EARLY DIAGNOSIS AND REFERRAL OF IS CRITICAL LYMPHOMA IS A SIGNIFICANT HEALTH ISSUE IN NEW ZEALAND WHERE IT IS ONE OF THE MOST RAPIDLY INCREASING CANCERS, WITH ONE OF THE HIGHEST INCIDENCE RATES IN THE WORLD.

Kenneth The number of cases of lymphoma has doubled neoplasms is characterised by proliferation of Bradstock in the last 20 years1 and there is no satisfactory malignantly transformed T- or B-lymphocytes. BSCMED, MB BS, PHD, explanation as to why. FRACP, FRCPA Lymphoma is one of the more common Senior Staff Specialist, Ranked the sixth most common cancer in malignancies in New Zealand and is among the Haematology New Zealand, lymphoma is the most commonly most diverse, due to its origin from varying cell and Head of Bone occurring blood cancer and over 800 cases of types at different stages of maturation and the Marrow Transplant the disease will be diagnosed this year. molecular process of malignant transformation. Service, Westmead Hospital, Sydney While lymphoma is potentially fatal, some The manner of their presentation, the clinical Clinical Associate forms are curable and a patient’s survival may course of the diseases and their response Professor of Medicine, be enhanced by early diagnosis. Comprehensive to therapy varies widely and presents GPs University of Sydney, and accurate diagnosis is essential for optimal with diffi culties in establishing the diagnosis NSW, Australia management of the diverse forms of lymphoma. from symptoms that may mimic many benign disorders. Peter Browett Diagnosing lymphoma is often diffi cult due BMedSci, MBChB, to a range of non-specifi c symptoms, many of FRACP, FRCPA TYPES OF LYMPHOMA which also occur after a variety of infections and Consultant other illnesses. There are two major categories of lymphoma: Haematologist, non- (NHL) is the most Auckland City Hospital The aim of this article is to fi rmly position common form and accounts for 89% of lymphoid Professor of lymphoma on the radar of every general tumours and Hodgkin lymphoma (HL) accounts Pathology and Head practitioner in New Zealand by: 2 of Department, for 11% of cases . • providing an update on the signs and Department of Based on biological, pathological and Molecular Medicine symptoms of lymphoma and advice on clinical criteria, there are more than 30 specifi c and Pathology, investigations to assist in the early diagnosis subtypes (different syndromes) of NHL. These University of Auckland of these diseases classifi cations have evolved over the last 2–3 Medical Director, • advising early referral to a haematologist Leukaemia & Blood decades and refl ect an increasing understanding Foundation or medical oncologist with expertise in of the molecular basis of lymphomagenesis and lymphoma, or to a general physician for clinically important distinctions between the rural patients, and subtypes. • helping GPs to support their patients through The subtypes are derived from B- or T-cells. complex, intensive courses of treatment and Most cases of NHL are derived from malignant their progress over the long term. transformation of B-lymphocytes in lymph This more detailed article expands on the nodes. B-cell represent more early diagnostic process for lymphoma that than 90% of NHL, with follicular and diffuse is outlined in the accompanying diagnostic large B-cell lymphomas the most frequent support tool Is Lymphoma On Your Radar? forms, compromising around 20% and 50% (respectively) of total cases of NHL. T-cell ABOUT LYMPHOMA lymphomas account for less than 10% of NHL2. Lymphoma is a generic term that refers to a The clinical behaviour of NHL is diverse complex group of many related but biologically and ranges from highly malignant and rapidly discrete diseases, each with its own separate growing tumours in people of all ages, to molecular pathogenetic features, anatomical relatively benign and even non-progressive sites, and differing response to treatment. lymph node enlargement in elderly people. This heterogeneous group of haematological Therefore simpler groupings are based on

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clinical behaviour and tend to be There is an untreated survival time of children under the age of 14 years2. considered in two groups: indolent months, or weeks in the case of highly Lymphoma accounts for 4% of or low grade, and aggressive or high aggressive forms (a small minority of newly diagnosed cancers. grade. cases). Although these forms are highly progressive, in contrast to indolent Lymphoma is the fi fth most Indolent lymphomas, including 2 diseases, these lymphomas, in many common cause of cancer death with and marginal- cases, are curable with conventional both the incidence and mortality rates zone lymphoma, are characteristically drug therapy. increasing with age, peaking in the diseases of older people (mainly men seventh decade. The lifetime risk of over the age of 50 years), with a median While patients with indolent NHL is 1 in 64 for men and 1 in 88 untreated survival time measured in lymphomas may live for years even for women. years. The usual presenting feature is with only a partial response to therapy, lymphadenopathy, most commonly in in the aggressive lymphomas, only Over the last several decades the the neck. Most patients are otherwise patients with a complete response to incidence of NHL has been increasing asymptomatic, but a few report weight therapy are likely to have a favourable in New Zealand, in both men and women. The reasons for this increase loss, sweats and . Enlarged outlook. lymph nodes are usually fi rm, mobile are not known. Hodgkin lymphoma is a biologically and non-tender, and may fl uctuate in Hodgkin lymphoma is uncommon and histologically distinct disease, size, with spontaneous regression well and can occur in patients of any age distinguished by the presence of documented. Rapid growth of nodes but generally affects younger people Hodgkin or Reed Sternberg cells. is unusual. The response to therapy is compared to NHL. The incidence of generally good, but relapse is common. These tumour cells are present in HL peaks between the ages of 15 – This group of diseases is considered the abnormal lymph nodes in only 34 years, and again after the seventh incurable with conventional therapy. small numbers, against a background decade. The lifetime risk of HL is 1 in of reactive cells. There are four sub- 559 for men and 1 in 766 for women types based on the lymph node and the incidence has remained pathology, including the common relatively stable over time. subtypes of nodular sclerosing and mixed-cellularity HL, and a rarer variety, lymphocyte predominant HL. Males Rates by age group The clinical presentations of 150 these types vary. Nodular sclerosing disease classically presents as early- 125 stage disease in younger people, with

a preponderance in females, and 100 generally has an excellent response

to therapy. Mixed cellularity and 75

lymphocyte-predominant forms may per 100,000 present later in life, with a tendency to 50 Diffuse large B-cell Mantle cell present with advanced or extranodal

Follicular Burkitt disease. 25

T-cell Other high grade The distinctions between the lymphoma subtypes help determine 0 Small lymphocytic Other low grade 1956 1966 1976 1986 1996 2006 2016 the most appropriate therapy and Figure 1: Common types of non- can predict the clinical behaviour of Figure 2: Incidence and projected Hodgkin lymphoma and their relative a given tumour and the response to incidence of non-Hodgkin lymphoma, frequency. (Source: World Health by age group, in the New Zealand male therapy. Organisation.) population, 1956-20163 HL is the most curable of all the The aggressive lymphomas include lymphomas with the overall chance of RISK FACTORS diffuse large B-cell lymphoma and cure being 60% to 80%. Burkitt’s lymphoma/leukaemia. These The causes of most cases of lymphoma are unknown and no predisposing risk may present at any age but occur more EPIDEMIOLOGY frequently in the elderly. Staging exposure can be identifi ed. investigations show that only a small In 2007, lymphoma was the fi fth most Efforts to identify constitutional or minority of cases are truly localised, common cancer in males, the fi fth environmental risk factors have been with spread of disease to adjacent or most common cancer in females, and limited by the diversity of types of distant sites evident in 90% of cases. the third most common cancer in lymphoma.

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Certain subtypes of lymphoma 20 times higher than the general Lymphomas have been reported in have been associated with infection. population, and similar increases most sites of the body (including the NHL of mucosal-associated lymphoid are evident in patients on chronic central nervous system, gonads, skin, tissues (MALTomas) is strongly immunosuppressive regimens breast and bone), as well as primary associated with following solid organ transplantation. intravascular and effusion lymphomas, but most lymphomas arise within the infection and some rare T-cell Autoimmune diseases, including lymphatic glands. lymphomas are caused by human coeliac disease, SLE, rheumatoid T-cell lymphotrophic virus. arthritis and Sjögren syndrome, Patients may have palpable lymphadenopathy plus or minus have also been associated with the Females splenomegaly, or a constitutional illness development of lymphoma. Rates by age group characterised by weight loss, and 150 There is also an increased risk of malaise. Extranodal lymphoma, which lymphoma in families with a history of may involve a specifi c organ or organs, 125 lymphoma or leukaemia among fi rst- is less common. degree relatives. For people at risk of 100 DIAGNOSING LYMPHOMA immunodeficiency-associated lymphoma, surveillance is 75 On average, a GP may encounter seven recommended. to eight lymphoma patients during per 100,000 * Predominant presentations can 50 their career . include: Diagnosing lymphoma can be 25 diffi cult. The symptoms of lymphoma • Enlarged, usually painless lymph are often very non-specifi c and can be nodes anywhere in the body 0 similar to the common symptoms of (commonly in the neck, axilla or 1956 1966 1976 1986 1996 2006 2016 less serious or minor conditions, such groin) Figure 3: Incidence and projected as having the fl u or being rundown or • Unexplained fever incidence of non-Hodgkin lymphoma, stressed. • Night sweats by age group, in the New Zealand An aim of the Leukaemia & Blood female population, 1956-2016 3 • Unintentional weight loss/anorexia. Foundation (LBF), as a primary Less common but possible Epstein Barr virus infection, in provider of information and support to presentations may include: conjunction with immune defi ciency, lymphoma patients and their families, is associated with increased risk is to raise the profi le of lymphoma and Persistent fatigue/lack of energy; of lymphoma, and infectious clearly position this increasing health fl u-like illness; generalised itching; mononucleosis is a moderate risk problem on the radar for GPs and abdominal pain; recurrent infections; factor for HL, increasing risk two- to health agencies. The result being that anaemia and other low blood counts; three-fold. when a patient describes or presents bone pain; shortness of breath/ protracted cough; and neurologic a range of potential lymphoma signs Other infectious organisms, symptoms. occupational exposure to pesticides and and symptoms, GPs ‘think lymphoma’ Most often, these symptoms herbicides, and certain other chemicals, and conduct the correct initial investigations to either eliminate will be due to other conditions, not medical procedures, medical history, lymphoma or provide early detection. lymphoma. and lifestyle factors including smoking represent a moderate to weak risk in Educating GPs to assist in the early INITIAL INVESTIGATIONS diagnosis of lymphoma is the aim of the development of certain types of Full medical history (include fever, lymphoma. World Lymphoma Awareness Day (15 September). sweats, weight loss, malaise) An abnormal immune system *Based on current diagnostic rates, the Physical examination (particularly of increases the chances of developing number of GPs in New Zealand and an lymph nodes and spleen) lymphoma. People with acquired average career length of 30 years. Full blood count, creatinine, or congenital immunodefi ciencies electrolytes, LFTs, viral serological and immune dysregulation states OF studies (if clinically indicated) LYMPHOMA have an increased risk of developing Chest x-ray (to image the mediastinum) lymphoproliferative disorders, There are no screening tests for the CT scan (of chest, abdomen, pelvis, as including lymphoma. early diagnosis of lymphoma and clinically indicated) the spectrum of presentation for Having HIV/AIDS incurs a The aim of the initial investigations lifetime risk of lymphoma that is 10- lymphoma is diverse. is for GPs to eliminate the most

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common differential diagnoses for of any constitutional symptoms breathing, or vision problems lymphoma which include: (fevers, sweats and weight loss) and can result from superior vena • Infectious mononucleosis the time, course and progression of cava syndrome caused by • Toxoplasmosis the abnormality. lymph nodes in the centre of the chest enlarging quickly. • Cytomegalovirus Physical examination can indicate The compression of vital • HIV the likely cause of lymphadenopathy. internal structures such as the • Rubella In addition to the sites of lymphadenopathy, include fi elds ureter, trachea or major blood • Viral hepatitis and other viral draining to enlarged nodes, looking for vessels may occur with rapidly infections evidence of infection, infl ammation, progressive lymphomas, and • Cat-scratch disease. or malignant disease. Splenomegaly occasionally may result in GPs who think a patient may have in the absence of features of acute medical emergencies. lymphoma are urged to refer to a mononucleosis-like illness raises the Enlarged intra-abdominal haematologist, medical oncologist or possibility of a lymphoproliferative or retroperitoneal nodes are general physician with expertise in disease. usually malignant. lymphoma without delay. The size and texture of Indications for biopsy: lymphadenopathy also provides PERSISTENT diagnostic information, with lymph Careful clinical assessment LYMPHADENOPATHY nodes <1cm in diameter often being is required to establish the need to perform a biopsy Persistent lymphadenopathy is the non-malignant and those >2cm in on an enlarged lymph node, most common presentation for diameter being more frequently bearing in mind that in general lymphoma and is most often suspected associated with neoplastic disease. practice, only a small minority after the discovery of a progressively Tender lymph nodes are usually of enlarged nodes are due to enlarging or persistent non-tender benign. Nodes involved with malignancy. lymph node, most commonly in the lymphoma are most often fi rm or Factors that may predict neck, axilla or groin. rubbery, with a rock-hard node more malignancy are: Not all lymphadenopathy is due to commonly associated with non- • patients are aged 40 years lymphoma or is malignant. haemopoietic cancer. and over Infectious and immunological Lymphadenopathy can be slow and • supraclavicular location of enlarged diseases may cause benign insidious and occur in an otherwise lymph nodes lymphadenopathy and the vast asymptomatic person, or develop • an affected lymph node with a majority of patients who present to rapidly and be associated with local diameter >2cm their GP with lymphadenopathy will or constitutional symptoms such as • fi rm to hard in texture have non-specifi c or reactive aetiology fevers, sweats, weight loss or pruritus. • lack of tenderness to palpation that require few diagnostic tests. Rapid and progressive enlargement • present for several weeks Less than 1% of patients of lymph nodes often heralds the • abnormal CXR who present with peripheral diagnosis of an aggressive lymphoma, lymphadenopathy actually have whereas waxing and waning lymph • signifi cant constitutional symptoms. malignant disease. node size – including their complete The chance of malignant disease as When delineating the various disappearance and reappearance – is a cause of lymphadenopathy increases causes of lymphadenopathy, emphasis more frequently seen in the indolent over the age of 50 years. should be placed on possible exposure lymphomas. Further investigations to be to an infectious cause, or the presence The site of lymphadenopathy carried out by a GP before referral to may also provide a strong clue to its a specialist for a surgical biopsy: aetiology. • coagulation screen Lymph node swelling in the • fl ow cytometry (if a peripheral stomach or intestinal tract may result blood is present) in abdominal pain and/or bloating, or • ultrasound of lymph node(s) in the chest it may cause coughing, • consider fi ne needle aspirate shortness of breath or chest pain. (FNA) of enlarged lymph node. Headache, swelling (affecting Referral to a specialist or hospital Follicular lymphoma histology the head, neck or arms), diffi culty for biopsy is urgent if there is evidence

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of any emergent complications Where there is constitutional The combined expertise of of lymphoma including: illness, objective confi rmation that diagnostic and clinical experts in • spinal cord compression weight loss has occurred is important, multidisciplinary teams also enhances • pericardial tamponade with a focus on signs or symptoms that access to clinical trials which is critical are associated with systemic disease due to this rapidly evolving area of • superior or inferior vena that may cause weight loss. In the medicine. cava obstruction elderly, differential diagnoses include • airway obstruction Contact the Leukaemia & depression; malignant disease; and Blood Foundation for further • possible CNS mass lesions benign gastrointestinal disease, and in advice or information about your • intestinal obstruction younger patients differential diagnoses local multidisciplinary treatment • ureteric obstruction include diabetes; hypothyroidism; centre. 0800 15 10 15. • severe hepatic dysfunction psychiatric disturbance; and infection. • patient is unwell. Refer to a specialist for further BIOPSY investigations. Diagnosis depends on obtaining SYSTEMIC AND Patients with unexplained fever adequate tissue to evaluate the CONSTITUTIONAL and night sweats may have either histology of the tumour and subtype, SYMPTOMS malignancy or chronic infection. Further as well as immunohistochemical and Thoracic and abdominal investigation includes a careful history molecular diagnostic information. assessing the potential for systemic presentations include specifi c An open biopsy of an affected lymph disease (infection; infl ammatory disease; organ involvement such as node or tissue is usually necessary malignancy; drug reactions) and referral mediastinal enlargement on to make a defi nitive diagnosis of to a specialist. a chest x-ray and a protracted lymphoma. cough. Differential diagnoses HODGKIN LYMPHOMA The use of fi ne needle aspirate to consider are sarcoidosis; PRESENTATION (FNA), core or excision biopsy will ; metastatic depend on the nature and location of carcinoma and thymoma. The mode of presentation of HL the target lesion. Refer to a specialist for further is variable. Patients are generally investigations including: younger than those with NHL but It is critical that the appropriate the disease can occur at any age. biopsy is performed by an experienced • mediastinoscopy with biopsy; Some HL patients present with operator to ensure a satisfactory open thoracotomy and lung biopsy clinically localised lymphadenopathy, sample is obtained for histopathology, for mediastinal mass often in the neck or mediastinum, fl ow cytometry, chromosomal analysis • CT-guided core biopsies or without other symptoms. Others have and molecular studies. It should be laparoscopic lymph node biopsy more extensive disease that is often interpreted or reviewed by a pathologist for abdominal and retroperitoneal associated with systematic symptoms expert in haematopathology who can lymphadenopathy, and such as weight loss, sweats and fever. integrate the histological fi ndings with • bone marrow aspirate and biopsy. Patients less commonly present with the results of other investigations to For splenomegaly the differential symptoms or signs of involvement of a arrive at a precise fi nal diagnosis. diagnoses include portal hypertension; specifi c extranodal site such as the GI When a pathological node is not infi ltrative disease of spleen; or CNS. readily available, such as with intra- extramedullary haematopoiesis and abdominal disease, a needle core myeloproliferative disease. Refer to a REFERRAL biopsy is a reasonable initial procedure specialist for further investigations: All patients with suspected if open biopsy is not feasible. • ultrasonography lymphoma are to be referred to a Fine needle aspiration cytology is clinical haematologist or medical • CT (to show intra-abdominal generally considered inadequate for oncologist, who has appropriate lymph nodes). diagnosing lymphoma, but can provide expertise in the management of ancillary information or be useful in The presence of an enlarged lymphoma, and who works in confi rming a reactive lymph node. spleen is easily determined by association with a multi-disciplinary ultrasonography and is less costly than team which includes pathologists and CT. However, CT offers the advantage of visualising intra-abdominal lymph radiation oncologists. In rural areas, nodes which is important when refer to a general physician or surgeon, lymphoma is suspected. as appropriate. Burkitt’s lymphoma histology

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FNA may also be used to exclude symptoms. The staging system for Table 1: CLASSIFICATIONS solid malignancies of the head or neck both Hodgkin and non-Hodgkin OF LYMPHOMAS as a cause of lymphadenopathy, as lymphoma is the Ann Arbour Staging an open biopsy may prejudice later System which is vital for deciding the defi nitive surgical management. FNA correct treatment and helps estimate Based on presenting features may also have a role in diagnosing the prognosis. Indolent lymphomas recurrence of lymphoma. Stage 1: One lymph node area Aggressive lymphomas Peripheral lymph node excision involved Highly aggressive lymphomas biopsy is preferable and where there is Stage 2: Two or more lymph node intra-thoracic/abdominal or solid organ areas on the same side of the Based on WHO involvement, a radiologically-guided diaphragm Lymphoma Classification4 core biopsy is frequently adopted. Stage 3: Lymph nodes involved on Non-Hodgkin lymphoma Before biopsy, patients should have both sides of the diaphragm a full blood count and coagulation B-cell lymphomas Stage 4: Any of the above with screen to identify unexpected cases of Small lymphocytic involvement of sites other leukaemia or bleeding tendency, and than lymph nodes (most Lymphoplasmacytic a chest x-ray to exclude unexpected intrathoracic disease. An ultrasound commonly the bone marrow, Splenic marginal zone liver or lungs) Nodal marginal zone B symptoms: Fever, night sweats or Extranodal marginal zone, of signifi cant weight loss mucosa-associated lymphoid Staging relies on physical tissue (MALT lymphoma) examination, x-rays, CT scans ✢ (commonly of the abdomen and pelvis Follicular Microarray analysis of diffuse large B-cell lymphoma and sometimes of the neck and chest), Mantle cell and bone marrow examination. Nuclear Diffuse large cell✢ to further image the lymph node(s) medicine imaging, particularly PET Mediastinal large cell may be undertaken in some cases. and gallium scanning is assuming an increasingly important role. Intravascular large cell CLASSIFICATION Primary effusion Classifi cation of the subtype of TREATMENT Burkitt’s lymphoma is extremely complex and The major diffi culty in treating Post-transplant lymphoproliferative is used to decide what treatment is lymphoma is deciding the most ✢ necessary for each type of lymphoma appropriate management plan for �most common forms depending on whether the lymphoma each patient, given the wide spectrum Non-Hodgkin lymphoma is slow growing and can be managed of clinical behaviour, the curability T-cell lymphomas for many years, or requires intense of some lymphomas with optimal T-lymphoblastic chemotherapy in an attempt to cure treatment and the range of treatments the lymphoma. that are now available. Extranodal NK/T lymphoma, nasal In New Zealand, most Unlike most other cancers, the Enteropathy-type T-cell haematopathologists and clinicians treatment for most lymphomas is Subcutaneous panniculitis-like T-cell use the WHO classifi cation which based on the precise pathological was fi rst published in 2001, and subtype more so than the clinical and Sézary syndrome subsequently updated in 2008. It radiological stage of the disease at the subdivides lymphomas and other time of diagnosis. The pathological Primary cutaneous anaplastic large cell blood cancers based on cell type, subtype of a lymphoma predicts Angioimmunoblastic immunotype, molecular, cytogenetic strongly for both biological behaviour Peripheral T-cell and clinical characteristics. and treatment response. Therefore accurate histological diagnosis is Hodgkin lymphoma STAGING paramount and a close working Classical Hodgkin lymphoma Lymphoma is staged as I, II, III or relationship between the clinician Nodular lymphocyte predominant IV and divided into A or B, depending and the pathologist is the key to the Hodgkin lymphoma on the absence or presence of systemic management of lymphomas.

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Following a defi nitive histologic patient and their disease. The initial on those developed for the treatment diagnosis, patients begin a pathway treatment choice is infl uenced by the of childhood acute lymphoblastic typical of the management of all age and general health of the patient, leukaemia, including prophylactic patients with malignant disease disease ‘bulk’ (large tumour masses treatment to the central nervous that involves staging, prognostic or small lymph nodes) and extent system. (localised or widespread), the speed of assessment, and a treatment plan that Hodgkin lymphoma: The disease progression, and the presence refl ects either a curative or palliative management of HL is dictated by of symptoms due to lymphoma. approach. accurate staging of the disease. Truly For example, elderly asymptomatic localised disease can be cured by Often a combination of treatment patients with slowly progressive radiation therapy, but more recently, modalities is used, including surgery, localised non-bulky disease may in a combined modality treatment radiotherapy, chemotherapy, biological need no treatment initially and may approach, radiation therapy has been therapy (interferon), monoclonal be managed by observation alone. given in reduced doses and more Progressive localised disease may be antibody therapy (rituximab) and limited fi elds in conjunction with treated with local radiotherapy alone. bone marrow transplantation. abbreviated courses of combination Younger patients with progressive Some types of lymphomas grow chemotherapy (ABVD protocol). symptomatic disease will require slowly and need no treatment initially. chemotherapy. These patients may have extended TREATMENT FOR RELAPSED periods of non-progressive disease First line chemotherapy is most DISEASE and regular check-ups are all that is commonly combination chemotherapy Relapsed follicular lymphoma: required during this time. Others such as CVP or CHOP in conjunction Relapse is usual for follicular require treatment and lymphoma even when will respond, at least intensive combination initially, to a variety of chemotherapy is used chemotherapeutic drugs for initial treatment. and radiation therapy. Responses to subsequent Current practice is to therapy, including the manage lymphoma using same modality used a multidisciplinary team previously, are usually seen of experienced diagnostic and multiple re-treatments and clinical experts are possible. Agents that (pathologists, radiologists, have value in the treatment radiation therapists, of relapsed follicular physicians trained in lymphoma, including medical oncology or rituximab and the purine clinical haematology and analogue, fl udarabine palliative care physicians). (Fludara), are most useful They formulate a in combination with other comprehensive management plan that with rituximab (MabThera), a chimeric chemotherapy agents. can include access to clinical trials, monoclonal antibody against the CD20 In younger patients, high dose to enable optimal treatment and protein expressed on human B-cells, chemotherapy with haemopoietic coordinated care for each patient. including follicular lymphoma. stem cell rescue using the patient’s The highest priority of treatment is Aggressive lymphomas: Virtually stored cells (autologous stem cell to maximise patients’ overall survival, all patients with aggressive lymphomas transplantation) produces prolonged maintain quality of life and avoid have progressive and disseminated complete responses in more than 50% treatment-related morbidity. disease and require combination of cases after fi rst relapse. Allogeneic Treatment for NHL is largely stem cell transplantation also has a chemotherapy. The gold standard is dictated by histology and anticipated high response rate in younger patients R-CHOP given in courses every 14 clinical course rather than disease with relapsed disease. to 21 days for a total of six to eight stage, with predominantly palliative courses. The addition of rituximab Relapsed aggressive lymphomas intent for indolent NHL and curative and Hodgkin lymphoma: The to CHOP improves response rates intent for aggressive disease. treatment of relapsed aggressive without additional toxicity. Follicular lymphoma: The lymphomas and HL is a greater treatment for follicular lymphoma has Highly aggressive lymphomas: therapeutic challenge. Without stem not been standardised and is subject Lymphoblastic and Burkitt’s cell transplantation the outlook is to individual physician preference, lymphomas require prompt and highly usually grim, with less than 10% of the individual characteristics of each specialised care using protocols based patients surviving in the long term.

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Re-treatment with intensive salvage disease and monitoring for late effects The Leukaemia & Blood protocols is required to obtain of therapy as the long-term follow-up Foundation is the only organisation a second response prior to stem of patients who have been successfully in New Zealand dedicated to cell transplantation, and patients treated for lymphoma. Attention supporting patients and their whose lymphoma is refractory to to other aspects of their health families living with leukaemia, chemotherapy are usually considered includes their psychosocial wellbeing, lymphoma, myeloma and related ineligible for transplantation. encouraging the maintenance of a blood conditions. Patients who show a response to healthy lifestyle and preventive health salvage treatment are usually offered measures including screening for THE LEUKAEMIA & BLOOD autologous stem cell transplantation, other malignancies, as appropriate. FOUNDATION a procedure feasible up to the P O Box 99182, Newmarket, age of 70 years. There is a high DIAGNOSING LYMPHOMA Auckland 1149 response rate to this procedure with DECISION SUPPORT TOOL Ph: 0800 15 10 15 approximately 40% of patients with [email protected] relapsed chemotherapy-sensitive DIAgNOSINg LYMPHOMA SUSPECT LYMPHOMA www.leukaemia.org.nz aggressive lymphoma remaining free COMMON PRESENTATIONS LESS COMMON BUT POSSIBLE PRESENTATIONS • Enlarged, usually painless lymph nodes anywhere in the Persistent fatigue/lack of energy; flu-like illness; body (commonly in the neck, axilla or groin) generalised itching; abdominal pain; recurrent infections; anaemia and other low blood counts; • Unexplained fever of lymphoma after an autograft. bone pain; back pain; shortness of breath/protracted FOR MORE INFORMATION ON • Night sweats cough; neurological symptoms, skin rash • Unintentional weight loss/anorexia DIAGNOSING LYMPHOMA ELIMINATE DIFFERENTIAL DIAGNOSES INITIAL INVESTIGATIONS • Infectious mononucleosis PROGNOSIS • Full medical history (include fevers, sweats, weight loss, malaise) • Toxoplasmosis • Physical examination (particularly of lymph nodes and spleen) • Cytomegalovirus www.leukaemia.org.nz • Full blood count, creatinine, urea and LFTs, serological studies • HIV • Chest x-ray (to image the mediastinum) • Rubella The overall prognosis in lymphoma • Ultrasound scan (if splenomegaly alone is suspected) • Viral hepatitis and other viral infections Leukaemia & Blood Foundation • CT scan (of chest, abdomen, pelvis, as clinically indicated) • (Bartonella) Cat-scratch disease varies widely and depends mainly on SYSTEMIC PRESENTATIONS Ministry of Health (2009). Suspected STILL SUSPECT LYMPHOMA •Specific organ involvement such as mediastinal enlargement on CXR the type of disease and the response • Protracted cough PERSISTENT LYMPHADENOPATHY • Splenomegaly Cancer in Primary Care: Guidelines • Fever or weight loss to initial treatment. INDICATORS FOR INDICATORS FOR URGENT BIOPSY FINE NEEDLE ASPIRATE for investigation, referral and reducing DIFFERENTIAL DIAGNOSES • Spinal cord compression • Lymph node >2cm diameter Follicular lymphoma: In follicular • Pericardial tamponade •Firm-hard texture, mobile, not • Abnormal mediastinum: thymoma; tender metastatic carcinoma; tuberculosis; •Superior or inferior vena ethnic disparities. Wellington: New sarcoidosis cava obstruction • Persistent for six weeks or more Splenomegaly: Portal hypertension; Airway obstruction Abnormal CXR / CT scan if • • • infiltrative disease of spleen; lymphoma, the average survival from available • Possible CNS mass lesions extramedullary haematopoiesis; Zealand Guidelines Group. Significant constitutional Intestinal obstruction • myeloproliferative disease • symptoms (weight loss, drenching sweats) diagnosis is seven years. Around 20% • Ureteric obstruction • Severe hepatic dysfunction REFERRAL • Patient is unwell Refer all patients with FURTHER INVESTIGATIONS BY GP BEFORE of patients survive more than 10 years suspected lymphoma to a REFERENCES REFERRAL FOR SURGICAL BIOPSY URGENT HOSPITAL REFERRAL clinical haematologist, medical oncologist, or general physician Coagulation screen (if appropriate ie. in regional/rural Rapidly progressive lymphomas may • areas) who works in association without therapy, emphasising the result in acute medical emergencies •Peripheral blood flow cytometry with a multidisciplinary team and due to compression of vital internal (if lymphocytosis is present) has appropriate expertise in the 1. Ministry of Health (2010). Cancer: structures (urethra, trachea or major •LDH, Hepatitis screen, HIV, management of lymphoma. blood vessels) highly heterogeneous behaviour of the protein electrophersis Historical Summary, 1948-2006. disease. Retrieved 4 August 2010 from Aggressive lymphomas: Prognosis The Leukaemia & Blood Foundation http://www.moh.govt.nz/moh.nsf/1 in aggressive lymphomas is heavily has developed a diagnosing b6468406f6672eecc2570bb006b4 infl uenced by factors relating to both lymphoma decision support tool, Is d00/bb2f14b683b10765cc2575ea0 the patient (age and general health) and Lymphoma on your Radar? which 00caafe?OpenDocument the disease (tumour stage and bulk), accompanies this article. Further 2. Ministry of Health (2010). Cancer: but the most important determinant copies of this, and other materials, New Registrations and Deaths, 2007. is response to chemotherapy. About can be downloaded from the LBF’s Wellington: Ministry of Health. 60% of cases of diffuse large cell website: www.leukaemia.org.nz lymphoma have a complete response 3. Ministry of Health (2010). Cancer to R-CHOP. Those failing have a GLOSSARY Projections: Incidence 2004-08 to 2014-18. Retrieved 4 August 2010 very poor outlook. About one third ABVD: protocol acronym for from http://www.moh.govt.nz/moh. of complete responders relapse, often combination chemotherapy of nsf/indexmh/cancer-projections- within 12 months of treatment; some doxorubicin, bleomycin, vinblastine, incidence-2004-08-to-2014-18 of these may be rescued by stem cell dacarbazine (all intravenous). transplantation. 4. Jaffe ES, Harris NL, Stein R-CVP: protocol acronym for Hodgkin lymphoma: In HL, the H, Vardiman JW, eds. (2008). combination chemotherapy of prognosis is dependent on disease WHO classifi cation of tumours: rituximab cyclophosphamide, stage. Where the disease is localised, pathology and genetics of tumours vincristine, prednisone. patients have an excellent outcome, of haematopoetic and lymphoid with more than 90% having prolonged R-CHOP: protocol acronym tissues. Lyon: IARC Press. disease-free survival. The outlook for for combination chemotherapy of rituximab (intravenous), patients with more advanced disease The Leukaemia & Blood Foundation cyclophosphamide (intravenous), treated by chemotherapy is worse gratefully acknowledges the Leukaemia doxorubicin (intra venous), vincristine but more than 50% have prolonged Foundation of Australia for granting (intravenous), prednisone (oral). complete responses. permission to reproduce and adapt Follow-up: A GP plays a crucial this document for New Zealand. role in detecting relapsed or recurrent 08/2010 CC24498.

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