantly adenocarcinomas, arising from the Canada, while other regions with age-stan- Histological sampling of the endometrium endometrium, or lining, of the uterus. dardized rates in excess of 10 per 100,000 and cervix, either through biopsy or dila- include Europe, Australia and New Zealand, tion and curettage, should be undertaken Epidemiology the southern part of South America, and the in the event of symptoms. Endovaginal Cancer of the uterus is the seventh most Pacific Island nations. Low rates occur in echography and hysteroscopy are useful common cancer of women with 189,000 Africa and Asia (Fig. 5.63). adjuncts in the diagnosis of endometrial Some countries, such as the USA and pathology. Canada, are experiencing a clear decline in incidence and mortality from cancer of the Pathology and genetics uterus, particularly among young women. In Endometrioid adenocarcinoma (Fig. 5.64) Europe, rates appear stable in the south and is the most common histology (60-65%). to be decreasing in the north. Uterine can- This tumour type is characterized by the cer occurs primarily in elderly women, the disappearance of stroma between abnor- median age of onset being around 60 years old; only 5% of cases develop before age 40.

Etiology Cancer of the endometrium is linked to reproductive life with increased risk among nulliparous women and women undergoing late menopause (Reproductive factors and hormones, p76). The endometrium is normally a hormonally responsive tissue, responding to estrogens with growth and glandular proliferation and Fig. 5.64 A well-differentiated mucus-secreting Fig. 5.65 Five-year relative survival rates after to with maturation. endometrial adenocarcinoma with a glandular diagnosis of cancer of the uterus. Exogenous estrogens, as in unopposed architecture.

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KRAS Inheritance of high-penetrance genes Microsatellite instability (DNA mismatch repair Monoclonal proliferation PTEN/MMAC1 genes, BRCA1-2 and p53) KRAS and PTEN mutation p16/INK4a and low-penetrance genes (CYP1A1, Polyclonal Microsatellite instability Cyclin D1 MTHR) proliferation hMLH1 promoter methylation DCC c-fms Estrogen receptor

p53 c-erbB2/neu MRP E-Cadherin NON-ATYPICAL ATYPICAL 1p LOH CD44v HYPERPLASIA HYPERPLASIA

Type I tumours ENDOMETRIAL ENDOMETRIUM DISSEMINATION Type II tumours CARCINOMA

Fig. 5.66 A genetic model for endometrial tumorigenesis.

mal glands that have infoldings of their lin- for the genetic alterations involved in frequent follow-up is recommended. Post- ings into the lumens, disordered nuclear endometrial tumorigenesis is becoming operative radiation therapy is currently chromatin distribution, nuclear enlarge- characterized (Fig. 5.66). Patients with given to patients at a high risk of relapse ment, a variable degree of mitosis and is lesions which are positive for cytoplasmic following surgery. In inoperable cases, associated with necrosis and haemorrhage estrogen and progesterone receptors have pelvic radiation therapy, usually external [16]. Adenosquamous carcinoma, which a better rate of disease-free survival than beam and intracavity irradiation, may be comprises 7% or less of cases, has a poor those with no identifiable receptors [16]. the sole treatment [16]. prognosis. 5-10% of endometrial carcino- PTEN mutations are associated with a High levels of expression of MDR1 protein mas are uterine papillary serous carcino- more favourable prognosis; tumours with (multi-drug resistance) or associated pro- mas, a very virulent type. Clear cell carci- PTEN mutations tend to be of endometri- teins in a large number of endometrial noma is more frequent in older women. oid histology as opposed to clear cell tumours and normal endometrial tissues Endometrial cancer is a significant risk for serous cell types and have fewer p53 suggest there is a neoplasm which is women affected by the dominantly inherit- mutations. Aneuploidy is associated with intrinsically resistant to chemotherapy [18] ed hereditary nonpolyposis colorectal car- poor prognosis, as is the overexpression of (Box: Resistance to cancer chemo- therapy, cinoma (HNPCC) syndrome and by Li- c-erbB2/neu and p53 and mutations of p285). In fact, use of chemo- therapy is Fraumeni syndrome, due to germline codon 12 or 13 of the KRAS gene. restricted to those with advanced or mutations in mismatch repair genes and Decreased expression of CD44 and E-cad- recurrent metastatic disease, although p53 respectively [17]. An enhanced sus- herin are associated with metastasis and cisplatin, doxorubicin and cyclophos- ceptibility to endometrial cancer has also depth of myometrial invasion. phamide or a combination of methotrex- been linked with an insertional p53 muta- ate, vinblastine, doxorubicin and cisplatin tion, a rare mutant in the methylenete- Management can produce high response rates and trahydrofolate reductase gene and certain Pre-cancerous lesions of the endometrium prolonged remissions. Response to high germline variants of the CYP1A1 gene. and in situ tumours are treated by simple dose progesterone therapy in receptor- Endometrial tumours which occur in pre- hysterectomy. For frank carcinoma, total positive patients is about 70%. Estrogen- and perimenopausal women and are estro- abdominal hysterectomy and bilateral salp- replacement therapy is recommended gen-related, with hyperplasia ante- cedent ingo-oophorectomy (removal of the fallopi- initially only in patients with in situ dis- (adenomatous and atypical adenomatous an tubes and ovaries) are the definitive ease or with low risk stage I tumours. ) are of stable behaviour (Type treatment, although tailoring of therapy to Survival is usually good, overall around II). Non-endometrioid tumours which meet individual needs is important. More 75-85% and for localized disease up to appear in postmenopausal women tend to than 50% of recurrences occur in the first 90% (Fig. 5.65), although there is some have a virulent behaviour (Type I). A model two years post-surgery. Thus regular and evidence to suggest that black women

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Fig. 5.68 Magnetic resonance image (MRI) of a large, partly cystic ovarian carcinoma.

OC

OC UT < 4.0 < 5.1 < 7.1 < 10.3 < 16.1 Age-standardized incidence/100,000 population

Fig. 5.67 The global incidence of ovarian cancer. This cancer occurs predominantly in developed coun- Fig. 5.69 Surgical specimen of a bilateral ovarian tries. carcinoma (OC). UT = uterus.

have a poorer prognosis for survival from risk factor for ovarian cancer (5-10% of nal discomfort, bloating, abnormal vaginal endometrial carcinoma than their white cases), risk being increased four-fold in bleeding and gastrointestinal or urinary tract counterparts. women with an affected first-degree relative. abnormalities. Abdominal and vaginal ultra- Cancer of the ovary is influenced by hor- sonography may suggest the presence of an mones and reproductive factors (Reproduc- ovarian tumour, but definitive diagnosis OVARIAN CANCER tive factors and hormones, p76). Risk is requires and biopsy. Pelvic ultra- slightly increased with nulliparity and a per- sonography, tumour markers and clinical Definition sonal history of breast cancer. Decreased examination have proved ineffective in mass The majority of ovarian cancers are carci- risk follows the use of oral contraceptives. In screening [7] and are employed only for nomas, which arise from the surface contrast, hormonal treatment for infertility patients having a high familial risk of ovarian epithelium of the ovary. entails an increased risk, whereas treatment cancer. The comparison of molecular profiles at the menopause is only associated with a generated by laser capture microdissection Epidemiology small risk. Early menarche or late is hoped to identify patterns of proteins About 190,000 new cases and 114,000 menopause may also entail a slightly which are uniquely expressed in early dis- deaths from ovarian cancer are estimated increased risk [18]. Diet plays a role, with ease in order to generate valuable markers to occur annually. The highest rates are increased risk linked to obesity and height, as for early detection [20]. reported in Scandinavia and Eastern well as some nutritional factors (e.g. lactose). Europe, the USA, and Canada. Low rates A history of pelvic inflammatory disease, Pathology and genetics are found in Africa and Asia (Fig. 5.67). polycystic ovary syndrome and endometrio- Most ovarian tumours are of epithelial origin The risk of epithelial tumours increases sis have also been associated with increased and include serous (45% of epithelial with age, occurring predominantly in peri- risk, whilst tubal ligation and hysterectomy tumours), mucinous, endometrioid (Fig. and postmenopausal women. Tumours of may decrease risk. 5.70) and clear cell adenocarcinomas, as germinal or embryonic origin are more well as the rare Brenner tumour. Non-epithe- frequent in young adults. Detection lial tumours, including germ cell tumours, The great majority of patients with epithelial gonadal-stromal tumours and tumours which Etiology ovarian cancer present with disease that has have metastasized to the ovary, are less com- Although most ovarian cancers are sporadic, spread outside of the ovary and even the mon. Three categories of lesions are recog- a family history is the single most important pelvis [19]. Symptoms may include abdomi- nized: benign, low malignancy potential or

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invasive malignant. Malignant germ cell tance of nonpolyposis colorectal cancer tumours are uncommon. (Colorectal cancer, p198), endometrial can- A majority of familial ovarian cancer seems to cer and ovarian cancer and is linked to muta- be due to mutations in the BRCA1 and tions in DNA mismatch repair genes MSH2, BRCA2 genes, which are also associated with MLH1, PMS1 and PMS2 (Carcinogen activa- a predisposition for breast cancer (Genetic tion and DNA repair, p89)[18,19]. Prophylactic susceptibility, p71), (although BRCA1 is also oophorectomy is a potential option for geneti- mutated in a minority of sporadic tumours cally high-risk women. [18]). Familial syndromes linked to increased The ERBB2 (HER-2/neu) oncogene is overex- risk of ovarian cancer include breast-ovarian pressed in about 30% of ovarian tumours, as is cancer syndrome, rare families who present C-MYC [21]. KRAS mutational activation is also Fig. 5.70 Histopathology of a well-differentiated, with ovarian cancers only and Lynch type II implicated in ovarian cancer. p53 mutations mucus-secreting, endometrial-like adenocarcino- syndrome, which is characterized by inheri- have been found in 50% of cases. ma of the ovary.

MULTICULTURAL ISSUES sites in white people in 1990-96 was 167.5 the USA, women who do not subscribe to per 100,000 whilst in the black population it private health insurance are less likely to Although incidence of cancer is often was 223.4. The reasons for such differences undergo screening for breast, cervical and recorded with reference to national or oth- are likely to be complex and multifactorial. colorectal cancers (Hsia J et al., Prev Med, erwise large populations, the disease bur- 31: 261-70, 2000). Such differences involv- den is rarely distributed uniformly across Environmental/behavioural factors may dif- ing increased incidence provide an oppor- such groupings. This becomes apparent fer between ethnic/cultural groups. For tunity for strategic action. when consideration is given to specific instance, the diet to which some migrant minority groups within a wider communi- populations are accustomed (e.g. small Treatment and its outcome may also be ty. A number of variables may contribute quantities of red meat, large quantities of affected by ethnic and social differences. to such an outcome. One such variable, fruit and vegetables) may be protective in For example, the way that pain is per- genetic make-up, is not amenable to inter- relation to risk of colorectal cancer, but risk ceived and dealt with is influenced by the vention but nonetheless may have an increases with the adoption of a Western ethnocultural background of the patient impact. For example, there are large diet (e.g. Santani DL, J Assoc Acad Minor (Gordon C, Nurse Pract Forum, 8: 5-13, racial/ethnic differences in prostate can- Phys, 10: 68-76, 1999). 1997). Ethical dilemmas can develop in cer risk, with high rates of incidence in multicultural settings due to differing cul- African-Americans, which may be partly Timely visits to a medical practitioner and tural beliefs and practices. More research related to genetic differences in hormone participation in screening programmes are into the relationship between ethnicity metabolism (Farkas A et al., Ethn Dis, 10: critical for early detection and initiation of and accessibility of medical care, patient 69-75, 2000). However, mutations which treatment. Language may be a barrier to support, survival, and quality of life is confer susceptibility to cancer may be car- understanding health issues. Women from needed (Meyerowitz BE, Psychol Bull, 123: ried by individuals from any and all ethnic certain ethnic and racial minorities are less 47-70, 1998). groups (Neuhausen SL, Cancer, 86: 2575- likely to take up invitations to participate in 82, 1999). breast or cervical screening programmes. Recognition of multicultural issues is This may be partly attributable to the novel- becoming more widespread. The NCI has In many instances, there are clear indica- ty of the concept of preventive health, unfa- launched an initiative to investigate the tions that in some ethnic minorities, immi- miliarity with the disease, or with the health reasons for disparities in cancer in minor- grant populations and the poor and disad- system, as well as modesty and ity populations (the “Special Populations vantaged, the burden of cancer is greater religious/cultural barriers. Women of lower Networks for Cancer Awareness Research than that of the general population (e.g. socioeconomic status tend to present with and Training”, Mitka M, JAMA, 283: 2092- Kogevinas M et al., Social inequalities and a more advanced stage of breast cancer 3, 2000). Many areas have units designed cancer, Lyon, IARCPress, 1997). In the than women of higher socioeconomic sta- to improve equality of access to health USA, for example, whilst incidence and tus. African-American, Hispanic, American care (e.g. NSW Health Multicultural mortality rates for some cancers have Indian and Hawaiian women also tend to Health Communication Service, decreased in the population overall, rates present with a more advanced stage of http://www.health.nsw.gov.au). have increased in some ethnic minority breast cancer than white women (e.g. groups. The mortality rate for cancer at all Hunter CP, Cancer, 88: 1193-202, 2000). In

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early disease includes bilateral salpingo- ed with vincristine, actinomycin and oophorectomy and total abdominal hys- cyclophosphamide; cisplatin, vinblastine terectomy, total omentectomy, appendec- and bleomycin; or cisplatin, etoposide and tomy, collecting samples of peritoneal bleomycin. Recurrent ovarian cancer may washings for cytological analysis and pos- be treated with cytoreductive surgery plus sibly removal of pelvic retroperitoneal and chemotherapy and palliative radiotherapy. aortic lymph nodes. Reproductive function Hormonal therapy may include progesta- and fertility may be conserved in patients tional agents and anti-estrogens. with a unilateral, low-grade, unruptured Tumour stage (determined surgically) is epithelial ovarian tumour. Advanced stage the most important prognostic factor. ovarian cancer requires cytoreductive sur- Clear cell and small cell carcinomas are gery to remove all gross tumour, followed associated with a worse prognosis than by chemotherapy. External beam radio- other histological types. Aneuploidy has therapy may play a limited role in selected been linked to poor survival. In the assess- patients with minimal residual disease. ment of response to treatment, decrease Intraperitoneal implants may be used as in serum CA-125 measurements indicates adjuvant treatment for high-risk patients a more favourable prognosis. Early stage Fig. 5.71 Five-year relative survival rates after with early disease. disease has a very good prognosis. Overal diagnosis of ovarian cancer. A standard chemotherapy for advanced five-year survival rates for all stages com- stage ovarian cancer using cisplatin and bined (Fig. 5.71) range from 30-50%. Most Management paclitaxel achieves response rates of up to women, however, present with late stage Surgery is most often the first recourse in 60-80%. Germ cell tumours are very sen- disease which is associated with a five- diagnosis and treatment. Treatment of sitive to chemotherapy and may be treat- year survival rate of about 20%.

REFERENCES WEBSITES 1. Munoz N, Bosch FX, de Sanjose S, Herrero R, Castellsague 12. Cox JT (1999) Management of cervical intraepithelial neo- NCI Homepages for Cervical Cancer, Endometrial Cancer X, Shah K, Snijders P, and Meijer C. Epidemiological classifi- plasia. Lancet, 353: 857-859. and Ovarian Cancer: http://www.cancer.gov/cancer_information/cancer_type/ cation of human papillomavirus types associated with cervical 13. Brooks SE, Wakeley KE (1999) Current trends in the cancer. N Engl J Med 2003;348:518-27. management of carcinoma of the cervix, vulva, and vagina. The Alliance for Cervical Cancer Prevention: 2. Bosch FX, Lorincz A, Munoz N, Meijer CJ, Shah KV. The Curr Opin Oncol, 11: 383-387. http://www.alliance-cxca.org/ causal relation between human papillomavirus and cervical 14. Sabbatini P, Aghajanian C, Spriggs D (1998) National Ovarian Cancer Coalition (USA): cancer. J Clin Pathol 2002;55:244-65. Chemotherapy in gynecologic cancer. Curr Opin Oncol, 10: http://www.ovarian.org/ 3. IARC (1995) Human Papillomaviruses (IARC 429-433. Monographs on the Evaluation of Carcinogenic Risks to 15. IARC (1996) Some Pharmaceutical Drugs (IARC Humans, Vol. 64), Lyon, IARCPress. Monographs on the Evaluation of Carcinogenic Risks to 4. zur Hausen H (1999) Viruses in human cancers. Eur J Humans, Vol. 66), Lyon, IARCPress. Cancer, 35: 1174-1181. 16. Cohen CJ, Thomas GM (1997) Endometrial cancer. In: 5. Walboomers JMM, Jacobs MV, Manos MM et al. Human Holland JF, Bast, RC, Morton, DL, Frei, E, Kufe, DW, papillomavirus is a necessary cause of invasive cervical can- Weichselbaum, RR eds, Cancer Medicine, Williams and cer worldwide. J Pathol 1999;189:12-9. Wilkins. 6. Webb MJ (1998) Female Genital Cancers. In: Morris D, 17. Esteller M, Xercavins J, Reventos J (1999) Advances in Kearsley J, Williams C eds, Cancer: a comprehensive clinical the molecular genetics of endometrial cancer. Oncol Rep, 6: guide, Harwood Academic Publishers. 1377-1382. 7. Wharton JT (1997) Neoplasms of the cervix. In: Holland 18. Holschneider CH, Berek JS (2000) Ovarian cancer: epi- JF, Bast, RC, Morton, DL, Frei, E, Kufe, DW, Weichselbaum, RR demiology, biology, and prognostic factors. Semin Surg eds, Cancer Medicine, Williams and Wilkins. Oncol, 19: 3-10. 8. Shipman SD, Bristow RE (2001) Adenocarcinoma in situ 19. Ozols RF, Schwartz PE, Eifel PA (1997) Ovarian cancer, and early invasive adenocarcinoma of the uterine cervix. Curr fallopian tube carcinoma and peritoneal carcinoma. In: Opin Oncol, 13: 394-398. DeVita VTJ, Hellman S, Rosenberg SA eds, Cancer Principles and Practice of Oncology, Philadelphia, Lippincott-Raven 9. Duggan BD, Dubeau L (1998) Genetics and biology of Publishers, 1502-1539. gynecologic cancer. Curr Opin Oncol, 10: 439-446. 20. Jones MB, Krutzsch H, Shu H, Zhao Y, Liotta LA, Kohn 10. Rosenthal AN (1998) Screening for gynecologic cancers. EC, Petricoin EF, III (2002) Proteomic analysis and identifica- Curr Opin Oncol, 10: 447-451. tion of new biomarkers and therapeutic targets for invasive 11. Larson AA, Liao SY, Stanbridge EJ, Cavenee WK, ovarian cancer. Proteomics, 2: 76-84. Hampton GM (1997) Genetic alterations accumulate during 21. Aunoble B, Sanches R, Didier E, Bignon YJ (2000) Major cervical tumorigenesis and indicate a common origin for mul- oncogenes and tumor suppressor genes involved in epithelial tifocal lesions. Cancer Res, 57: 4171-4176. ovarian cancer. Int J Oncol, 16: 567-576.

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OESOPHAGEAL CANCER

SUMMARY

>Cancer of the oesophagus is the sixth most common cancer worldwide (more than 400,00 cases per year). Incidence varies markedly, and is highest in Western and South Central Asia.

> Squamous cell carcinoma is most com- mon in developing countries, and is typ- ically associated with tobacco smoking and alcohol abuse. Other risk factors include consumption of very hot bever- ages and .

> Adenocarcinoma occurs predominantly in white men from developed countries, the most important etiological factors being obesity and chronic gastro- oesophageal reflux. < 1.9 < 3.2 < 5.9 < 10.0 < 38.7 Age-standardized incidence/100,000 population > Most cancers of the oesophagus are detected at an advanced stage; five-year Fig. 5.72 The global burden of oesophageal cancer in men. High incidence rates occur in Northern Iran, the survival rates are less than 15%. Central Asian republics, North-Central China, parts of South America and in Southern and Eastern Africa.

noma is essentially a tumour of more mous cell carcinoma is up to five in developed, industrialized countries. males and one in females per 100,000 The differences between incidence of population. However, in particular areas, oesophageal cancer in distinct geograph- such as Normandy and Brittany in France ical areas are more extreme than and in the north-east of Italy, the inci- Definition observed for any other cancer. Regions dence rates are much higher in males (up The great majority of oesophageal can- of high incidence of squamous cell carci- to 30 per 100,000), while remaining rela- cers (over 95%) are either squamous cell noma in Asia [1] stretch from the tively low in females. The incidence of carcinomas or adenocarcinomas. Tum- Turkoman plain in northern Iran through adenocarcinoma is steadily increasing in ours of the cardia, which arise within the the central Asian republics to Henan Europe and the USA at a rate of 5-10% gastro-oesophageal junction, are some- province in North-Central China, charac- per year. This type of cancer now times classified in the same group as terized as the “oesophageal cancer belt” accounts for more than 50% of all adenocarcinomas of the oesophagus. (Fig. 5.72). Incidence rates are as high as oesophageal cancers in the USA and in 200 per 100,000 and in some areas some European countries [2]. Trends in Epidemiology there is a female predominance. Other incidence of all oesophageal cancers Cancers of the oesophagus are the sixth high-incidence areas are found in parts vary greatly (Fig. 5.75). most frequent cancers worldwide. In of South America and in Southern and 2000, the number of deaths due to Eastern Africa. Even within these high- Etiology oesophageal cancer amounted to some risk areas, there are striking local varia- Consumption of tobacco and alcohol, 337,500 out of a total of 6.2 million can- tions in risk. Studies of migrant popula- associated with low intake of fresh fruit, cer deaths worldwide. About 412,000 tions suggest that when they move to vegetables and meat, is causally associat- cases of cancer of the oesophagus occur areas of low-risk, they lose their high ed with squamous cell carcinoma of the each year, of which over 80% are in devel- rates, confirming the importance of local oesophagus worldwide. However, the rela- oping countries. While squamous cell environmental factors in causation. tive contribution of these risk factors carcinoma occurs at high frequency in In Europe and the USA, the age-stan- varies from one geographic area to anoth- many developing countries, adenocarci- dardized annual mortality from squa- er. In more developed countries, it is esti-

Oesophageal cancer 223 WCR-S5.Q (suite 39a49) 27/01/03 10:55 Page 224

being the outcome of chronic mucosal The vast majority of patients initially injury. Other risk factors include con- complain of progressive dysphagia, sumption of pickled vegetables, betel which may not become apparent until chewing in South East Asia, and oral con- some two-thirds of the lumen has been sumption of opium by-products in the obstructed, especially in the case of Caspian Sea area. Conflicting reports squamous cell carcinoma [7]. Regur- have proposed a role for human papillo- gitation and pain on swallowing are fre- maviruses in squamous cell carcinoma quent, as is weight loss. Laryngeal nerve [5]. Other environmental risk factors involvement may be indicated by hoarse- include nitrosamines, food contamination ness. Patients with adenocarcinomas of with fungi such as Geotrichum candidum the cardia may also suffer from gastro- and Fusarium sp. (Food contaminants, intestinal bleeding [8]. A barium swallow p43) and deficiency of vitamins A and C, (ingestion of liquid containing barium molybdenum, copper and zinc. prior to X-ray) (Fig. 5.76) may indicate Fig. 5.73 Drinking the scalding beverage maté is Adenocarcinoma of the oesophagus has narrowing or mucosal irregularity, where- associated with an increased risk of oesophageal been associated with chronic gastro- as a chest X-ray may reveal late signs cancer. oesophageal reflux, which most often such as the presence of a mass, tracheal underlies repetitive mucosal injury and compression, aspiration pneumonia or predisposes to metaplasia [6]. This metastases. Endoscopic ultrasonography Balloon tumour type is directly associated with is currently the most accurate staging Barrett oesophagus, a premalignant method, but is not widely available. CT lesion. scanning remains the mainstay of stag- ing prior to resection, supplemented by Sponge Mesh Sponge Detection laparoscopy (for lower one-third cancers) Although endoscopic or cytologic screen- or bronchoscopy (for upper one-third Fig. 5.74 Devices used to collect histological sam- ing may be useful for early diagnosis in cancers). ples from the oesophagus, used for screening in Iran. regions of high incidence, there are no widely accepted protocols for such inter- Pathology and genetics ventions. Cytologic screening of high-risk Squamous cell carcinoma (Fig. 5.77) mated that 90% of squamous cell carcino- asymptomatic populations is carried out develops from squamous epithelium mas are attributable to tobacco and alco- in China with a swallowed balloon according to a classical dysplasia-carci- hol, with a multiplicative increase in risk catheter and in Japan with a swallowed noma sequence (Multistage carcinogene- when individuals are exposed to both fac- encapsulated brush (Fig. 5.74). Endo- sis, p84). The most common site of squa- tors [3]. The consumption of scalding hot scopic dye-staining with Lugol’s iodine or mous cell carcinoma is the middle third of beverages, such as maté in South America toluidine blue aids detection of early the oesophagus. Microscopically, most (Fig. 5.73), is a risk factor [4], malignancy lesions. squamous tumours contain islands of

Singapore Japan, Myagi India, Bombay USA UK Slovakia

50 50 50 50 50 50 25 25 25 Chinese 25 25 Black (m) 25 Males Males 10 10 10 10 10 Males 10 Males Malay Females White (m) 5 5 5 5 5 5 Females Black (f) 2.5 Indian 2.5 2.5 2.5 2.5 2.5 Females White (f) 1 1 1 1 1 1 Females

.25 .25 .25 .25 .25 .25

1960 1970 198 0 1990 200 0 1960 1970 198 0 1990 200 0 1960 1970 198 0 1990 200 0 1960 1970 198 0 1990 200 0 1960 1970 198 0 1990 200 0 1960 1970 198 0 1990 200 0

Fig. 5.75 Trends in incidence of oesophageal cancer differ considerably according to geography and reflect differences in prevalence of the two main histo- logical types. D.M. Parkin et al. (2001) Eur J Cancer, 37 Suppl. 8: S4-66.

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in 35-70% of tumours, depending on geo- graphic origin. Tumours from high-inci- SE SE dence areas of Western Europe show a SE high proportion of mutations at A:T base SE pairs. These mutations may reflect a con- tribution of metabolites of alcohol. In East Asia, mutations at A:T base pairs are less common, but transversions at G:C base pairs occur at a higher rate than in Western Europe [10]. Mutations in p53 have been observed in dysplasia, and in Fig. 5.77 Moderately differentiated squamous cell normal mucosa adjacent to cancer carcinoma of the oesophagus, ulcerated, deeply lesions [11]. invasive and extending below the normal squa- mous epithelium (SE). In squamous cell carcinoma, other com- monly mutated genes are those encoding proteins involved in the control of the G1/S cell-cycle checkpoint, such as well-defined preneoplastic lesion called cyclin D1 and p16INK4A (Cell cycle, p104). Barrett mucosa (or Barrett oesophagus) Amplification of the cyclin D1 gene (Fig. 5.79). Barrett mucosa is a glandular, CCDN1 (11q13) occurs in 20-40% of metaplastic mucosa of the normal squa- tumours. The gene encoding p16INK4A is mous epithelium. It is often associated often subject to hypermethylation of the with chronic gastro-oesophageal acid Fig. 5.76 A radiographic view of an oesophageal promoter region, resulting in down-regu- reflux. However, it also occurs in the con- cancer taken following a barium swallow. Arrows lation of expression. Amplification of a text of chronic biliary alkaline reflux, as indicate a filling defect caused by obstruction by the tumour. number of proto-oncogenes (HST-1, HST- well as, in some cases, the absence of a 2, EGFR, MYC) has also been reported detectable reflux. Men are seven times [12]. In the Japanese population, a poly- more commonly affected than women atypical squamous cells which infiltrate morphism in the gene encoding aldehyde [14]. the underlying normal tissue and contain dehydrogenase 2 (ALDH2), which plays a The estimated risk of developing an ade- keratin pearl formation and intercellular role in ethanol metabolism, is significant- nocarcinoma for patients with Barrett bridges [9]. ly associated with squamous cell carci- mucosa is 30-125 times greater than in The sequence of genetic events leading noma [13]. the general population. There are three to squamous cell carcinoma is only par- Adenocarcinoma of the oesophagus subtypes: fundic (base of oesophagus), tially understood (Fig. 5.78). Mutation of mostly occurs within the distal third of cardiac (the region between the oesoph- the p53 gene is an early event, detected the oesophagus and is preceded by a agus and the stomach), and intestinal.

Multiple loss of heterozygosity (LOH) Amplification of C-MYC, EGFR, CYCLIN D1, HST1... Overexpression of CYCLIN D1 LOH at 3p21; LOH at 9p31

LOH 3p14 (FHIT); LOH 17q25 (TOC) p53 mutations

Normal oesophagus Oesophagitis Low-grade High-grade Invasive squamous intraepithelial neoplasia intraepithelial neoplasia cell carcinoma

Fig. 5.78 Sequence of genetic alterations in the development of squamous cell carcinoma of the oesophagus.

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adenocarcinoma, reduced expression of the cadherin/catenin complex and incre- Factor Alteration ased expression of various proteases is detectable [15]. Tumour suppressor genes p53 60% mutation -- high-grade intraepithelial neoplasia Management and carcinoma Endoscopic ultrasonography is used to APC Late in intraepithelial neoplasia-carcinoma sequence evaluate both depth of tumour infiltration FHIT Common, early abnormalities CDKN2A (p16INK4A) Hypermethylation common in intraepithelial neoplasia and para-oesophageal lymph node involvement. In advanced carcinomas, CT Growth factor receptors and MRI give information about local and CD95/APO/Fas Shift to cytoplasm in carcinoma systemic spread. Tumour growth is char- EGFR Expressed in 60% of carcinomas, gene amplification c-erbB2 Late in dysplasia-carcinoma sequence, gene amplification acterized as swelling of the oesophageal wall, with or without direct invasion to sur- Cell adhesion rounding organs. The primary treatment E-cadherin Loss of expression in intraepithelial and invasive carcinoma Catenins Similar loss of expression to E-cadherin for local disease is oesophagectomy. This surgical approach is rarely curative (even- Proteases tually 85 to 90% of the patients die of UPA Prognostic factor in carcinoma recurrent disease) but palliation of dys- Proliferation phagia is an important secondary objec- Ki-67 Abnormal distribution in high-grade intraepithelial tive. Placement of a prosthetic tube or neoplasia stent across the tumour stenosis (narrow- Membrane trafficking ing) may be indicated to restore swallow- rab11 High expression in low-grade intraepithelial neoplasia ing in patients not suitable for surgery. Radiotherapy (external beam or brachy- Table 5.9 Genes and proteins involved in the development of adenocarcinoma from Barrett oesophagus. therapy) as well as multiple chemothera- peutic protocols have also been proposed (alone or combined with surgery), but Mutation of the p53 gene is common in these approaches are rarely curative. the early stages of adenocarcinoma of Palliation with radiation alone is an alter- the oesophagus (Table 5.9). The pres- native to surgery, particularly if combined ence of a p53 mutation in Barrett mucosa and in dysplasia may precede the development of adenocarcinoma. In high-grade dysplasia, a prevalence of NSW, Australia 13.7 p53 mutations of approximately 60% is found, similar to that found in adenocar- USA (Whites) 13.2 cinoma. Almost half of these are C to T Netherlands 12 transitions at dipyrimidine sites (CpG Osaka, Japan 11. 7 islands). Shanghai, China 11. 2 Alteration in transcription of FHIT and of USA (Blacks) 9.1 INK4A p16 may be early events in adeno- France 9 carcinoma. In contrast, a number of Slovakia 8 other loci are altered at a relatively late 6.5 stage with no obligate sequence of Madras, India events. Prevalent changes (>50%) include Denmark 5 loss of heterozygosity on chromosomes Qidong, China 4.2 4q, 5q (several loci including APC), 17p Chiang Mai, Thailand 3.8

and amplification of the gene encoding c- 050100 erbB2. Molecules involved in membrane % survival, both sexes traffic, such as rab11, have been report- ed to be specific for the loss of polarity Fig. 5.79 A highly infiltrative adenocarcinoma in a (rounding-up of cell nuclei) seen in low- Fig. 5.80 Five-year relative survival after diagnosis Barrett oesophagus. grade dysplasia. In invasive oesophageal of oesophageal cancer.

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with a stent; laser recannulation, alcohol logical and molecular features of the poor (Fig. 5.80), survival ranging from injection and dilation may be used to tumour, for squamous cell carcinoma the about 10% in patients with squamous cell maintain the oesophageal lumen [8]. depth of invasion and for adenocarcinoma carcinoma to 20% in patients with adeno- Prognostic factors include stage at diag- presence of lymphatic metastases. carcinoma. nosis, patient’s general health, morpho- Overall five-year relative survival rates are

REFERENCES WEBSITE 1. Muñoz N, Day NE (1996) . In: oesophagus. In: Hamilton SR, Aaltonen LA, eds, World NCI Esophageal Cancer Homepage: Scottenfeld D, Fraumeni FJ eds, Cancer Epidemiology and Health Organization Classification of Tumours. Pathology http://www.cancer.gov/cancer_information/cancer_type/ esophageal/ Prevention, Oxford, New York, Oxford University Press, and Genetics of Tumours of the Digestive System, Lyon, 681-706. IARCPress, 11-19. 2. Parkin DM, Whelan SL, Ferlay J, Raymond L, Young J, 10. Taniere P, Martel-Planche G, Puttawibul P, Casson A, eds (1997) Cancer Incidence in Five Continents, Vol. VII Montesano R, Chanvitan A, Hainaut P (2000) TP53 muta- (IARC Scientific Publications No. 143 and IARC tions and MDM2 gene amplification in squamous-cell car- Cancerbase No. 2), Lyon, IARCPress. cinomas of the esophagus in south Thailand. Int J Cancer, 3. Launoy G, Milan CH, Faivre J, Pienkowski P, Milan CI, 88: 223-227. Gignoux M (1997) Alcohol, tobacco and oesophageal can- cer: effects of the duration of consumption, mean intake 11. Mandard AM, Hainaut P, Hollstein M (2000) Genetic and current and former consumption. Br J Cancer, 75: steps in the development of squamous cell carcinoma of 1389-1396. the esophagus. Mutat Res, 462: 335-342. 4. De Stefani E, Muñoz N, Esteve J, Vasallo A, Victora CG, 12. Montesano R, Hollstein M, Hainaut P (1996) Genetic Teuchmann S (1990) Mate drinking, alcohol, tobacco, diet, alterations in esophageal cancer and their relevance to eti- and esophageal cancer in Uruguay. Cancer Res, 50: 426- ology and pathogenesis: a review. Int J Cancer, 69: 225- 431. 235. 5. de Villiers EM, Lavergne D, Chang F, Syrjanen K, Tosi P, 13. Yokoyama A, Muramatsu T, Ohmori T, Yokoyama T, Cintorino M, Santopietro R, Syrjanen S (1999) An interlab- oratory study to determine the presence of human papillo- Okuyama K, Takahashi H, Hasegawa Y, Higuchi S, mavirus DNA in esophageal carcinoma from China. Int J Maruyama K, Shirakura K, Ishii H (1998) Alcohol-related Cancer, 81: 225-228. cancers and aldehyde dehydrogenase-2 in Japanese alco- holics. Carcinogenesis, 19: 1383-1387. 6. Spechler SJ, Goyal RK (1986) Barrett's esophagus. N Engl J Med, 315: 362-371. 14. Werner M, Flejou JF, Hainaut P, Höfler H, Lambert R, 7. Goodnight J, Venook A, Ames M, Taylor C, Gilden R, Keller G, Stein HJ (2000) Adenocarcinoma of the oesopha- Figlin RA (1996) Practice Guidelines for Esophageal gus. In: Hamilton SR, Aaltonen LA eds, World Health Cancer. Cancer J Sci Am, 2: S37. Organization Classification of Tumours. Pathology and Genetics of Tumours of the Digestive System, Lyon, 8. Law S, Wong J (1998) Cancer of the Esophagus. In: Morris D, Kearsley J, Williams C eds, Cancer: A compre- IARCPress, 20-26. hensive clinical guide, Harwood Academic Publishers, 155- 15. Tselepis C, Perry I, Jankowski J (2000) Barrett's 162. esophagus: disregulation of cell cycling and intercellular 9. Gabbert HE, Shimoda T, Hainaut P, Nakamura Y, Field adhesion in the metaplasia-dysplasia-carcinoma sequence. JK, Inoue H (2000) Squamous cell carcinoma of the Digestion, 61: 1-5.

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BLADDER CANCER

SUMMARY

> is the ninth most com- mon cancer worldwide, with 330,000 new cases and more than 130,000 deaths per year.

>Bladder cancer is primarily attributable to smoking, which accounts for 65% of male and 30% of female cases in some developed countries. Other less impor- tant causes include analgesic abuse (phenacetin), some types of cancer chemotherapy and, historically, occupa- tional exposure to chemicals such as 2- naphthylamine. In Egypt and some Asian regions, chronic cystitis caused by Schistosoma haematodium infection is a major risk factor. < 3.2 < 5.3 < 9.2 < 15.5 < 45.3 > Treatment based on endoscopy, surgery, Age-standardized incidence/100,000 population radiotherapy and cytotoxic drugs often permits long-term survival in developed Fig. 5.81 The global incidence of bladder cancer in men. Although the majority of cases occur in devel- countries, where 65% of patients live for oped countries, bladder cancer also occurs at high rates in some developing countries, including parts at least five years after diagnosis. of Northern Africa and South America.

are observed throughout Southern, risk associated with tobacco smoking, and Western and Northern Europe, North in particular with black tobacco smoking, America, Australia, Western Asia, Northern is likely to be due to the presence in the Definition Africa and Uruguay (Fig. 5.81) Bladder can- smoke of aromatic amines including ben- More than 90% of bladder cancers are cer incidence is either rising moderately or zidine, 4-aminobiphenyl, 2-naphthylamine transitional cell carcinomas. Much less is steady in most developed countries. and 4-chloro-ortho-toluidine. Bladder can- common are adenocarcinoma (6%), squa- About 132,000 people each year die from cer risk increases approximately linearly mous cell carcinoma (2%) and small cell bladder cancer, men throughout the world with duration of smoking, reaching a five- carcinoma (less than 1%). having a mortality rate of 10 per 100,000 fold risk after 40 years (Fig. 5.82). The risk population, and women 2.4, although these also increases with the number of ciga- Epidemiology values nearly double for developed coun- rettes smoked, up to approximately 20 Bladder cancer accounts for approximately tries. cigarettes per day; above that level, no fur- two-thirds of all urinary tract cancers. By ther increase in risk is observed. Upon incidence, bladder cancer is the ninth most Etiology smoking cessation, a substantial decrease common cancer worldwide, although in the The most important risk factor for bladder in risk of bladder cancer is observed with- USA, for example, bladder cancer is the cancer is cigarette smoking, which in several years, implying an effect in late fourth most frequent tumour among men. accounts for approximately 65% of male stages of the carcinogenic process. Approximately 336,000 new cases cases and 30% of female cases in popula- Work in the rubber and dyestuff industries occurred in 2000, two-thirds of which were tions of developed countries [2]. It is like- and specifically occupational exposure to in developed countries [1]. Incidence and ly that smokers of black (air-cured) tobac- aromatic amines, particularly including 2- mortality rise sharply with age and about co are at a greater risk than smokers of naphthylamine and benzidine, are correlat- two-thirds of cases occur in people over the blond (flue-cured) tobacco and this may ed with a high risk of bladder cancer [3]. age of 65. The male:female ratio is approx- explain some of the disparity observed in Exposure to polycyclic aromatic hydrocar- imately 3:1. High incidence rates (>12 per European incidence rates and also the bons, polychlorinated biphenyls, formalde- 100,000 men and >3 per 100,000 women) high incidence observed in Uruguay. The hyde, asbestos and solvents, and work in

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Fig. 5.83 A canal in a poor housing district in Egypt. Such canals may provide a habitat for the snails which are host to Schistosoma parasites. Chronic infection with causes cystitis and often bladder cancer.

Fig. 5.82 Risk of bladder cancer among men who smoke relative to never-smokers, according to daily cig- arette consumption.

leather manufacturing, as a painter and as vitamin A and carotenoids; evidence con- a barber or hairdresser have been various- cerning a risk associated with coffee con- ly associated with increased risk. The sumption is inconsistent. uncertainty surrounding these associa- tions is partly due to difficulty in measur- Detection Fig. 5.84 Carcinoma in situ of the bladder; the ing past exposure to specific chemical Detection of neoplastic alterations in ex- normal transitional epithelium has been replaced agents. foliated bladder cells collected in the urine by a disorganized, poorly-differentiated cell layer In common with cancer of the renal pelvis, a has been proposed as a screening (arrows). consistent relationship has been observed approach for bladder cancer, in particular between use of phenacetin-containing anal- among industrial workers potentially B gesics and bladder cancer, with relative risks exposed to aromatic amines, but there is varying from 2.4 to over 6-fold. Use of the no evidence in favour of its effectiveness. T T anticancer drug cyclophosphamide, an alky- Other methods are also under investiga- lating agent, has been strongly and consis- tion [5]. tently linked to bladder cancer. Non-Hodgkin Haematuria, usually painless, is the pre- lymphoma patients treated with cyclophos- senting symptom for the majority of T phamide therapy have a dose-dependent patients with bladder cancer. Patients increased risk of bladder cancer. may also present with bladder irritability, Infection by the trematode worm, including urinary frequency, urgency and Fig. 5.85 Transitional cell carcinoma of the blad- Schistosoma haematobium, is associated dysuria. Diagnosis is made by urine analy- der, moderately differentiated, with a papillary with an up to five-fold increased risk. In sis and after visualization of the bladder architecture. B = blood vessel, T = tumour. endemic areas, which include most of Africa by ultrasound and cystoscopy. Tissue for and in several West Asian countries, infec- histopathological analysis may be tion as a result of ingestion of contaminated obtained through transurethral resection. take several clinical forms, not necessari- water occurs from childhood (Fig. 5.83), and ly associated with high grade or high risk risk of bladder cancer, especially of the Pathology and genetics of progression (Fig. 5.84) [6]. Spread can squamous cell type, increases as from the Approximately 90% of bladder cancers are occur by growth into the submucosa and third decade of life. The infection is respon- classified as transitional cell carcinoma muscularis of the bladder wall (25% of sible for about 10% of bladder cancer cases and are believed to originate in intra- cases). About 70% of transitional cell car- in the developing world and about 3% of epithelial neoplastic transformation of the cinomas are of the papillary type (Fig. cases overall [4]. bladder transitional epithelium. The local- 5.85) and do not invade the muscularis Decreased risk of bladder cancer is asso- ized proliferation of transformed cells can propria of the bladder wall, 10% are ciated with consumption of foods rich in give rise to a carcinoma in situ, which may described as nodular and 20% as mixed.

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Infection with S. haematobium is associat- bladder cancer, and the cyclin-dependent ed with the development of squamous cell kinase inhibitors p16INK4A and p15 are also carcinoma and in endemic areas, such as implicated in this context. Altered expres- Egypt, this type constitutes 90% of bladder sion of the phosphorylated form of the tumours [7]. protein is common, and A number of genes which regulate most often encountered in invasive enzymes involved in the metabolism of tumours. Nuclear overexpression of p53 bladder carcinogens have been identified protein, essentially attributable to muta- and it has been hypothesized that sub- tion of the gene, is common and is associ- jects carrying specific genotypes could be ated with disease progression (Fig. 5.86) at an increased risk of bladder cancer [8]. [9]. For example, a dominant mutation in the NAT2 gene causes slow metabolism of Management aromatic amines, favouring their transfor- Most patients with carcinoma in situ mation into active carcinogens; slow progress to muscle invasion within 10 metabolizers may be at a 40% increased years, but can achieve good responses to risk of bladder cancer. Similarly, individu- intravesical therapy - the administration of als who are null for the GSTM1 gene, a therapeutic agent directly into the blad- which encodes an enzyme involved in the der, thereby exposing the mucosa to high Fig. 5.87 Five-year relative survival rates after detoxification of polycyclic aromatic drug concentrations [10]. The most com- diagnosis of bladder cancer. hydrocarbons, have been reported to be monly used agent in intravesical therapy at increased risk of bladder cancer. There for superficial transitional cell carcino- is no evidence for high-penetrance gene mas, to prevent recurrence, and possibly of the bladder, prostate and seminal vesi- mutations that carry an elevated risk of decrease progression and improve sur- cles in males or the bladder, ovaries, bladder cancer. The oncogene HRAS is vival, is bacille Calmette-Guérin (BCG), an uterus, urethra and part of the vagina in mutated at codon 12 in about 40% of attenuated strain of the females. Urinary diversion, and some bladder tumours. Overexpression of the bovis bacterium which causes tuberculo- restoration of bladder function, may be epidermal growth factor receptor is asso- sis. Cytotoxic drugs such as thiotepa, dox- achieved through a range of reconstruc- ciated with invasive disease. The gene orubicin, mitomycin C and/or ethoglucid tion options that continue to be refined encoding c-erbB2 (ERBB2) is amplified in may be used for superficial tumours to and improved. Adjuvant chemotherapy a small proportion of bladder tumours. prevent recurrence. (e.g with cisplatin, methotrexate and vin- Cytogenetic and molecular techniques The currently preferred treatment for blastine, or the latter combination plus have implicated aberration/partial loss of patients with invasive bladder cancer is doxorubicin) may be employed. Several chromosome 9 as a common feature in radical cystectomy. This involves excision new agents have been identified [11].

VEGF upregulation Cyclin D activation Cyclin D1 amplification PAPILLARY RECURRENT Chromosome 9 LOH TRANSITIONAL CELL TRANSITIONAL CELL CARCINOMA CARCINOMA “superficial”

TRANSFORMED UROTHELIAL CELL

CARCINOMA in situ INVASIVE p53 gene inactivation (pre-invasive transitional TRANSITIONAL CELL cell carcinoma) CARCINOMA

p53, RB gene inactivation PDECGF expression Fig. 5.86 Genetic alterations associated with the development of bladder cancer. LOH = loss of heterozygosity, VEGF = vascular endothelial growth factor, PDECGF = platelet derived endothelial factor.

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Partial cystectomy is appropriate for only a etc.) have been determined. Tumour stag- improvement during the last decades. minor proportion of patients with invasive ing is based on the degree to which the Survival is poorer in developing countries, bladder cancer. Radical radiation therapy tumour has invaded the bladder wall. with five-year relative survival rates of 30- as sole treatment has been evaluated, and In more developed countries, five-year rel- 50%. criteria contributing to a favourable out- ative survival is in the order of 65% (Fig. come (tumour size, stage, morphology, 5.87), and there has been a steady

REFERENCES WEBSITE 1. Ferlay J, Bray F, Parkin DM, Pisani P, eds (2001) 7. Noss M, Klotz L (1998) Male urogenital cancer. In: NCI Bladder Cancer Homepage. Globocan 2000: Cancer Incidence and Mortality Worldwide Morris D, Kearsley J, Williams C eds, Cancer: a compre- http://www.cancer.gov/cancer_information/cancer_type/ (IARC Cancer Bases No. 5), Lyon, IARCPress. hensive clinical guide, Harwood Academic Publishers, 213- bladder/ 2. Brennan P, Bogillot O, Cordier S, Greiser E, Schill W, 222. Vineis P, Lopez-Abente G, Tzonou A, Chang-Claude J, Bolm- 8. d'Errico A, Malats N, Vineis P, Boffetta P (1999) Review Audorff U, Jockel KH, Donato F, Serra C, Wahrendorf J, of studies of selected metabolic polymorphisms and can- Hours M, T'Mannetje A, Kogevinas M, Boffetta P (2000) cer. In: Vineis P, Malats N, Lang M, d'Errico A, Caporaso N, Cigarette smoking and bladder cancer in men: a pooled Cuzick J, Boffetta P eds, Metabolic Polymorphisms and analysis of 11 case-control studies. Int J Cancer, 86: 289- Susceptibility to Cancer (IARC Scientific Publication No. 294. 148), Lyon, IARCPress, 323-393. 3. Silverman DT, Morrison AS, Devesa SS (1996) Bladder 9. Brandau S, Bohle A (2001) Bladder cancer. I. Molecular cancer. In: Scottenfeld D, Fraumeni, FJ eds, Cancer and genetic basis of carcinogenesis. Eur Urol, 39: 491-497. Epidemiology and Prevention, Oxford, New York, Oxford University Press, 1156-1179. 10. Metts MC, Metts JC, Milito SJ, Thomas CR, Jr. (2000) Bladder cancer: a review of diagnosis and management. J 4. Pisani P, Parkin DM, Muñoz N, Ferlay J (1997) Cancer Natl Med Assoc, 92: 285-294. and infection: estimates of the attributable fraction in 1990. Cancer Epidemiol Biomarkers Prev, 6: 387-400. 11. Maluf FC, Bajorin DF (2001) Chemotherapy agents in transitional cell carcinoma: the old and the new. Semin 5. Saad A, Hanbury DC, McNicholas TA, Boustead GB, Woodman AC (2001) The early detection and diagnosis of Urol Oncol, 19: 2-8. bladder cancer: a critical review of the options. Eur Urol, 39: 619-633. 6. Lee R, Droller MJ (2000) The natural history of bladder cancer. Implications for therapy. Urol Clin North Am, 27: 1- 13, vii.

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HEAD AND NECK CANCER

SUMMARY

> The most common cancer of the head and neck, namely , ranks eleventh worldwide (390,000 new cases per year), while cancers of the pharynx (65,000 cases) and larynx (160,000 cases) are less common.

> Head and neck cancers mainly afflict men, with sex ratios exceeding 10:1, and are typically caused by smoking, togeth- er with alcohol abuse. In some regions (e.g. India) oral cancer is mainly due to tobacco chewing. Multiple primary car- cinomas are not uncommon.

> Early-stage tumours can be surgically resected, but many patients are diag- nosed with advanced disease and prog- < 2.9 < 4.6 < 6.2 < 9.7 < 45.8 nosis is poor. Oral cancer patients have Age-standardized incidence/100,000 population a five-year survival rate of less than 50%. Fig. 5.88 The global incidence of oral cancer in men. Oral cancer is common in India, Australia, Hungary, France, Brazil and Southern Africa. >Nasopharyngeal cancer is largely restricted to Southern Chinese popula- tions and strongly associated with patterns and trends in incidence for these generally predominate in developing coun- Epstein-Barr virus infection. cancers vary depending upon the anatomical tries, whereas pharyngeal cancers are com- sub-sites concerned, a phenomenon that is mon in developed countries and in Central often explicable by the influence of risk fac- and Eastern Europe. In most countries, tors, such as tobacco use and alcohol con- oral/pharyngeal cancer incidence and mor- sumption. A high incidence of these cancers tality rates have either been stable or increas- Definition is observed in the Indian subcontinent, ing in the last four decades. Sharp increases Head and neck cancers as described here Australia, France, South America (Brazil) and in incidence have been reported in Germany, will be restricted to squamous cell carcino- Southern Africa (Fig. 5.88). Oral cancer is the Denmark, Scotland, Central and Eastern mas of the upper aerodigestive tract (which 11th most common cancer in the world in Europe, and there are increases in Japan, extends from the surface of the lips to the terms of number of cases, while cancer of Australia and New Zealand, and in the USA neck region of the oesophagus) and include the pharynx (apart from nasopharynx) ranks among non-whites. the oral cavity, larynx and pharynx (compris- as 20th. Worldwide, about 389,000 new New cases of cancer of the larynx occurring ing the oropharynx, hypopharynx and cases occurred in 2000, two-thirds of which worldwide number about 160,000, i.e. about nasopharynx). Other tumours which occur in were in developing countries, and these can- 2% of the total world cancer cases, making this area, such as those of the brain and thy- cers are responsible for some 200,000 laryngeal cancer the 18thmost common can- roid and , are conventionally dealt deaths each year. cer. The disease is markedly more frequent in with separately (Tumours of the nervous sys- The male:female ratio of occurrence varies males than in females (male:female ratio of tem, p265; , p257; Melanoma, from 2-15:1 depending on the anatomical 12:1 and 6:1 in developing and developed p253). sub-site, with extreme ratios characteristic of countries respectively). There is a large geo- tongue, floor of mouth and pharyngeal can- graphic variability in disease frequency, high- Epidemiology cers. The highest incidence among males is risk countries being in Southern Europe Cancers of the oral mucosa and oro- and reported in Bas-Rhin and Calvados in France, (France, Italy, Spain), Eastern Europe (Russia, hypopharynx can be considered together, as whereas among females the highest occur- Ukraine), South America (Uruguay, there are similarities in their epidemiology, rence is observed in India. Cancers of the Argentina), and Western Asia (Turkey, Iraq) treatment and prognosis. The geographic mouth and anterior two-thirds of the tongue (Fig. 5.89). Mortality from laryngeal cancer is

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poorly known since hypopharyngeal cancer deaths are often mis-certified as deaths from cancer of the larynx. Carcinomas of the salivary glands and nasopharynx are distinguished from head and neck cancers at other sites both by epi- demiology and by etiology. Nasopharyngeal cancer is relatively rare on a world scale (65,000 new cases per year, or 0.6% of all cancers), but it has a very distinctive geo- graphic distribution. Age-standardized inci- dence rates are high for populations living in or originating from Southern China, whilst populations elsewhere in China, South East Asia, North Africa, and the Inuits (Eskimos) of Canada and Alaska, all have moderately ele- vated rates (Fig. 5.90). Males are more often affected than females (sex ratio 2–3:1), and in most populations, there is a progressive < 2.4 < 3.7 < 5.8 < 8.5 < 20.1 increase in risk with age. In moderate-risk Age-standardized incidence/100,000 population populations, however, most notably in North Fig. 5.89 The global incidence of cancer of the larynx in men. High-risk countries are found in Southern Africa, there is a peak in incidence in adoles- and Eastern Europe, Latin America and Western Asia. cence. There appears to have been a decrease in incidence over time in some high-risk populations (e.g. Hong Kong). end of the cigarette is placed in the mouth so sive cervical carcinoma have a two to four- Etiology that an intense heat is experienced) is a risk fold increased risk of oral or laryngeal cancer, Smoking and drinking are the major risk fac- factor for cancer of the hard palate. Oral in addition to increased risks of other can- tors for in developed snuff use is an emerging risk factor for oral cers associated with HPV. Additional risk fac- countries, in the Caribbean and in South cancer, particularly among young males in tors implicated in cancer of the larynx include American countries [1-3]. Smoking is esti- the USA. chronic laryngitis, chronic gastric reflux and mated to be responsible for about 41% of A generally impoverished diet, particularly exposure to wood dust, asbestos or ionizing laryngeal and oral/pharyngeal cancers in lacking in vegetables and fruits, is another radiation. men, and 15% in women worldwide and risk factor for oral cancer [5]. Consistently, Infection with Epstein-Barr virus is important these proportions vary amongst different studies also indicate a protective effect of a in the etiology of nasopharyngeal cancer. populations. Tobacco smoking has also been diet rich in vegetables and fruits (20-60% This virus is not found in normal epithelial found to be an important risk factor for reduction in risk). A high intake of salted fish cells of the nasopharynx, but is present in all nasopharyngeal cancer in otherwise low-risk and meat and the release of nitrosamines on nasopharyngeal tumour cells, and even in populations. These risk factors have been cooking such foods have been linked to dysplastic precursor lesions [7] (Chronic shown, for laryngeal and oropharyngeal can- nasopharyngeal cancer in endemic regions. infections, p56). cers, to have a joint “multiplicative” or syner- Oral human papillomavirus (HPV) infection gistic effect. (transmitted sexually or perinatally) is associ- Detection In the Indian subcontinent, chewing tobacco ated with an increased risk of head and neck Although many head and neck cancers arise in the form of betel quid (a combination of squamous cell carcinoma development [6]. in anatomically accessible areas, delayed betel leaf, slaked lime, areca-nut and tobacco Overall estimates for HPV prevalence in head diagnosis is common. Symptoms of oral can- with or without other condiments), bidi (a and neck squamous cell carcinoma are very cer include pain, bleeding, difficulty in open- locally hand-rolled cigarette of dried tem- variable, ranging from 8-100%, but an unusu- ing the mouth, chewing, swallowing and burni leaf containing coarse tobacco) smok- al laryngeal pathologic subtype, verrucous speech, and a swelling in the neck. Early ing and drinking locally brewed crude alco- laryngeal carcinoma, has a 100% prevalence lesions are often painless and present as holic drinks are the major causative factors. of HPV. Tumours of the oropharynx (and in slightly elevated, velvety red mucosal patch- The role of betel quids without tobacco is not particular, tonsillar tissue) have been found es, as punctate lesions, or as indurated small clear, though a recent case-control study to be three times more likely to be HPV-pos- ulcers or growths. In more advanced stages, from Pakistan reported a high risk of oral itive than tumours at other head and neck a large ulceroproliferative mass, with areas of cancer [4]. Reverse smoking (in which the lit sites. Women with a history of in situ or inva- necrosis, and extension to neighbouring

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structures such as bone, muscles and skin may be evident. Cancers of the oral cavity may be preceded by, and present with, leuko- plakias (Fig. 5.92) or with mucosal rigidity and fibrosis, restricted mouth opening and tongue mobility (oral submucus fibrosis). Some 5-15% of patients with cancer of the lip mucosa present with lymph node metas- tases, compared with more than 50-70% of those with tongue and floor of the mouth cancers. Distant metastases from oral can- cer are uncommon. A careful oral examina- tion and palpation of the neck leads to diag- nosis, which is confirmed by biopsy. Oral visual inspection in high-risk individuals leads to early diagnosis of oral precancer [8,9]. However, the effectiveness of organ- ized screening in reducing incidence of and mortality from oral cancer remains to be < 0.4 < 0.6 < 0.8 < 1.9 < 25.2 established. Age-standardized incidence/100,000 population An asymptomatic high neck mass in an adult Fig. 5.90 The global incidence of nasopharyngeal cancer in men. This cancer is very common in Southern is frequently associated with a primary China. oropharyngeal (tongue base and tonsil) or hypopharyngeal primary tumour. Fine needle aspiration biopsy and careful direct laryn- goscopy in order to identify the primary lioma [10]. The vast majority of nasopharyn- tumour are mandatory. Frequently, a surgical geal cancers in endemic regions is com- panendoscopy with tonsillectomy is indicat- prised of non-keratinizing and undifferentiat- ed. Patients with pharyngeal cancers may ed histological types, whereas in non-endem- complain of difficulty in swallowing and ic countries, some 30-50% are keratinizing hoarseness of voice, particularly in advanced squamous cell carcinomas [11]. stages. The early symptoms of laryngeal can- Conditions carrying increased risk of head cer are hoarseness with dysphagia, pain and and neck cancer include epithelial differenti- a neck mass. In most cases, the first sign of ation disorders, such as dyskeratosis con- nasopharyngeal cancer is a mass in the neck genita, and DNA repair deficiency syndromes (due to lymph node metastasis). Because the such as Blooms’ syndrome, Fanconi tumour is close to the foramina through anaemia, ataxia telangiectasia and xeroder- which several cranial nerves pass, there may ma pigmentosum (Carcinogen activation and be signs due to their compression, as well as DNA repair, p89). pain, blocked Eustachian tubes and nasal A strong genetic component to the risk of stuffiness. Early detection of nasopharyngeal developing nasopharyngeal cancer is evi- cancer by screening for elevated antibody dent. Migrant populations of Chinese or titres to Epstein-Barr virus has been widely North African origin appear to retain their ele- performed in populations of Southern China, vated risk, as do their children, born in a new although so far, it is not known whether this host country. An association between human procedure can prevent deaths. leucocyte antigen (HLA) profile and risk of nasopharyngeal cancer has been reported, Pathology and genetics and a study of affected siblings in Singapore Most cancers of the head and neck are squa- identified a gene locus close to HLA with a mous cell carcinoma, which may be poorly, 20-fold increased risk for nasopharyngeal moderately or well-differentiated, according cancer. to the degree of keratinization (Fig. 5.94). Cytogenetic abnormalities have been report- Fig. 5.91 A paan-tobacco chewer in Kerala, South India, with ingredients for betel quid (betel leaf, Other variants of squamous cell carcinoma ed in head and neck squamous cell carcino- areca-nut, lime and tobacco). This habit is associ- include verrucous carcinoma, sarcamoid ma, including gain or loss of the Y chromo- ated with a high risk of oral cancer. squamous cell carcinoma and lymphoepithe- some and abnormalities at other loci; very

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Fig. 5.92 Oral leukoplakia with mild dysplasia; Fig. 5.93 A moderately advanced invasive cancer Fig. 5.94 A well-differentiated, invasive squamous leukoplakia is a precursor to oral cancer. in the buccal mucosa. cell carcinoma of the larynx.

complex karyotypes are frequent [12] (Fig. dissection with or without post-operative ment, size of the primary lesion, primary site 5.96). The genetic alterations observed in radiotherapy. For patients with cancer of the of cancer within the oral cavity and age. The oral cancer include activation of proto-onco- larynx, very early tumours and cancer in situ presence of a lymph node metastasis is the genes such as cyclin D1, MYC, RAS, EGFR can be managed with local surgery, while most important negative prognostic factor in and inactivation of tumour suppressor genes early invasive tumours can be managed with squamous carcinoma of the mouth and phar- such as those encoding p16INK4A and p53 radiation therapy. More advanced tumours ynx. Aggressive histopathologic features and other putative suppressor loci [13]. Early can be treated primarily with induction include significant lymphovascular invasion, changes include loss of tumour suppressor chemotherapy or chemoradiotherapy, reser- perineural infiltration or high grade. genes on chromosomes 13p and 9p, fol- ving laryngectomy as a salvage procedure. Overexpression of Bcl-2 is associated with lowed by 17p. p53 mutations and over- Early nasopharynx cancer is treated with improved survival in head and neck cancer expression are seen in the progression of intensive radiotherapy while more advanced patients undergoing radiation therapy, as preinvasive lesions to invasive lesions. p53 cancers should be treated with a combina- well as with better local control and the mutations are more frequently reported in tion of chemoradiotherapy and adjuvant absence of local lymph node involvement. developed (40-50%) than in developing coun- chemotherapy. Abnormalities of 11q13 are associated with a tries (5-25%). Tumours from India and South Radiotherapy may also be used to sterilize poor prognosis [12]. East Asia are characterized by the involve- microscopic residual cancer after surgery. In Overall population based five-year survival ment of RAS oncogenes, including mutation, frail patients with accessible tumours (< 3 cm from oral cancer is mostly less than 50% (Fig. loss of heterozygosity (HRAS) and amplifica- in size), brachytherapy over a 3-5 day period 5.95) [17]. Females, in general, have a higher tion (KRAS and NRAS). Various genetic poly- may be curative. Radiotherapy to the head morphisms in genes such as GSTM1 or and neck can lead to troublesome side- CYP450A1 are associated with oral carcino- effects. Acute skin and mucosal inflamma- genesis. tion and sometimes ulcerations, as well as superinfection with Candida (fungus), may Management make normal food intake impossible and Surgery and radiotherapy have been the necessitate use of a feeding tube. Later mainstay of treatment for oral cancer. Those effects may include loss of taste, reduced with early or intermediate tumour stages are and thick saliva production and a dry mouth treated with curative intent with moderate [14]. Dental hygiene assessment and treat- morbidity while those with more advanced ment prior to commencement of radiothera- disease are treated with definitive radiation py are extremely important. therapy and chemotherapy. Radical surgery Chemotherapy has not been demonstrated aims for tumour-free surgical margins with to elicit an overall improvement in survival, the preservation of critical anatomical struc- although combinations of cytotoxic drugs tures. However, a major challenge is recon- such as cisplatin, methotrexate, 5-fluo- struction after resection to preserve function rouracil and bleomycin can cause dramatic and cosmesis. Definitive radiotherapy is tumour reduction in 80-90% of cases. A delivered either by external beams of radia- combined approach, chemoradiotherapy, tion from a telecobalt machine or linear appears to improve overall survival [15]. Fig. 5.95 Five-year relative survival after diagnosis accelerator. The mainstay management of The most important prognostic factors for of cancer of the oral cavity. USA data include both lymph node metastases is by radical neck oral cancer are regional lymph node involve- oral and pharyngeal cancers.

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11q, 13q, 14q loss Chromosome 9p loss 3p, 17p loss p53 mutation 6p, 8, 4q loss (21-75% of cases)

NORMAL MUCOSA PRECURSOR LESION DYSPLASIA CARCINOMA in situ INVASION

Fig. 5.96 Genetic alterations in squamous cell carcinoma of the head and neck. The accumulation and not necessarily the order of these genetic changes deter- mines progression.

survival rate than males. There has been on to develop a second primary tumour 70% in Europe and North America, but is very little improvement in five-year sur- although initially cured. Patients may also lower in developing countries. It is highly vival from this cancer, or other head and face serious reductions in quality of life dependent on the sub-site of the disease neck cancers, over the last four decades after definitive surgical therapy; despite which itself is dependent on the etiologi- [18]. Early-stage head and neck cancers improving rehabilitation and reconstruc- cal factors involved. In countries with ele- have a good cure rate, but over 60% of tive surgery, residual cosmetic and func- vated alcohol consumption the prognosis patients present with advanced disease. tional debilities may be significant. is poorer because there are more tumours Moreover, a significant percentage of The overall relative survival of laryngeal of the upper part of the larynx, which have patients with squamous cell carcinoma go cancer patients varies between 60 and a lower survival.

REFERENCES WEBSITE 1. IARC (1985) Tobacco habits other than smoking; betel- 10. Schantz SP, Harrison LB, Forastiere AA (1997) Tumours NCI Head and Neck Cancer Homepage: quid and areca-nut chewing; and some related of the nasal cavity and paranasal sinuses, nasopharynx, http://www.cancer.gov/cancer_information/cancer_type/ nitrosamines (IARC Monographs on the Evaluation of oral cavity and oropharynx. In: DeVita VTJ, Hellman S, head_and_neck/ Carcinogenic Risks to Humans, Vol. 37), Lyon, IARCPress. Rosenberg SA eds, Cancer: Principles and Practice of 2. IARC (1986) Tobacco Smoking (IARC Monographs on Oncology, Philadelphia-New York, Lippincott-Raven, 741- the Evaluation of the Carcinogenic Risk of Chemicals to 799. Humans, Vol. 38), Lyon, IARCPress. 11. Chan AT, Teo PM, Johnson PJ (1998) Controversies in 3. IARC (1988) Alcohol drinking (IARC Monographs on the the management of locoregionally advanced nasopharyn- Evaluation of Carcinogenic risks to Humans, Vol. 44), Lyon, geal carcinoma. Curr Opin Oncol, 10: 219-225. IARCPress. 12. Oh Y, Mao L (1997) Biomarkers in head and neck car- 4. Merchant A, Husain SS, Hosain M, Fikree FF, Pitiphat cinoma. Curr Opin Oncol, 9: 247-256. W, Siddiqui AR, Hayder SJ, Haider SM, Ikram M, Chuang 13. Schwartz JL (2000) Biomarkers and molecular epi- SK, Saeed SA (2000) Paan without tobacco: an independ- demiology and chemoprevention of oral cancer. Crit Rev ent risk factor for oral cancer. Int J Cancer, 86: 128-131. Oral Biol Med, 11: 92-122. 5. Steinmetz KA, Potter JD (1991) Vegetables, fruit, and 14. Norman JE de B (1998) Cancers of the head and neck. cancer. I. Epidemiology. Cancer Causes Control, 2: 325- In: Morris D, Kearsley J, Williams C eds, Cancer: a compre- 357. hensive clinical guide, Harwood Academic Publishers, 6. Gillison ML, Koch WM, Shah KV (1999) Human papillo- 15. Adelstein DJ (1998) Recent randomized trials of mavirus in head and neck squamous cell carcinoma: are chemoradiation in the management of locally advanced some head and neck cancers a sexually transmitted dis- head and neck cancer. Curr Opin Oncol, 10: 213-218. ease? Curr Opin Oncol, 11: 191-199. 16. Khuri FR, Nemunaitis J, Ganly I, Arseneau J, Tannock IF, 7. IARC (1997) Epstein-Barr Virus and Kaposi's Sarcoma Romel L, Gore M, Ironside J, MacDougall RH, Heise C, Herpesvirus / Human Herpesvirus 8 (IARC Monographs on Randlev B, Gillenwater AM, Bruso P, Kaye SB, Hong WK, the Evaluation of Carcinogenic Risks to Humans, Vol. 70), Kirn DH (2000) a controlled trial of intratumoral ONYX-015, Lyon, IARCPress. a selectively-replicating adenovirus, in combination with 8. Fernandez-Garrote L, Sankaranarayanan R, Lence anta cisplatin and 5-fluorouracil in patients with recurrent head JJ, Rodriguez-Salva A, Parkin DM (1995) An evaluation of and neck cancer. Nat Med, 6: 879-885. the oral cancer control programme in Cuba. Epidemiology, 17. Berrino F, Capocaccia J, Estève J, Gatta G, Hakulinen T, 6: 428-431. Micheli A, Sant M, Verdecchia A, eds (1999) Survival of 9. Sankaranarayanan R, Mathew B, Jacob Bj, Thomas G, Cancer Patients in Europe: The EUROCARE-2 Study (IARC Somanathan T, Pisani P, Pandey M, Ramadas K, Najeeb K, Scientific Publications, No. 151), Lyon, IARCPress. Abraham E (2000) Early findings from a community-based, 18. Clayman GL, Lippma SM, Laramore GE, Hong WK cluster randomized, controlled oral cancer screening trial (1997) Head and neck cancer. In: Holland JF, Bast RC, in Kerala, India. The Trivandrum Oral Cancer Screening Morton DL, Frei E, Kufe DW, Weichselbaum RR eds, Cancer Study Group. Cancer, 88: 664-673. Medicine, Williams and Wilkins.

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LYMPHOMA

SUMMARY

> Malignant are classified as either Hodgkin disease or non-Hodgkin lymphoma.

> Hodgkin disease afflicts mainly children and the elderly in developing countries and young adults in more developed countries; 62,000 new cases are diag- nosed annually.

> The incidence of malignant non-Hodgkin lymphomas is increasing worldwide; more than 280,000 new cases occur annually, predominantly in more devel- oped countries.

> Burkitt lymphoma is a subtype of malig- < 3.7 < 6.8 < 8.9 < 16.1 nant B-cell lymphoma common in Africa < 5.0 in regions with endemic malaria. B-cell Age-standardized incidence/100,000 population lymphomas may also be caused by Fig. 5.97 Global incidence of non-Hodgkin lymphoma in men. The disease is most common in developed immunosuppression. Both are common- countries, although there are areas of moderate to high incidence in some Middle-Eastern countries and ly associated with the Epstein-Barr virus. in parts of sub-Saharan Africa.

> Advances in chemotherapy have led to a five-year survival rate for Hodgkin dis- ease of more than 70% and that for non- per year. More males than females are changing classification systems. However, Hodgkin lymphomas has increased to affected (17.1 cases per 100,000 males these considerations together do not 60-70%. compared to 11.2 cases per 100,000 account for the extent of increase. females in the USA) and incidence Likewise, the fact that non-Hodgkin lym- increases with age. Geographically, non- phoma is a complication of AIDS (occur- Hodgkin lymphoma is most common in ring in up to 5-10% of AIDS cases in devel- developed countries (52% of the world oped countries) does not completely Definition total cases, and the seventh most com- account for the increasing trend. In con- The term lymphoma covers a heteroge- mon cancer in more developed countries), trast to incidence, mortality rates have, in neous group of neoplasms of lymphoid tis- although in the developing world there are general, been declining as a consequence sue. Traditionally, lymphomas are catego- areas of moderate to high incidence in of improvement in therapy. rized as either Hodgkin disease or non- some Middle-Eastern countries (Saudi Hodgkin disease comprises about 23% of Hodgkin lymphoma, these distinct entities Arabia, Israel) and in parts of sub-Saharan malignant lymphomas worldwide (about having different patterns of behaviour and Africa (Fig. 5.97). The latter is due to the 62,000 annual cases). There is a male pre- response to treatment. Within each of high incidence of Burkitt lymphoma, an dominance (sex ratio 1.6:1). In developing these two entities there is a range of aggressive subtype of non-Hodgkin countries, Hodgkin disease (predominant- diverse subtypes. lymphoma, particularly in children in trop- ly the mixed cellularity subtype) occurs ical Africa. Papua New Guinea also has mainly in children and in the elderly, while Epidemiology high rates of Burkitt lymphoma. in developed countries there is a peak in Non-Hodgkin lymphomas are a very varied The incidence rates of non-Hodgkin lym- young adults (mainly the nodular scleros- group of neoplasms. Excluding the types phoma have risen dramatically in the last ing subtype). The disease is rare in that generally manifest as leukaemias 20 years, particularly in developed coun- Eastern and South-Eastern Asian popula- rather than single or multiple aggregates tries, including Western Europe, North tions at any age (Fig. 5.100). The pattern of cells, there are around 287,000 cases America and Australia (Fig. 5.99). This of Hodgkin disease in black Americans of non-Hodgkin lymphoma in the world may in part reflect better diagnosis, or more closely resembles that of white

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Fig. 5.98 Non-Hodgkin lymphoma in the neck of a patient suffering from AIDS.

Americans than that of black Africans, suggesting that socioeconomic conditions may be more important than ethnicity in determining risk. In developed countries, incidence has fallen in the last 20 years [1]. Mortality rates are also decreasing, Fig. 5.99 Trends in incidence of non-Hodgkin lymphoma in the USA. Rates are increasing, as they are worldwide. probably due to effective therapy.

Etiology especially in cases in tropical Africa, where tion by the virus is ubiquitous. Suspicion has Non-Hodgkin lymphoma over 95% of tumours contain the virus. The fallen upon intense malaria infection as pre- Patients with HIV/AIDS (Box: Tumours proportion of EBV-positive tumours is much disposing to Burkitt lymphoma in the pres- associated with HIV/AIDS, p60), or who less in the sporadic cases of Hodgkin dis- ence of EBV infection. Chronic exposure to have received immunosuppressant thera- ease occurring in Europe and North wood or wood products has also been asso- py (Immunosuppression, p68), have a America. The singular geographic distribu- ciated with increased risk. The risk of higher risk of developing non-Hodgkin tion of Burkitt lymphoma is not explicable on Hodgkin disease is also increased in lymphoma [2]. Viral infections such as the basis of EBV alone, however, since infec- patients with HIV infection. HIV-1, HTLV-1 and EBV are also associat- ed with non-Hodgkin lymphoma. Infection of the stomach with Helicobacter pylori is associated with gastric lymphoma. Agricultural work with possible exposure to pesticides (particularly chlorophenoxy herbicides) and occupational exposure to solvents or fertilizers have been implicat- ed but have yet to be confirmed as caus- es of non-Hodgkin lymphoma. There is an increased risk of non-Hodgkin lymphoma among persons with a family history of lymphoma or haematologic can- cer [2].

Hodgkin disease A subset of Hodgkin disease cases, particu- larly the mixed cellularity type, has been linked to the Epstein-Barr virus (EBV) [2]. Overall, around 45% of cases may be attrib- utable to EBV. The presence of EBV in < 0.8 < 1.7 < 2.1 < 2.7 8.0 tumours seems also to be related to age and Age-standardized incidence/100,000 population socioeconomic circumstances. EBV is Fig. 5.100 Global incidence of Hodgkin disease in men. The disease is rare in Eastern and South-Eastern involved in the etiology of Burkitt lymphoma, Asian populations.

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have important therapeutic implications. East Asia. A follicular lymphoma is Hodgkin disease usually originates in defined by the retention of the follicles lymph nodes (often in the neck), and only within a lymph node (Fig. 5.102), whereas rarely spreads outside primary lymphoid a diffuse lymphoma results from the infil- tissues. Diagnosis requires a tissue biop- tration of the node with effacement of the T sy, ideally a whole lymph node. Many of follicles by the malignant cells. The size of the staging techniques employed are the the malignant lymphocytes is also impor- same as for non-Hodgkin lymphoma, and tant. the system is used to In contrast, Hodgkin disease is character- provide treatment planning information ized by the presence of multinucleate, and aid response assessment. giant so-called “Reed-Sternberg” cells, which may be rare in a particular biopsy Pathology and genetics specimen and the surrounding cell prolif- Lymphomas constitute a diverse range of eration. The Revised European-American Fig. 5.101 Nuclear magnetic resonance imaging scan of the brain of an HIV-infected patient show- diseases (Table 5.10). Advances in molec- Lymphoma classification [4] also covers ing a large lymphoma (T) in the basal ganglia. ular biology, genetics and immunology Hodgkin disease; four histological sub- have meant that there have been pro- types of Hodgkin disease are recognized: found changes in the classification of nodular sclerosing, mixed cellularity, lym- neoplasms of lymphoid cells over the last phocyte predominance and lymphocyte 20 years. In the Revised European- depletion. American Lymphoma classification sys- Many cytogenetic and molecular abnor- tem, three broad categories are recog- malities in non-Hodgkin lymphoma, in nized: Hodgkin disease and T-cell and B- particular Burkitt lymphoma, are caused cell non-Hodgkin lymphomas. A WHO by a translocation of the oncogene C- classification has recently been published MYC from chromosome 8 to either the [3]; prior to this the International Working immunoglobulin heavy chain region on Formulation (IWF) was the most widely chromosome 14 or to one of the light Fig. 5.102 Follicular non-Hodgkin lymphoma. used classification. chain loci on chromosomes 2 or 22 [5]. Non-Hodgkin lymphomas are derived Technological innovations, such as from B or T lymphocytes. In Western microarrays, are revolutionizing diagnosis Detection countries, B-cell tumours are more com- (Fig. 5.105). The most common presentation of non- mon (about 75% of cases), whereas T-cell Genetic abnormalities in Hodgkin disease Hodgkin lymphoma is painless swelling of tumours are less common but are gener- are less frequently described, perhaps the lymph nodes in the neck, armpit or ally more biologically aggressive. T-cell due to the paucity of malignant cells in groin. This may be associated with so tumours are relatively more common in the biopsy specimen. called “B symptoms” of unexplained fever, night sweats and weight loss. Other relat- ed symptoms include fatigue, malaise, Diagnosis % of total cases pruritus, or those related to organ involve- ment (e.g. indigestion caused by gastric Diffuse large B-cell lymphoma 30.6 lymphoma). Extranodal involvement is Follicular lymphoma 22.1 common. Diagnosis is dependent on MALT lymphoma 7.6 obtaining a tissue biopsy, usually by exci- Mature T-cell lymphomas (except ALCL) 7.6 sion of an enlarged node. Pathological Chronic lymphocytic leukaemia/small lymphocytic 6.7 review is crucial to identify the type of lymphoma lymphoma. 6.0 Mediastinal large B-cell lymphoma 2.4 Staging practice commonly involves full Anaplastic large cell lymphoma (ALCL) 2.4 blood count, biochemical screen including Burkitt lymphoma 2.5 tests of liver function and renal function, Nodal marginal zone lymphoma 1.8 chest X-ray, CT scan of neck, chest, Precursor T lymphoblastic 1.7 abdomen and pelvis, and bone marrow Lymphoplasmacytic lymphoma 1.2 biopsy. In some instances, lumbar punc- Other types 7.4 ture may be required to assess central nervous system involvement, which can Table 5.10 Frequency of various types of non-Hodgkin lymphoma.

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Management usually mucosal (gastrointestinal, lung, sali- The treatment of non-Hodgkin lymphomas vary gland etc.) when they are termed MALT depends on the pathological classification, (mucosa associated lymphoid tissue) lym- the stage of the disease, the biological phomas. Gastric MALT lymphomas are often behaviour of the disease, the age of the associated with H. pylori infection and patient and their general health [6,7]. In gen- appropriate antibiotic treatment often eral, it is convenient to classify the patholog- results in resolution of the lymphoma, albeit ical entities into indolent, aggressive or high- over six to twelve months [8]. Splenic mar- ly aggressive non-Hodgkin lymphomas, ginal zone lymphoma, often called splenic which parallels the IWF classification. lymphoma with villous lymphocytes, pres- Fig. 5.103 Classical Hodgkin disease. Hodgkin ents with splenomegaly and usually (arrow) and Reed-Sternberg cells (arrowhead) Indolent non-Hodgkin lymphomas responds to splenectomy. infected by the Epstein-Barr virus strongly express About two-thirds of indolent lymphomas in the virus-encoded latent membrane protein LMP1. developed countries are follicular lym- Aggressive non-Hodgkin lymphomas phomas and often present as advanced Diffuse large cell lymphoma is the most stage disease in patients over 50 years of common of these types. Biologically age. This disease usually runs a prolonged these tumours are more aggressive than course and is rarely cured (except in a few the indolent lymphomas, although remis- cases of early stage disease). The median sion and even cure may be obtained with survival is eight to ten years, and therapy is appropriate therapy in a significant often palliative. Local radiotherapy is useful proportion of cases. The factors asso- for early stage localized disease, and other ciated with prognosis in these patients options include alkylating agents, purine are age, stage, performance status, the analogues, combination chemotherapy, presence of extranodal disease, and lac- interferon, monoclonal antibodies and high tic dehydrogenase levels, which can be dose therapy with autologous stem cell sup- summed to form the International port. Lymphoplasmacytoid lymphoma is Prognostic Index. Using this model, four Fig. 5.104 Burkitt lymphoma presenting as a large often associated with a monoclonal para- risk groups can be identified with a pre- tumour of the jaw in an African child. protein and, like small lymphocytic lympho- dicted five-year survival of 73%, 51%, 43% ma/chronic lymphocytic leukaemia, will and 26% when treated with conventional often respond to alkylating agent therapy. anthracycline based chemotherapy (e.g. Marginal zone lymphomas can be divided cyclophosphamide, doxorubicin, vin- into those at nodal sites (monocytoid B-cell cristine, prednisone). Attempts to improve lymphomas) and those at extra nodal sites, outcome with more aggressive chemo-

Histology Translocations

Small cleaved cell, follicular t(14;18)(q32;q21.3) Small non-cleaved cell (Burkitt and non-Burkitt) t(8;14)(q24;q32) t(2;8)(p12;q24) t(8;22)(q24;q11) Centrocytic/mantle cell t(11;14)(q13;q32) Large cell, diffuse, B-cell t(3;14)(q27;q32) t(3;22)(q27;q11) Fig. 5.105 Microarray technology can be used to t(2;3)(p12;q27) identify two major patterns of gene expression among diffuse large B-cell lymphomas (DLBCL). Small lymphocytic/extranodal (MALT) t(11;18)(q21;q21.1) One displays a germinal centre T-cell signature, the other an activated B-cell signature. The analy- Large cell, anaplastic t(2;5)(p23;q35) sis is based on the expression of about 12,000 genes. Table 5.11 Some common chromosomal translocations found in non-Hodgkin lymphomas.

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therapy protocols, so-called “second and involved sites, bulk of disease and ery- third generation regimens”, have met with throcyte sedimentation rate. Using such little success. However, the introduction models it may be possible to identify poor of the International Prognostic Index may prognosis patients who will benefit from help to identify patients who will benefit more aggressive high-dose therapies, from more aggressive strategies [9]. In such as Stanford V (doxorubicin, vinblas- patients who relapse after conventional tine, mustard, bleomycin, vincristine, therapy, and who still have “sensitive dis- etoposide and prednisone) or BEACOPP ease”, high-dose chemotherapy with stem (bleomycin, etoposide, adriamycin [dox- cell rescue appears to offer a reasonable orubicin], cyclophosphamide, oncovin salvage option. [vincristine], procarbazine and pred- nisone) from the outset (Medical oncolo- Hodgkin disease gy, p281). In contrast to non-Hodgkin lymphomas, Survival for both Hodgkin disease and the management of Hodgkin disease is non-Hodgkin lymphomas has improved usually dictated by the stage of disease markedly with time, in response to the rather than the histology [10,11]. Most development of more effective Fig. 5.106 Five-year relative survival rates after centres would use radiotherapy for early chemotherapy and bone marrow trans- diagnosis of Hodgkin disease. stage (IA or IIA) disease, although there is plantation. Five-year survival after diagno- a trend towards considering limited sis of non-Hodgkin lymphoma patients in chemotherapy as an option. All other most developed countries is more than stages should have chemotherapy, and 50%, but only 17-35% in developing coun- the traditional “gold standard” MOPP tries (Fig. 5.107). Currently, survival of (mustine, vincristine, procarbazine and Hodgkin disease patients is related to prednisone) therapy has been superseded extent of disease at diagnosis; overall, at by ABVD (adriamycin [doxorubicin], five years it is between 70% and 90% in bleomycin, vinblastine and dacarbazine) North America and Europe, but only 30- which appears to be as efficacious with- 55% in developing countries (Fig. 5.106). out the adverse effects (particularly relat- ed to fertility and the development of sec- ond malignancies). The German Hodgkin Disease Study Group has proposed a prognostic model for advanced stage dis- ease, and has identified seven factors which influence outcome. These are age, Fig. 5.107 Five-year relative survival rates after sex, histology, B symptoms, number of diagnosis of non-Hodgkin lymphoma.

REFERENCES

1. Cartwright RA, Gilman EA, Gurney KA (1999) Time Group. Blood, 84: 1361-1392. non-Hodgkin's lymphoma. The International Non- trends in incidence of haematological malignancies and 5. Macintyre EA, Delabesse E (1999) Molecular Hodgkin's Lymphoma Prognostic Factors Project. N Engl J related conditions. Br J Haematol, 106: 281-295. approaches to the diagnosis and evaluation of lymphoid Med, 329: 987-994. malignancies. Semin Hematol, 36: 373-389. 2. Baris D, Zahm SH (2000) Epidemiology of lymphomas. 10. Horwitz SM, Horning SJ (2000) Advances in the treat- Curr Opin Oncol, 12: 383-394. 6. Bierman PJ, Armitage JO (1996) Non-Hodgkin's lym- ment of Hodgkin's lymphoma. Curr Opin Hematol, 7: 235-240. phoma. Curr Opin Hematol, 3: 266-272. 3. Jaffe ES, Lee Harris N, Stein H, Vardiman JW, eds 11. Aisenberg AC (1999) Problems in Hodgkin's disease 7. Pinkerton CR (1999) The continuing challenge of treat- (2001) World Health Organization Classification of management. Blood, 93: 761-779. ment for non-Hodgkin's lymphoma in children. Br J Tumours. Pathology and Genetics of Tumours of Haematol, 107: 220-234. Haematopoietic and Lymphoid Tissues, Lyon, IARCPress. 8. Zucca E, Bertoni F, Roggero E, Cavalli F (2000) The 4. Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary gastric marginal zone B-cell lymphoma of MALT type. ML, Delsol G, Wolf-Peeters C, Falini B, Gatter KC (1994) A Blood, 96: 410-419. revised European-American classification of lymphoid neo- 9. International Non-Hodgkin's Lymphoma Prognostic plasms: a proposal from the International Lymphoma Study Factors Project (1993) A predictive model for aggressive

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LEUKAEMIA

SUMMARY

> Leukaemia is the eleventh most com- mon cancer worldwide with more than 250,000 new cases each year. It typical- lyresults from malignant transformation of white blood cells or their precursors. Subtypes are identified on the basis of the cell of origin (lymphocytic or myeloid, etc.) and clinical course (acute or chronic).

> The etiology of leukaemia is largely unknown, although a small proportion of cases is attributable to treatment with anticancer drugs or exposure to ionizing radiation. The genetic characteristics of many leukaemias have been elucidated.

> Treatment of acute leukaemia has made < 2.4 < 3.2 < 4.3 < 5.4 < 10.2 muchg progress and helped to establish Age-standardized incidence/100,000 population general principles of cancer chemother- Fig. 5.108 Global incidence of leukaemia in women. apy and management.

> Survival varies greatly according to type, in the USA, Canada, Western Europe, lation, the usual form of the disease in with acute lymphoblastic leukaemia Australia and New Zealand, whilst rates are adults being acute myeloid leukaemia patients having a five-year survival rate of up to 70%, whilst for those with acute generally low in most African and Asian (AML) accounting for 70% of all cases. myeloid leukaemia it is only 20-30%. countries with rates less than half those in The more differentiated, or chronic the former group (Fig. 5.108). The trends in forms of leukaemia, are predominantly overall incidence of leukaemia have gener- adult diseases, rarely occurring below ally been stable or slowly increasing. the age of 30, then increasing progres- However, a substantial reduction in death sively in incidence with age. Chronic rates from leukaemias, particularly in child- myelogenous leukaemia (CML) accounts Definition hood, have been observed since the 1960s, for 15-20% of all cases of leukaemia, Leukaemias involve clonal, neoplastic pro- thanks to advances in treatment and con- with a worldwide incidence of 1-1.5 liferation of immature cells, or blasts, of sequent improvement in survival. cases per 100,000 population. For the haematopoietic system. Principal sub- Leukaemia has a peak in incidence in the patients over 50, chronic lymphocytic types are identified on the basis of malig- first four years of life, which is predomi- leukaemia (CLL) is the dominant type of nancy involving either lymphoid (B-cells nantly due to acute lymphoblastic leuk- leukaemia. All types of leukaemia com- and T-cells) or myeloid (i.e. granulocytic, aemia (ALL), the most common paediatric bined cause some 195,000 deaths erythroid and megakaryocytic) cells, and malignancy, accounting for nearly 25% of worldwide. upon whether disease is acute or chronic all such disease. After infancy, there is a in onset [1]. steep decline in rates of leukaemia with Etiology age, lowest incidence being at age 15 to The cause of most leukaemias is not Epidemiology 25, after which there is an exponential known. A range of risk factors has been Leukaemias comprise about 3% of all rise up to age 85 (Fig. 5.110). The frequen- predominantly, although not exclusively, incident cancers worldwide, with about cy of leukaemia per 100,000 individuals at associated with particular leukaemia sub- 257,000 new cases occurring annually. risk at age 85 is more than 300 times that types. Ionizing radiation (nuclear bombs, Incidence rates for all types taken together for those in the second decade of life. medical procedures, [e.g. 2, 3]) and occu- vary from about 1 to 12 per 100,000 popu- The overall incidence of acute pational exposure to are lation. A relatively high incidence is evident leukaemia is 4 cases per 100,000 popu- associated with acute myeloid leukaemia.

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Fig. 5.109 The immediate aftermath of a nuclear explosion. An increased incidence of leukaemia and some other cancer types occurred amongst the survivors of the bombing of Hiroshima and Nagasaki.

Leukaemia (mainly acute myeloid) may occur in a small proportion of cancer patients treated with chloroambucil, cyclophosphamide, melphalan, thiotepa, treosulphan or etoposide, as well as cer- tain combination chemotherapy (Medicinal drugs, p48). Leukaemia has followed induction of aplastic anaemia by the antibi- otic, chloramphenicol. Certain risk factors, such as Down’s syndrome, have been iden- tified for childhood leukaemia, but general- ly the causes of the disease are not known. Some studies have shown a risk of child- hood leukaemia with exposure to high level residential extremely low frequency elec- tromagnetic fields, but causality has not Fig. 5.110 Age-specific incidence rates in the USA of leukaemia overall and of different subtypes. AML = been established [4]. acute myeloid leukaemia, ALL = acute lymphoblastic leukaemia, CLL = chronic lymphocytic leukaemia, Infection with the virus HTLV-I has been CML = chronic myelogenous leukaemia. Note the high incidence of ALL in children. established as a cause of leukaemia. This virus is responsible for adult T-cell leukaemia, a disease mainly observed in resulting in increased risk of haemor- acute lymphoblastic leukaemia additional- tropical countries and Japan, and rarely in rhage. Patients with chronic myelogenous ly present with bone and joint pain and the USA and Europe. In experimental ani- leukaemia, usually adults aged 30-50, multiple lymph node enlargement (lym- mals, particularly in mice, there are many present with slow onset of symptoms of phadenopathy). Chronic lymphocytic leuk- retroviruses which can cause a variety of anaemia, weight loss and massive aemia presents with multiple lymph node leukaemias, but such retroviruses have not enlargement of the spleen. enlargement, with or without splenic been identified in humans. In the case of lymphoid malignancies, the enlargement. As the disease progresses, primary effect is on the host immune anaemia sets in slowly. For leukaemia gen- Detection response, with an increased susceptibility erally, diagnosis may be suspected from In the case of the myeloid leukaemias, the to infection and, in the advanced stages, examination of peripheral blood and is primary manifestations result from sup- interference with bone marrow function. confirmed by bone marrow examination. pression of normal haematopoiesis. This Children with acute lymphoblastic leuk- causes anaemia, leading to weakness, aemia (or young adults with acute myeloid Pathology and genetics leukopenia (decreased numbers of white leukaemia) may present with anaemia, Leukaemias are clonal neoplastic prolif- blood cells) resulting in an increased fre- features of infection and bleeding, which erations of immature haematopoietic quency of infection, and thrombocytope- are of rapid onset. Enlargement of the cells characterized by aberrant or arrest- nia (decreased numbers of platelets) liver and spleen is common. Patients with ed differentiation. Leukaemic cells rapid-

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T-cell phenotypes, expressing CD2, CD3, CD5 and CD7 surface antigens, make up 15-20% of acute lymphoblastic leukaemia cases. Acute myeloid leukaemia (Fig. 5.113) is a clonal expansion of myeloid blasts in bone marrow, blood or other tissue [5]. The dis- ease is heterogeneous and consists of sev- eral subtypes, which can be identified by ABkaryotype [7]. Approximately 20% of Fig. 5.111 (A) Bone marrow smear from a patient with acute lymphoblastic leukaemia. (B) Precursor B patients have favourable cytogenetic lymphoblastic leukaemia. This bone marrow smear shows several lymphoblasts with a high nuclear cyto- abnormalities, including t(8;21), inv(16) plasmic ratio and variably condensed nuclear chromatin. and t(15;17). These types are uniformly distributed across age groups, suggesting a distinct etiologic agent. Approximately ly accumulate in the bone marrow, ulti- both childhood and adult disease), and dis- 30% (predominantly patients over the age mately replacing most of the normal cells tinguished from lymphomas which involve of 50, with a progressive increase in inci- and circulate in the peripheral blood. As more mature lymphoid cells and primarily dence with age) have unfavourable cytoge- already noted, leukaemias are catego- inhabit lymph nodes and spleen. Precursor netic abnormalities, which include dele- rized in relation to clinical course and cell B-lineage blasts (Fig. 5.111B) exhibit a tions of the long arm of chromosome 5 or lineage. In addition, reference may be range of cytogenetic abnormalities. The 7 or trisomy of chromosome 8. made to the morphology, degree of dif- t(9;22) translocation, which results in Approximately half have diploid cytogenet- ferentiation, immuno-phenotype and fusion of the “breakpoint cluster region” ics and an intermediate prognosis. A sig- genetic character of the malignant cell BCR on chromosome 22 and the cytoplas- nificant fraction of the favourable cytoge- population [5]. mic tyrosine kinase ABL on chromosome netic group and a small fraction of the Acute lymphoblastic leukaemia (Fig. 5.111 9, is associated with poor prognosis. B-lin- diploid group can be cured with combina- A) is characterized by lymphoblasts, most eage blasts express surface antigens such tion chemotherapy. One subtype, acute often of B-cell phenotype (about 80% of as CD10, CD19 and CD22 [6]. Precursor promyelocytic leukaemia, is characterized by t(15;17) (Fig. 5.114, 5.116). The break point on chromosome 17 occurs within the 8605Met ABL gene for an all-trans-retinoic acid receptor (RARα) and generates the fusion gene 1b 1a a11 a2a3 PML-RARα on the derivative chromosome 15 [8]. Chronic myelogenous leukaemia (Fig. 5.117) originates in an abnormal pluripo- BCR e1 e1’ e2’ e6 b2 b3 e19 tent bone marrow stem cell [5,9]. The dis- ease has a cytogenetic hallmark, the Philadelphia chromosome, namely t(9;22) (Fig. 5.115). This translocation relocates the C-ABL proto-oncogene from chromo- BCR-ABL some 9 to the breakpoint cluster region on chromosome 22 to form a new hybrid BCR- e1a2 ABL oncogene. The BCR-ABL transcript is present in over 95% of chronic myeloge- b2a2 nous leukaemia cases, and encodes a novel tyrosine kinase that is involved in b3a2 pathogenesis, possibly by perturbing apop- tosis. e19a2 Chronic lymphocytic leukaemia is now recognized as being the same disease Fig. 5.112 Schematic representation of the disruption of the ABL and BCR genes in the t(9;22)(q34;21) entity as small cell lymphoma, being a chromosomal abnormality found in chronic myeloid leukaemia, which results in the formation of onco- genic BCR-ABL fusion genes. Segments of DNA which are transcribed to form the protein (exons) are neoplasm of monomorphic small, round labelled a, b and e. Arrows mark the breakage points. B-lymphocytes in the peripheral blood,

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AB Fig. 5.113 Acute myeloid leukaemia; agranular myeloblasts (A) and granulated myeloblasts (B). Fig. 5.114 A bone marrow biopsy of acute promye- locytic leukaemia. Abnormal promyelocytes have abundant hypergranulated cytoplasm. The nuclei are generally round to oval, several being irregular and invaginated.

bone marrow and lymph nodes, admixed from malignancy in children under 15; cur- prevent possible involvement of or relapse with prolymphocytes and paraim- rently, more than 80% of children with in the central nervous system. The use of munoblasts, usually expressing CD5 and acute lymphoblastic leukaemia can be radiotherapy is limited because of the CD23 surface antigen [5]. Chronic lympho- cured with chemotherapy [12]. Treatment potential long-term side-effects, particular- cytic leukaemia [10] is a heterogeneous involves induction of remission with com- ly effects on the growth of the young child disease which can occur in an indolent binations of agents (such as vincristine, and the risk of second malignancies. The form with very little progression, whilst at daunorubicin, cytarabine [cytosine arabi- adult form of acute lymphoblastic the other extreme it may present with noside], L-asparaginase, 6-thioguanine, leukaemia is also susceptible to therapy severe bone marrow failure and a poor and steroids) followed by consolidation, and can be cured, (although not as readily prognosis. maintenance and post-remission intensifi- as childhood leukaemia), with intensive cation therapy to eradicate residual combination therapy [13]. Management leukaemic blast cells, aiming at cure. For acute leukaemia in adults, the initial Remarkable progress in the understanding Intensive supportive care throughout treat- aim of management is to stabilize the and treatment of leukaemia has been ment is of major importance. Prophylactic patient with supportive measures to coun- made in the past century [11]. In the first treatment with intrathecal methotrexate teract bone marrow failure which leads to instance, this generalization refers specifi- injections, with or without craniospinal anaemia, neutropenia and thrombocy- cally to paediatric disease. Prior to 1960, irradiation, is mandatory in the manage- topenia. Most patients with leukaemia leukaemia was the leading cause of death ment of acute lymphoblastic leukaemia to who die in the first three weeks of diagno-

Fig. 5.115 Spectral karyotyping of a chronic myeloid leukaemia case reveals Fig. 5.116 Acute promyelocytic leukaemia cells with t(15;17)(q22;q12) a variant Philadelphia chromosome involving translocations between chro- translocation. Fluorescence in situ hybridization with probes for PML (red) mosomes 3, 9, 12 and 22. Secondary changes involving chromosomes 1, 5, and RARα (green) demonstrates the presence of a PML/RARα fusion protein 8, 18 and X are also seen, indicating advanced disease. (overlapping of red and green = yellow signal) resulting from the breakage and fusion of these chromosome bands.

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THE MOLECULAR DETECTION OF amongst 104-106 normal cells can routinely plagued by false positivity of normal bone MINIMAL RESIDUAL DISEASE be achieved, a level of sensitivity that is marrow and peripheral blood samples, some 3 to 5 orders of magnitude more sen- particularly since it has been shown that sitive than conventional techniques. PCR by using RT-PCR it is possible to detect The accurate identification of submicro- can, therefore, serve as an ultrasensitive the expression of otherwise tissue-specif- scopic numbers of residual cancer cells tool for accurately identifying small num- ic genes in any cell type. This process has has important clinical implications for bers of cancer cells in patient samples. been termed “illegitimate” transcription many malignancies. Treatment efficacy is (Chelly J et al., Proc Natl Acad Sci USA, 86: frequently monitored by the disappear- The potential clinical utility of minimal 2617-21, 1989) and in order to avoid this it ance of tumour cells from the blood or residual disease detection for both may be necessary to employ multiple bone marrow, and while microscopic haematopoietic malignancies and solid markers for use in residual disease test- examination of marrow is extremely valu- tumours has been demonstrated in a range ing. able, it is a relatively insensitive tool for of studies. For example, there is now the detection of this “minimal residual strong evidence that the level of minimal The molecular detection of minimal resid- disease”. Much effort has therefore been residual disease measured in the first few ual disease undoubtedly offers great directed towards the development of sen- months of therapy in children undergoing potential as an aid in the management of sitive and specific molecular assays of treatment for acute lymphoblastic cancer patients. However, there is also an minimal residual disease with the main leukaemia is highly prognostic of outcome urgent need to develop appropriate treat- molecular strategy involving the use of (Cave H et al., New Engl J Med, 339: 591-8, ment strategies for use in conjunction the polymerase chain reaction (PCR) tech- 1998; van Dongen JJM et al., Lancet, with this new tool. It is at present nique. Since its inception in 1985, this 352:1731-8, 1998). These studies have uti- unknown whether patients in whom per- technique has been widely utilized as a lized clone-specific rearrangements of anti- sistent minimal residual disease is means of amplifying (i.e. repeatedly copy- gen receptor genes as the targets for PCR detected will benefit from adjuvant thera- ing) target DNA sequences up to a million- amplification of genomic DNA. Other stud- py, although a number of clinical trials fold with great specificity, due to the use ies, particularly those involving solid have begun in order to address this ques- of oligonucleotide primers unique to the tumours, have relied on reverse transcrip- tion. Critical to their success will be the sequence of interest (Saiki RK et al., tase (RT-PCR) amplification of cancer-spe- use of uniform and standardized minimal Science, 230: 1350-54, 1985). Numerous cific messenger RNA as an indicator of the residual disease methods that provide studies have reported the use of PCR- presence of residual disease. While these accurate and reproducible results. The based techniques for detecting minimal RT-PCR techniques offer valuable clinical use of multiple molecular minimal resid- residual disease in a range of cancers information, especially in tumour staging, ual disease markers and the development including leukaemia, lymphoma, breast there is currently enormous variability of “real-time” PCR assays (e.g. Kwan E et cancer, prostate cancer and melanoma. when comparing inter-laboratory assays. al., Brit J Haem, 109: 430-34, 2000) may Detection limits of one Such ultrasensitive methods can be be particularly helpful in this regard.

sis die of infection or, less commonly, Retinoic acid derivatives, particularly all- bleeding. Large gains in survival in acute trans-retinoic acid, given by mouth can myeloid leukaemia have come with the induce haematologic remissions of acute introduction of improved supportive care promyelocytic leukaemia without signifi- and combination chemotherapy. Effective cant myelosuppression, although this drugs include cytarabine, anthracyclines, therapy itself is not curative. etoposide, mitoxantrone, amsacrine, 6- Treatment is essentially palliative in chron- thioguanine and 5-azacytidine. Intensive ic leukaemias. The major risk to patients therapy is applied until a complete remis- with chronic myelogenous leukaemia is sion is achieved with <5% blasts in the transformation to an acute phase, which marrow. Typically, 50-70% of patients resembles acute leukaemia and is referred achieve complete remission. Bone marrow to as the blastic phase of the disease. This Fig. 5.117 A biopsy section from a patient with transplantation from an HLA-matched development is highly malignant and chronic myelogenous leukaemia, myeloid blast phase. Sheets of abnormal megakaryocytes, includ- donor is one form of therapy for the late refractory to conventional treatment and ing micromegakaryocytes, are illustrated. Blasts intensification of remission in younger results in a short survival. The anti-tyro- infiltrate between the abnormal megakaryocytes. patients with acute myeloid leukaemia. sine kinase compound “Gleevec”, or

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ST-571, α-interferon and arabinosyl cyto- (“CAMPATH”), has been found to be highly sine, a chemotherapeutic agent, can pro- effective in this disease. At the present duce complete cytogenetic remissions, pre- time, combinations of antimetabolite, alky- vention of blastic transformation and signif- lating agents and monoclonal antibody in icant prolongation of survival, with a small various combinations and sequences are fraction of patients being cured. However, being aggressively investigated and the the development of resistance to ST-571 prognosis for patients in this category of may cause patients to relapse within a few disease has substantially improved. months [14]. Without treatment, the life Generally, 60-70% of patients with acute span for the average individual with chron- lymphoblastic leukaemia, and 20-30% of ic lymphocytic leukaemia is under five patients with acute myeloid leukaemia (Fig. years from diagnosis. The treatment for 5.118) survive in excess of five years. this disease historically was with alkylating Approximately 30-50% of the patients diag- agents. Recently the purine antimetabolite, nosed with chronic leukaemias survive five fludarabine, has substantially increased the years. Survival is much poorer in develop- frequency and the quality of response to ing countries (generally <20%) due to the chemotherapy. A new monoclonal antibody cost and lack of access to these complex Fig. 5.118 Five-year relative survival rates after diagnosis of leukaemia. directed against the T-cell antigen, CD52 therapeutic regimes.

REFERENCES WEBSITE 1. Freireich EJ, Lemak N (1991) Milestones in D, Minucci S, Fagioli M, Pelicci PG (2001) Common themes NCI Leukemia Homepage: Research and Therapy, Baltimore, Maryland, Johns Hopkins in the pathogenesis of acute myeloid leukemia. Oncogene, http://www.cancer.gov/cancer_information/cancer_ University Press. 20: 5680-5694. type/leukemia/ 2. IARC (2000) Ionizing Radiation, Part 1: X- and Gamma 9. Faderl S, Talpaz M, Estrov Z, Kantarjian HM (1999) Radiation and Neutrons (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Vol. 75), Chronic myelogenous leukemia: biology and therapy. Ann Lyon, IARCPress. Intern Med, 131: 207-219. 3. Noshchenko AG, Moysich KB, Bondar A, Zamostyan 10. Keating MJ, O'Brien S (2000) Conventional manage- PV, Drosdova VD, Michalek AM (2001) Patterns of acute ment of chronic lymphocytic leukemia. In: Foa R, leukaemia occurrence among children in the Chernobyl Hoffbrand, AV eds, Reviews in Clinical and Experimental region. Int J Epidemiol, 30: 125-129. Haematology, 118-133. 4. IARC (2002) Non-ionizing Radiation, Part 1: Static and Extremely Low-Frequency Electric and Magnetic 11. Brenner MK, Pinkel D (1999) Cure of leukemia. Semin Fields (IARC Monographs on the Evaluation of Hematol, 36: 73-83. Carcinogenic Risks to Humans, Vol. 80), Lyon, IARCPress. 12. Pui C-H, Campana D, Evans WE (2001) Childhood 5. Jaffe ES, Harris NL, Stein H, Vardiman JW, eds (2001) acute lymphoblastic leukaemia - current status and future World Health Organization Classification of Tumours. perspectives. Lancet Oncology, 2: 597-607. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues, Lyon, IARCPress. 13. Kantarjian HM, O'Brien S, Smith TL, Cortes J, Giles FJ, 6. Farhi DC, Rosenthal NS (2000) Acute lymphoblastic Beran M, Pierce S, Huh Y, Andreeff M, Koller C, Ha CS, leukemia. Clin Lab Med, 20: 17-28, vii. Keating MJ, Murphy S, Freireich EJ (2000) Results of treat- ment with hyper-CVAD, a dose-intensive regimen, in adult 7. Estey EH (2001) Therapeutic options for acute myel- ogenous leukemia. Cancer, 92: 1059-1073. acute lymphocytic leukemia. J Clin Oncol, 18: 547-561. 8. Alcalay M, Orleth A, Sebastiani C, Meani N, 14. McCormick F (2001) New-age drug meets resistance. Chiaradonna F, Casciari C, Sciurpi MT, Gelmetti V, Riganelli Nature, 412: 281-282.

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PANCREATIC CANCER

SUMMARY

> is the 14th most com- mon cancer worldwide, with approxi- mately 216,000 new cases per year. Highest incidence rates occur in more developed countries.

> In countries with high smoking preva- lence, more than 40% of cases is attrib- utable to tobacco consumption. Familial risk, often involving hereditary pancre- atitis, is evident in up to 10% of cases.

> No effective early diagnostic test or pop- ulation-based screening procedure is available.

> KRAS and p53 gene mutations are impli- cated in the development of the most < 2.1 < 5.6 < 9 < 1.5 < 98.9 common type, ductal adenocarcinoma. Age-standardized incidence/100,000 population

> Five-year survival rates are poor (less Fig. 5.119 Global burden of pancreatic cancer in women. Incidence rates are generally high in the Americas, Europe and Australia. than 5%) and the vast majority of pan- creatic cancer patients die within a year of clinical diagnosis. of Papua New Guinea and Sri Lanka [1] and fish. Smoking and diet are believed to (Fig. 5.119). In the developed world, inci- account for much of the increased inci- dence has risen three-fold since the dence observed since the 1920s. Coffee 1920s, stabilizing in the late 1970s. consumption was once thought to be a Pancreatic cancer is significantly more risk factor, but recent studies have not Definition common in younger men than in younger established significant associations. Most (90%) pancreatic tumours are ade- women, the sex ratio varying from Working in mines, metalworks, sawmills, nocarcinomas arising from the ductal between 1.25-1.75:1 [2]. However, the chemical plants, coke plants, rubber fac- epithelium of the exocrine . gender bias decreases with increasing tories, and the petrochemical industry Some 70% of these tumours develop in age. Prognosis is very poor and pancreat- have been variously indicated as risk fac- the head of the pancreas. Endocrine ic cancer causes some 213,000 deaths tors, as has exposure to solvents, napthy- tumours of the pancreas, which are rare, each year. In the USA, cancer of the pan- lamine, benzidine, and polychlorinated arise from the islets of Langerhans. creas is now the fourth leading cause of biphenyl used in transformers. Other risk cancer-related death in both men and factors include chronic and hereditary Epidemiology women. pancreatitis, diabetes (although the signif- Pancreatic cancer is the 14th most com- icance of the latter is much weaker if mon cancer worldwide, with more than Etiology cases of recent onset are excluded) and 216,000 new cases occurring each year. About 30% of cases of pancreatic cancer cirrhosis. The sex ratio of pancreatic can- Groups with the highest incidence include are attributable to smoking. Cigarette cer incidence has suggested a role for sex black male Americans, New Zealand smokers develop this disease two to three hormones in disease development [3]. Maoris, Korean Americans and native times more often than non-smokers. A female Hawaiians, as well as the male number of dietary factors have been puta- Detection population of Kazakhstan. The lowest tively connected with pancreatic cancer, The diagnosis of pancreatic cancer is rates are in Ahmedabad Indians and in the including a diet low in fibre and high in rarely made at an early stage and the populations of some African countries meat and fat, and a diet rich in the hete- most frequently recognized clinical symp- such as Tanzania and Guinea, and in those rocyclic amines present in cooked meat toms are usually portents of advanced dis-

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Fig. 5.121 Cigarette smoking is one of the main risk factors for pancreatic cancer.

Fig. 5.120 Age-specific incidence and mortality of pancreatic cancer in men and women in North G America. The small differences between incidence and mortality reflect the very poor prognosis of this T disease. Men are somewhat more frequently affected than women. L ease. These include unexplained weight Cytological or histological confirmation is K K loss, nausea, diarrhoea, weakness, jaun- obtained from samples taken during endo- S dice (caused by compression of the intra- scopic retrograde cholangiopancreatogra- pancreatic common ) and upper phy, or by fine needle aspiration and core abdominal and back pain. Mature onset biopsy under radiological guidance. How- diabetes in the absence of a family history ever, it is often difficult to obtain histologi- Fig. 5.122 A CT image of a mucinous cystic neo- may also indicate the possibility of pan- cal proof for small lesions, which have the plasm in the pancreas. The thick wall shows focal creatic cancer. Insulin antagonism by best potential for curative surgery. calcification. T = tumour, K = kidney, L = liver, S = tumour-produced factors (islet amyloid Patients who are candidates for surgery spinal cord, G = . peptide, glucagon and somatostatin) is undergo ultrasound and laparoscopy, believed to be the cause [4]. Whilst 85% of which identify those with small peritoneal patients have systemic disease or locally and liver nodules below the resolution of unresectable tumours on clinical evalua- current imaging. T tion, some 25% have symptoms compati- ble with upper abdominal disease up to six Pathology and genetics months prior to diagnosis and 15% of The first stage of neoplasia (Fig. 5.124), patients seek medical attention more than flat hyperplasia, entails the columnariza- SI six months prior to diagnosis [5]. tion of the ductal epithelium. It is estimat- Ultrasonography is the initial diagnostic ed that as many as half the normal elderly imaging system currently employed, population may exhibit flat hyperplasia [6]. Fig. 5.123 Surgical specimen of a pancreatic duc- although visualization of the body and tail This may advance to papillary hyperplasia, tal adenocarcinoma (T) in the head of the pan- of the pancreas is often unsatisfactory due the presence of a crowded mucosa with a creas. SI = . to the presence of intestinal gas. Com- folded structure, which may possess vary- puted tomography (CT) scanning allows ing degrees of cellular and nuclear abnor- clearer imaging of the tail and body and malities. True carcinoma is characterized can detect lesions of >1 cm with accuracy, by invasion of the ductal wall and a ma, tumours of uncertain biological as well as secondary signs of pancreatic desmoplastic response, i.e. acollagenous, behaviour, including mucinous cystic cancer, such as dilation of common bile inflammatory reaction, such that the tumour and solid cystic tumour, as well as and main pancreatic ducts, invasion of sur- tumour may comprise less than 25% can- malignant forms, such as adenocarcino- rounding structures, liver secondaries, cer cells. The major histological types ma, microcystic serous adenocarcinoma lymphadenopathy and ascites (Fig. 5.122). include benign microcystic serous adeno- and mucinous .

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Gene Chromosome Mechanism of alteration % of cancers Oncogenes KRAS 12p Point mutation > 90 MYB, AKT2, AIB1 6q, 19q, 20q Amplification1 10-20 ERBB2 (HER/2-neu) 17q Overexpression 70 Tumour suppressor genes p16INK4A 9p Homozygous deletion 40 Loss of heterozygosity 40 and intragenic mutation Promoter hypermethylation 15 Fig. 5.124 Pancreatic duct showing high-grade intraepithelial neoplasia. p53 17p Loss of heterozygosity 50-70 and intragenic mutation DPC4 18q Homozygous deletion 35 Loss of heterozygosity 20 and intragenic mutation BRCA2 13q Inherited intragenic 7 mutation and loss of heterozygosity MKK4 17p Homozygous deletion, 4 loss of heterozygosity and intragenic mutation Fig. 5.125 Well-differentiated, mucus-secreting LKB1/STK11 19p Loss of heterozygosity 5 invasive ductal adenocarcinoma of the pancreas. and intragenic mutation, homozygous deletion Hereditary conditions ALK5 and TGF βR2 9q, 3p Homozygous deletion 4 Around 10% of cases of pancreatic cancer DNA mismatch repair exhibit some degree of familial risk, this MSH2, MLH1, others 2p, 3p, others Unknown <5 fraction being the highest for any human

organ site [6]. In this context, germline 1In cases of amplification, it is generally not possible to identify the key oncogene unambiguously due to the involvement of multiple mutations have been identified in a num- genes. ber of oncogenes and tumour suppres- sors, including BRCA2, (predisposing to Table 5.12 Genetic alterations found in pancreatic ductal carcinoma. breast and pancreatic carcinoma) and p16INK4 (predisposing to melanoma and which carry increased susceptibility to e.g. EGF, TGFα, TGFβ1-3, αFGF and their pancreatic cancer) (Table 5.13). The pancreatic cancer include intraductal pap- receptors [10, 11]. Mutation of the gene STK11/LKB1 gene is mutated in Peutz- illary mucinous tumour, familial adenoma- encoding c-erbB2 is associated with late Jeghers syndrome patients, this group tous polyposis, familial atypical multiple stage pancreatic adenocarcinoma and being predisposed to pancreatic cancer mole melanoma syndrome, cystic fibrosis, that encoding c-erbB3 with shorter post- [7]. Sufferers from hereditary pancreatitis heritable nonpolyposis colon cancer and operative survival. (Table 5.12) [12]. experience attacks of acute pancreatitis Li-Fraumeni syndrome [9]. from an early age and face a 40% risk of Management cancer by age 70. Most families appear to Sporadic genetic alterations Currently, surgery offers the patient the possess one of two mutations in the Mutations of the KRAS oncogene, most only chance of cure. However, treatment cationic trypsinogen gene (chromosome frequently of codon 12, occur in 95% of can improve quality of life by controlling 7q35) [8] which cause the production of a sporadic pancreatic tumours and may rep- the symptoms and complications of this mutant protein. Consequently, associated resent an early molecular event in pancre- disease. Pancreaticoduodenectomy, the enzymatic activity is not inactivated and is atic carcinogenesis; they may also be “Whipple procedure”, involves the resec- hypothesized to contribute to autodiges- present in some benign lesions [6]. tion of all of the duodenum with a short tion of the pancreas and pancreatitis; can- Alterations in tumour suppressor genes section of the jejenum, the pancreatic cer may then be a consequence of the such as p53, p16INK4, DCC and DPC4/ head, cholecystectomy and excision of prolonged inflammatory microenviron- SMAD4 have also been detailed, as has the common bile duct and a distal gas- ment in the pancreas. Other conditions overexpression of some growth factors trectomy followed by reconstruction.

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Hereditary condition Mode of inheritance Gene (chromosomal location) Lifetime risk of pancreatic cancer

Early onset familial pancreatic Autosomal dominant Unknown About 30%; 100-fold increased risk adenocarcinoma associated of pancreatic cancer; high risk with diabetes (Seattle family) of diabetes and pancreatitis Hereditary pancreatitis Autosomal dominant Cationic trypsinogen (7q35) 30%; 50-fold increased risk of pancreatic cancer

FAMMM: familial atypical multiple Autosomal dominant p16INK4A/CMM2 (9p21) 10% mole melanoma Familial breast cancer Autosomal dominant BRCA2 (13q12-q13) 5-10%; 6174delT in Ashkenazi Jews, 999del5 in Iceland Ataxia telangiectasia Autosomal recessive ATM, ATB, others (11q22-q23) Unknown; somewhat increased (heterozygote state) Peutz-Jeghers syndrome Autosomal dominant STK11/LKB1 (19p) Unknown; somewhat increased HNPCC: hereditary non-polyposis Autosomal dominant MSH2 (2p), MLH1 (3p), others Unknown; somewhat increased colorectal cancer Familial pancreatic cancer Possibly autosomal Unknown Unknown; 5-10 fold increased risk dominant if a first-degree relative has pancreatic cancer

Table 5.13 Hereditary conditions predisposing to the development of pancreatic cancer.

unresectable tumours may also be Survival is poor and the majority of pan- relieved by surgery. creatic cancer patients die within one In Western countries and Japan, different year of diagnosis, although five-year sur- classification systems for staging of pan- vival rates can reach >30% for lesions of creatic cancer have evolved, resulting in less than 2 cm, negative lymph nodes difficulties in assessing the efficacy of dif- and clear surgical margins. In American ferent therapies. Both to overcome the bar- males, for example, the overall five-year riers inherent in international classification survival rate is 3.7%, and for females, systems and to achieve a universal 4.4% (Fig. 5.126). prospective data acquisition, a uniform International Documentation System for Exocrine Pancreatic Cancer has been developed by an international group of pan- creatologists [13]. Palliative treatment is required for the treatment of jaundice, gastric outlet obstruction and pain. Adjuvant Fig. 5.126 Five-year relative survival rates after diagnosis of pancreatic cancer. Less than 5% of chemotherapy (5-fluorouracil and folinic patients survive more than five years. acid), but not adjuvant radiotherapy, appears to confer a slight survival bene- fit. Confirmatory trials with newer agents are ongoing. Despite substantial evi- However, morbidity remains high at 30- dence for hormone-dependence of pan- 40%, and complications are common. In creatic cancer, there are no data current- a total pancreatectomy, the entire pan- ly confirming a role for estrogens, andro- creas, as well as the duodenum, common gens, cholecystokinin or their antago- bile duct, gallbladder, spleen, and nearby nists in clinical treatment of exocrine lymph nodes are removed. Symptoms of pancreatic cancer [2].

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REFERENCES WEBSITES 1. Jorgensen J, Imrie CW (1998) Pancreatic cancer. In: 9. Lowenfels AB, Maisonneuve P (1999) Pancreatic can- NCI Pancreatic Cancer Homepage: Morris D, Kearsley J., Williams C. eds, Cancer: a compre- cer: development of a unifying etiologic concept. Ann N Y http://www.cancer.gov/cancer_information/cancer_type hensive clinical guide, Harwood Academic Publishers. Acad Sci, 880: 191-200. /pancreatic/ 2. Andren-Sandberg A, Hoem D, Backman PL (1999) 10. Sakorafas GH, Tsiotou AG, Tsiotos GG (2000) The Johns Hopkins Medical Institution, Pancreatic Cancer Other risk factors for pancreatic cancer: hormonal aspects. Molecular biology of pancreatic cancer; oncogenes, Homepage: Ann Oncol, 10 Suppl 4: 131-135. tumour suppressor genes, growth factors, and their recep- http://www.path.jhu.edu/pancreas/ 3. Gold EB, Goldin SB (1998) Epidemiology of and risk tors from a clinical perspective. Cancer Treat Rev, 26: 29- factors for pancreatic cancer. Surg Oncol Clin N Am, 7: 67- 52. 91. 11. Schutte M (1999) DPC4/SMAD4 gene alterations in 4. Barkin JS, Goldstein JA (1999) Diagnostic approach to human cancer, and their functional implications. Ann pancreatic cancer. Gastroenterol Clin North Am, 28: 709- Oncol, 10 Suppl 4: 56-59. 22, xi. 12. Klöppel G, Hruban RH, Longnecker MP, Adler G, Kern 5. DiMagno EP (1999) Pancreatic cancer: clinical presen- SE, Partanen TJ (2000) Ductal adenocarcinoma of the pan- tation, pitfalls and early clues. Ann Oncol, 10 Suppl 4: 140- creas. In: Hamilton SR, Aaltonen LA eds, World Health 142. Organization Classification of Tumours. Pathology and Genetics of Tumours of the Digestive System, Lyon, 6. Hilgers W, Kern SE (1999) Molecular genetic basis of IARCPress, 221-230. pancreatic adenocarcinoma. Genes Chromosomes Cancer, 26: 1-12. 13. Birk D, Beger HG, Fortnagel G, Hermanek P (1997) International documentation system for pancreatic cancer 7. Hruban RH, Petersen GM, Goggins M, Tersmette AC, (IDS). The future in pancreatic cancer evaluation. Offerhaus GJ, Falatko F, Yeo CJ, Kern SE (1999) Familial Digestion, 58: 578-579. pancreatic cancer. Ann Oncol, 10 Suppl 4: 69-73. 8. Whitcomb DC (1999) The spectrum of complications of hereditary pancreatitis. Is this a model for future gene ther- apy? Gastroenterol Clin North Am, 28: 525-541.

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MELANOMA

SUMMARY

> Approximately 133,000 new cases of malignant melanoma are diagnosed worldwide each year.

> The risk of developing this highly malig- nant skin tumour varies markedly according to racial background (skin pigmentation) and geography (sunlight- derived irradiation); highest incidence rates occur in white popula- tions in Australia.

> In Nordic countries, a steep increase in melanoma incidence has been attrib- uted to excessive exposure during vacations in Southern countries.

> Prognosis for patients with early-stage < 0.5 < 1.3 < 2.6 < 4.7 < 34.9 melanoma is very good, while metastat- Age-standardized incidence/100,000 population ic melanoma is largely resistant to cur- rent therapies. Fig. 5.127 The global burden of melanoma of the skin in women. Incidence rates are high in North America, Europe, Australia and New Zealand.

occurs in Australia where the population 5.3 for men, and 2.5 and 3.2 for women, is predominantly white, there is an aver- respectively [1]. age of six hours of bright sunlight every Definition day of the year and there is an essentially Etiology Melanoma is a malignant proliferation of outdoors lifestyle. The lifetime risk of It is estimated that 80% of melanoma is melanocytes, the pigment-forming cells of developing melanoma in Australia is 4-5% caused by ultraviolet damage [2] to sensi- the skin, which is the site of most (>95%) in men and 3-4% in women. tive skin, i.e. skin that burns easily, fair or disease. Dark-skinned people have a low risk of reddish skin, multiple freckles, skin that melanoma. In Africa and South America, does not tan and develops naevi in Epidemiology the sole of the foot, where the skin is not response to early sunlight exposure. There are about 133,000 new cases of pigmented, is the most frequent site Prevention of melanoma is based on limi- melanoma worldwide each year, of which affected in the context of a low incidence. tation of exposure to ultraviolet radiation, almost 80% are in North America, Europe, Asian peoples have a low risk of particularly in the first 20 years of life Australia and New Zealand. Incidence is melanoma despite their paler skins; naevi (Reduction of exposure to UV radiation, similar in men and in women. in Asian people, though common, are pre- p141). Malignant melanoma of the skin occurs dominantly of the acral-lentiginous type Ultraviolet radiation is particularly haz- predominantly in white-skinned popula- which have low malignant potential. ardous when it involves sporadic intense tions (“Caucasians”) living in countries Marked increases in incidence and mor- exposure and sunburn. Most damage where there is high intensity ultraviolet tality are being observed in both sexes in caused by sunlight occurs in childhood radiation but this malignancy afflicts to many countries (e.g. Fig. 5.128), even and adolescence, making this the most some degree all ethnic groups (Fig. 5.127). where rates were formerly low, such as important target group for prevention pro- Assessed in relation to skin colour, Japan. In the Nordic countries, for exam- grammes. Established but rare risk factors melanoma incidence falls dramatically as ple, this averages some 30% every five include congenital naevi, immunosuppres- skin pigmentation increases and the dis- years. Mortality rates are slightly higher in sion and excessive use of solaria. While ease is very rare in dark skinned people. men than in women, with Australia and melanoma may occur anywhere on the The highest incidence of melanoma New Zealand registering rates of 4.8 and skin, the majority of melanoma in men is

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pigmentation, an ill-defined margin and often exist in multiples. Of particular risk is the dysplastic naevus syndrome (famil- ial atypical mole syndrome) (Fig. 5.130), in which the patient may have more than 100 of these irregular naevi; risk is highest in those patients with dysplastic naevus syndrome who have a near relative diag- nosed with melanoma. The clinical features of melanoma are asymmetry (A), a coastline border (B), multiple colours and quite often some areas of blue/black pigmentation (C), and a diameter greater than six mm (D). As the melanoma progresses, part or all of the lesion will become elevated (E) (Figs. 5.131, 5.132). This ABCDE system has been the basis for clinical diagnosis for melanoma for many years. Surface microscopy [4] (dermoscopy, epi- luminescence microscopy) has developed Fig. 5.128 Trends in the incidence of malignant melanoma in New South Wales, Australia. New South Wales Central Cancer Registry, Australia as an aid to the clinical diagnosis of melanoma. In this technique, the skin sur- face is rendered translucent by the appli- on the back, while in women the majority dysplastic naevi, junctional and dermal cation of oil and a hand-held instrument is on the legs. This difference in site inci- naevi and blue naevi. However, the risk for providing magnification of at least ten dence is not completely explained by dif- melanoma development from mature der- times is used to view the internal details of ferential exposure to ultraviolet light. mal, junctional and blue naevi is quite the tumour. Many additional characteris- small, estimated at approximately 1 in tics, such as pseudopods, radial stream- Detection 200,000. Congenital naevi are also known ing, blue/grey veil, peripheral black dots Melanoma is usually asymptomatic but a precursors of melanoma but the risk for and multiple colours are visible and have person with melanoma sometimes com- malignant change is related specifically to been used in diagnostic systems now plains of an intermittent itch. Pain, bleed- the size of the naevus. Naevi greater than readily accessible to the clinician with an ing and ulceration are rare in early 20 mm in diameter and, in particular, the interest in cutaneous diagnosis (Fig. melanoma. A melanoma often arises from large bathing trunk naevi have a high risk 5.133). a pre-existing pigmented lesion of the skin of malignant degeneration. The highest (a mole or “naevus”) but these tumours risk naevus is the dysplastic (atypical) Pathology and genetics can also develop in unblemished skin. The naevus. These are naevi that are larger Melanocytes occur primarily in the skin common predisposing skin lesions are than six mm in diameter, have irregular (where more than 95% of cases of melanoma occurs) but are also found in the mucous membranes of the mouth, nose, anus and vagina and, to a lesser extent, the intestine; melanocytes are also present in the conjunctiva, the retina and the meninges. The morphological classifi- cation system for melanoma defines four types: superficial spreading melanoma, nodular melanoma, acral-lentiginous melanoma, and lentigo maligna melanoma. However, this classification has been Fig. 5.129 Intentional sun exposure by holiday- Fig. 5.130 Dysplastic naevus syndrome, predis- superseded by a system based on the makers on a beach in Nice, France. The majority of posing to non-familial malignant melanoma. The cases of melanoma is attributable to sporadic, patient shows atypical cutaneous naevi, usually histopathological parameters of the excessive exposure to ultraviolet radiation which exceeding 5mm in diameter, with variable pigmen- excised lesion. Melanoma is now classi- may clinically manifest as sunburn. tation and ill defined borders. fied essentially on the vertical diameter of

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nosis. Alterations in the cyclin-dependent kinase PITSLRE have been identified in advanced [8]. The recent dis- covery of a role for the BRAF gene in melanoma illustrates the impact of large scale international collaboration [9].

Management Treatment of primary melanoma is essen- tially surgical and is related specifically to Fig. 5.131 Primary melanoma with a coastline bor- Fig. 5.132 Melanoma with an elevated nodule. the tumour thickness measurement. The der and multiple colours, including classic blue primary tumour is excised with a margin of black pigmentation. normal skin, the excision being based on the tumour thickness measurement [10]. As the primary melanoma becomes thick- the lesion from the granular cell layer of Loss-of-function mutations in the human er (deeper), the risk for metastatic spread the epidermis to the deepest detectable melanocortin-1 receptor (MC1-R) have rises and thus survival outcomes are relat- melanoma cell (tumour thickness). In been associated with red hair, fair skin ed specifically to the tumour thickness recent years, one additional criterion, and decreased ability to tan [5], all physi- measurement (Fig. 5.134). ulceration, has been shown to be impor- cal characteristics which affect suscepti- Melanoma metastasizes via the lymphatic tant in prognosis and is included in the bility to . About 20% of system and also via the systemic circula- AJCC/UICC classification system (Table melanoma-prone families possess tion. Approximately 50% of melanomas 5.14). germline mutations in the CDKN2A gene, metastasize first to the lymph nodes, thus While it is clear that the genetic make-up which encodes p16INK4A [6]. Mutations in making the management of lymph node of the melanoma-prone population is very the gene encoding CDK4 have been iden- metastases an important part of the treat- important, few melanomas can be tified but are extremely rare [7]. ment. Elective lymph node dissection (i.e. ascribed to specific genetic defects in Genes identified as having a role in spo- prophylactic removal of lymph nodes) is these populations. While 10% of mela- radic melanoma development include now rarely practised in the management noma patients have a first degree relative CDKN2A and PTEN, while chromosomal of primary melanoma. The standard man- affected, less than 3% of melanomas in regions 1p, 6q, 7p and 11q may also be agement for lymph nodes in patients with Australia (where the incidence of involved [6]. About 20% of melanomas primary melanoma is an observation poli- melanoma is high) can be ascribed to an possess mutations in the p53 gene. cy and therapeutic node dissection if inherited gene defect [3]. Familial mela- Nodular melanomas display amplification lymph nodes become involved. However, noma is even more rare in lower incidence of the MYC oncogene. Inactivation of selective lymphadenectomy [11] is under countries. p16INK4A is associated with a poorer prog- clinical trial at the present time. This tech-

Classification Surgical excision margins Tis in situ melanoma/no invasion 5 mm of the dermis T1 ≤ 1 mm (in thickness) 10 mm T2 1.1 mm – 2.0 mm 10 mm T3 2.1 mm – 4.0 mm Minimum 10 mm, maximum 20 mm T4 > 4 mm Minimum 20 mm, maximum 30 mm Each T level is classified: There is no evidence that a margin A – if ulceration is present greater than 1 cm improves survival but B – if no ulceration is present it may decrease local recurrence.

Table 5.14 Classification of melanoma (American Joint Committee on Cancer/International Union Fig. 5.133 Surface microscopy of a melanoma, Against Cancer) and corresponding recommended excision margins. showing pseudopods, blue-grey veil and multiple colours.

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tracer (the sentinel node) is identified. proportion of people (<5%) live more than This lymph node is then removed for two years once systemic metastases histopathological examination; only pa- become evident [12]. The mainstay for the tients with positive lymph nodes are sub- treatment of systemic metastases is jected to full lymph node dissection. chemotherapy. However, no highly effective However, pending completion of an inter- single agent or combination has yet been national trial, the survival benefit of this developed and metastatic melanoma is technique is unknown. characterized by drug resistance [13]. Spontaneous regression of melanoma, as a Metastatic melanoma result of natural and induced immune rejec- The greater the number of nodes involved, tion, is seen in about 0.4% of cases and this the higher the risk of systemic metastases has lead to increasing interest in and poor prognosis. As the thickness of the immunotherapy [14] (Medical oncology, melanoma increases and as the number of p281). At the present time this modality Fig. 5.134 Ten-year relative survival for melano- lymph nodes involved rises, the risk of sys- remains experimental, although response ma, according to stage. temic metastases becomes greater. rates of 15-20% to cytokines, such as inter- Melanoma metastasizes widely, with the feron-α and interleukin-2, have been report- nique enables mapping of the lymphatics lungs, liver and brain being the most com- ed, and clinical trials of vaccines containing in the skin by lymphoscintigraphy: mon sites. Vitiligo (a skin condition charac- whole cells, lysates, dendritic cells or radioactive tracer is injected at the site of terized by failure to form melanin) is a melanoma-associated antigens, such as the primary and its flow through the skin favourable prognostic sign in metastatic MAGE, TRP and MART, are underway [15]. to the first lymph node that takes up the melanoma. At the present time, only a small

REFERENCES WEBSITE 1. Ferlay J, Bray F, Parkin DM, Pisani P (2001) Globocan 8. Halachmi S, Gilchrest BA (2001) Update on genetic The Melanoma Foundation, Australia: 2000: Cancer Incidence and Mortality Worldwide (IARC events in the pathogenesis of melanoma. Curr Opin Oncol, http://www.medicine.usyd.edu.au/melanoma/ Cancer Bases No. 5), Lyon, IARCPress. 13: 129-136. 2. IARC (1992) Solar and Ultraviolet Radiation (IARC 9. Davies H, Bignell GR, Cox C, Stephens P, Edkins S et Monographs on the Evaluation of Carcinogenic Risks to al. (2002) Mutations of the BRAF gene in human cancer. Humans, Vol. 55), Lyon, IARCPress. Nature, 417: 949-954. 3. Aitken JF, Duffy DL, Green A, Youl P, MacLennan R, 10. National Health and Medical Research Council, ed. Martin NG (1994) Heterogeneity of melanoma risk in fami- (1999) Clinical Practice Guidelines. The Management of lies of melanoma patients. Am J Epidemiol, 140: 961-973. Cutaneous Melanoma. 4. Steiner A, Pehamberger H, Wolff K (1987) In vivo epilu- 11. Morton DL (2001) Lymphatic mapping and sentinel minescence microscopy of pigmented skin lesions. II. lymphadenectomy for melanoma: past, present and future. Diagnosis of small pigmented skin lesions and early detec- Ann Surg Oncol, 8: 22S-28S. tion of malignant melanoma. J Am Acad Dermatol, 17: 584- 591. 12. Coates AS (1992) Systemic chemotherapy for malig- nant melanoma. World J Surg, 16: 277-281. 5. Schaffer JV, Bolognia JL (2001) The melanocortin-1 receptor: red hair and beyond. Arch Dermatol, 137: 1477- 13. Helmbach H, Rossmann E, Kern MA, Schadendorf D 1485. (2001) Drug-resistance in human melanoma. Int J Cancer, 93: 617-622. 6. Pollock PM, Trent JM (2000) The genetics of cutaneous melanoma. Clin Lab Med, 20: 667-690. 14. Weber JS, Aparicio A (2001) Novel immunologic approaches to the management of malignant melanoma. 7. Goldstein AM, Chidambaram A, Halpern A, Holly EA, Curr Opin Oncol, 13: 124-128. Guerry ID, Sagebiel R, Elder DE, Tucker MA (2002) Rarity of CDK4 germline mutations in familial melanoma. Melanoma 15. Hersey P (2002) Advances in the non-surgical treat- Res, 12: 51-55. ment of melanoma. Expert Opin Investig Drugs, 11: 75-85.

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THYROID CANCER

SUMMARY

> Cancer of the thyroid gland is relatively rare, but incidence is increasing in most developed countries. About 120,000 cases occur annually.

> Apart from ionizing radiation, environ- mental causes have not been well char- acterized. In Eastern Europe (Belarus, Ukraine, Russia), several hundred chil- dren developed thyroid cancer following the Chernobyl accident.

> Prognosis is usually good (around 90% five-year survival for some tumour types), even when lymph node metas- tases are present. < 2.1 < 2.9 < 3.4 < 4.4 < 23.2 Age-standardized incidence/100,000 population Fig. 5.135 Global differences in the incidence of thyroid cancer in women.

Definition Most thyroid cancers are well-differentiat- case per million per year in most devel- confirmed by the study of persons ed malignancies, which are predominantly oped countries; the age-specific incidence exposed as children to fall-out from the papillary (80-85%), and to a lesser extent, rates increase rapidly with age (Fig. Chernobyl accident in the most contami- follicular (10-15%) and Hürthle cell carci- 5.137). In the past three decades, inci- nated territories in Belarus, Ukraine and nomas (3-5%). Anaplastic carcinoma and dence rates have been increasing in most Russia, where a dramatic increase in thy- medullary carcinoma are rare. developed countries, while mortality rates roid cancer incidence attributable to have been slowly decreasing. In the year radioactive iodines has been observed. Epidemiology 2000, the annual mortality rate per Iodine deficiency is thought to be involved Carcinoma of the thyroid gland is an 100,000 people was 0.3 for men and 0.6 in the development of thyroid cancer uncommon cancer although it is the most for women [1]. Thyroid cancer causes because thyroid cancer incidence rates common malignancy of the endocrine sys- some 26,000 deaths every year. tem (Fig. 5.135). Generally, thyroid cancer accounts for approximately 1% of total Etiology cancer cases in developed countries. An association between thyroid cancer There are about 122,000 new cases per and exposure to ionizing radiation was year worldwide. already suggested in 1950 [2]. Many stud- Incidence of this disease is particularly ies have documented the increased risk of high in Iceland and Hawaii, where the rate papillary or follicular thyroid carcinoma in is nearly twice that in North European individuals exposed to X- and γ-rays [3]. countries, Canada and USA. In Hawaii, the The risk of radiation-induced cancer is incidence rate of thyroid cancer in all eth- considerably greater in those exposed as nic groups is higher than in the same eth- young children than as adults. Before the nic group living in their country of origin Chernobyl accident, epidemiological stud- Fig. 5.136 The Chernobyl fol- lowing the 1986 accident. A marked increase in and is particularly high among Chinese ies appeared to indicate that radioactive the incidence of thyroid cancer in children has males and Filipino females. Thyroid iodines were much less carcinogenic than been observed in areas exposed to radioactive tumours are rare in children, less than one external X- or γ- irradiation. This is not iodine.

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Pathology and genetics Thyroid follicular cells give rise to both well-differentiated cancers and also to poorly differentiated and undifferentiated (anaplastic) cancers. Well differentiated cancers are further classified into papillary and follicular carcinomas and other rare types. Stromal and immune cells of the thyroid are responsible for sarcoma and lymphoma, respectively. Approximately 90% of malignant thyroid nodules are well- differentiated cancers. Papillary and follicular cancers have the lowest degree of clinical malignancy. Papillary carcinoma has a propensity to invade lymphatic spaces and leads to microscopic multifocal lesions in the gland and a high incidence of regional lymph node metastases. Follicular carci- Fig. 5.137 Age-specific incidence of thyroid cancer in men and in women in the Ukraine, Iceland and noma is unifocal and thickly encapsulated. Germany. Incidence is higher in women and shows a marked peak. It has a propensity to invade veins and not lymphatics. Thyroid parafollicular cells (C cells) give are high in mountainous areas, such as are the strongest risk factors with a rela- rise to medullary carcinomas which usual- the Alps, Andes, and Himalayas, where tive risk of approximately 3 and 30, ly produce calcitonin. severe iodine deficiency was or still is respectively [9]. The role of hypothy- Insular (poorly differentiated) carcinomas common [4]. However, several high-risk roidism and hyperthyroidism is less clear. are considered to be of intermediate dif- populations live on islands (such as ferentiation and consequently to exhibit Hawaii and Iceland), where iodine intake Detection is generally high. The relationship Thyroid cancer commonly causes no obvi- between iodine intake and risk of thyroid ous symptoms in its early stages. The vast cancer appears to be complex, since both majority of cancers become clinically evi- deficiency and excess may inhibit the syn- dent as thyroid nodules. However, only a thesis of thyroid hormones and cause minority of all thyroid nodules is malig- goitre [5]. The two main types of thyroid nant. Many nodules are found in asympto- carcinoma (papillary and follicular) may be matic patients on physical examination of linked to iodine-rich and iodine-deficient the neck. Some cases have a history of diets, respectively [6]. Other dietary fac- rapid increase in size and/or pain in the tors, including cruciferous and goitrogenic region of the nodule. Hoarseness, dysp- vegetables [7], may play a role in thyroid noea and dysphagia reflect local invasion Fig. 5.138 Clinical examination of the thyroid carcinogenesis. of the recurrent laryngeal nerve, trachea gland of a child at risk following radioactive expo- Thyroid cancer occurs approximately and oesophagus, respectively. A small sure as a result of the Chernobyl accident. three times more frequently in women subset of patients presents with palpable than in men, reaching a maximum at cervical lymphadenopathy without an about age 45. Hormonal factors may play identifiable thyroid primary. High-resolu- a role in etiology. Results from epidemio- tion ultrasonography is useful for size logical studies, however, have been incon- assessment of nodules and for detection sistent: some have found an association of unpalpable nodules. Differences in between parity and risk of thyroid cancer echogenicity, vascularity or tests of thy- while others did not. The most current roid function cannot distinguish benign data suggest that menstrual and repro- from malignant nodules. The single most ductive factors are weakly related to thy- important diagnostic procedure is the fine roid cancer risk [8]. Apart from irradiation needle aspiration biopsy, performed under Fig. 5.139 Histopathological features of a papil- in childhood, goitre and benign nodules ultrasound guidance. lary thyroid carcinoma.

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cell, are found in more than 95% of indi- Gsp THYROID viduals with hereditary medullary thyroid EPITHELIAL CELL Toxic carcinoma (codons 609, 611, 618, 620, or adenoma 634). Mutation of codon 634 is the most commonly observed and is found in LOH 3q,18q about 80% of all patients with hereditary medullary thyroid carcinoma. A germline Follicular adenoma point mutation in the tyrosine kinase por- tion of the RET receptor (codon 918) has RET/PTC PAX8-PPARγ been identified in 95% of individuals with TRK LOH3p MEN2B [10]. BRAF RAS Follicular MET Management carcinoma Patients with malignant lesions diagnosed on the basis of fine needle aspiration, as RAS well as patients with a suspicious aspira- Growth factors which may contribute to tion, combined with other risk factors tumour development at multiple sites include: (such as prior radiation exposure or local PTEN Thyroid stimulating hormone (TSH) symptoms) should have surgical resec- p53 Insulin-like growth factor 1(IGF-1) tion. It has been recommended that total β β) Papillary RAS Transforming growth factor (TGF- thyroidectomy should be performed at p53 carcinoma around the age of six years in children who POORLY DIFFERENTIATED β-catenin AND UNDIFFERENTIATED are MEN2A gene carriers and shortly after CARCINOMA birth in children with the MEN2B mutation [11]. Benign nodules can be monitored by Fig. 5.140 Proposed genetic model of thyroid tumour formation. Genes in bold type have a well-estab- ultrasound examination. Acceptable surgi- lished role. cal procedures include lobectomy, subto- tal thyroidectomy, near-total thyroidecto- my and total thyroidectomy. Modified rad- an intermediate degree of clinical malig- mocytoma and hyperparathyroidism; ical neck dissection is indicated in case of nancy. Insular carcinoma invades both multiple endocrine neoplasia type 2B lymph node metastases. All patients who lymphatics and veins, and nodal and dis- (MEN2B) which is associated with medul - have undergone a total or near-total thy- tant metastases are common. lary thyroid carcinoma, pheochromocy- roidectomy for a papillary or follicular car- Approximately 33% of tumours displaying toma, mucosal neuromas, and marfanoid- oncocytic (Hürthle cell) features show his- like features; and familial medullary thy- tological evidence of malignancy (e.g. roid carcinoma. nuclear features typical of papillary carci- The genes implicated in the pathogenesis noma) or invasive growth. The remainder of thyroid carcinoma generally form a behave as and may be treated subset of important cell growth and dif- conservatively. ferentiation regulatory factors that can There is evidence of familial risk in a small be separated into membrane and nuclear percentage of papillary and follicular thy- factors. Two different mechanisms are roid carcinomas. The associations of involved in the genesis of papillary thy- Gardner syndrome (familial adenomatous roid and medullary thyroid carcinomas. polyposis) and Cowden disease (familial As a result of intrachromosomal goitre and skin ) with differ- rearrangements, the RET proto-oncogene entiated thyroid carcinoma provide well- becomes attached to the promoter of defined examples. About 25 to 35% of all one of three genes expressed constitu- medullary thyroid carcinomas are identi- tively in the follicular cell, which results fied as a component of one of the clinical in the so-called “papillary thyroid carci- syndromes. These syndromes include: noma oncogene” (RET/PTC1, 2, and 3). multiple endocrine neoplasia type 2A Germline point mutations of the RET (MEN2A) which is associated with proto-oncogene, which is normally Fig. 5.141 Five-year relative survival after diagno- medullary thyroid carcinoma, pheochro- expressed in the thyroid parafollicular sis of thyroid cancer.

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cinoma of greater than 1.5 cm should be overall survival. Independent predictors of to histological type, ranging from 98% for considered candidates for radioiodine prognosis include patient’s age, gender, papillary carcinoma and 92% for follicular ablation [12]. tumour size, histological grade and type, carcinoma, to 11% for anaplastic carcino- In contrast to other solid neoplasms, the local invasion, multicentricity and the ma [13]. Overall five-year survival rates presence of regional lymph node metas- presence of systemic metastatic disease. vary significantly geographically (Fig. tases with a well-differentiated thyroid Five-year relative survival rates for this 5.141). cancer has no strong correlation with type of malignancy vary greatly according

REFERENCES WEBSITES 1. Ferlay J, Bray F, Parkin DM, Pisani P, eds (2001) 9. Franceschi S, Preston-Martin S, Dal Maso L, Negri E, The British Thyroid Association: Globocan 2000: Cancer Incidence and Mortality Worldwide La Vecchia C, Mack WJ, McTiernan A, Kolonel L, Mark SD, http://www.british-thyroid-association.org/ (IARC Cancer Bases No. 5), Lyon, IARCPress. Mabuchi K, Jin F, Wingren G, Galanti R, Hallquist A, Glattre The European Thyroid Association: 2. Duffy BJ, Fitzgerald PJ (1950) Thyroid cancer in child- E, Lund E, Levi F, Linos D, Ron E (1999) A pooled analysis http://www.eurothyroid.com/ hood and adolescence. Report of twenty-eight cases. J Clin of case-control studies of thyroid cancer. IV. Benign thyroid Endocrinol Metab, 10: 1296-1308. diseases. Cancer Causes Control, 10: 583-595. 3. Shore RE (1992) Issues and epidemiological evidence 10. Hofstra RM, Landsvater RM, Ceccherini I, Stulp RP, regarding radiation-induced thyroid cancer. Radiat Res, Stelwagen T, Luo Y, Pasini B, Hoppener JW, van Amstel HK, 131: 98-111. Romeo G (1994) A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and 4. Franceschi S, Boyle P, Maisonneuve P, La Vecchia C, sporadic medullary thyroid carcinoma. Nature, 367: 375- Burt AD, Kerr DJ, MacFarlane GJ (1993) The epidemiology 376. of thyroid carcinoma. Crit Rev Oncog, 4: 25-52. 11. Gagel RF, Goepfert H, Callender DL (1996) Changing 5. Braverman LE (1990) Iodine induced thyroid disease. concepts in the pathogenesis and management of thyroid Acta Med Austriaca, 17 Suppl 1: 29-33. carcinoma. CA Cancer J Clin, 46: 261-283. 6. Williams ED, Doniach I, Bjarnason O, Michie W (1977) 12. Fraker DL, Skarulis M, Livolsi V (1997) Thyroid tumors. Thyroid cancer in an iodide rich area: a histopathological In: DeVita VTJ, Hellman S, Rosenberg SA eds, Cancer study. Cancer, 39: 215-222. Principles and Practice of Oncology, Philadelphia, 7. Franceschi S, Talamini R, Fassina A, Bidoli E (1990) Lippincott-Raven Publishers, 1629-1652. Diet and epithelial cancer of the thyroid gland. Tumori, 76: 13. Gilliland FD, Hunt WC, Morris DM, Key CR (1997) 331-338. Prognostic factors for thyroid carcinoma. A population- 8. Negri E, Dal Maso L, Ron E, La Vecchia C, Mark SD, based study of 15,698 cases from the Surveillance, Preston-Martin S, McTiernan A, Kolonel L, Yoshimoto Y, Jin Epidemiology and End Results (SEER) program 1973-1991. F, Wingren G, Rosaria GM, Hardell L, Glattre E, Lund E, Levi Cancer, 79: 564-573. F, Linos D, Braga C, Franceschi S (1999) A pooled analysis of case-control studies of thyroid cancer. II. Menstrual and reproductive factors. Cancer Causes Control, 10: 143-155.

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KIDNEY CANCER

SUMMARY

> Cancer of the kidney is the 15th most common cancer in the world and most prevalent in developed countries. Close to 190,000 cases are diagnosed each year worldwide and men are generally affected more frequently than women.

> Tobacco smoking is an established cause. Excess body weight (obesity) has also been identified as a risk factor, par- ticularly in women.

> Patients with late stage diagnosis face a poor prognosis. Recent advances in imaging allow the early detection of asymptomatic tumours. The five-year < 1.3 < 2.1 < 3.6 < 8.3 < 22.2 survival rate is approximately 50%. Age-standardized incidence/100,000 population Fig. 5.142 Global burden of in men, showing a generally higher incidence in more devel- oped countries.

Definition In adults, 85-90% of cases of kidney can- and among Scandinavian populations. and has now been extended to renal cell cer are renal cell carcinomas, a very het- Kidney cancer is relatively less common carcinomas, the risk increasing two-fold erogeneous group of tumours (mainly among Asian and African peoples, for heavy smokers [6]. An increased risk adenocarcinomas) which arise from cells although renal cell carcinoma appears to of renal cell carcinoma has been linked to of the proximal convoluted renal tubule. be increasing in black American men [4]. obesity, particularly in women, as has Transitional cell carcinoma is a less Men are affected by kidney cancer more diuretic therapy, again especially in common tumour type that arises from than women, the sex ratio being 1.6- women [7]. Leather tanners, shoe workers the transitional cell epithelium in the 2.0:1 [5]. Most cases occur between and dry cleaning employees have an renal pelvis, ureter and urethra. Wilms ages 50-70, but kidney cancer may be increased risk as reported in some stud- tumour (nephroblastoma) is an embryon- diagnosed over a broad age range ies, as do workers exposed to asbestos al malignancy that afflicts 1 in 10,000 including young adults [1]. Wilms tumour and trichloroethylene. The influence of children. is responsible for 5-15% of childhood beverages, in particular coffee and alco- cancers, affecting females slightly more hol, has not been clearly determined Epidemiology than males. This tumour occurs with despite many studies. Phenacetin is car- The incidence of kidney cancer is con- highest frequency in the black popula- cinogenic: patients with kidney damage siderably higher in developed countries tion of USA and Africa, and with lowest secondary to phenacetin-containing anal- than in less developed countries (Fig. in Eastern Asia [1]. Kidney cancer caus- gesic abuse have an increased risk of tran- 5.142) and appears to be increasing over es the deaths of more than 91,000 peo- sitional cell carcinoma (Medicinal drugs, the past decade [1,2]. More than ple each year. p48). Patients with multicystic kidney dis- 189,000 new cases are diagnosed world- ease consequent on long-term dialysis, wide each year. In Western Europe, for Etiology adult polycystic kidney disease and tuber- example, kidney cancer is the sixth most Kidney cancer has consistently been ous sclerosis also have an increased frequently occurring cancer, incidence found to be more common in cigarette propensity to develop renal cell carcinoma being particularly high in the Bas-Rhin smokers than in non-smokers. The associ- and von Hippel-Lindau disease, an autoso- region of France [3]. Incidence is also ation was first established as causative for mal dominant condition, is a predisposing exceptionally high in the Czech Republic transitional cell carcinoma of the bladder factor.

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The presence of a tumour may be initial- Cytogenetics have shown, for example, ly defined by intravenous urogram. Com- that the two main types of renal cell car- puted tomography (CT) is the imaging cinomas, clear cell (non-papillary) carci- procedure of choice for diagnosis and noma and papillary carcinoma, are genet- staging [1]; scanning of the abdomen ically distinct (Table 5.15), although there and pelvis confirms tumour extent, can often be difficulties in distinguishing lymph node status and contralateral kid- them histologically. Corresponding ney functionality. Selective renal arteri- changes in transitional cell carcinoma ography via percutaneous femoral artery have been less well-defined. The papillary catheterization may be used for diagno- form has a better prognosis than the non- Fig. 5.144 A patient receiving kidney haemodialy- sis and staging [1]. Less invasive than papillary [9]. Mitochondrial DNA changes sis: long-term dialysis predisposes to acquired arteriography is magnetic resonance have been observed in early-stage onco- cystic disease of the kidney which may increase imaging (MRI), which can also be used to cytic and chromophobe tumours [10], but the risk of subsequent cancer. assess thrombus of renal vein or vena are not yet used clinically. cava involvement (Fig. 5.145). Chest Von Hippel-Lindau disease is character- radiographs (commonly with CT) and ized by the development of multiple technetium-99m radiopharmaceutical tumours, including bilateral renal cell car- VC bone scans are employed to determine cinoma, pheochromocytomas, heman- whether lung or skeletal metastases are gioblastomas of the central nervous sys- present. tem, retinal angiomas and pancreatic [1,11]. Von Hippel-Lindau patients T Pathology and genetics have a >70% lifetime risk for renal cell Renal cell carcinoma (Figs. 5.146, 5.147) carcinoma and it is the cause of death in is commonly represented by adenomas, 15-50% of cases. Such patients thus Fig. 5.145 Magnetic resonance image of a renal although there is some controversy over require regular screening; currently some cell carcinoma (T), with a tumour thrombus in the the difference between renal cortical ade- 30-50% of patients with von Hippel- inferior vena cava (VC). noma and renal cell adenocarcinoma [1]. Lindau disease who are identified with In terms of renal cell carcinoma histology, renal cell carcinoma as a result of symp- grade I cells have a lipid-rich cytoplasm toms have metastases on presentation, Detection and a small peripheral nucleus. As grade and hence respond poorly to treatment. Kidney cancer commonly causes no advances from I to IV, the nuclear pleo- Most families with von Hippel-Lindau dis- obvious symptoms in its early stages. morphism increases and the lipid-rich ease (80%) have mutations in the VHL Subsequently, symptoms include haema- cytoplasm reduces. The tumour is initially gene, a probable tumour suppressor turia, loin pain and a palpable kidney capsulated (in 50-60% of diagnosed gene. Sporadic forms of renal cell carci- mass [8] and these usually indicate cases), tends to spread to lymph nodes noma, as well as familial forms, are asso- patients with advanced disease. As a (10% of cases diagnosed) or may metas- consequence of increasing use of renal tasize to the lungs, bone, brain and liver imaging techniques, increasing numbers (20-30% of cases). There is a tendency for of asymptomatic, incidental tumours are the tumour to spread within the renal vein being detected [5]. Diagnosis of renal and into the inferior vena cava, extending cell carcinoma may be preceded by in extreme cases into the right atrium [8]. paraneoplastic syndromes, the systemic Transitional cell carcinoma accounts for and humoral manifestations of the dis- 5-8% of kidney tumours [8] and is derived ease, which result from the overproduc- from the renal pelvis transitional cell tion of normal kidney proteins or hor- epithelium, which is identical to that of mones (e.g. renin, erythropoetin, the bladder and ureter; 50% of patients prostaglandins) or inappropriate expres- with renal transitional cell carcinoma also sion of non-kidney factors (e.g. parathy- develop the same tumour type of the roid hormone). Symptoms may include bladder. hypertension, fever, anaemia, erythrocy- Cytogenetics and molecular biology have tosis (elevated number of red blood allowed significant advances to be made cells), abnormal liver function and hyper- in the differentiation and staging of kid- calcaemia (abnormally high calcium lev- ney cancer tumours, which may be histo- Fig. 5.143 Mortality from kidney cancer in various- els) [2, 8]. logically complex and heterogeneous [9]. countries.

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Stage Clear cell carcinoma Papillary carcinoma Adenoma Loss of 3p Loss of Y chromosome Partial trisomy of 5q Trisomy of 7, 17 Loss of Y chromosome Gain of 3p Gain of 7, 12, 16, 17, 20 Carcinoma p53 mutations Loss of 6q, 9, 11, 14q, 17/17p, 21 Loss of 8, 9, 13, 14, 6q, 10q, 18q, 11, 17/17p Gain of 8, 20 Gain of 12, 20 Loss of MET function Loss of VHL function Metastatic tumours Excess of minichromosomes, comprising 7q31 containing the MET oncogene Fig. 5.146 Surgical specimen of a bisected kidney showing a large renal cell carcinoma. Much of the Table 5.15 Genetic alterations in renal cell carcinoma. kidney has been replaced by tumour tissue.

ciated with structural alterations of the Management short arm of chromosome 3 and with VHL Radical nephrectomy (removal of the gene mutations [1,11]. kidney, perinephric fat, adjacent lymph Wilms tumour of the kidney occurs in nodes and often the adrenal gland) is both sporadic and familial forms. It has a currently the main therapy for renal cell specific syndrome associated with abnor- carcinoma. This procedure has been malities including aniridia (absence of the shown to produce better survival rates iris), hemihypertrophy (overgrowth of one than simple nephrectomy (kidney half of the body or a body part), and cryp- removal only), since involvement of torchidism (failure of the testes to regional lymphatics and periaortic lymph descend into the scrotum). A number of nodes has been noted in almost 25% of Fig. 5.147 Clear cell carcinoma of the kidney loci involved in the development of Wilms patients [1]. Treatment for transitional showing a monomorphic proliferation of distinc- tumour have been characterized, key cell carcinoma is radical nephrou- tive tumour cells, with an abundant clear, lipid- amongst these being WT1, a tumour sup- reterectomy, although more conserva- containing cytoplasm, arranged in a trabecular pressor gene located on chromosome tive therapy may be appropriate for pattern. 11p [12]. smaller low-grade tumours. In patients possessing a single kidney, or in the case of bilateral simultaneous tumour, tissue [14]. Most chemotherapeutic and either partial nephrectomy or radical hormonal agents appear to show little nephrectomy with dialysis and possible efficacy, although there is some controver- later transplantation is indicated [1]. sy over the efficacy of vinblastine and 5- However, immunosuppression associat- fluorouracil as single agents or in combi- ed with transplantation raises the risk of nation therapy [13,8]. In contrast, in the potential tumour recurrence (Immuno- treatment of transitional cell carcinoma, suppression, p68). cisplatin combination therapy seems to Accurate staging depends on histologi- be effective. cal evaluation of the resected tumour. For the systemic treatment of metastat- Up to 30% of patients present with ic kidney cancer, interferon-α and inter- metastases at diagnosis or relapse fol- leukin-2 have been shown to elicit a lowing surgery. Metastatic kidney can- modest response rate of 10-15% [8], cer is extremely resistant to systemic allowing complete response in some therapy [13]. A potential reason for this patients and an increased survival bene- is the high level of expression of the fit in others. Although overall survival multi-drug resistance gene MDR1 which rates are poor (Fig. 5.148), the five-year encodes P-glycoprotein (Box: Resistance survival for patients with early stage Fig. 5.148 Five-year relative survival after diagno- to cancer chemotherapy, p285) in both tumours is greater than 80% [8]. The sis of kidney cancer. normal proximal tubules and in tumour indication of renal vein/inferior vena

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cava involvement reduces five-year sur- lar extension also indicates a much carries a very poor prognosis (5% five- vival rates to 25-50%, whilst regional reduced rate of 15-50%. The presence of year survival rate) [1]. lymph node involvement or extracapsu- distant metastases or stage IV cancer

REFERENCES WEBSITES 1. Richie JP, Kantoff PW, Shapiro CL (1997) Renal cell car- la cytogénétique à la cytogénomie oncologique. NCI Kidney Cancer Homepage: cinoma. In: Holland JF, Bast RC, Morton DL, Frei E, Kufe Medecine/Sciences, 16: 528-539. http://www.cancer.gov/cancer_information/cancer_type/ kidney/ DW, Weichselbaum RR eds, Cancer Medicine, Williams and 10. van den Berg, Dijkhuizen T (1999) Classification of Wilkins. renal cell cancer based on (cyto)genetic analysis. Contrib The Kidney Cancer Association (USA): 2. Godley PA, Ataga KI (2000) Renal cell carcinoma. Curr Nephrol, 128: 51-61. http://www.nkca.org/ Opin Oncol, 12: 260-264. 11. Couch V, Lindor NM, Karnes PS, Michels VV (2000) 3. Ferlay J, Bray F, Parkin DM, Pisani P, eds (2001) von Hippel-Lindau disease. Mayo Clin Proc, 75: 265-272. Globocan 2000: Cancer Incidence and Mortality Worldwide 12. Hata J (1999) Wilms tumor and the WT1 gene. Contrib (IARC Cancer Bases No. 5), Lyon, IARCPress. Nephrol, 128: 62-74. 4. McLaughlin JK, Blot WJ, Devesa SS, Fraumeni FJ (1996) 13. Motzer RJ, Russo P (2000) Systemic therapy for renal Renal cancer. In: Schottenfeld D, Fraumeni, JFJ eds, Cancer cell carcinoma. J Urol, 163: 408-417. Epidemiology and Prevention, New York, Oxford University Press, 1142-1155. 14. Vogelzang NJ, Stadler WM (1998) Kidney cancer. Lancet, 352: 1691-1696. 5. Chow WH, Devesa SS, Warren JL, Fraumeni JF, Jr. (1999) Rising incidence of renal cell cancer in the United States. JAMA, 281: 1628-1631. 6. Doll R (1996) Cancers weakly related to smoking. Br Med Bull, 52: 35-49. 7. Schmieder RE, Delles C, Messerli FH (2000) Diuretic therapy and the risk for renal cell carcinoma. J Nephrol, 13: 343-346. 8. Watkin N, Christmas TJ (1998) Renal Tumours. In: Morris D, Kearsley J, Williams C eds, Cancer: a compre- hensive clinical guide, Harwood Academic Publishers. 9. Bernheim A, Vagner-Capodano A, Couturier J, et le Groupe Francais de Cytogenetique Oncologique (2000) De

264 Human cancers by organ site WCR-S5.Q (suite 39a49) 27/01/03 10:56 Page 265

TUMOURS OF THE NERVOUS SYSTEM

SUMMARY

> Tumours of the nervous system account for less than 2% of all malignancies (about 175,000 cases per year world- wide); the incidence does not vary markedly between regions or popula- tions.

> Etiology is largely unknown; the only unequivocal cause is therapeutic irradia- tion, but occurrence in these circum- stances is very rare.

>The nervous system is frequently involved in inherited tumour syndromes, including neurofibromatosis (NF1/NF2 germline mutations), von Hippel-Lindau disease (VHL), tuberous sclerosis (TSC1/TSC2) and Li-Fraumeni syndrome < 6.6 < 7.8 < 9.1 < 10.2 < 11.6 (p53). Age-standardized incidence/100,000 population Fig 5.149 Incidence of cancers of the brain and nervous system in men, in Europe. > are the most common brain tumours and mainly affect adults. These tumours are surgically incurable Epidemiology Generally, incidence rates are higher for and largely resistant to radiation and The age distribution of brain tumours is men; in particular, malignant brain tumours chemotherapy; only 3% of patients sur- vive more than 3 years. bimodal, with a peak incidence in children occur more frequently in males while the and a second larger peak in adults aged benign occur predominantly >Embryonal tumours, including cerebellar 45-70 [1]. In most developed countries, in females. During the past decade, the medulloblastomas, and brain tumours are the 12th most frequent incidence of glioblastomas in the elderly peripheral , predominant- cause of cancer-related mortality in men has increased by 1-2% per year but to some ly afflict children, ranking second after [2]. Geographical variation in incidence is extent this may be due to the introduction leukaemia as the most common types of less than for most other human neo- of high-resolution neuroimaging. The brain paediatric cancer. plasms [2] (Fig. 5.149). However, inci- is also a frequent site of metastases, with dence tends to be higher in more devel- carcinomas of the breast and lung as most oped countries. In most North American frequent primary tumours. and European countries, incidence rates for malignant tumours of the nervous sys- Etiology tem are 6-8 new cases per 100,000 pop- With the exception of brain tumours associ- Definition ulation per year. Highest rates are ated with inherited cancer syndromes and The majority of tumours of the central observed in Sweden, Greece, Iceland and the very rare cases caused by therapeutic nervous system (CNS) are derived from Croatia. In multiracial communities, both irradiation, no causative environmental or glial cells (gliomas), the most malignant adults and children of African or Asian lifestyle factors have been unequivocally and frequent being . Malig- descent tend to be less frequently affect- identified. Radiation-induced meningiomas nant embryonal tumours typically mani- ed than whites. It has been reported that may follow low-dose irradiation for tinea fest in children and occur in the central white Americans have a 3.5 times greater capitis (a fungal infection of the scalp) and nervous system (medulloblastomas) and risk of glioblastoma and germ cell high-dose irradiation for primary brain the sympathetic nervous system and adre- tumours than African Americans [1]. tumours [3]. Children who received prophy- nal gland (). Tumours orig- However, the lower incidence recorded lactic CNS irradiation for acute lymphoblas- inating from the brain coverings (menin- for Singapore and Japan may be due to tic leukaemia seem to have an increased risk giomas) are usually benign. inadequate registration. of developing malignant gliomas.

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Tumour Typical location Age at clinical manifestation Five-year survival Genetic alterations (WHO Grade) (% of cases) (% of patients) 0-20 yrs 20-45 yrs >45 yrs Pilocytic astrocytoma Cerebellum, optic nerve 74 20 6 >85 NF1 (neurofibro- (Grade I) matosis cases) Low grade diffuse Cerebral hemispheres 10 61 29 >50 p53 mutation astrocytoma (Grade II) Glioblastoma Cerebral hemispheres 3 25 72 <3 EGFR amplification, PTEN (Grade IV) mutation, p16 deletion, LOH chromosome10 Oliogodendroglioma Cerebral hemispheres 8 46 46 >50 LOH 1p, 19q (Grade II/III) Ependymoma Ventricles, spinal cord 37 38 25 <30 NF1 (Grade II) (spinal tumours) Medulloblastoma Cerebellum 74 23 3 >50 Isochromosome 17, (Grade IV) mutations of p53, PTCH, ß-catenin Neuroblastoma Abdomen >95 >90 (<1 yr old) LOH 1p, 11q, MYCN (Grade IV) 20-50 (>1 yr) amplification, trisomy 17q

Table 5.16 Summary of epidemiological data on intracranial tumours.

Some studies have suggested an malignant gliomas remain to be substanti- as computed tomography (CT) and magnet- increased incidence of CNS neoplasms ated. Similarly, the role of diet in brain ic resonance imaging (MRI). associated with certain occupations, tumour etiology, and specifically in- including farming, fire-fighting, metal- volvement of N-nitroso compounds (which Pathology and genetics working and the rubber and petrochemi- are potent neuro-carcinogens in rod- The WHO classification of tumours of cal industries, and with those who work as ents) formed in nitrite-preserved food, is the nervous system contains more than anatomists, pathologists and embalmers, unclear. 50 clinico-pathological entities with a but most of these reports have not been The nervous system is frequently affected great variation in biological behaviour, confirmed and causative agents have not in inherited tumour syndromes, often in response to therapy and clinical out- been identified. Suggestions that radio- association with extraneural tumours and come [4]. The most frequent ones are frequency radiation generated by mobile skin lesions (Table 5.17). listed in Table 5.16. Of all intracranial phones and microwave telecommunica- tumours, approximately 60% are of neu- tions may play a role in the etiology of Detection roepithelial origin (gliomas), 28% are Signs and symptoms largely depend on the derived from the brain coverings location of the neoplasm and include paresis (meningiomas) and 7.5% are located in (slight/incomplete paralysis), speech distur- cranial and spinal nerves. Lymphomas bances and personality changes. Patients and germ cell tumours account for 4% with oligodendroglioma often have a long and 1% respectively. history of epileptic seizures. Eventually, malignant brain tumours cause life-threaten- Astrocytic tumours ing intracranial pressure that may result in Tumours of astrocytic origin constitute visual disturbance and ultimately lead to the largest proportion of gliomas. They unconsciousness and respiratory arrest. vary greatly in morphology, genetic pro- Since the brain does not contain pain recep- file and clinical behaviour. tors, headache is only present if the tumour Pilocytic astrocytoma (WHO Grade I) is Fig 5.150 A large glioblastoma multiforme in the infiltrates the meninges. The presence of the most frequent CNS neoplasm in chil- left frontal lobe, extending into the corpus callo- symptoms usually leads to a detailed neuro- dren, and is predominantly located in the sum and the contralateral white matter. logical examination, using techniques such cerebellum and midline structures, includ-

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ing the optic tract, brain stem and spinal cord. It infiltrates adjacent brain struc- tures but grows slowly and usually has a favourable prognosis with five-year sur- vival rates of more than 85% (WHO Grade I). Some pilocytic astrocytomas occur in the setting of neurofibromatosis type 1 (NF1), particularly those of the optic nerve (optic glioma). Other astrocytomas usually develop in the cerebral hemispheres of adults and diffusely infiltrate adjacent brain structures. Low grade diffuse astrocytomas (WHO grade II) occur in young adults and grow slowly. However, they diffusely infiltrate the brain and cannot, therefore, be com- pletely surgically resected. Morphologically, tumour cells resemble differentiated astrocytes. Mutations in p53 are found in two-thirds of cases and Fig. 5.151 An MRI scan of a primary glioblastoma in a 79 year-old patient. A small cortical lesion rapid- are considered an early event. The five- ly developed into a full-blown glioblastoma with perifocal oedema and central necrosis. year survival rate is more than 60%. Anaplastic astrocytomas (WHO grade III) often develop from low-grade astrocy- precursors and are typically found in the nosis. Genetic hallmarks of oligoden- tomas, grow relatively fast and typically cerebral hemispheres of adults, often drogliomas are LOH on chromosomes 1p progress to glioblastoma within two to including the basal ganglia. Histologically, and 19q. Oligodendrogliomas that carry three years, accompanied by genetic alter- they are isomorphic, with a typical honey- these genetic alterations show a remark- ations, including loss of heterozygosity comb pattern and delicate tumour ves- able sensitivity to chemotherapy. (LOH) on chromosome 19. sels (“chicken wire” pattern). Anaplastic oligodendrogliomas (WHO Grade III) show Ependymomas Glioblastomas (WHO grade IV) features of anaplasia and high mitotic These gliomas develop from the ependy- This is the most frequent and most malig- activity and carry a less favourable prog- mal lining of the cerebral ventricles and nant nervous system tumour. Secondary glioblastomas develop by malignant pro- gression from low-grade and anaplastic astrocytoma and are characterized by p53 Differentiated astrocytes or precursor cells mutations and LOH on chromosome 10q. Primary glioblastomas are more frequent mutation (>65%) (>80% of cases) and develop rapidly in the α amplification (~40%) elderly (mean age, 55 years), with a short overexpression (~60%) overexpression (~60%) clinical history of less than three months. Low grade astrocytoma Their genetic profile includes amplification amplification (<10%) and overexpression of the EGF receptor overexpression (~50%) INK4A (~50%) gene, PTEN mutations, p16 deletions alteration ( 25%) and loss of chromosome 10. Both glioblas- ~ deletion (30-40%) toma types diffusely infiltrate the brain, Anaplastic astrocytoma including the opposite hemisphere and mutation (~30%) show high cellularity and large areas of alteration necrosis despite excessive vascular prolif- mutation (5%) loss of expression (~50%) eration. α amplification (<10%) Secondary glioblastoma Primary glioblastoma Oligodendrogliomas de novo These neoplasms develop from myelin- producing oligodendroglial cells or their Fig 5.152 Genetic pathways in the evolution of primary and secondary glioblastoma.

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Syndrome Gene Chromo- Nervous system Skin Other tissues some Neurofibromatosis 1 NF1 17q11 Neurofibromas, MPNST, optic Café-au-lait spots, Iris hamartomas, osseous lesions, nerve gliomas, astrocytomas axillary freckling phaeochromocytoma, leukaemia Neurofibromatosis 2 NF2 22q12 Bilateral vestibular schwannomas, - Posterior lens opacities, retinal peripheral schwannomas, meningiomas, meningioangio- matosis, spinal ependymomas, astrocytomas, micro-hamartomas, cerebral calcifications von Hippel-Lindau VHL 3p25 Haemangioblastomas - Retinal haemangioblastomas renal cell carcinoma,

Tuberous sclerosis TSC1 9q34 Subependymal giant cell Cutaneous Cardiac , TSC2 16p13 astrocytoma, cortical angiofibroma adenomatous polyps of the tubers (“adenoma duodenum and the small intestine, sebaceum”) cysts of the lung and kidney, peau de chagrin, lymphangioleiomyomatosis, renal, subungual Li-Fraumeni p53 17p13 Astrocytomas, glioblastomas, - Breast carcinoma, bone and soft medulloblastomas tissue , adrenocortical carcinoma, leukaemia Cowden PTEN 10q23 Dysplastic gangliocytoma of the Multiple Hamartomatous polyps of the (MMAC1) cerebellum (Lhermitte-Duclos), trichilemmomas, colon, thyroid neoplasms, breast megalencephaly fibromas carcinoma Turcot APC 5q21 Medulloblastoma - Colorectal cancer hMLH1 3p21 Glioblastoma Café-au-lait spots Colorectal cancer hPSM2 7p22 Naevoid basal cell PTCH 9q31 Medulloblastoma Multiple basal Jaw cysts, ovarian fibromas, carcinoma palmar and skeletal abnormalities syndrome (Gorlin) plantar pits

Table 5.17 Major familial tumour syndromes involving the nervous system.

the central canal of the spinal cord. They cytoma). They often cause a long-term tions). Neuroblastomas originate from manifest preferentially in children and history of epileptic seizures. migrating neuroectodermal cells targeted young adults and usually have an intraven- for the adrenal medulla and sympathetic tricular or spinal location. Histologically, Embryonal tumours nervous system, which are the principal they are cellular, with typical perivascular These neoplasms are derived from embry- rosettes. Spinal ependymomas show a onal or fetal precursor cells, typically man- high frequency of mutations in the neu- ifest in children, and are highly malignant rofibromatosis gene NF2. but often respond to radio- or chemother- apy. In the central nervous system, cere- Glioneuronal tumours bellar medulloblastomas are most com- This group of brain tumours is less fre- mon. The peak age at manifestation is 3-6 quent and generally carries a favourable years; only 20% develop in adults. prognosis. Some manifest preferentially Occasionally, they occur in the setting of in children (desmoplastic infantile astro- inherited cancer syndromes, including cytoma/ganglioglioma, dysembryoplas- Turcot syndrome (in association with tic neuroepithelial tumour), others pref- familial polyposis colon cancer) and erentially in adolescents and adults (gan- naevoid basal cell carcinoma syndrome Fig 5.153 Macroscopic image of a medulloblastoma gliocytoma, ganglioglioma, central neuro- (associated with PTCH germline muta- of the cerebellar vermis, compressing the brainstem.

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nerve sheath tumours represent typical manifestations of the neurofibromatosis type 1 syndrome.

Meningiomas These slowly growing, usually benign, neo- 36 yr 47 yr 29 yr plasms develop from arachnoidal cells in Low-grade Low-grade Anaplastic the meninges. They preferentially affect astrocytoma, astrocytoma astrocytoma women, particularly those located in the 37 yr glioblastoma mut/- in tumour mut/- in tumour spine. Meningiomas do not infiltrate the mut/wt in blood wt/wt in blood 29 yr brain but may cause symptoms of intracranial pressure due to compression of adjacent brain structures (WHO Grade I). Preferential sites are the cerebral hemi- mut/wt in blood 8 months wt/wt in blood spheres. Meningiomas can often be cured mut = mutant p53 Choroid plexus 3 months by surgical resection. Malignant menin- wt = wildtype p53 carcinoma _ = deletion of p53 giomas are much less frequent; they may mut/- in tumour infiltrate the brain and often recur locally. Blue shading = carrier of CGG>TGG mutation in the p53 gene (resulting in a change of amino acid from arginine to tryptophan). Outlook Fig. 5.154 Pedigree of a family with by Li-Fraumeni syndrome, caused by a germline mutation in codon 248 of the p53 tumour suppressor gene. Blood samples of affected family members have a mutation in one allele. Although not very frequent, brain tumours In tumours, the second allele is usually deleted. This family shows a remarkable clustering of brain tumours. contribute significantly to morbidity, often affect children and overall have a poor prognosis. Due to marked resistance to tumour sites. They manifest as an abdom- Tumours of peripheral nerves radiation and chemotherapy, the progno- inal mass almost exclusively in children Most of these tumours develop from sis for patients with glioblastomas is very less than 10 years old, with a peak inci- myelin-producing Schwann cells and are poor. The majority of patients die within 9- dence of 1-4 years. Tumours in very young termed neurinomas or schwannomas. 12 months and less than 3% survive more children and tumours outside the adrenal Bilateral acoustic schwannomas are diag- than 3 years. Many genetic alterations medulla have a better prognosis, and nostic of the inherited neurofibromatosis involved in the development of nervous some lesions regress spontaneously. type 2. They are benign (WHO Grade I) and tissue tumours have been identified and Amplification of the N-MYC gene indicates rarely recur after surgical resection. may lead to novel therapeutic approaches, a poor prognosis. Neurofibromas and malignant peripheral including gene therapy.

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