sign in sign up
<<
Home , Adenomyoma, Pelvic tumor, Sarcoma botryoides

THE JOURNAL OF RESEARCH

VOLUME XIV JUNE. 1930 NUMBER2

THE AGE AND SEX DISTRIBUTION AND INCIDENCE OF NEOPLASTIC DISEASES AT THE MEMORIAL HOSPITAL, NEW YORK CITY *

GEORGE T . PACK AND ROBERT G . LEFEVRE

TABLE OF CONTENTS I . Introduction ...... 169 I1. Statistical Data ...... 171 A . Tumors of the Skin ...... 172 1. Epidermoid ...... 172 2 . Basal-cell epithelioma ...... 175 3 . ...... 176 4 . of skin ...... 177 5 . Hemangioma ...... 177 B. Tumors of the Nervous System ...... 177 1. Brain tumors ...... 177 2 . Spinal cord tumors ...... 177 3 . Neurofibroma ...... 177 4 . Neurogenic sarcoma ...... 179 C. Tumors of Bone and Cartilage ...... 179 1. Chondroma and Chondrosarcoma ...... 179 2 . Giant-cell tumor ...... 181 3. Bone sarcoma ...... 182 4 . Endothelial myeloma ...... 183 5 . Multiple myeloma ...... 184 D . Tumors of the Intra-oral Group ...... 185 1. Epidermoid carcinoma of lip ...... 185 2 . Epidermoid carcinoma of floor of mouth ..... 186 3 . Epidermoid carcinoma of tongue ...... 186 4 . Epidermoid carcinoma of buccal mucosa ..... 188 Aided by a grant from the Mrs . John L . Given Fund . 167 12 168 GEORGE T . PACK AND ROBERT a. LBFEVRE 5. Adenoid cystic epithelioma of mucous mem- branes ...... 188 6 . Epidermoid carcinoma of antrum and superior maxilla ...... 191 7 . Epidermoid carcinoma of inferior alveolus .... 191 8 . Epithelioma of faucial tonsil ...... 192 9 . Epidermoid carcinoma of larynx ...... 197 10. Carcinoma of nasal mucosa ...... 199 11. Tumora of parotid gland ...... 200 E . Tumors of Gastro-Intestinal Tract (exclusive of oral cavity) ...... 201 1. Carcinoma of esophagus ...... 201 2 . Carcinoma of stomach ...... 202 3 . Carcinoma of small intestine ...... 206 4 . Carcinoma of appendix ...... 207 5. Carcinoma of colon ...... 208 6. Carcinoma of rectum ...... 208 7 . Carcinoma of anus ...... 210 8 . Carcinoma of pancrem ...... 210 9 . Carcinoma of gall-bladder ...... 210 10. Primary carcinoma of liver ...... 211 F . Tumors of the Genito-Urinary System ...... 211 1. Carcinoma of urethra ...... 211 2. of ...... 215 3. Carcinoma of urinary bladder ...... 215 4 . Carcinoma of kidney ...... 216 5. Adenomyosarcoma of kidney ...... 216 6. Hypernephroma ...... 217 7. Epidermoid carcinoma of penis ...... 218 8 . testis ...... 219 9 . Sarcoma of testis ...... 221 10. Carcinoma of prostate gland ...... 222 11. Sarcoma of prostate gland ...... 223 12. Epidermoid carcinoma of vulva ...... 224 13 . Epidermoid carcinoma of ...... 224 14. Sarcoma of vagina ...... 225 15. Carcinoma of cervix uteri ...... 226 16. Ca'rcinoma of body of ...... 229 17. Leiomyofibroma of uterus ...... 230 18. of uterus ...... 231 AGE AND SEX DISTRIBUTION 169

19. Carcinoma of ...... 231 20 . Sarcoma of ovary ...... 233 21. Benign ovarian ...... 234 G . Tumors of the Breast ...... 234 1. Fibro- ...... 234 2. Intra-cystic benign papilloma ...... 235 3 . Carcinoma of breast ...... 235 4 . Sarcoma of breast ...... 240 5 . PagetJa disease of nipple ...... 240 H . Tumors of the Soft Somatic Tissues ...... 241 1. ...... 241 2 . ...... 241 3 . Sarcoma of aoft parts ...... 241 I. Tumors of Lymphoid Tisaue and Allied Diseases ... 245 1. Lymphosarcoma ...... 245 2 . Sarcoma of spleen ...... 245 3 . Thymic tumor ...... 246 4 . Endothelioma of lymph nodes ...... 246 5. Hodgkin's diaesae ...... 247 6. Lymphatic ...... 247 7 . Spleno-myelogenous leukemia ...... 248 J . Miscellaneou Tumors ...... 249 1. Ocular tumors ...... 249 2 . Primary carcinoma of lungs ...... 249 3. Sarcoma of lung ...... 252 4 . Sarcoma of thyroid ...... 252 5. Thyroid adenoma ...... 254 6. Thyroid carcinoma ...... 254 I11 . Ascending Scale of Average Age Occurrence of Different Malignant ...... 256 IV . Relation of Cancer to Old Age and Youth ...... 258 V. Influence of Sex on the Distribution of Neoplastic Diseases . 283 VI . Summary ...... 286 VII . References ...... 290

INTRODUCTION The purpose of this study is a consideration of the age and sex distribution and incidence of benign and malignant tumors at the Memorial Hospital of New York City. In the usual statistical study of tumors, there are several 170 GEORGE T. PACE AND ROBERT G. LEFEVRE palpaple sources of error. One such source is the variable latent period existing between the time the tumor begins and its dis- covery. This variability depends on many factors such as the type and nature of the particular tumor, the intelligence and personal concern of the patient and the diagnostic acumen of his physician. The difference in time is not so important as regards the age of patients with malignant tumors, because few exist longer than one to two years without discovery by the patient. Proper consideration should be given to the length of time during which the tumor existed subsequent to its dis- covery and prior to the admission of the patient to the clinic. This period is considerable for such slow-growing tumors as basal-cell cancers, and neurofibromas. The patient's estimation of this time interval is frequently unreliable. An- other disturbing source of error is the obscurity of the primary location of certain secondarily involving the liver or cervical lymph nodes. Some statistics covering cancer ages are based on mortality figures, which are naturally later than the ages of onset. The data of the Memorial Hospital are unique in several respects: The sole function of this hospital is the diagnosis and treatment of cancer and allied diseases; a central admitting office is maintained, wherein the primary and presumptive diag- noses are made, after which the patients are referred to suitable departments for confirmation of the diagnoses and appropriate treatment; the personnel of the different departments through long experience has become proficient in the clinical diagnosis of cancer; the pathology laboratory under the direct supervision of one pathologist for many years, has enjoyed an unusual opportunity in the histological diagnosis of neoplastic diseases; equal numbers of beds are available for men and women. Because of this abundance of material with unity of source, a considerable degree of reliability can be assumed for statistical data based on tumor diagnosis in this institution. Some of the facts to be determined in this study are: (1) the percentage of admissions to the hospital and clinics, comprised by each tumor group; (2) the age distribution of benign and AGE AND SEX DISTRIBUTION 171 malignant tumors; (3) the age incidence of the more malignant tumors; (4) the average age of the patient at the onset of each type of tumor; (5) the youngest and oldest age in each tumor group; (6) the quinquennial age-period of maximal liability; (7) the sex distribution in five year periods of all benign and malig- nant tumors; (8) the percentage occurrence of the benign and malignant tumors in each sex; (9) the percentage of the different histological tumor entities in each regional group, e. g., the breast, or the mouth; (10) the statistical determination of the tumors of youth and of old age. By age distribution, we refer to the particular number of cases found at each age period. By age incidence, we refer to the ratios found at any given age period, which are secured by a comparison of the percentage of carcinoma at that age period with the percentage of the general population at the same period. The average age at which any tumor occurs is usually less than the quinquennial age-period of maximal liability, due to the fact that a greater number of cases of this particular tumor occurs previous to this period than occurs subsequently. Finally, we shall insert certain brief case reports, for the pur- pose of illustration and to record certain tumor occurrences at unusual ages, particularly in the extremes of life.

STATISTICAL DATA During the inclusive period, January 1, 1917 to January 1, 1929, nineteen thousand, one hundred and twenty-nine (19,129) patients with neoplastic diseases were accepted for diagnosis and treatment at the Memorial Hospital. Of these tumors, 16,565 were malignant; of these malignant tumors 8,007 occurred in males, 8,558 in females. This distribution according to sex is not the true ratio for the population at large; the unusually large number of male subjects can be explained by the disproportion- ate size of certain clinics, e.g., the intra-oral department, as compared with other departments which are concerned with the treatment of cancers peculiar to females. The ratio of sex found in the different histological and regional varieties of can- cer is statistically accurate within each group. 172 GEORGE T. PACK AND ROBERT Q. LEFEVRE The comprised 10.4 per cent of the malignant tumors; 89.6 per cent were carcinomas. The average age of the patients with sarcomas was 38.2 years; with carcinomas, 53.9 years, a difference of 15.7 years.

TUMORS OF THE SKIN Epidermoid Carcinoma of the Skin. One of every twenty patients admitted to the Memorial Hospital had epidermoid carcinoma of the skin. The average age of these 1091 patients was 58 years, which is within the five-year period of the greatest distribution, namely 55-59 (16.5 per cent). The incidence of this cancer tends to increase with each year of life; the liability is greatest, according to our data, after the century mark is reached. Three-fifths of the total number of these cancers occurred in males; the males predominate in every quinquennial period until extreme old age is reached. The reason for this late exception to the rule is that women live longer than men; 75 per cent of centenarians are women. Occupational hazards and weather exposure possibly account for the male majority. Four and one-quarter per cent occurred in patients under 35; this percentage is in agreement with Roland (127) who found 5 per cent of his 864 cases under this age. Only 0.64 per cent were in individuals under 25 years (7 instances); of these, the youngest was a male infant aged 15 months, whose tumor was embryonal in character. Are there any significant skin changes to account for the in- creasing frequency of with progressive ageing? The deposition of pigment in the rete Malpighii, the atrophy of the sudoriparous glands with resultant skin dryness, the loss of subcutaneous fat, the sclerosis of the derma and disappearance of elastic fibers, belong to senescence, but do not necessarily constitute precancerous changes. The cutaneous sensibilities are impaired, consequently the recognition of many chronic irritations may be lost. Senile seborrhoea, eczema and other common skin diseases of the aged, are predisposed to by the atrophy of the skin, which is naturally less resistant to chemical and thermal influences. Verruca senilis or senile keratoses TABLE NO. 1 Tunwr~oj the Skin I I I 174 QEORGE T. PACK AND ROBERT G. LEFEVRE such as Oliver Cromwell's famous wart, are potential starting points for skin cancers in elderly persons. Ewing (42) states that the pigmented epidermoid carcinoma of the skin (synonym. -malignant lentigo) is definitely associated with the ageing process. Ninety-five (8.7 per cent) of these patients were over 74 years of age. One woman, aged 101, was the oldest person ever treated in this hospital. Case Report No. 1. G. D., a white male infant aged 15 months, developed a tumor in the perineal skin in January, 1919. On June 21, 1919, a partial excision of the tumor was done at another hospital. It extended from the triangular ligament anteriorly to both ischial tuberosities laterally and to the rectum posteriorly. The histological diagnosis was: A very cellular of undetermined origin; the cells are large, polyhedral and occupied mostly by hyper- chromatic nuclei; no pigment (Ewing). By July 16, 1919, the peri- neum was occupied by a reddened recurrent tumor, 6 centimeters in diameter. During the next six months, four treatments by external radium therapy, at 3 centimeters distance and with 2 mm. of brass filtration to give a total of 7668 millicurie hours, were effective in causing a complete disappearance of this radiosensitive tumor. In December 1919, a perineal recurrence was noted accompanied by palpable left inguinal lymph nodes. Dr. Quick buried 21.5 millicuries of radon in glass tubes in the recurrent and 4.9 milli- curies in the left inguinal wound after dissection. By March 15, 1920, the patient had complete amblyopia from cerebral metastases, the liver was greatly enlarged and the right inguinal nodes were palpably involved. There was an early fatal termination. Case Report No. 2. A. S., a white female, aged 101, was admitted on January 29, 1924, with a solid fungating tumor mass, 3 centimeters in diameter and one centimeter thick, which was situated on the fore- head. The pathological report was: squamous carcinoma. Dr. William S. Stone completely excised the tumor under local anesthesia. The patient died at home, February 24, 1924, with no evidence of recurrence. Case Report No. 9. E. J., a white female, aged 96, had a lesion on the right side of the nose for three months and a similar ulcer, 1-112 centimeters in diameter, in the right preauricular region. Both were squamous carcinomas. They were successfully treated by irradiation. AGE AND SEX DISTRIBUTION 175

She died one and one-half years later at the age of 98, with no evidence of the original disease. Basal-cell Epithelioma of the Skin. The basal-cell cancers of the skin are of more frequent occurrence than the epidermoid carcinomas; 1374 patients or 7.18 per cent of all admissions had this particular lesion. These patients averaged three years older (61 years) than those with epidermoid carcinomas. On the average the females were two years younger than the males; the period of greatest age distribution for males was 65 to 69, for females 60 to 64 years. Two hundred and twenty-two (16.16 per cent) of these patients were older than 74 years; this group comprised almost 30 per cent of all the malignant tumors beyond this age, which definitely places the basal-cell cancer as one of the most common tumors of old age. The adenoid cystic epithelioma of the skin is included as a sub-group of basal-cell epithelioma. Ewing (42) has called attention to the sudden and excessive growth of single hairs in the skins of aged persons as evidence of late hyperactivity of the hair follicles; many of these basal-cell epitheliomas have their origin in hair follicles (hair matrix carcinoma or tricho-carcinome). We have observed basal-cell lesions whose duration has been given as forty years. Molesworth (112) in his monograph on rodent ulcer states that no patient in his series was under 40 years of age; he be- lieves that 40 years of exposure to sun, wind etc., are necessary for the development of rodent ulcers in susceptible people. At the Memorial Hospital, 87 persons under 40 years were treated for basal-cell epithelioma, the youngest of whom was 17. Case Report No. 4. G. B., a white boy, aged 17, had a small basal- cell epithelioma on the right ala nasi. The history was of six months duration; an attempt at surgical removal elsewhere was followed by prompt recurrence. Radium therapy effected a cure, which is now of two years duration. Case Report No. 6. A. C., a white Spanish girl, aged 20, was ad- mitted to the Memorial Hospital on March 3, 1924. In 1919 when she was only 15 years of age a small nodule appeared on the left side of her nose. Several excisions were attempted in San Domingo, but in each 176 GEORGE T. PACK AND ROBERT G. LEFEVRE instance a recurrence followed. On admission, the tumor involved the entire tip of the nose and extended outward into the deeper structures of the cheek on the left side with exposure of the cartilage. The histo- logic diagnosis was basal-cell epithelioma. Radium therapy afforded some palliation but never controlled the disease. Zinc chloride caustic paste was finally employed. On March 15, 1926, she died of extensive pulmonary tuberculosis. Case Report No. 6. J. S., a white male, aged 94, had a circular, elevated, ulcerated, freely movable plaque, one centimeter in diameter on his left cheek. It was a basal-cell epithelioma of slow growth. The history was of six months duration. Radium therapy effected a complete cure. Case Report No. 7. H. S., a white male, aged 90, had a slowly- growing basal-cell epithelioma of one years duration on the bridge of his nose. The lesion measured 1 X 1-112 centimeters in its diameters. Radium therapy effected a cure. Case Report No. 8. M. V.,a female, aged 90, had a flat, irregularly shaped, ulcerated, indurated, slightly elevated basal-cell epithelioma of six years duration, which was situated in the skin over the right scapula. The patient is now clinically free of disease, two years after the application of radium. Melanoma. Under the caption "Melanoma" are included all the malignant melanin-producing tumors of various regions as the vulva, breast, scrotum, conjunctiva, nasal septum and skin of the trunk and extremities. The average age of the 208 pa- tients with was 48, of 8 patients with ocular melano- mas, 50 years. There is a striking difference in the average ages of occurrence of the two common malignant intra-ocular tumors, namely melanoma and glioma. The melanomas occur in middle life at age 50, the gliomas at the average age of 8 years. Melanomas in general may occur at any age; the youngest patient in this series was a baby girl 15 months old, the oldest a woman aged 98. The incidence of melanomas tends to increase with the advancing years, probably because time affords oppor- tunity for the malignant transformation of previously benign pigmented naevi. Males and females are equally affected, as they share alike in the congenital occurrence of pigmented naevi, the precursors of melanomas. AGE AND SEX DISTRIBUTION 177 Sarcoma of the Skin. Primary sarcoma of the skin included Kaposi's multiple hemorrhagic sarcoma and two instances of lymphosarcoma cutis. Kaposi's tumor is said to occur chiefly in elderly males, but the oldest patient in this series was only 53 years of age. Males predominated 5 to 1, but the total num- ber of cases (6) is too small to permit an accurate deduction of the normal sex ratio. Hemangioma. These congenital tumors comprised 22 per cent of all the benign tumors admitted to the clinics. Over three- fifths of the 454 patients were girls, although theoretically the hemangiomas occur with equal frequency in boys. We ascribe this statistical discrepancy to the parents' greater concern about the cosmetic disfiguration of the girls.

TUMORS OF THE NERVOUS SYSTEM Brain Tumors. Brain tumors are not common in elderly people. The average age of the 19 patients with gliomas of the brain was 27 years; with the 27 unclassified brain tumors the average age was 32 years. According to Bailey and Cushing the spongioblastoma is the only one of the brain tumors which occurs with any frequency in aged people. Over 50 per cent of the gliomas of the brain occurred in persons younger than 25: 76 per cent of the gliomas of the eye were in children less than 5 years of age. Not one instance of brain tumor was found in patients seventy years of age or older. Spinal Cord Tumors. It has been said that these tumors oc- cur more commonly in males, but this is questionable. In our small series of 12, comprising only 3.34 per cent of the tumors of the nervous system, the males and females were equally represented. Only 4 of these were histologically proven gliomas. Of Frazier's 330 cases, 28 were in the first two decades of life; 84 were in the fifth decade. The ages in our small group ranged from 6 to 65 years. NeuroJibroma. Some of the patients had a single tumor, others had neurofibromatosis of the von Recklinghausen type. Many of these tumors were discovered coincidentally by the examiner when the patient came for diagnosis and treatment of TABLE NO. 2 Tumors oj the Nervous System

Age % of sex ~~~~l Tumors of Tp~e Nervoua M 5-9 10-14 1519 S24 35-39 45-49 5&M 55-59 8044 7579 &stem 25-29 30-34 4044 ------85-89 70-74 Brain Tumors-Type Un- known...... Male 411113 5 1 2 19 Female 1 12 1 2 1 8 Total141 112 5 0 6 123 27 7.62% Glioma of Brain...... Male 2 1 1 3 14 1 1 14 Female 2 1 1 1 5 Total 4 1 1 4 15 2 1 19 5.370/0 Gliorna of Eye...... Male 7 2 1 1 11 Female 15 1 11 18 Total 22 2 2 111 29 8.270 Spinal Cord Tumor...... Total 2 2221 2 1 12 3.39% Pituitary Tumor...... Total 11 3 1 6. 1.69% Neurofibroma...... Male 2 112145311 21 Female 15 32624321 29 Total 216 1531077431 50 14.13% NeurogenicSarcoma ..... Male 13 3 4 10 6 7 14 14 13 18 14 12 2 4 1 126 Female 1 2 3 7101511 4 8 3 9 5 2 3 285 Total 2 3 5 7 17 16 22 25 18 21 21 23 17 4 7 3 211 59.6% I 354 100.70 AGE AND SEX DISTRIBUTION 179 an unrelated cancer. It is our belief that this tumor is of fairly common occurrence, but causes so little concern to the patient that it is usually ignored. Although the tendency or predisposition to neurofibromatosis is frequently inherited, this tumor usually makes its recognizable appearance at irregular ages. The average age of these 50 patients was 36 years; 35 to 39 was the quinquennial age period in which the greatest distri- bution occurred. Neurogenic Sarcoma. From the pathologic material in the Memorial Hospital, Ewing has derived the opinion that many of the so-called fascial, spindle-cell and myxo-sarcomas are of neurogenic origin. Hence the number of neurogenic sarcomas in this study is unusually large as compared with the relative in- frequency of neurosarcomas reported from other sources. They constituted 81 per cent of the tumors of the peripheral nerves; 19 per cent only were neurofibromas. Some of these sarcomas probably resulted from malignant transformation of previously benign neurofibromas; this could only be inferred by the presence of multiple benign neurofibromas in the same indi- vidual; other neurogenic sarcomas seem to begin as sarcoma de novo. Sixty per cent of the neurogenic sarcomas occurred in males, whereas about 60 per cent of the neurofibromas were in females. The average age of the 211 patients in this group was 42 years; over 16 per cent were under 25 years of age. The ages varied from one to 79 years. When percentage corrections are made for the incidence of this tumor on the basis of the propor- tionate number of persons living (Table 23), we perceive that this sarcoma, as with many other malignant tumors, varies only slightly in frequency from age 30 to age 80. This fact alone proves conclusively that age alone has no in- fluence on the development of neurogenic sarcomas.

TUMORS OF BONE AND CARTILAGE Chondroma and Chondrosarcoma. Almost 213 of the chon- dromas were in male subjects; this disparity in sex ratio did not obtain for the chondrosarcomas. The chondrosarcoma differs from most other malignant connective tissue tumors in its age 180 GEORGE T. PACK AND ROBERT G. LEFEVRE

E8 $ 6? E88 s 2 Mr; 2 oiw 24-slq z - r( f I 22% "*% t. 88% 5Jzg --a -

4- r(

- - m-l*

wmt.

rl r( 2"Z " -'3m Z"2 --'3 m -

~m*zmw m m --

pmmm mm 22% -6

-dm am m*t. 2"- --'3 m 4 fl - '3 mwg 82s -- - m 222 mm* - wmm z.3 - - - *

$l-mm mm - -wm gqg m*w d * m*t. $42 m-w

w gR< W*"

'3 11 -- - --'3 2O08 -- 11- - mc~am-m - -w w -w w &,-- +r3 z 213 383 +I3 2 !, Zhb ZZG b ZZG zsz&g b b ...... i F : AGE AND SEX DISTRIBUTION 181 distribution; not a single instance of this tumor was encountered before the age of 22. In addition to the chondrosarcomas listed in Table 3, a significant number of chondrosarcomatous elements were found among the osteogenic sarcomas arising in persons of middle or later life. Giant-cell Tumor of Bone. For the purpose of classification, the giant-cell tumors of bone are listed as benign, although in some of these tumors there were microscopic evidences of malignancy. With the exception of the osteomas (7 cases), the giant-cell tumor was the only of bone which oc- curred with greater frequency in females (58.3 per cent) than in males. The average age of the 60 patients with giant-cell tumors of bone (aet. 34) was four years older than patients with true bone sarcoma (aet. 30). Eleven and one-half per cent of these giant-cell tumors were in children under 15 years of age. The youngest individual in this series was five years old; in Ge- schickter and Copeland's (56) analysis of over 400 cases of tumors in the giant-cell group, this type of lesion in any locality waa not observed under 5 years of age. They state that the explanation of this lies in the fact that the vascular subperiosteal layer of the epiphysis does not begin to atrophy until after the age of three, so that at these early ages a possible giant-cell lesion will be transformed into a bone by the active healing powers of the periosteum, The giant-cell tumor of bone occurs in the epiphysis where osteogenesis proceeds until relatively late in life; the giant-cell tumor is a destructive lesion and the epiphyseal periosteum loses its reparative power with each advancing year. The corrected incidence for this tumor in proportion to the number of people living in each age group, shows that the giant-cell tumor is relatively frequent in middle and later life. The oldest patient was 78 years of age. If the bone cyst does represent the healed lesion and the giant-cell tumor the destructive phase of this same process, possibly the assertions of Geschickter and Copeland are correct, because bone cysts are several times more frequent than giant-cell tumors in children, possibly due to the greater healing capacity of youthful bone. 182 GEORGE T. PACK AND ROBERT G. LEFEVRE Bone Sarcoma (osteogenic and periosteal). At first glance the bone sarcomas seem to be tumors of adolescence and early adult life; the average age of occurrence of 400 cases was 30; 46 1/4 per cent were in persons under 25 years, in fact 29 per cent of all malignant tumors found in persons under 25 years were bone sar- comas. Many authors give the second decade as the period of greatest distribution; this is true in this series of cases, but the corrected incidence of occurrence for these tumors, shows us that the percentages in the age-periods of 15-19 and 60-64 are practically equal (Table 23). Furthermore, there is little varia- tion in the relative proportion of bone sarcomas to the number of persons living in all of the quinquennial age-periods from 10 to 70. Bone sarcomas therefore are not peculiar to any age nor is it likely that the cumulative effects of age hasten or lessen the incidence of these tumors. One speculative relationship does exist in the development of osteosarcomas in bones previously affected by Paget's osteitis deformans; this is said to be partic- ularly significant in the case of osteosarcomas developing in patients over 50 years of age, and there are several instances in this group of tumors which lend support to this belief. The usual senile changes in bone, namely, the dense, hard, white bone-marrow and the osteoporosis of the short bones, the diploe of flat bones and epiphyses of long bones are apparenrly not related to the genesis of bone sarcoma. The scapula is said to be a site of predilection for bone sarcomas in infancy and childhood; we have been unable to verify this assertion because the regional survey of this group of bone sarcomas did not furnish data to indicate that the involvement of any particular bone was signifi- cantly frequent during any particular age period. The distribution in the sexes was 62.5 per cent males and 37.5 per cent females; these figures are in agreement with statistics from other sources. No explanation is available for this disparity in sex, except that the male is more frequently exposed to trauma. The ability and interest of Dr. Wm. B. Coley in bone sarcomas, account for the fact that they comprise 70 per cent of all the bone tumors in this institution, a percentage much greater than the natural proportion. One of every four malignant connective tissue tumors was a bone sarcoma. AGE AND SEX DISTRIBUTION 183

Endothelial Myeloma of Ewing. The endothelial myeloma was found in comparatively young people, the youngest of any who were afflicted with bone tumors. The average age of the 37 patients was only 22 years; 67.5 per cent of the patients were under 25 years of age. The males averaged 5 years younger than the females. The ages 10-14 formed the period of the greatest distribution of these tumors. Case Report No. 8. V. G., a white girl, aged 18 months was ad- mitted February 16, 1926. On January 1, 1926, when the patient was 17 months old, her mother observed a small painless lump on her right temple. This lump gradually increased in size and soon caused some displacement of the right eye. On admission, there was an additional hard fixed mass apparently arising from the pelvic bones; this mass could be palpated in the lower abdomen. Treatment was instituted, using external radium therapy at a distance, and X-irradiation; both skull and pelvic tumors regressed remarkably. Radiographs showed no abnormality of skull, but revealed a broad band of newly formed periosteal bone, surrounding the ramus of the left pubis. By June 13, 1926, the skull tumor measured 3 X 2-112 centimeters and was firmly fixed to the underlying bone. A small string of enlarged nodes was palpated in each upper cervical region. On July 19, a large tumor 5 centimeters in diameter was found at the head of the left humerus. This quickly disappeared after irradiation. On August 16, 1926, a new tumor appeared on the opposite (left) temple; this also responded rapidly to X-ray therapy. On October 14, 1926, a new tumor (4 X 5 cms.) was discovered on the left pubic bone. The marked proptosis of the eyeball recurred and the patient died on December 14, 1926. The radiographical and clinical diagnosis was endothelial myeloma of Ewing. Case Report No. 10. A. S., a Jewish boy, aged 2112 yean, was ad- mited October 31, 1927. Nine weeks previously the child fell out of bed; on the succeeding day the mother felt a lump on the outer aspect of the lower third of the right thigh, which she attributed to this fall. There was a continued painless growth of this lump. On admission, the lower 213 of the right thigh was occupied by a large firm tumor, fusiform in shape. The X-ray diagnosis by Dr. Herendeen was endo- thelial myeloma of the right femur. Following X-ray treatment, the tumor had clinically disappeared by December 8, 1927. On January 5, 1928, a radiograph showed some Uing in of the destroyed areas of 13 184 QEORQE T. PACK AND ROBERT Q. LEFEVRE the femur. However, the endothelial myeloma soon recurred and the patient died in April, 1928, with metastasea to lungs, left humerus, left ulna and skull. Multiple Myeloma. In contradistinction to the endothelial myeloma, the multiple myeloma is characterized by the rela- tively late age at which it occurs. Of all tumors of bone, it affects patients of the oldest average age, i.e., 42 years. All the persons in this series of 11 cases were adults older than 29, with the exception of one case of doubtful diagnosis, which had some of the characteristics of Ewing's tumor. As a tumor entity it constituted 1.9 per cent of all bone tumors and 0.066 per cent of all the malignant tumors comprising this review. In this series, 72.7 per cent were males; this is in close agreement with the statistics of other authors, 70 per cent-Geschickter and Copeland (55), 76 per cent-Charlton (22), 80 per cent of 33 cases-Anders and Boston (3), 68 per cent of 98 cases-Walgren (155). The reason for the predominance in men is not known.

TUMORS OF THE ALIMENTARY TRACT Cancer of the alimentary tract is of far greater prevalence in males; the degree of prevalence is not the same in all organs or parts of the digestive system. Thus the major liability of the male to cancer seems uniformly and gradually to approach the female liability as we consider the ratio of sex from the mouth through the digestive tube to the anus. The excess of male over female was as follows: Ca. of lip-16.2 to 1 ; Ca. of floor of mouth -18.8 to 1; Ca. of buccal mucosa-8.5 to 1; Ca. of tongue- 6.6 to 1; Ca. of tonsil-9.8 to 1; Ca. of esophagus4.1 to 1; Ca. of stomach-2.2 to 1; Ca. of small intestines-1.7 to 1; Ca. of colon-1.3 to 1; Ca. of rectum 1.6 to 1; Ca. of anus-1.5 to 1. The alimentary tract and accessory organs of digestion contained 48 per cent of all the cancers in males, but only 11.4 per cent of all cancers in females; therefore cancer in this location was roughly four times as prevalent in males as in females. Lazarus- Barlow (86) observed that in cancer of the alimentary tract, the disease occurs, on the average, distinctly later when the primary AGE AND SEX DISTRIBUTION 185 site is one which is usually attacked by carcinoma of the aqua- mous cell type. The Memorial Hospital data confirmed this statement; the patients with squamous cell lesions averaged five years older than those with glandular carcinomas of the digestive tube.

(a) TUMORS OF THE INTRA-ORAL GROUP AND NEIGHBORING ORGANS Epidermoid Carcinoma of the Lip. Only 3.56 per cent of these 589 carcinomas involved the upper lip, although it is of the same anatomical structure and has the same function as the lower lip. As stated previously, the ratio of males to females for cancer of the lip was 16.2 to 1 ; for the upper lip the male had the prevalence of 4.25 to 1. The explanation of this inequality is probably that males are more prognathous than females, their lower lips are more commonly exposed to wind and sun (chronic solar cheilitis), some of their upper lips are protected by mous- taches, they continue to be the heavier smokers particularly of pipes. Cancer of the lip comprised almost 7 per cent of all the malignant tumors occurring in males. Like epidermoid carci- noma of the skin elsewhere, these lip cancers are tumors of in- creasing frequency with age (Table 23). They are rare in early life; Stephen's (139) case of histologically proven epithelioma of the upper lip in a 14 year old boy was the youngest we could find in the literature. Case Report No. 11. T. M., a single white man, aged 24, had a small indurated ulcer with pearly edges, on the right side of his lower lip for a period of two months. It measured 314 cm. in diameter and was not accompanied by palpable cervical lymphadenopathies. He smoked 20 cigarettes daily. This early epidermoid carcinoma was treated by radium in 1920. Eight years later there was no evidence of recurrence. Case Report No. 12. N. N., a white man, aged 90, had an ulcer of four years duration on his lower lip. It was a squamous carcinoma of slow growth. At the time of admission it measured 1-112 X 2-112 cms. and was not accompanied by cervical lymph-node metastases. It was healed and cured to date by the application of radium. Case Report No. 13. J. M., a white man, aged 91, had a squamous 186 GEORGE T. PACK AND ROBERT Q. LEFEVRE carcinoma removed from his lower lip by surgery 30 years before ap- plying for admission to the Memorial Hospital. Twenty-seven years later it recurred and was incompletely removed by another surgeon. On admission, the neoplastic ulcer on the lower lip measured 3 X 1 centimeters and infiltrated the lip to a depth of 3 centimeters. There were no obviously involved cervical nodes. Dr. Quick treated the cancer by radium therapy; 18 months later, the last report was no evidence of disease. The particular interest in this case is the ex- tremely long interval before recurrence-27 years. The old age of this patient, the adult characters of the carcinoma and its feeble capacity for growth are putative reasons for the prolongation of this free inter- val. Someone has said half-seriously that no patient should be reckoned cured of cancer until he dies from some other disease. Epidermoid Carcinoma of the Floor of the Mouth. There was only one malignant tumor, namely prostatic carcinoma, which occurred in patients of greater average age than those who had epidermoid carcinoma of the floor of the mouth. This latter tumor was found in 274 patients averaging 61 years of age; it wm definitely among the tumors of old age, being most frequent in patients aged 50 to 95 years. Epidermoid Carcinoma of the Tongue. In the tongue, the 788 epidermoid carcinomas had their greatest age distribution in the decade 50 to 60 years, but the period of maximal incidence was from 60 to 70 years; after this peak it diminished somewhat with increasing old age. Cancer of the tongue is infrequent in early life, although several authentic instances have been re- ported, viz.- c~ aged 11 (Variot) ; Q aged 12 (Liston) ; o aged 18 (Morestin); Q aged 19 (Massabuau); Q aged 19 (Hutchin- son) ; 8 aged 20 (Gose) ; 9 aged 20 (Harrison) ; 8 aged 21 (Garlich). The reasons for the rarity of tongue cancers in youth are: the responsible irritants may not be present as yet, the irri- tants when present have had insufficient time to act and syphilis is relatively not common in young people. The youngest patient with lingual cancer in our group was 24 years old. Lingual cancers in early life occur as frequently in females as in males. In the entire group irrespective of age 13.1 per cent were in females; the percentage of females in other statistical AGE AND SEX DISTRIBUTION 187

studies are comparable, as 15 per cent-Whitehead, 5 per cent- Kocher, 5 per cent-Kronlein, 4.2 per cent-Dorrance and McShane (37), 3 per cent-Wolfler. Women as a rule observe better oral hygiene than men; their teeth are cleaner and in better repair on the average; they have less pyorrhea, less leu- coplakia, less syphilis and the majority still have less irritation from tobacco; they have fewer intra-oral cancers.

Case Report No. 14. F. I<., a single white female, aged 24, the youngest patient with lingual cancer, was admitted to the Memorial Hospital on November 2, 1928. Her father had died of cancer of the liver. In September, 1928, she experienced a sensation of swelling or of a mass at the base of her tongue, together with odynophagia. At another hospital the diagnosis was made of absceuiJ at the base of the tongue. The mass was incised four different times but no pus was ever obtained. The teeth and mouth were in an excellent hygienic state. No tangible source of irritation was discovered. On admission, a centrally located, non-ulcerated, nodular tumor mass was found at the base of the tongue, posterior to the linea terminalis and circum- vallate papillae and extending into the valleculae. It was 3 centi- meters in diameter and 1-112 centimeters in height. A single movable lymph node was palpated in each tonsillar area. Over the thyroid region, the thyroid gland could not be palpated and the tracheal rings were unusually prominent. A clinical provisional diagnosis was made of either transitional cell carcinoma of the base of the tongue or lingual thyroid. The treatment consisted of X-radiation to both sides of the neck, the insertion of gold radon seeds in the primary tumor and finally surgical exposure of the secondarily involved nodes with implantation of gold radon seeds by Dr. S. Johnson. Microscopical examination of the cervical lymph nodes led to the diagnosis of metastatic squamous carcinoma. Several weeks later the patient died of sudden accidental hemorrhage. Case Report No. 16. M. D., a man aged 91, had diabetes, multiple cutaneous epitheliomas and a discoid papillary epidermoid carcinoma which involved the left antero-lateral edge of the tongue. Symptoms had been experienced for four weeks only. There were no adeno- pathies. Recent treatment consisted of bilateral high voltage X-ir- radiation of his neck and gold radon seed implantation in the lingual lesion. Insufficient time has elapsed to pronounce a cure. 188 GEORGE T. PACK AND ROBERT Q. LEFEVRE Epidermoid Carcinoma of the Buccal Mucosa. Almost 9.5 per cent of carcinomaa of the buccal mucosa were in patients over 75 years of age. They comprised 4 per cent of all the malig- nant tumors in males. The average age of occurrence (58) was not in the period of maximal age distribution (60-64). Com- pared with the percentage of the general population living, the 362 carcinomas of the buccal mucosa were fairly evenly distri- buted among the quinquennial age periods from 60 to 95. The oldest patient was 97, the youngest was 14 years of age.

Case Report No. 16. J. P. M., a white man, aged 97, had a bulky ulcerated tumor occupying the left cheek and extending onto the left upper alveolar ridge and left side of the palatal roof. There were no palpable cervical nodes. Histologically, it was a squamoud carcinoma, Grade 11, Radio-resistant. Treatment by Dr. S. Johnson consisted of external radium therapy at a distance, supplemented by interstitial radon seed implantations. To-day, 6 months later, the lesion is almost healed. Case Report No. 17. C. L., a white girl, aged 14, observed a small papillary growth on the inner surface of the right side of her lower lip. She bit this protuberance off; it bled profusely and later recurred. The recurrence grew rapidly. On admission May 6, 1921, one month after her discovery of its presence, an elevated, indurated, ulcerated neoplasm, circular in shape, meaauring 2-112 centimeters in diameter and infiltrating to a depth of 314 centimeter, was found involving the mucosa of the cheek immediately posterior to the right oral commis- sure. The histological report was squamous carcinoma. In the right carotid area was a hard palpable lymph node. The treatment pursued by Dr. Quick was heavy external radium therapy at a distance to the cheek and neck supplemented by the insertion of unfiltered glass radon tubes into the primary lesion and followed by neck dissection. At the last observation 3 years later there was no evidence of disease.

Adenoid Cgstic Epithelioma of Mucous Membranes. The intra-oral adenoid cystic epithelioma has three unique differences from other malignant tumors of the mouth: (1) it was distri- buted equally among males and females, (2) the average age (43 years) of patients in whom it occurred was at least 5 years younger than for any other intra-oral carcinoma, (3) the loca- AGE AND BEX DISTRIBUTION 189 tions of all the tumors of this group was either at the central part of the base of the tongue or in the midline of the hard palate. These three facts indicate that the adenoid-cystic-epithelioma does not have the relation to chronic irritation, which is so characteristic of the epidermoid carcinomas of the mouth. We believe their location, early age at onset and parity of sex ratio can be satisfactorily explained by Cohnheim's theory of em- bryonal rests or cell inclusions. The nasofrontal process of the early fetus grows downward between the optic stalks to form the nose and philtrum; it fuses bilaterally with the superior

FIG.1. TEE DEVP~LOPMENTOF THE UPPERLIP AND ROOFOF THE MOUTH.The dotted lime represent the fusion of the anterior naao-frontal process and the lateral superior maxillary proceaaes. The adenoid cyetic epitheliomas were distributed along these lines. maxillary processes to complete the face; the roof of the mouth is formed by a Y-shaped fusion of these maxillary processes with each other posteriorly and the nasofrontal process anter- 190 GEORGE T. PACK AND ROBERT G. LEFEVRE iorly (Fig. 1). Along this line of fusion the adenoid cystic epitheliomaa were situated. The tongue develops by the forward growth and fusion of two mandibular rudiments around a centrally placed portion, the tuberculum impar; the posterior segment of the tongue results from the growing together of two lateral masses which develop from the antero-lateral walls of the pharynx. As this anterior (mandibular), central (tuberculum impar) and pos- terior anlagen develop and grow together, they surround a diverticulum to the thyroid gland to constrict it and form the

FIG. 2. T~EDEVELOPMENT OF THE TONGUE. A. Mandibular rudiment. B Tuberculum impar. C. Foramen caecum. D. Hyoid rudiment. E. Aperture of larynx. The adenoid cystic epitheliomaa of the tongue were distributed along the lines of fusion of the lingual anlagen. thyreoglossal duct or canal of His (Fig. 2). At this line of fusion, other adenoid-cystic-epitheliomas were situated. It is conceiva- ble that they developed from the inclusion of cell rests. Case Report No. 18. G. W., a white boy, aged 10, complained to his mother in June, 1920, of a nodule on his hard palate. At another hospital it was excised, recurred and was excised again on August 2, 1920. On admission to the Memorial Hospital, August 25, 1920, an ulcerated perforating lesion 2 centimeters in diameter was found on the AGE AND SEX DISTRIBUTION 191 hard palate. The edges were indurated. There were no adenopathies. The histological diagnosis by Dr. Ewing was: Malignant cellular tumor; suggestive of basal cell carcinoma of adenoid type. The lesion was cured by radium application; on May 2, 1929, there was no evidence of recurrence. Epidermoid Carcinoma of Antrum and Superior Maxi1l.u. Because of the difficulty of determining the primary source in many advanced cancers of the superior maxilla and antrum, the carcinomas of these two locations are considered together. This modifies the sex distribution, because primary tumors of the superior maxilla (oral side) are predominantly male and car- cinomas of the maxillary antrum are about equally distributed between the two sexes. Many of the antral carcinomas develop on the basis of a pre-existing empyema of the antrum; sinus in- fections are as frequent in the female as in the male. As a single group, two-thirds of the epidermoid carcinomas of the antrum and superior maxilla, were in mares; the proportion of males was lower in this group than in any other of the intra- oral carcinomas. They comprised 1.2 per cent of all the malig- nant tumors in females, which was the highest percentage of any intra-. Grant (60) reported a case of squamous-cell carcinoma of the superior alveolus in an 18-year-old boy and stated how infrequently this cancer appeared in youth. Four of the 307 patients in the Memorial Hospital series were younger than 18 years; the youngest patient was a 9 year old girl. Al- most 50 per cent of these patients were in the 15 year age period of 50 to 65. The incidence in proportion to the percentage of living population at all the age periods showed that the greatest age incidence (45 per cent) was from 60 to 75 years. Epidermoid Carcinoma of the Inferior Alveolus. Four and one-half per cent of all tumors in the intra-oral group were epidermoid carcinomas of the inferior alveolus. The average age of 58 years fell within the quinquennial period of greatest age distribution, 55 to 59 years; the period of maximal incidence was ten years later, 65 to 69 years. The incidence of occurrence of this tumor varied little during the age years 55 to 85. About 7 per cent of the 173 patients were older than 75 years. 192 QEORGE T. PACK AND ROBERT Q. LEFEVRE

Case Report No. 19. S. G. W., a white boy, aged 10, had a bean- shaped growth appear on his right lower jaw. It slowly increased in size. Two and one-half years later, the nodule waa surgically removed. Three months later it recurred; he was admitted to the Memorial Hospital on May 10, 1921, 4-112 years after the known date of onset. At this time the tumor was 114 inch thick and extended over the last three molar teeth. It was removed by cautery excision. There were no adenopathies. Histologically, it was an epidermoid carcinoma, possibly related to the adamantinoma group. The patient was lost to further observation. Case Report No. $0. oj the Inferior Maxilla. R. C., a white boy, aged 18 months, had a slight enlargement of the left side of his lower jaw. During the next year it became ulcerated and measured 2 centimeters in width. It was situated in the middle third of the horizontal ramus of the left lower mandible. Dr. Janeway curetted the lesion and buried glass radon seeds in the tumor bed. The histological report by Dr. Ewing was: " A fibrosarcomatous lesion of periosteal origin; whorls of cellular connective tissue surrounding hyaline blood vessels; considerable absorption of bone trabeculae; it probably will pursue a relatively benign course." The defect healed completely until seven years later when a small sequestrum was re- moved from the mandible. On December, 1927, nine yeara after the initial appearance of the tumor, there was no evidence of disease. These last two cases are presented not only because of their youth, but because they furnish examples of low grade malignant neoplasia occurring in childhood. This is contrary to the usual behavior of malignant neoplasms in children. The epidermoid carcinoma of case 19 may be of slow growth, because of its pos- sible origin from an enamel organ, whose neoplastic derivatives are seldom endowed with rapid growth propensities. The enamel-organ tumors or adamantinomas develop from embry- onal rests and theoretically should be of equal frequency in the two sexes; two-thirds of the 21 cases presented in this study were in males, whose average age (42) was 9 years older than the females who had the same type of tumor. (Table 4.) Epithelioma of the Faucial Tonsil. The great majority of these tumors were the common histologic types of epidermoid carcinoma; others were transitional-cell carcinomas and lympho- - -Eg $ Ka $ s\" 2 g 2 " 3 E: $ $ t-- N 6 d .i-' .i-' 2 CI r( d

1 13" 81" 35s 3%: 2 82s 582r( YP k $1 r( 3 flmm -3---3

$1- m 3 - --@4 qzm2- ", m-m a - -4'" * ' m -318 8 PN2 EN% E R am02 t--GO 2'2 2'2 %Z% R'R Xm8 ZN!2 m am$ 8:g 3-g m 2-2 gag m m $lez% s-a 2-5 - 4s g-R

$1~~2ZmI 32%4 @ sCO ZZS B"$ 4 X~"H~S 2~2OM- r-mgm N gee2 2~8a a $10~8S'X 83% Gw% ~2%2'2 N-m

b t- a&" $15'3 2-2 at-% 8'3 m wg

* * "2 am CV zwvc" NN*

f 12-2 be2 WNW - 3om2 NU^ ~-m f lwam -- a-m - - - mmw dm El- - u- N N z I N -I-N CV hl ij 1 3 4 UHN 3 M -3 $ I -4 2 l H - -a2 -Q, 382 113 311 3 si~'3- =i0+!$ Egg Egg Egg B E& Ekb Ek,b

' .-. : 0: : 5 7

C TABLE NO.

AIR % of Type 0ex Total Int~-Or8l Tumm W 5-9 10-14 15-19 2(t24 s29 S34 3539 40-44 45-49 S.54 55-59 60-64 65-59 70-74 75-79 80-84 85-89 90-94 9599 --A ------~pu~is...... ~otal 14 31222 2 3 20 0.5~2% Carcinoma-Tonsil ...... Male 3 4 2 8 11 41 64 70 5740 23 9 3 335 Female 2 11 23642633 1 34 Total 2 4 5 2 10 14 47 68 72 63 43 26 9 4 369 9.64% Lymphoearmma-Tonsil...... Male 2 222445 11 23 Female 1 2 1 11111 9 Total 122 232556121 32 0.836% Epithelioma-Nasopharynx and Pharynx...... Male 1 1 3 5 4 3 9 812106 111 65 Female 1 11212 3631 21 Total 2 11 15 663121415116111 86 2.247% Sarcoma-Nasopharynx and Pharynx...... Male 1 1 1 1 3 321 11 15 Female 1 2 1 1 5 Total 1 1 2 1 3 3411 2 1 20 0.522%

Primary Carcinoma-Epiglottis . . Total 1 54756211 32 0.836% Fibro-adenoma-Larynx...... Total 1 1 0.026% Papilloma-Larynx...... Male 2 2 1 32121 11 16 Female 1131 2 1 9 Total 2 22163141 2 1 26 O.W% Carcinoma-larynx...... Male 2 1 5 14 24 42 76 78 77 58 31 12 5 425 Female 14 225 93113 1 41 Total 3 5 5 16 26 47 85 81 88 61 31 13 5 466 12.176% Age % of Type Sex Total Intm-Od Tumors ------Ck4 5-4 10-14 15-19 20-24 %29 30-34 35-39 40-44 45-49 X-54 55-59 804 65-68 70-74 75-79 80-84 -89 ---90-94 9599 Sarcoma-Larynx...... Total 1 1 1 3 0.078% Carcinoma-Frontal and Sphe- noidal Sinuses...... Total 1 1 2 0.062% Carcinoma-Nasal Septum...... hlale 13 1322 3 2 2 1 20 Female 1 1 32211 11 Total 13 1 2322 352412 31 0.81% Primary Carcinoma-Submaxil- lary Gland...... Total 111 2141 11 0.287% Carcinoma-Parotid Gland...... Male 114 45453 11 29 Female 111 1121 251 16 Total 112151 66478111 45 1.175% Mixed Tumors-Parotid and Puh- maxillary Gland...... Male 1 1 122 4 7611 312 153 1 60 Female 1152510985345221 64 Total111 2 7 4 9171519 815 510 5 2 2 124 3.24% Endothelioma-Parotid Gland. .. Total 1 1 0.026% Adenoma-Parotid Gland...... Total 1 1 0.026% Sarcoma-Parotid Gland...... Total 1 1 1 3 0.078% Branchiogenic Carcinoma...... Total 5 3362113 24 0.6270/0 3,8W 100% 196 GEORGE T. PACE AND ROBERT G. LEFEVRE epitheliomas (Schminke's tumor). Primary cancers of the tonsillar pillars were included in this group as it was often im- possible to determine whether many of these cancers originate from the tonsillar epithelium proper or from the tonsillar pillars. Epitheliomaa of the tonsil comprised 9-112 per cent of all the intra-oral tumors. The male predominance-9.8 to 1 is prob- ably due to the same factors of chronic irritation, which have been mentioned as influential in determining the sex ratio in labial and lingual cancers. One unusual finding waa that the average age, the period of greatest age distribution and the period of greatest incidence corrected for the comparative percentage of the living population, all fell within the quinquen- nial period of 55 to 59. Indeed, the tonsillar cancer did not increase in relative incidence with age as did many of the epider- moid carcinomas of other locations; the oldest patient was only 81 years of age. The average age of the 369 patients with epithelioma of the tonsils was 2 to 5 years younger than in the case of other intra-oral carcinomas. Sir Wm. Milligan (110) recently wrote: "Primary malignant disease is rare in the tonsil. It is rarely seen before the age of 45 and occurs almost exclu- sively in men." At the Memorial Hospital 10 per cent of these carcinomas were in patients younger than 45 years. In fact we found that in the age period 1 to 25 years, carcinoma of the tonsil was 13 times as frequent as carcinoma of the tongue. It is true that squamous-cell carcinoma of the tonsil is quite infrequent in young people; the more cellular-forms such as the transitional cell carcinoma and lympho-epithelioma were the histologic varieties comprising most of the tonsillar carcinomas of youth and young adulthood, but these latter varieties are not at all confined to youthful subjects. We have the distinct impression that the pharyngeal ring, consisting of soft palate, tonsil and tonsillar pillars, pyriform sinuses, valle- culae and base of tongue posterior to the linea terminalis and V of the circumvallate papillae, is predisposed in relatively youth- ful persons, to develop cellular, rapidly growing, highly malig- nant but radiosensitive carcinomas of the pavement cell type. AGE AND SEX DISTRIBUTION 197

Case Report No. 21. C. M., a white girl, aged 3 years, had a hard lump in the right side of her neck below the mastoid process. Previ- ously she had measles at 10 months and pertussis at one year of age. Her mother observed the gradual growth of this lump until six months later, September 13, 1927, when she was brought to the Memorial Hospital. At this time the right tonsil was greatly enlarged and firm in consistence. The mass in the upper right cervical region measured 5 X 7 centimeters. X-irradiation caused some subsidence in size, but the response was not typical of lymphosarcoma. On November 2, 1927, Dr. Quick performed a tonsillectomy and implanted gold radon seeds in the neck mass; on December 5, 1927, this group of large hard cervical nodes was dissected and removed. The histological diagnosis was: cellular epidermoid carcinoma of the transitional-cell type. Later a radiograph showed mottling in the left lung suggestive of metastases. A recurrent tumor appeared in the scar of the neck wound and the child died, March 17, 1928. Case Report No. 22. I. R., a white girl, aged 19, had chronic tonsil- litis for many years. She felt hard, movable nodes in the left side of her neck. Three months later a soreness developed in the left tonsillar area, so she had a tonsillectomy performed one month later. One year after the onset of symptoms, she was admitted to the Memorial Hospital complaining of hoarseness, rapid growth of nodes in her neck and pain on swallowing. Radiograph of chest was normal. A recur- rence was detected in the left tonsillar bed. Gold radon seeds were implanted in the tonsil and heavy external radium therapy was given. Now, four months later there is no evidence of disease.

TABLE NO. 5 Tumora of the Larynx Number Percentage Epidermoid carcinoma...... 488 94.14% Sarcoma ...... 3 0.01% Papilloma...... 25 5.05% Fibro-adenoma ...... 1 0.20% - 495 100.0 % Epidermoid Carcinoma of the Larynx. The ratio of males to females with carcinoma of the larynx was 10.4 to 1. These can- cers embraced 5.3 per cent of all the malignant neoplasms in males, but only 0.48 per cent of the malignant tumors in females. The larynx of the male is larger and coarser than the larynx of the female, but this anatomical difference does not explain the 198 GEORGE T. PACK AND ROBERT G. LEFEVRE marked disparity in frequency of occurrence in the sexes. The overwhelming predominance of intra-oral sources of chronic irritation, infection and the inhalation of acrid pipe smoke in males is the only tangible explanation available. Female sub- jects averaged 5 years younger than males with laryngeal can- cers. The benign of the larynx occurred in patients 22 years younger on the average than those with cancer; there were two males to every female with papilloma of the larynx, but this male preponderance is only one-fifth as great as occurs in carcinoma of the larynx. About 55 per cent of the cases of laryngeal cancer occurred between the ages of 50 and 65 years. The incidence of laryngeal cancer is greatest in the quinquennial period 60 to 64, then it decreases gradually in the older age groups; however at age 75, the incidence of this type of cancer is 32 times as great as at age 25. Carcinoma of the larynx is rare in youth; only 0.64 per cent of the 466 patients in this group were younger than 25 years. St. Clair Thomson (149) reported two instances of intrinsic laryngeal carcinoma, occurr- ing in patients 16 and 18 years of age. Case Report No. 23. A. O., a white girl, aged 22, had a severe laryn- gitis of three weeks duration in December, 1924. Tha hoarseness persisted and increased until July, 1926, when she could merely whisper. On August 5, 1926, a tracheotomy was performed for the emergency relief of acute dyspnea with cyanosis. On admission to the Memorial Hospital in December, 1926, the larynx was filled with a vascular tissue which surrounded the tracheotomy opening. The disease involved the isthmus of the thyroid gland, anterior wall of the trachea, cricoid cartilage, and anterior walls of the thyroid cartilage. The histological diagnosis was: infiltrating squamous-cell carcinoma, Grade 11. On December 13, 1926, Dr. Hayes E. Martin did a laryngotomy and in- serted gold radon seeds into the laryngeal tumor. There was rapid and complete clinical disappearance of the cancer. On March 8, 1929, certain tremors in the upper extremities were diagnosed by Dr. George Hyslop as parathyroid tetany; the blood calcium at this time was only 4.4 milligrams for a hundred cc. of blood. To-day September 6, 1929, she is apparently free of disease. AGE AND SEX DISTRIBUTION 199

Carcinoma of the Nasal Mucosa. The average age of the 31 carcinomas of the nasal mucosa was 46 years; the females aver- aged 56 years, the males only 40. The incidence in the decade 50 to 70 was relatively quite high. There were two distinct groups of patients with carcinomas okiginating in the nasal mucosa; one group was of an age distribution and incidence, which corresponded with the majority of the epitheliomas of the nasopharynx and the great group of intra-oral cancers; the other smaller group was in the period of pre-pubertal adoles- cence. Sixteen per cent of all the cases were under 25 years of age. Case Report No. 24. A. T., a white male, aged 9, was admitted to the Memorial Hospital in June, 1924. Six years previously, when 3 years old, enlarged lymph nodes were removed from his neck; these were not subjected to histological examination. In January, 1924, he had frequent epistaxis and constant obstruction to the right nostril. In May, 1924, a growth was noticed in the right nasal orifice. On admission, a friable vascular tumor growth was observed to originate from the region of the right middle turbinate bone. The histologic diagnosis by Dr. Ewing was Schneiderian carcinoma. Radium therapy caused a complete clinical disappearance of the cancer. When last seen, December 27, 1928, there was no evidence of recurrence. Case Report No. 26. P. Z., a white girl, aged 9, had a brisk epistaxis and a gradual proptosis of the right eye in March, 1920. In May, 1920, a tumor was removed from her nose at another hospital. On admission to the Memorial Hospital, May 21, a radiograph showed a destructive process in the right antral and ethmoidal regions, with involvement also of the inner wall and floor of the right orbit. Dr. Quick performed an exenteration of the right orbit and antrum and buried radon in the wound. The patient later developed liver metas- tases with ascites and died on December 30, 1920. The histologic diagnosis by Dr. Ewing was: " A very cellular, freely infiltrating malig- nant growth. The cells are polyhedral but are usually compressed to spindle and rounded forms. A diffuse carcinoma of the Schneiderian membrane type; probably embryonal." Case Report No. 26. J. H., a boy aged 10, was admitted August 24, 1920, with a large friable mass occluding the post-nasal space and de- forming the soft palate. The left antrum was invaded. Histologic- ally, it was a carcinoma of the Schneiderian membrane. Radium 14 200 GEORGE T. PACK AND ROBERT G. LEFEVRE therapy was successful; when last seen on December 5, 1928, he was clipically free of disease. Case Report No. 87. J. I?., a boy aged 10, held his mouth constantly open during the summer of 1927, because of absolute obstruction to his left nostril. In September, 1927, a tumor presented externally at the left nasal orifice. In Decembcr, 1927, an incomplete operation was performed at another hospital. In March, 1928, he was admitted to the Memorial Hospital, where the tumor was found to involve the left nostril and nasopharynx. Dr. Quick employed radium therapy externally and interstitially. At the present time September 9, 1929, he is clinically free of disease. The histologic diagnosis by Dr. Ewing was: "Diffuse carcinoma, probably arising from mucous glands. It resembles lympho-epithelioma. Grade I11 Radiosensitive." Case Report No. 28. N. F., a boy aged 16, had nasal obstruction since July, 1917, together with purulent rhinorrhea and intermittent epistaxis. Tonsillectomy was done in 1918. On admission March 8, 1920, 2-314 years after the onset of symptoms, the left nasal cavity, left antrum, left orbit and ethmoid sinuses were found to be invaded by an ulcerated nodular mass, The soft palate was also infiltrated by the tumor. Histologically, the tumor was a carcinoma of the Schneiderian membrane. Palliative irradiation only was employed because of the hopeless extent of the disease. The patient died on November 23, 1920. TABLE NO. 6 Tumors of Me Parotid Gland No. Percentage Carcinoma...... 45 26.16% ...... 125 72.68% Sarcoma ...... 1 0.58% Adenoma ...... 1 0.58% Total...... 172 100.0 % Tumors of the Parotid Gland. The mixed tumors and carci- nomas constituted almost all the parotid tumors; some of these carcinomas undoubtedly originated in pre-existent slowly growing mixed tumors. We classify the mixed tumors of this type as essentially malignant because of the high percentage of recurrences after surgical removal; histologically, it may seem to be a . In the group of mixed tumors, they were equally distributed between the sexes, as would be expected of AGE AND 8EX DISTRIBUTION 201

tumors originating from congenital or embryonal cell rests or inclusions. Two-thirds of the carcinomas of the parotid were in males. The disparate average ages of the patients with these tumors is interesting; those patients with carcinoma averaged 10 years older than those with mixed tumors of the parotid. The period of maximal age distribution for parotid carcinoma was 70 to 74 years, for mixed tumors, 45 to 49 years. The inci- dence of both tumors increases slightly with advancing age. In McFarland's (102) study of 380 mixed tumors of the parotid gland, the greatest distribution was from 21 to 30 years; 17 per cent of these tumors were in people younger than 20 years. In the Memorial Hospital series only 9.67 per cent of the mixed tumors were in patients under 25 years of age.

Case Report No. 19. F. R., an Italian boy, aged 4, had a small nodule appear in the parotid region in front of and below the right ear, in February, 1918. It rapidly increased in size. On March 2, 1918, an attempted operative removal was done; a rapid recurrence followed. On March 26, 1918, a second operation was attempted; again there was an immediate recurrence. On admission to the Memorial Hos- pital, April 22, 1918, there was a recurrent parotid tumor which pushed in the right lateral pharyngeal wall to occlude partly the oral pharynx. There was dyspnea, ptosis of the right eyelid and fixed dilatation of the pupil of the right eye. Histologically, the tumor was a plexiform epidermoid carcinoma. Palliative radium therapy did not check the fatal progress of the disease. The patient died on July 18, 1918.

TUMORS OF OASTRO-INTESTINAL TRACT AND ACCESSORY ORGANS (EXCLUSIVEOF ORAL CAVITY) Esophageal Carcinoma. Carcinoma of the esophagus resem- bles the intra-oral group of cancers more than it does the gastro- intestinal cancers of glandular origin; this resemblance is evident in three ways: (1) the epidermoid carcinoma is the common histological type, (2) the age and sex distributions are strikingly similar, (3) they have a common etiological relationship to chronic irritants. The average age (57 years) of patients with carcinoma of the esophagus, the period of greatest age distribu- tion and the period of maximal age incidence, all fell within the 202 QEORQE T. PACK AND ROBERT Q. LEFEVRE quinquennial epoch of 55 to 59 years. This is a singular age pattern. Indeed, the sixth decade of life (50-59 years) con- tained 45 per cent of all the patients in this large category. Less than one per cent of these patients were over 75 years old. Of the 421 patients with esophageal carcinoma treated at the Memorial Hospital, the youngest was 25 years old. We find that epidermoid carcinoma of this regional distribution is very rare in youth. Guisez (62) has reported one case, which oc- curred in a boy of 14 years. The sex distribution was in accordance with the reports of other investigators; the per- centages of males were as follows: at the Memorial Hospital 80.5 per cent of 421 cases; 75 per cent of 772 cases-Kraus (82) ; 92 per cent of 50 cases-Sherman (132); 93 per cent of 145 cases -Buchbinder (18); 83 per cent-Vinson (152); 84 per cent of 409 cases-Guisez (62) ; 82 per cent of 128 cases-Friedenwald, Zinn and Feldman (50) ; 90 per cent-Jackson (77) ; 95 per cent of 41 cases-Clayton (24); 88 per cent of 342 cases-Klein. According to our calculations, carcinomas of the esophagus com- prised 4.33 per cent of all the malignant tumors which occurred in males. Gastric Carcinoma. Only 334 gastric cancers, constituting 1.75 per cent of the hospital admissions, were examined and treated during this period. The actual proportion of cancers of the stomach among the general population is many times this figure, but gastric cancer presents essentially a surgical problem and consequently is treated to a large extent by the general surgeon rather than in special cancer institutions. The average age of patients with this disease at the Memorial Hospital was 54 years; this corresponds to the findings of other inves- tigators, viz., 54 years-Balfour and Hargis (5), 52.7 years- Stinson (141). We found carcinoma of the stomach to be quite uncommon in elderly people; only 1.19 per cent of these pa- tients were over 75 years. The oldest patient with gastric can- cer, whom we could find recorded in the literature was a man aged 92, reported by Gurlt in 1880 (63). The peak of age incidence in our small series was from 65 to 69 years. Increasing age is not accompanied by an increasing incidence AGE AND SEX DISTRIBUTION

AGE AND SEX DISTRIBUTION 205 of gastric cancer. The digestive tract undergoes sundry deter- iorative changes with the onset of senility, such as atrophy of the salivary, gastric, intestinal, pancreatic and hepatic glands; gastric juices contain less hydrochloric acid; all the digestive juices are decreased in quantity and quality, so the rate of di- gestion is dower and fermentation and putrefaction of food consequently occur; there may be no teeth for proper mastica- tion; the fibers of gastric and intestinal walls have diminished elasticity; the stomach is usually dilated and atonic. These profound changes are not wholly responsible in causing gastric cancer as it is essentially a disease of middle life. In 1911, R. Schmidt (129) described two types of persons who were prone to develop carcinoma of the stomach; he termed these the dynamic and adynamic types. The former were ro- bust, active, heavy-eating individuals who developed the dis- ease late in life; the latter were thin, asthenic, chronic dyspeptics who developed the disease early in life, frequently on the basis of a gastric ulcer. We have been able to find ten early cases of gastric carcinoma recorded in the literature; their ages are as follows : 13-Moore (113) ; 14-Scheffer (128) ; 17-Koster (81) ; 17-Landouzy (84) ; 17-Hirtz (73) ; 18-Hammesfahr (66) ; 18 -Fowler (45) ; 18-Smithies (136) ; 20-Balfour and Hargis (5) ; 20-Lazarus-Barlow (86). At the Memorial Hospital, 1.2 per cent of all the patients were under 30 years of age; Welch (161) found 2.8 per cent of 2,038 instances and Smithies (136) 2.2 per cent of 721 instances of gastric cancer below this age limit. The youngest patient in our series was a woman aged 25 years. Cra- ver has recently reported two cases of gastric carcinoma in young adults in the Bulletin of the Memorial Hospital. The disease usually pursues a rapid course in young subjects; one of Craver's cases, included in this series, developed pulmonary lymphatic carcinosis, which is especially frequent in young people. Mathieu (98) and Dock (34) in independent articles assumed a divergent view from that generally believed as they maintained that gastric cancer runs a somewhat slow course in early life. Ewing (42) states that a high proportion of the early cases appear to be . Fowler (45) re- 206 GEORGE T. PACE AND ROBERT a. L~FEVRE ported 9 patients with gastric cancer, who were under 26 years of age; clinically they gave a fairly good history of peptic ulcer; histologically, the tumors were rapidly growing adenocarci- nomas. Eight (50 per cent) of Smithies' 16 cases of gastric can- cer under 30 years, were ulcero-cancers. Although gastric ulcers in middle life are more common in males, in young adults they occur with equal frequency in both sexes. In the gastric cancers of young adults, the sex distribution is also equally di- vided between the two sexes. We cannot say with certainty whether or not this is because the ulcero-cancer is the predomi- nant type in youth. Smithies (136) states that in gastric cancer of young people there is a greater tendency to find hydrochloric acid present in the stomach contents, than in carcinoma of the stomach in older persons; 15 of his 16 reported cases had free hydrochloric acid (averaging 86") in their gastric contents. MacCarty and Mahle (95) studied the cellular differentiation of gastric cancer in patients of various ages; the greatest fre- quency of cancers with no differentiation occurred in patients between 29 and 40 years of age; the greatest frequency of cancers with the maximal degree of differentiation occurred in patients between 40 and 50 years of age. Gastric cancers are predomi- nant in males, 79 per cent-Balfour and Hargis (5), 68 per cent- Kaufmann (79), 69.2 per cent-Memorial Hospital cases. There were only 2 sarcomas, in contrast to 334 carcinomas of the stomach. Carcinoma of Small Intestine. Cancer seems to prefer the beginning and the end of the alimentary tract. The inter- mediate portion, particularly the small intestines, is seldom the site of malignant neoplasia. This is a remarkable fact, when we consider the great surface area exposed to irritation and other factors, in the mucosa of the small intestines. The average age of the 8 patients at the Memorial Hospital was only 43 years. Case Report No. 30. G. C., a white man, aged 25, was admitted on July 20, 1921. In 1917, a laparotomy was done for the relief of intestinal obstruction. Two years later he began to experience pain in the right lower abdominal quadrant, obstipation and strangury. He had lost 30 pounds in weight in 3 years' time. Shortly after ad- AGE AND SEX DISTRIBUTION 207 mission to the Memorial Hospital, an exploratory laparotomy revealed an irremovable gelatinous carcinoma of the ileum. Palliative irradirt- tion was employed, but 18 months later the patient died of broncho- pneumonia. Carcinoma of the Appendix. Carcinoma of the vermiform appendix must be a rare disease, if we consider the vast number of appendices which are removed for infections and supposedly infectious disturbances and the infrequency of the discovery of carcinoma in these specimens. We do not know why carcinoma of the appendix seems to be more common in females than in males, unless it be because more are discovered at operation or in the pathology laboratory since more women are subjected to laparotomies and appendicectomies than men. The percent- ages of females as given by different authors are as follows: 82.4 per cent-J. Selinger (130), 66 per cent-A. S. Jackson, 57 per cent-C. A. McWilliams (105), 66 per cent-Memorial Hos- pital series. Carcinomas of the appendix occurred in patients with the youngest average age of all the group of gastro-intes- tinal cancers, namely 32 years. Selinger (130) found the aver- age age to be 34 years, A. S. Jackson41 years, and J. M. Graham (59)-51.8 years. Three of our six patients were under 25 years of age. MacCarty and McGrath (96) reported an in- stance of appendiceal carcinoma in a child 5 years old.

Case Report No. 91. R. H., a single white girl, aged 17, had symp toms of chronic appendicitis of one year's duration. Two months prior to application to the Memorial Hospital, an appendicectomy had been done elsewhere. The pathologic histology was a colloid carcinoma of the appendix. Since the operation there was a bloody diarrhoea. On admission, the patient was anemic, a mass was palpable in the right lower abdominal quadrant, and the entire circumference of the rectum was involved by an extensive secondary growth extending as high as the finger can reach. Palliative external radium therapy did not prevent death, which occurred seven monthe later. Case Report No. 32. L. B., a single white girl, aged 18, had a severe pain in her right lower abdominal quadrant, which she attributed to bathing in cold water when menstruating. An immediate appendicec- tomy was done in another hospital; the appendix was not reported as 208 GEORGE T. PACK AND ROBERT G. LEFEVRE containing a tumor. Five months later (November 1, 1918), a sinus appeared in the scar and led to a palpable mass in the region of the caecum. Exploration led to the removal of tissue which was diagnosed as of appendix and caecum. External radium therapy was employed and the patient survived for 2-112 years, dying in July, 1921. Carcinoma of the Colon. The 107 cases of cancer of the colon comprised only 0.65 per cent of all the malignant tumors studied at Memorial Hospital. The sex ratio was 56 per cent $44 per cent 9 ; this differs somewhat from the percentages found by other authors as 60 per cent 840per cent Q (W. H. Mc- Guffin (104)); 70 per cent 8-30 per cent 9 (W. McK. Craig and W.' C. MacCarty (28)). Approximately one-fifth (20.6 per cent) of the carcinomas of the colon were situated in the caecum; these had the same average age as the carcinomas of other por- tions of the colon. Two-thirds of the caecal carcinomas oc- curred in male subjects. The quinquennial period of greatest age distribution was 50 to 54 years; the period of maximal inci- dence was 75 to 79 years. The incidence tended to increase with age. Five of these patients (4.7 per cent) were older than 75 years. Wainwright (154) reported a carcinoma of the colon in a girl, aged 11 years; V. E. Mertens (109) observed a car- cinoma of the colon in a stillborn child. Our youngest patient was 22 years of age (vide infra).

Case Report No. 99. C. S., a single white girl, aged 22 years, was admitted with the diagnosis of sub-acute intestinal obstruction follow- ing obstipation of long duration. She was severely anemic. Explora- tory laparotomy showed an irremovable growth originating in the sigmoid colon. The histological diagnosis was adenocarcinoma of the colon. The patient survived the operation only a few days. Carcinoma of the Rectum. Almost one of every 25 patients studied in this institution had carcinoma of the rectum; a total of 755 cases or 4 per cent of all admissions. These cases com- prised 44 per cent of all the neoplasms, benign and malignant, originating in the gastro-intestinal tract below the esophagus. Six per cent of all the malignant tumors in males were indigenous AGE AND SEX DISTRIBUTION 209 to the rectum. The sex ratio was 61.7 per cent males and 38.3 per cent females; this closely agrees with Friedenwald and Rosen- thal (49) who found 66 per cent of rectal cancers in males. On the average, the males were four years older than the female subjects. In the group of patients under 30 years of age, the females outnumbered the males by the proportion of 58 per cent 9 to 42 per cent 8. The greatest age distribution was in the period 55 to 59 years; the maximal age incidence was in the 60 to 64 year epoch; in the older ages, the incidence gradually de- creased, thereby demonstrating that cancer of the rectum is not a disease of old age. Only 2.5 per cent of all our patients were older than 75 years. Rankin and Broders (124) have commented on the frequency of rectal cancer in persons under 30 years of age. We found 15 instances (1.98 per cent) of rectal cancers in subjects younger than 25 years. A considerable number of the rectal cancers in young people are associated with or originated from benign rectal polyps. We have the clinical impression that carcinoma of the rectum in young subjects is attended by a prognosis increasingly severe in direct proportion to their youth. Fowler (46) likewise has stated that in rectal cancer of the young, a higher percentage of lymph node involvement was found and the average post-operative life was shorter than in similar cases in the adult. Numerous case reports of rectal cancers in young people have been reported in medical literature, viz: 7 yrs. 8 (H. H. Hines) (72); 11 yrs. Q (Stern (140)) ; 12 yrs. 8 (J. A. Milne (111)) ; 13 years # (Czerny (31)) ; 15 yrs. 8 (R. H. Fowler (46)); 16 yrs. (Lazarus-Barlow (86)); 17 yrs. (Cripps (30)); 17 yrs. (Schoening); 18 yrs. 3 (S. A. Loewenberg (92)); 19 yrs. 9 (A. W. Jacobs (78)). Case Report No. 34. F. G., a single girl, aged 17-112, had a colostomy at another hospital for palliative relief of a rectal carcinoma. Eighteen months later, the patient was admitted to the Memorial Hospital with metastases t,o the spinal column, extension to the vagina, intractable pain in the legs and pelvis and severe anemia. There were only 688,000 red blood cells per cu. mm. of blood. She died two weeks later. Case Report No. 36. H. C., a white married woman, aged 21, was 210 GEORGE T. PACK AND ROBERT Q. LEFEVRE admitted to the hospital on July 20, 1921. Three weeks prior to this date she began to experience hourly liquid evacuations accompanied by severe rectal pain which she described as shooting and throbbing. Beginning 2 crns. above the anal canal and rectal sphincter and extend- ing upward 8 to 10 crns., there was a bulky, ulcerated neoplasm involv- ing the posterior and left lateral rectal walls. The mass was firmly adherent to the sacrum. It was adjudged inoperable. Palliative ir- radiation was employed subsequent to colostomy. The report on the pathological tissue, was gelatinous carcinoma (Ewing). The patient died on June 10, 1922. Case Repmt No. 36. A. L., a white male, aged 18, had severe rectal hemorrhages from a rectal neoplasm. Histologically, this tumor waa an hemangio-endothelioma originating in a naevus of the rectal mucosa. Following a colostomy, a Krasky resection of the rectum was done. occurred in the right kidney, which was removed. The patient was treated palliatively by Roentgen-rays. To-day, two years later, he is still living. Carcinoma of the Anus. The average age (48 years) of the 10 patients with carcinoma of the anus was 5 years younger than the average age of subjects with carcinoma of the rectum proper. Carcinoma of the anus is the youngest group among all the regional distributions of epidermoid carcinoma. Three- fifths of these cases were in males. Our youngest patient was a man, aged 20 years. Carcinoma of the Pancreas. Pancreatic cancer is predominant in males, who comprised 71.4 per cent of the 21 cases in this group. Although the average age of these patients was only 50 years, the incidence tended to increase with advancing age from 40 to 68 years, which was the age of the oldest patient. The ageing process affects the pancreas, anatomically and functionally; it becomes fibrotic and shrunken. The inade- quacy of pancreatic function is frequently shown in the so-called benign glycosurias of the aged. Just how these changes could account for the increasing incidence of pancreatic cancer with age is unknown and questionable. Carcinoma of the Gall-Bladder. Cancer of this location is overwhelmingly more common in females; 81 per cent females and 19 per cent males. Females are generally believed to have AGE AND SEX DISTRIBUTION 21 1 gall-stones with greater frequency than males. As age increases so does the frequency of gall stones and cancer of the gall bladder. Of all patients in whom gall stones are known to be present, five per cent are said to have cancer of the gall bladder. Parker Syms found gall-stones present in one hundred per cent of cases of primary cancer of the gall-bladder and bile ducts. This offers one possible explanation for the predominance in females. Cancer of the gall-bladder is distinctly a disease of mature life; the youngest patient was 40 years of age. The average age of our 21 patients was 57 years; the maximal age incidence and distribution were in the quinquennium 60-64 years. Primary Carcinoma of the Liver. Primary hepatic cancers are infrequent; they form 0.17 per cent of the admissions to this institution. The majority of these 28 tumors-71.4 per cent, were in males. The patients averaged 49 years of age; the youngest subject was a male aged 22 years. Ewing (42) has said: "two forms of liver cancer appear to be characteristic of old age (1) the cancerous cirrhosis in which an old cirrhotic process terminates slowly in a general cancerous degeneration of the incarcerated liver lobules; (2) the solitary malignant hepatoma, which usually occurs in middle life but may appear in elderly subjects and run a rapid course."

TUMORS OF THE GENITO-URINARY SYSTEM Carcinoma of the Urethra. J. English (41) analyzed 16,667 cases of neoplasms distributed among various organs and failed to find one instance of urethral cancer. At Memorial Hospital, they are uncommon but the 18 cases comprised 0.1 per cent of all admissions. We found 83.3 per cent in females and 17.7 per cent in males; Hugh Young (168) believes that carcinoma of the urethra is of equal frequency in the sexes. The average age of the patients with this disease was 55 years; the males on the average were eleven years younger than the females. Turnoj the Geniburinary System I I Age &r % of(=enito- TYW Civil Total urinary state tlllnom. ------0-4 54 10-14 15-19 20-24 25-29 ----30-34 35-39 40-44 4549 ------W.54 5559 60-64 65-69 70-74 75-79 m84 8589 Carcinoma-Penis...... Single 1123511 2 1 17 Married 13368131314967 83 Total 125 611 914131610 6 7 lo0 2.03% Papilloma-Penis ...... Total 1 1 2 o.0470 Teratoma-Testis...... Single 1 2 1 6 7 14 11 6 6 1 1 56 Married 2 18292512 8 6 5 23 1 111 Total 12 1 6 9 32 40 31 18 8 7 5 2 3 1 1 167 3.370 Sarcoma-Testis...... Total 1 2 3 2 8 0.16270

Carcinoma-Prostate . . . Single 1 411134782 32 Married 2 4 10 25 53 63 69 47 21 8 302 Total 1 4 3 5 11 28 57 70 77 49 21 8 334 6.781y0 Sarcoma-Prostate . . . . . Total 2 113 1 1 9 0.183% Carcinoma-\'ulva. . . . . Single 1 1 2 532311 19 Married 1 2 7 12 12 14 15 17 12 5 1 98 Total 1 1 3 7 14 12 19 18 19 15 6 1 1 117 2.375% Adenocsrcinoma- Bartholin's Gland. . . . Total 1 1 2 0.O4yo Papilloma-Vulva ...... Total 121 4 0.08170 Carcinoma-Vagina. . . . . Single 1111 211 8 Married 1211115 61311 18 9 2 3 2 94 Total 1 3 2 12 16 6 15 12 19 9 2 3 2 102 2.071% 8- Age % ofCenita- Cavil Total 'lbe tumors. 0-4 &9 1&14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 7W74 75-79 80-84 --85-89 Sarcoma-Vagina ..... Total 1 11 3 0.06% Carcinoma--Cervix uteri Single 3 5 912 81315 5 5 75 Married 4 54 122 274 348 382 322 250 163 82 44 13 1 2,059 Total 7 59 131 286 356 395 337 255 168 82 44 13 1 2,134 43.329% Carcinoma-Body of Uterus...... Single 1 2 34610212 31 Married 1 4 3 14 18 42 47 33 25 13 2 202 Total 11 6 3 17 22 48 57 35 26 15 2 233 4.731% Myoaarcoma-Uterus. .. Total 1 1 1 153211 16 0.324% UterinePolyp...... Single 1 1 Married 16331211 18 Total 16341211 19 0.385% Adeno-myoms-Uterus . Total 2 1 3 2 8 0.162% Fibroid Tumor-Uterus . Single 4 7 14 18 28 19 10 3 1 1 105 Married 3 24 47 129 186 I93 68 24 8 10 6 3 701 Total 7 31 61 147 214 212 78 27 9 10 6 4 806 16.365% Carcinoma--Ovary ..... Single 262527233 32 Married 1 2 2 13 8 27 23 17 16 15 5 1 29 Total 3 8 4 18 10 34 25 20 19 15 5 161 3.269% Ssrcoma--Ovary...... Total 1 1 1 1 4 0.081% Ovarian Cyste--includ- ing Demoids ...... Single 16 21315 9 6 8 22 64 Married 311 11 1 8 Total 19 3141510 7 8 23 72 1.461 % 4,925 1007, AGE AND SEX DISTRIBUTION 215

TABLE NO. 9 Tumor8 of the Urinaqy Bladder No Percentsge Epidermoid carcinoma (including papillary type) ... 453 80.78% Sarcoma ...... 2 3% Papilloma (Benign)...... 66 12.65% ...... - 1 .IS% Total ...... 522 100.0 % Papilloma of the Urinary Bladder. Two-thirds of the papil- lomas of the urinary bladder were in males. They included 3.2 per cent of all the benign tumors. Carcinoma of the Urinary Bladder. Of all the malignant tumors in this study, 2.74 per cent were carcinomas of the urinary bladder. These 453 neoplasms formed 9.2 per cent of all the tumors of the genito-urinary system. It has been generally stated that is a disease of old men; J. Gaudy and M. Schillings (53) found 75 per cent in males. In this series, 77.8 per cent were'in males and 22.2 per cent in females. Of all can- cers in the male sex, 4.37 per cent were carcinomas of the urinary bladder. The average age of the patients was 57 years; this was seven years older than the average age for patients with benign papillomas of the bladder. However, the quinquennium in which the maximal distribution as well as maximal incidence of bladder cancer occurred, namely 60-64 years, was the same as for benign papilloma of the bladder. After this age, cancer of the urinary bladder decreased in frequency; 4.6 per cent were in patients over 75 years of age.

Case Report No. 97. T. J., a single male, aged 20, complained of nocturia, polyuria, dysuria and frequency of urination. This increased in severity for one year, when he applied for treatment. For the previous six weeks he had hematuria and incontinence; vomiting was intermittent. A cystotomy was done and radium tubes were inserted in the bladder; a severe hemorrhage at this time was almost impossible to control. The patient died five days later. The necropsy findings reported by Dr. Ewing were: (1) extensive papillary villous carcinoma of the urinary bladder, (2) horseshoe kidney, (3) healed endocarditis, (4) status lymphaticus, (5) pyelonephritis, (6) diffuse purulent bronchi- tis with one area of lobular pneumonia. 15 216 GEORGE T. PACK AND ROBERT G. LEFEVRE Carcinoma of the Kidney. (19 cases.) Carcinomas of the kidney comprised only 0.385 per cent of the tumors of the genito-urinary system. They rarely occur before the fifth decade of life. Our youngest patient was a female, aged 22 years. Cases reported in earlier life are usually mixed tumors. Ewing (42) has said that one form of renal cancer which belongs exclusively to old age is the rare multiple adenocarcinoma arising in old arteriosclerotic kidneys. The papillary and infiltrating types of carcinoma of the kidney pelvis are associated with renal lithiasis in about 35 per cent of the cases and occur later than middle life. The remaining adult papillary adeno-carcinomas of the kidney parenchyma originated from the nephridial blas- tema. Adeno-myo-sarcoma of Kidney. (Tumor of Wilms.) Wilms' postulate was that the adenomyosarcoma originated from aber- rant cells of the myotome which had entangled uriniferous tubules in their growth. This hypothesis classifies the tumor as one of those whose manner of origin is best explained by the Durante-Cohnheim embryonal theory of prenatal rests. These early embryonal renal neoplasms are a heterogenous but related group. There is no histologic nor histogenetic identity which characterizes every member of this group of tumors. Some con- tain leiomyoblasts and others contain rhabdomyoblasts, etc., yet on the whole their history and behavior are quite similar. In keeping with the congenital origin of these tumors, males and females are equally represented. The renal adenomyosar- coma is definitely a tumor peculiar to infancy and childhood. The average age of the subjects with this neoplasm was less than three years, the youngest average age among a hundred different histological varieties of tumors. The oldest patient was only 8 years of age, whereas the tumor wae discovered in the youngest subject at the age of one month. Ten of our 14 patients were 4, or less than 4 years old. These 14 instances constituted 2.19 per cent of all the malignant tumors occurring in subjects under 25 years of age. We have analyzed the 14 cases in this series; 5 were admitted with the primary tumor intact, 9 were post- operative recurrences. Eleven of these patients died of the AGE AND SEX DISTRIBUTION 217 disease; 3 were lost to further observation, but one of these had been well for a period of two years after . The average duration of the disease was 13 months from the date of discovery to the time of death. The right kidney was involved in 10 instances. The common signs and symptom were: a paIpable abdominal tumor, abdominal pain, frequency of urination, hematuria, pyuria, and fever. The terminal signs and symptoms were vomiting, asthenia, anemia, cachexia and loss of weight. The presence of fever is singularly frequent in these patients as it is in other children who have malignant neoplasms, such as lymphosarcoma and endothelial myeloma. The initial response of these Wilms' tumors to radium or X-ray therapy was startling in its rapidity; they melt away very quickly under irradiation and approach the lymphosarcoma in their degree of radiosensi- tivity. The inability to effect a cure has been due to inaccessi- bility and depth of the tumor in addition to the faculty of speedily acquiring a relative immunity to radiation, the so-called acquired radio-resistance. Radiosensitivity is a property which is found frequently in the malignant neoplasms of childhood and youth. One of the reasons for this phenomenon is the lack of cellular differentiation in these tumors. Hypem~ephroma. Two-thirds of the 50 subjects with hyper- nephromas were males. Their average age was 44, six years younger than the patients with carcinoma of the kidney. In our statistical analysis, the hypernephroma was two and one- half times as frequent in occurrence as the renal carcinoma. The period of greatest age distribution and incidence was from 55 to 59 years. Ten per cent of these subjects were younger than 25 years. The theory of Grawitz that adrenal inclusions in the kidney substance may proliferate to form the intra-renal type of hypernephroma, furnishes a satisfactory explanation of some of these hypernephromas, particularly in youthful subjects. Other so-called hypernephromas are instances of mistaken identity; the clear-cell papillary adeno-carcinoma of the kidney simulates the hypernephroma in appearance. In this indefinite group are included a few primary adrenal tumors of medullary 218 GEORGE T. PACK AND ROBERT G. LEFEVRE origin. The youngest patient in the entire series, aged 1-114 years, had such a tumor, an adrenal neurocytoma. Case Report No. 38. J. T., a male baby, aged 15 months, in April, 1923, had lumps appear on both sides of his head in the temporal areas. The right-sided lump disappeared spontaneously, but the left one continued to grow. On June 1, a tonsillectomy, adenoidectomy and circumcision were done; shortly after this he developed measles. Ecchymoses appeared in both eyes and his irritability increased. On July 1, 1923, a bulging prominence waa apparent over his left eye; on July 15th, the mass reappeared on the right side of his temple. He was admitted to the Memorial Hospital on July 28, 1923, where he received external radium therapy to his head over the three prominent areas. There was some temporary improvement but he died October 28,1923. A necropsy by Dr. Lloyd F. Craver showed that one adrenal gland was replaced by a hemorrhagic tumor mass the size of a hen's egg; the liver, lungs and abdominal lymph nodes contained large tumor deposits. The temporal bones were infiltrated and partly destroyed by the tumor invasion. Microscopically, Dr. Ewing observed that the tumor was made up of small rounded and polyhedral cells which grew diffusely and failed to differentiate. The tumor resembled in structure and distribution an anaplastic adrenal neurocytoma. Epidermoid Carcinoma of the Penis. These 100 cases of penile cancer comprised 2 per cent of all of the tumors of the genito- urinary system and 1-114 per cent of all the malignant tumors in males. Seventeen were single and 83 were married men. The average age of the married men was 57 years, of the single men 43 years; this disparity of 14 years is difficult to explain. Phimo- sis is more common in single men and phimosis is admittedly a contributing factor in inciting cancer of the penis. It is con- ceivable that phimosis and in the other extreme, sexual intem- perance and irregularities, both of which are more common in single men, afford sources of chronic irritation which may induce cancer of the penis in a shorter time or at an earlier age than obtains in the case of married men. Coutt's (26) statistics for Chile in 1925, gave 41 per cent of the penile cancers as occurring between 25 and 35 years of age. This decennium in our studies contained only 7 per cent of the patients with carcinoma of the AGE AND SEX DISTRIBUTION 219 penis, hence there may be geographical variations for the age incidence of these and other cancers. Domucci (35) recently reported the instance of a man aged 28 with generalized leuco- plakia of the mucous membranes, who had an early epidermoid carcinoma on his prepuce. Domucci considered this an un- usually early age. Our youngest patient was 24 years old. Seven per cent of our patients were over 75 years of age. The quinquennial age period in which the greatest distribution oc- curred was from 60 to 64; the maximal age incidence was from 75 to 79. The incidence of penile cancers tended to increase with age.

Case Report No. 99. N. C., a single negro, agcd 24, was circumcised at another hospital in January, 1921; the wound never healed. He contracted syphilis when 19 years old, had successful anti-leutic treat- ment and 18 subsequent negative Wassermann tests. On admission in June, 1921, the glans penis, prepuce and under surface of the shaft were involved by an indurated lesion 12 sq. cms. in size. The diagnosis was papillary epithelioma. Palpable adenopathies were present in the left inguinal region. He refused operation so palliative irradiation was employed by Dr. Archie Dean. Later at another hospital the penis and scrotum were amputated. He is now alive.

Teratoma Testis. Benign neoplasms of the testicle are so rare that they are of very little clinical importance. Under the caption, teratoma testis, we have included the tumors called seminomas as well as other primary carcinomas of the testicle. The 167 tumors of this group comprised 3.39 per cent of all the tumors of the genito-urinary system, 2.09 per cent of all of the malignant tumors in males and 1.008 per cent of all the malig- nant tumors of both sexes. This corresponds to the frequency reported by other investigators of 1 to 3 per cent of all malig- nant tumors, Bouchard and Laquiere (ll), Weiser, and Morris (114). One-third of our subjects were single men; the average age of the single men was 28 years, of the married men 39 years, a difference of 11 years. Naturally singleness must precede the marital state and many of these single patients might have 220 GEORGE T. PACK AND ROBERT Q. LEFEVRE married at an older age, so it is probable that little correct infer- ence can be drawn from the relative frequency of teratoma testis and the disparity in ages of these subjects. Allowing for the probability of some later marriages, still the proportion of teratoma testis in single men seems somewhat high; this may be due in part to certain genital abnormalities which restrain the young man from marrying, such as cryptorchism, an ac- cepted . Sexual activity may have some important significance in the genesis of these tumors as they occur most frequently during the period of greatest sexual vigor. The average age of all our patients was 35 years (34 years-C. C. Higgins (71)). 74 per cent occurred before the age of 40 years, 62 per cent between the ages of 25 and 40, and 11.37 per cent in patients younger than 25 years. Tumors of the testis are said to be of comparatively rare occurrence in children (A. A. Kutzmann and T. E. Gibson (83)). Chevassu (23) found 5 cases of teratoma in children in a series of 128 testicular tumors. StefTen (138) stated that when tumors of the testis occurred in children, it was chiefly in early infancy, generally in the first six months of the first year; the incidence then gradually diminished in the second, third and fourth years and the tumors seldom occurred in later childhood. The youngest patient with teratoma testis was 3 years old; the oldest was an aged single man of 80 years. The age period of greatest distribution and maximal incidence was from 30-34 years; then the incidence declined toward old age. Case Report No. 40. S K., a Jewish boy, aged 4 years, had an en- larged left testicle which was first observed Aug. 14, 1923. The tumor grew rapidly and was excised at another hospital on August 29, 1923. The histologic diagnosis was teratoma testis. Prophylactic irradiation was given by Dr. Archie Dean. At the present time the boy is clinically free of disease. Caee Report No. 41. G. C., a white boy, aged 3, had always had a slightly larger right testicle. He had varicella, pertussis and morbilli at a younger age. In February, 1925, the right testicle increased rapidly in size and became quite hard but painlws. In April, 1925, a AGE AND SEX DISTRIBUTION 221 right orchidectomy was done in Philadelphia; Dr. Ewing classified the tumor as an Embryoma-Grade 3-Radiosensitive, with foci of large spindle cells of probable myosarcomatous nature. On February 28, 1928, the mother happened to discover a large mass in the boy's lower abdomen; he was otherwise healthy and made no complaint. On ad- mission to the hospital on March 1, 1928, the lower abdomen up to the level of the umbilicus was filled with a bulky cystic mass; it was central in location. Radiograph of the chest was negative for metastasis. The red blood count was 3,800,000 per cu. mm. Following X-irraditc tion the tumor had subsided to the size of a lemon by May 31, 1928. Then it began to grow again, developed radioresistance and became painful. The patient died on December 13, 1928. Case Report No. 42. W. R., a white boy, aged 7, was admitted on March 18, 1924, when a teratoma testis was excised. Then he was treated post-operatively by prophylatic external radium therapy. He was in good health until November 14, 1926, when the perineum, right groin and scrotum were found extensively involved by the recur- rent tumor. Death occurred in June, 1927. Case Report No. 43. M. W., a white boy, aged 14, observed a swell- ing of his right testicle in December, 1921; this increased continuously in size. Other signs and symptoms were loss of weight, asthenia, anorexia and anemia. In February, 1922, an orchidectomy was done. The histologic diagnosis was teratoma testis; the majority of cells were ovoid and spheroidal, others were spindle-shaped. By June 1, 1922, pain appeared in right abdomen and right leg. A metastatic mass the size of an orange was palpated in the right kidney region. A destruc- tive infiltration of the right ilium was seen in a radiograph. Death occurred on June 21, 1922.

Sarcoma of the Testis. Fifty per cent of the 8 subjects with sarcoma of the testis were married. The average age of these men was 25 years, ten years younger than the subjects with teratoma testis. Many of the contained sarcomatous elements.

Case Report No. 4.4. R. H., a baby, aged 14 months, had a swollen left testicle in May, 1917. It grew in three weeks to the size of an orange; the scrota1 skin became purplish over it. An orchidectomy was done, but a recurrence developed within three weeks. The histologic diagnosis was spindle-cell sarcoma. By October, 1917, the 222 GEORGE T. PACK AND ROBERT Q. LEFEVRE recurrent tumor was ulcerated, infected and as large as a grape-fruit. On October 19,,1917, Dr. W. B. Coley removed this recurrent tumor; on April 3, 1919, a small nodule was removed from the left side of the scrotum; On Dec. 23, 1919, Dr. Coley removed another small nodule from the scrotum. The child was given Coley's toxin. The histologic diagnosis on the latter specimens was: A very cellular round and poly- hedral-cell embryonal tumor. The last note by Dr. Coley, dated March 27, 1925, found the child well and in splendid health. This is a remarkable result in view of the uniformly bad prognosis of malignant testicular tumors in these very young people. Carcinoma of the Prostate Gland. The 334 prostatic carcino- mas comprised 1.75 per cent of all hospital admissions, 6.78 per cent of all tumors of the genito-urinary system, 4. 17 per cent of all the malignant tumors in males and 2 per cent of all the malig- nant tumors in both sexes. Ninety per cent of these men were married. The average age of all the patients was 63 years (65 years-H. C. Bumpus (19)). This was the oldest average age of subjects, of all the tumors included in this study. The mar- ried men averaged 64 years and the single men averaged 56 years in age, a difference of 8 years. Bumpus analyzed 1,000 cases of prostatic cancer at the Mayo clinic and found the young- est patient to be 42 years old. In R. Purckhauer's (122) series of 53 cases, only one was younger than 50 years. At the Mem- orial Hospital, 24 patients with prostatic cancer were under 50 years of age; the youngest of these was a single man, aged 22 years. Younger cases have been reported in the literature; S. J. Gardner and W. T. Cummins (52) observed an adenocar- cinoma of the prostate gland in a youth, aged 17 years. Our oldest patient was 84 years old. Two-thirds of the pa- tients were older than 60 years; 44 per cent were between 60 and 70 years of age; 8.68 per cent were over 75 years. The peak of age distribution and incidence occurred between 65 and 69 years (Table 23) ; the incidence then declines with each succes- sive age epoch. Here we are impressed by the singular fact that the one cancer occurring in patients at the oldest average age, is nevertheless not a disease which increases with old age but is expressive of the accidental factors attendant on the AGE AND SEX DISTRIBUTION 223 relatively late decay of the prostate gland. Ewing (42) explains the old age of patients with prostatic cancer as due to the origin of this disease on the basis of chronic prostatitis, which is seldom established before the sixtieth year. The senile changes accompanying the so-called male climacteric may also be in- fluential in determining the genesis of cancer in the prostates of elderly men. Prostatic atrophy occurs in only 10 per cent of men; in the remaining 90 per cent the gland either maintains its size or becomes enlarged by connective tissue or glandular increase. The prostatic ducts may be blocked by the fibrosis and deposition of lime salts, and the resultant stasis of secretion leads to epithelial proliferation. A certain number of prostatic cancers develop in prostate glands which are the sites of benign hypertrophic changes. Case Report No. 45. P. S., a white single male, aged 22, had pain, burning and frequency of urination terminating in acute retention in August 1922. He had never had sexual intercourse nor venereal dis- ease. The patient attributed his trouble to frequent masturbation. On rectal examination the prostate was tender, smooth, tense and four times its normal size. The median furrow was obliterated; the right lobe was larger. On September 21, 1922, at another hospital an attempted perineal drainage of a supposed prostatic abscess was unsuc- cessful. On October 13, 1922, Dr. Keyes did a cystotomy for supra- pubic drainage and did a biopsy of the tumor. Histologically, it was a diffuse infiltrating careinoma of the prostate. The new growth was made up of small hyperchromatic cells, growing in irregular strands and broad sheets with crude alveolar formation. He was admitted to the Memorial Hospital on Nov. 27, 1922, when Dr. Barringer treated him by interstitial prostatic irradiation by radium and X-ray high-voltage pelvic cycle. The patient died on February 13, 1923. Sarcoma of the Prostate Gland. Prostatic sarcomas comprised only 2.6 per cent of all the malignant prostatic tumors. Two- thirds of these patients were married. Their average age was 35 years; this was 28 years younger than the average age for prostatic carcinoma. Proust and Vian (121) found that 44 per cent of the prostatic sarcomas occurred during the first decade of life; R. Smith and W. R. Torgerson (135) observed 30.5 per cent in the first decade and maintained that this is the age 224 GEORGE T. PACK AND ROBERT Q. LEFEVRE

period of greatest frequency for sarcomas of the prostate. Mc- Farland (101) has stated that sarcoma of the prostate is not found in adult life. Descums (33) has asserted that after childhood, the greatest number of cases occurs in old age; our limited group of nine cases doea not confirm this statement (Table 8). Our youngest patient was 16 years of age; Laquiere and Bouchard (85) have reported an instance in a 9 months' old infant. Herrick's (70) conclusions are in agreement with our observations. He states that in almost 75 per cent of the cases the growths occur before the cancer age of 40 years and in about 80 per cent before the usual age of prostatic adenoma (50 years). He concludes, therefore, that a prostatic tumor occurring before 50 years of age is possibly sarcoma and one occurring in adoles- cence is probably of such a nature. Epidermoid Carcinoma of the Vulva. There were two instances of adenocarcinomas of Bartholin's glands in married women, whose ages averaged 46 years. The remaining 117 vulvar can- cers were epidermoid carcinomas. They comprised 3.38 per cent of the genito-urinary tumors in both sexes and 1.37 per cent of all the malignant tumors in females. The average age of these patients was 60 years; this was the oldest average age among the tumors of the female genitalia and was surpassed by only three other tumors of different regional distributions. The peak of the age incidence, i.e., in proportion to the relative number of people living, was in the years 70 to 74; this epoch was the one of greatest liability to . Over 6.8 per cent of all the patients with vulvar carcinoma were over 75 years of age. Four patients with benign vulvar papiIIomas had an average age of 43 years, which was 17 years younger than for epithelioma of the vulva. Our youngest patient with vulvar epithelioma was a single woman, aged 27 years. Single women totalled 16.2 per cent of all the cases. Primary carci- nomas of the clitoris comprised 2.5 per cent of the vulvar group; the 3 carcinomas of the clitoris were all in single women. Epidermoid Carcinoma of the Vagina. The 102 cases of epider- moid carcinoma of the vagina comprised 2.07 per cent of all the tumors of the genito-urinary system and 1.19 per cent of all AGE AND SEX DISTRIBUTION 225 the cancers in females. The average age of these patients was 52 years; the married women averaged 53 years, the single women 45 years of age, a difference of 8 years. The single women made up 7.8 per cent of all the vaginal cancers; we are unable to estimate the percentage of occurrence in virgins. The age periods of greatest distribution and maximal incidence of vaginal cancers coincide from 60 to 64 years. Over 4.7 per cent of these patients were over 74 years of age. The youngest patient was a married woman, aged 20 years. F. Ganghofner (51) reported a carcinoma of the portio in an 8 year old girl. Case Report No. 46. M. F., a Swedish married woman, aged 20, had profuse and constant vaginal bleeding with abdominal pain of two month's duration. She had one child. The right lateral wall of the vagina from the hymen to the vaginal vault was the site of a papillary ulcerated squamous carcinoma. There were bilateral inguinal lymphadenopathies. Radium therapy was unsuccessful as the patient died three and one-half months later. Sarcoma of the Vagina. The chief feature in the neoplastic pathogeny df the vagina in early life is said to be the great relative frequency with which multiple polypoid sarcomas arise from its mucosa. The infantile type, peculiar to little girls is the so-called or grape-like sarcoma, which usually appears before the third year of life. J. McFarland (100) found vaginal sarcomas to be most common in the first, fourth and sixth decades of life. We found 3 vaginal sarcomas in adults, averaging 46 years of age; these three patients consti- tuted only 2.85 per cent of the malignant vaginal tumors. This adult type is practically never found in infancy.

TABLE NO. 10 Tumors oj the Ulerua No. Percentage Epidermoid carcinoma of cervix uteri...... 2,125 66.07 % Adeno-carcinoma of cervix uteri...... 9 0.28 % Adeno-carcinoma of body of uterus...... 233 7.25 % Myosarcoma of uterus...... 16 0.488% Leiomyofibroma of uterus...... 806 25.062y0 Uterine polyp...... 19 0.59 % Adeno-myoma of uterus...... -8 0.25 Qj, Total ...... 3,216 100.0 % 226 GEORGE T. PACK AND ROBERT G. LEFEVRE

Carcinoma of the Cervix Uteri. The 2134 cases of carcinoma of the cervix uteri comprised 11.16 per cent of all admissions to the hospital, 12.88 per cent of all the malignant tumors in both sexes, 24.94 per cent of all the cancers in females and 43.33 per cent of all the tumors of the genito-urinary system. Only 9 adenocarcinomas or 0.42 per cent of all cervical cancers were found; two of these patients were single. The average age of the patients with adenocarcinoma of the cervix was the same as for the epidermoid carcinomas of the same location. Seventy-five or 3.5 per cent of all the cervical cancers were in single women; some of these women were multiparous. Therefore, we can say that epidermoid carcinoma of the cervix is uncommon in unmrtr- ried women; when this cancer is present, the same factors of irri- tation and injury which precede the carcinomatous changes in married women, are frequently present. Dr. Seelye W. Little (91) has conducted a statistical survey of Rochester, N. Y.; in a personal communication to us he gave the following interesting table : Uterine cancers-10.4 per cent of the total cancers in single women. Uterine cancers-25.8 per cent of the total cancers in barren married women. Uterine cancers-22.8 per cent of the total cancers in mothers with few children. Uterine cancers-21.1 per cent of the total cancers in mothers with many children. Accordingly he says that the more children a married woman has the less is her liability to develop ; if a married woman is childless she has a greater liability to uterine cancer than has the mother of few children, and a still greater liability than the mother with many children. He further states that the barren married woman dies at an earlier age from cancer, than does the single woman or mother and that the more children a woman has the later the age period at which she develops uterine cancer. F. C. Hammond (67) found only 3 to 4 per cent of cervical cancers in nulliparous women. The average age of our patients was 48 years; the single women with this disease were five years younger, as their aver- age age was 43 years. In Reuben Peterson's analysis of 406 cases of , he found the average to be 45.5 years. Fifty-one per cent of our patients were between 40 and 54 years TABLE NO. 11 Carcinoma of the Cerc6.z Uteri in Young Women - Race Marital Gynecological Eiatory Prenent History Phyical Rndinga Pathologio Diagnonis Treatment State I 1 Ikdt - -- - I - - I No. 47 White Single Mensea began at 16 Profuse leucorrhea wedulcer on cer- Malignant epithelial Palliative Nine months laterhad Jewisk yrs. Always irregu- for 4 yrs. For one VIX. tumor of adenocarci- radium nodulsr vaginal recur- lar . year vaginal bleeding nomatous type. Pro- therapy. rences. Four years ~ Imbecile. bably from embry- later died with ste- onal rest. nodrectum and vag- inal recurrences. No. 48 Black Married Menses began at 11 Profuse leucorrhea Cervix greatly en- Plelciform epidermoid Palliative Death--6 months yrs. Married when since childbirth. For larged and irregular. carcIlnoma. radium I later. 13 yrs. old. Only 8 months had irregu- Major portion of tu- therapy. child born at 14 lar ssng+eous die- mor is supra-vaginal. I years. charge myth hemor- Bilateral pelvic mass- ! rhages. es. Utemfixed. No. 49 Whik Normal menses since Onset 4 months pre- Mushroom-like. cer- Squamous Carcinoma Palliative Death - 10 months age 12. Para 11. viously with metror- VIX. Infiltration of Grade 111. 1rradiat.ion. later. Two normal labore; rhagia. Bleeds 3 days vaginal wall close to one child aged 7, one weekly. Late abdom- rectum. Bilateral aged 5 years. inal pain. parametrial infiltra- tion. KO. 50 Black Married Mensea at 12 yrs. Symptoms of 4 Large, ulcefated fun- Squamous Carcinoma Palliative Death - 3 months (4 X 28). one child. m o n t h s duration. gating mealtumor Irradiation. later. Had. laparotomy for Menaes ceased but ir- which bleeds easily. ovarlan t u m o r . regular staining. Marked infiltration Bartholin's abscess 3 Cramp-like pains in bilaterally and pos- ym. ago. epigsstrium. teriorly. C- Age --Report No. 51. 24 White Married Menses began at age Metrorrhagia for 2% Cauliflower papillary Plexiform epidermoid Palliative Ir- Irish 13. 3 X 28 day type. months. Pain in low- growth of cervix carcinoma. radiation. No pregnancies. er abdomen for one measuring 5 cma. in Radium tan- w=rmann ++ +. month. diam. Parametrial dem, bomb hiiitrstion. Fixed and X-rag uterus. cycle. No. 52. 25 Black Married Me- began at age Symptoms of 3 lrrephr growth oc- Epidermoid mcino- Radium in- Treatment only re- 15. Had one child months duration. In- cupylng cervix and ma. tra-uterine cent. when aged 17. termenstnur!bleeding extending posteriorly. and x-ray and yellod die- Some early paramet- cycle. charge. Gevere ab- rial invasion. dominal pain. No. 53. 25 Black Married Me- regular. Be- S y m p t o me of 4 Cervix wae large Epidermoid carci- Trated b y Living and well. No gan at age 13. Mar- months. duration hard, irregular and noma Grade I11 R.S. Dr. Healey evidence of disease. ried at age 14. Nor- Brown foul discharge. ulcerated. Bpdy of wit4 intra- ma1 labor at age 15. For 3 months haa had utem was tmce the uterine radi- daily vaginal bleed- normal size. Some um and x-ray induration of para- cycle. metrium. No. 54. 25 White Married Mewbegan at age Fow months ago felt Cervix replaced by Infiltrating squa- Radium Patient lost to further 14. Mew irregu- growth obstructing ulcerated tumor mous-cell carcinoma. therapy. obsewation. lar for last 6 yrs. vaginal outlet. Con- growth. Married at age 21. stant pain. Base of left broad No pvciea. Dye ligament fixed. pvand bleeding on lnterequree ever smce manage. AGE AND SEX DISTRIBUTION 229 of age; the maximal number of cases in any one age period was between 45 and 49 years. The greatest relative incidence fell in the quinquennial age-period from 55 to 59 years, then sharply declined with advancing age. Our oldest patient was 80 years. Carcinoma of the cervix was exactly twice as frequent after age 75 as before age 25. Seven of our 2134 patients were under 25 years of age; Geo. Van S. Smith, R. H. Smithwick and H. Rogers, Jr., (134) reported that in 433 microscopically verified carcinomas of the uterine cervix, there were only two patients younger than 25 years. Our youngest patient was a single girl, aged 20 years. Earlier cases have been reported by various authors, e.g., (a) 7 years-Glockner (57); (b) 13 years-A. Bonner (10); (c) 14 years-A. Aguinaga (4); (d) 18 years- DeRoubille (32); (e) 18 years-E. B. Cragin (27). Carcinoma of the Body of the Uterus. The 233 instances of carcinoma of the body of the uterus comprised 1.22 per cent of admissions to the hospital, 2.61 per cent of all the cancers in females and 1.41 per cent of all the cancers in both sexes. Thirty-one patients (13.3 per cent) were single; the percentage of single women with carcinoma of the body of the uterus was 4 times as great as the percentage of single women with carci- noma of the cervix. In the married women, the cervix is natur- ally exposed to greater injury and more frequent infection, so we might expect the disparity of cancer frequency which occurs in married and unmarried subjects. In the body of the uterus, cancer was just about as frequent in single as in married women, if we consider the relative numbers of these two groups living during the age periods when uterine cancer is common. A. E. Mahle (97) found 9.63 per cent of carcinomas of the body of the uterus in single women. On the average, the single women in our series were 4 years younger than the married women. The aver- age age of all the subjects with carcinoma of the corpus was 55 years; as a group these patients were seven years older than those who had carcinoma of the cervix. Forty-five per cent of the patients were between 50 and 59 years of age. The great- est incidence was from 55 to 59 years, after which there was a gradual decline in relative frequency with increasing age. 230 GEORGE T. PACK AND ROBERT G. LEFEVRE Ewing (42) states that: "The typical corpus carcinoma of elderly women and spinsters occurs in a small atrophic uterus and usually involves the entire endometrium. It arises on the basis of atrophic endometritis in which isolated glands escape atrophy and proliferate slowly." After the menopause, glandu- lar of the endometrium may occur instead of atrophy; this may be physiological; then again it may be carci- nomatous. The youngest patient was a single girl, 19 years of age. There were two married women, aged 19 and 22 years, who had chorion- epitheliomas but they are not listed under uterine cancers. Early cases have been reported by other authors: 3 under 20 years-Gayraud (54); 2-112 years-J. E. Adams (1); 18 years- E. B. Cragin (27); 19 years-Tschop (150). Some of these corpus carcinomas' in young women are probably genetically related to errors in development. (See Case Reports Nos. 55 and 56.) The vagina and uterus are formed by the coalescence of the Miillerian ducts; in this fusion it is possible that aberrant sequestrations occur with cell inclusions and subsequent neo- plastic transformation as maintained by Cohnheim. The comparative frequency of corpus and cervical carcinomas has been variously given by different investigators: 1 to 2.36- A. E. Mahle (97); 1 to 4.32-R. Peterson (119); 1 to 4.46- Smith, Smithwick and Rogers (134); and 1 to 8.16-Memorial Hospital cases. Case Report No. 55. R. S., a single Jewess, aged 19, began to menstruate at 14 years of age; the menses occurred every 28 days and lasted for three days. Four months prior to admission, she began to experience severe abdominal pain at her menstrual periods, accom- panied by menorrhagia. Pelvic examination showed a small globular mass extruded through the cervical 0s. This mass was removed by torsion. The histological diagnosis by Dr. Ewing was: "An embryonal cellular malignant tumor-exact origin and type uncertain, probably adenocarcinoma." Dr. Wm. P. Healy treated this patient by radium and X-ray therapy. To-day, 6 years later, there is no evidence of the disease. Leiomyofibroma (Fibroid Tumor) of the Uterus. These 806 tumors comprised 4.21 per cent of all admissions to the Memorial AGE AND SEX DISTRIBUTION 23 1 Hospital, 16.38 per cent of all genito-urinary tumors and 39 per cent of all the benign tumors included in this study. Of these patients, 13.03 per cent were single and 86.97 per cent were married women. The average age of these patients was 43 years; the single women averaged 3 years younger than the married women. The decennium of 40 to 49 years contained 52.85 per cent of all the cases in our series. Myosarcoma of the Uterus. The 16 cases of myosarcoma of the uterus constituted 0.67 per cent of all the malignant tumors of the uterus. P. J. Reel and P. H. Charlton (125) stated that 1.5 to 2.5 per cent of all the fibroid tumors in their study, showed sarcomatous changes. At the Memorial Hospital the myosar- comas of the uterus comprised 1.98 per cent of all the uterine tumors of mesodermal origin; some but not all of these tumors originated in pre-existing benign fibroids; some of them probably began as sarcoma de novo. Only one of these 16 tumors was in- digenous to the cervix, the remainder were in the body of the uterus. Two of these patients had not married; they were not old enough to be of marriageable age. The average age of these subjects was 45. Case Report No. 66. Baby J. H., a little girl, aged 11 months, had a large palpable abdominal tumor. This was in the body of the uterus. After hysterectomy at another hospital, a rapid recurrence followed. This was treated futilely by palliative irradiation. Histologically, the tumor was a myosarcoma containing cells of probable embryonal origin. Uterine Polyp. These benign uterine polyps did not include the polypoid adenoma malignum nor the pedunculated submu- cous fibroids. The average age of these 19 subjects was 51 years. Only 1 (5.26 per cent) was single. of the Uterus. The eight subjects, all married, who had this particular tumor averaged 47 years of age. One of these tumors occupied the recto-vaginal septum. Carcinoma of the Ovary. The ovary in its function and dys- function plays an important and oftentimes disturbing part in the life history of a woman. From 15 to 50 years of life, its periodic and pathologic influence are far more manifest than in 232 GEORGE T. PACK AND ROBERT Q. LEFEVRE the case of its male counterpart, the testicle. Yet the changes, normal and pathologic, functional and anatomical, which occur in the ovary are probably not carcinogenic influences; many of the ovarian carcinomas are derived from embryonic cell rests. Another potent argument for this assumption is that the number of ovarian carcinomas (161) and the number of teratomas of the t,estis (167) were practically equal. Ovarian carcinomas comprised 0.84 per cent of all hospital ad- missions, 3.27 per cent of all tumors of the genito-urinary system and 1.88 per cent of all the malignant tumors in females. Almost 20 per cent of these women were unmarried. The statement of Frederick Hoffman (75) that the mortality of single women from cancer of the ovary has been twice as great as that of the married, due allowance being made for the different age distribution of these two sections of the population, has not been substantiated by the statistical data from Memorial Hospital. The average age of all subjects with ovarian carci- noma was 45 years; single women were on the average 12 years younger than the married women with the same disease. The oldest patient was only 65 years of age. Ewing has observed two anaplastic ovarian carcinomas in old women in atrophic organs, 40 and 50 years after functional activity had virtually ceased. More than one-fifth of all these cases occurred within the age period 40 to 44 years. C. A. Byron and H. S. Birkoff (21) found that 60 per cent of their patients' ages were between 40 and 60 years; in the Memorial Hospital series, 60.87 per cent of the patients with this disease came within the same 20 year age-period. The quinquennial age period of maximal incidence was from 55 to 59 years. Eleven patients (6.83 per cent) were under 25 years of age. The youngest patient was 15 years old. Younger patients with true ovarian carcinomas have been reported, viz: 1-112 years-V. C. Hunt and H. E. Simon (76); 5 years-M. P. Mendoza-Guazon (107); 7 years-M. Leneuf and M. Heroux; 8 years-Mengershausen (108) ; 8-years-Gussenbauer (64) ; 8 years-Masson and Ochsenhirt. AGE AND SEX DISTRIBUTION 233

Case Report No. 67. H. B., a single Jewess, aged 15, was admitted to the Memorial Hospital, April 27, 1923. Shortly after her first menstrual period in January, 1923, her abdomen became greatly swollen. At another hospital, an exploratory laparotomy was done on March 13,1923. At this time 9200 cc. of encysted fluid were found; the right ovary measured 8 X 12 crns. and was friable and adherent to the uterus; bilateral salpingo-oophorectomies and a supracervical hysterectomy were done. The histological diagnosis was adenocarci- noma of the ovary, probably of teratomatous origin. On admission, a recurrence was found beneath the lower half of the scar. On June 6, 1923, the pelvis was full of tumor masses. Palliative irradiation only was done. The patient died on November 13, 1923. Case Report No. 68. A. S., a single girl, aged 16, experienced pain in her lower back and abdomen, on February 22, 1922. A pelvic tumor was found. At another hospital, a cystic tumor was removed on lapa- rotomy. The report by Dr. Ewing was as follows: " The cyst is 15 crns. in diameter. The inner wall is lined by 5-10 mms. of crumbly opaque tumor tissue. The tumor is made up of large, polyhedral epithelial cells, many containing large hyaline globules. In structure it re- sembles an atypical adenocarcinoma." In June, 1922, she began to lose weight and complained of backache. Ascites developed, followed by vomiting and death on December 22, 1922. Case Report No. 69. P. J., a single girl, aged 17, had her left ovary removed on April 18, 1926; it was cystic and 15 centimeters in diameter. Histologically it was an embryonal alveolar carcinoma. Since Novem- ber 15, 1926, she had severe abdominal pain and ascites. The pelvis and lower abdomen were filled with nodular masses. The disease progressed to a fatal ending. Sarcoma of the Ovary. Sarcoma of the ovary is a rare disease; the 4 cases in our series comprised only 0.047 per cent of the malignant tumors in females. There were 40 times as many carcinomas as sarcomas of the ovary. The average age of these patients was 33 years-12 years younger than the group of subjects with ovarian carcinoma. Our youngest patient was 10 years of age; this is unusual because many of the reported cases of primary ovarian sarcomas occurred in infants, e.g., 7 monthsJ fetus-A. Doran (36) ; 9 monthsJ baby-Brown (14) ; 22 monthsJ old baby-R. H. Harris (68); 33 months' old girl- C. S. Hoffman (74). 234 GEORGE T. PACE AND ROBERT G. LEFEVRE

Benign Ovarian Cysts, including Dermoid Cysts. The 72 benign ovarian cysts comprised 3.5 per cent of all the benign tumors and 1.46 per cent of all tumors of the genito-urinary sys- tem at the Memorial Hospital. These tumors were found more frequently during the age period 35 to 44 years. The average age of these patients was 43 years; this was only 2 years younger than the average age of the ovarian carcinoma group. This find- ing seems remarkable because it was the only organ in the body, wherein the benign and malignant epithelial tumors affected subjects of the same approximate age. The single women were four years younger than the married women with this disease. The second singular fact was that single women seemed to be predominantly the hosts to these cystic tumors; 88.8 per cent were in unmarried women. There are two possible explanations of this irregular distfibution; either the tumors were caused by lack of functional stimulation by sexual intercourse, pregnancy, lactation, etc., or the same abnormality which induced the cystic changes in the , was responsible for a deficiency in mating instinct and the other conditions which may deter- mine the persistent single state.

TUMORS OF THE RREAST Fibro-adenoma of the Breast. The 151 fibro- of the breast comprised 5.22 per cent of all the breast tumors and 7.3 per cent of benign tumors from all locations. Males constituted 2.6 per cent of the total number of patients; 97.4 per cent were females. The average age of the entire group was 35 years; the males averaged 38 years of age; the single women were twelve years younger than the married women with the same disease. Only 29.25 per cent of these patients were unmarried women. In single women the curve of distribution and incidence in age periods was confined mostly to the early half of sexual life; the maximal incidence was in the quinquennium 20 to 24 years. In married women, the curve varied noticeably from that of single women, as an almost equal number of cases were found In each of the age periods from 25 to 50 years (Table 12). McFarland has said that the firmness of the juvenile breast as AGE AND SEX DISTRIBUTION 235 contrasted with its later soft consistence, makes it probable that the discovery of some of the deeply situated fibro-adenomas is deferred until after lactation or menopause when the patient is able to palpate them. The benign tumors of the female breast appear in the period of greatest ovarian and sexual activity. Of the groups as a whole there is a striking uniformity of distribution from age 20 to age 50 (Table 12). However, on the basis of frequency in comparison with the percentages of general population living during these various 5 year age periods, the incidence of mammary fibro-adenomas gradually increases from age 20 to 50. The youngest patient was a youth of 15 years, who with a second older youth had sub-areolar sweatgland adenofibromas. The oldest patient was a man aged 79 years. It is worth while to note that the fibro-adenomas of the breast occurred in patients who averaged 16 years younger than the patients with mammary carcinoma. Intra-cystic Benign Papilloma of the Breast. The 39 cases of benign intra-cystic papillomas of the breast included 1.34 per cent of all the breast tumors and 1.88 per cent of the benign tumors from all locations. There were no males in this group. The percentage of single patients (28.2 per cent) was practically the same as for fibro-adenomas. The average age of the sub- jects was 45 years; the married women were seven years older than the single women with the same disease. These patients with intra-cystic benign papillomas of the breast were 6 years younger than the group with mammary carcinomas and 10 years older than the group with mammary fibro-adenomas. The age distribution for 5 year periods from 25 to 55 years was practically the same throughout, except for the quinquennium 30 to 34; this indicated an increasing incidence for advancing years up to 55. Carcinoma of the Breast. About one of every seven patients who came to Memorial Hospital during the 12 year period, had mammary cancer. The 2663 glandular carcinomas of the breast comprised 13.9 per cent of hospital admissions, 92.1 per cent of all breast tumors, 16.08 per cent of all malignant tumors, 30.73 per cent of all cancers in females and only 0.41 per cent of TABLE NO. 12 Tumors nj the Rrcmt

Aee 6er T,, % ofbl~mt Type Civil State turnon, -----15-19 Xt-24 25-29 30-34 35-39 40-44 45-49 50-54 5%59 60-64 6569 70-74 75-79 80-84 85-88 90-94 Fibro-adeaoma...... Male 2 1 1 4 Married-female 1 8 13 18 14 20 19 7 1 1 2 104 Single-female 5 16 9 5 5 3 43 Total 8 24 22 23 20 23 19 7 1 1 2 0 1 151 5.22% Intra-cystic Papilloma...... Married-female 2 3 8 4 5 3 3 28 Singlefemale 3 4 13 11 Total 507858303 39 1.347,

Glandular Carcinoma...... Male 214556423 1 33 Married-female 3 35 114 231 319 364 356 277 231 130 87 47 11 3 1 2,209 Singlefemale 2 3 16 20 34 61 74 65 52 49 24 15 4 1 1 42 1 Total 2 6 51 136 266 384 443 426 335 284 156 105 51 13 4 1 2,663 92.11% Sarcoma...... Male 1 1 Mamed-female 11 2 2 2 1 1 1 11 Single--female 11111 1 6 Total 1221122122 1 1 18 0.64% Pagets' Disease of Nipple. .. Married-female 2 2 33241 17 Single-female 1 1 1 3 Total 122 34251 20 0.69% 2,891 100% AGE AND SEX DISTRIBUTION 237 all cancers in males. There were only 33 males (1.24 per cent) in this series; the census bureau for England and Wales in 1926 reported 5339 mammary cancers of which only 0.08 per cent were in the male sex. Of the females (98.7 per cent), 84 per cent were married and 16 per cent were single. The average age of all patients was 51 years; the single women averaged 50 years of age; the men averaged 54 years of age. Cancer of the male breast is generally believed to be of later occurrence than in the female, in spite of earlier recognition because of the small size of the male breast. Almost one-third of all the cases occurred in subjects between 45 and 55 years of age. The peak of age incidence was from 60 to 64 years, fol- lowed by a gradual decrease in relative frequency. Therefore cancer of the breast is obviously not a disease of old age. There were eight patients under 25 years of age, totalling 0.3 per cent of all breast cancers and 1.25 per cent of malignant tumors of all types in patients under 25 years. The youngest subject was 17 years old (Case Report No. 60); earlier cases have been re- ported, e. g., 8 12 years with mammary adenocarcinoma (A. N. Blodgett (8)); 8 14 years with scirrhous mammary cancer (R. C. Bryan (16)); 9 17 with scirrhous mammary cancer (R. H. Fowler (46)). Gross (61) tabulated 1622 cases of carcinoma of the breast, in which the youngest subject was 21 years of age. There were 69 subjects aged 75 or more years; they included 2.59 per cent of all breast cancers and 9.23 per cent of malignant tumors of all types in patients of 75 or more years. Our oldest patient was aged 90 years. (Case Report No. 64.) Lunn (94) reported a cancer of the male breast in a subject aged 91 years and Bryant (17) reported a mammary carcinoma in an old woman aged 96 years. Cancer in the aged senile breast is usually of slow growth, the patient reports late and is fre- quently uncertain of the approximate time the tumor began. The antithesis of this type is carcinoma mastitoides, or cancer in the lactating breast; this tumor is of unusually rapid growth, the patient reports early and the approximate date of onset can usually be ascertained correctly. At the menopause, the glandu- lar elements of the breast decrease and the connective tissue TABLE'-NO. 13 Carcinoma of t?te Breast in Young Women

Cane Marital Obetrical and htionand 8i Hist0logi.d Treatment Result Repoh Age --Stab Reoe Lsetatxonal History of Tumor Metastases Diagnolns A. M. 17 Single Jewish 0 Firm, irregular non- None Intraductal papil- Local excision by Cured No. 60 tender lump in low- lorn=, papillary Dr. Lee. Post- er outer quadrant of adenomas a n d operative irradia- right breast. Pain- early adenocar- tion. ful at menstmation. cmoma. S. P. 17 Single Jewish 0 Lump 3 X 1 cm. in None Cellular adeno- Local excision. No. 61 at onset upper segment of carcinoma of' left breast. TWO sweat gland type. years duration at No invasion of time of admission. stroma. Age 19 on admis- sion. G. R. 24 Single Jewish 0 Lump 3 X 3 cms. in Right axillary Solid infiltrating Local excision for Death No. 62 at onset upper outer qua- lymph node me- carcinoma, quite, diagnosis. Ampu- drant of r i g h t taatasee. cellular. tation refueed. breaet. Duration Palliative irradia- one year. Age 25 tion. on admission. H. R. 24 Married Jewiah One child-aged 2 Lump size of walnut To palpable nodes Infiltrating carci- Radical mastecb No. 63 at onset yrs. Nursed 13 in upper inner quad- m ads nor m noma. omy. months. No mss- rant of right b&. supra-clavicular titis. No trauma. Skin taut and blu- space on his- and vertebral ish over it. One s~on. symptoms. year duration. Age 25 on adxihion. J. M. 90 Married Iri Seven children. Lump 5 X 3 cms. in One left axihy Carcinoma sim - Treated with bare Lived for 5 years. No. 64 inner lower quad- lymph node. p l e x of breast. tube radon inser- Died aged 95 ears rant of left breast. .+ base14 car- tion. only by Dr. cawof dead un- Now ulcerating and clnoma of nose. Adam. known. bleeding. Skin fixa- t i o n . Duration seven months. AGE AND SEX DISTRIBUTION 239 increases in amount; the lumens of the ducts may become quite solid with overgrowth of epithelium, constituting in some instances a precancerous state. This factor may partially account for the increased incidence of mammary cancer at this time of life. Ewing (42) has contradicted a long-existent clinical impression by his statement that "it does not appear clearly that scirrhous cancer of the breast is more common in the aged." There seems to be no difference in the histological types in different ages, but in younger patients the cancers are more highly cellular, they are endowed with greater growth energy and propensities and have tendencies to metastasize earlier and more widely than do the same variety of cancers in older subjects. As a general rule the prognosis for cancer of the breast in youthful persons is very bad; the younger the indi- vidual the less hope there is for obtaining a cure of this disease. Burton J. Lee, chief of the breast service at the Memorial Hospital, in his clinical index of malignancy for cancers of the breast, considers the factor of age as one of the four important criteria for the determination of this index. Dr. Seelye Little (91) has told us that mammary cancer in- creases in relative frequency in the following classes of women; barren married women

TUMORS OF THE SOFT SOMATIC TISSUES Lipoma. Lipomas included 4.3 per cent of all the benign tumors. Females predominated greatly; 77.5 per cent were females, 22.5 per cent were males. The greater frequency of lipomas in females has been explained by their great tendency to the accumulation of fatty tissue. They are also more con- cerned about the cosmetic disfiguration caused by these lipomas, therefore, may report in greater percentage to the clinic. The average age of these 89 patients on admission was 43 years; 40 per cent of these cases occurred in the decennium 40 to 50 years at an age when fat usually begins to accumulate. The youngest patient was a boy, aged 2 years. Liposarcoma. At the Memorial Hospital, 4.3 per cent of all tumors of lipoblastic origin were . In our series, males predominated 4 to 1; in Robertson's (126) 49 cases, 25 were in males and 24 in females; in von Wahlendorf's (153) 148 cases, 72 per cent were in females and 28 per cent in males. The average age of these patients was 41 years, practically the same as for the benign lipomas.

Case Report No. 66. W. J., a boy, aged 7 years, noticed a tumor in his left groin in January, 1921. In a short time the parents observed another lump on his back and one on the left side of his abdomen. On admission, March 14, 1921, he was asthenic, anorexic, anemic and dyspneic. A radiograph of the chest revealed a mass in the mediasti- num and fluid in the left pleural sac. X-radiation was given to the chest (3-18-21 to 3-26-21) and external radium therapy to the abdominal and inguinal tumors (3-18-21). By March 20, 1921, the tumors were rapidly disappearing, an unusual event for this type of tumor, which is usually radioresistant. On March 21, 1921, Dr. Quick performed a biopsy. The report by Dr. Ewing was: "The fat tissue is completely replaced by the new cells which are large, pale and polyhedral. The process resembles some form of liposarcoma." By March 31, 1921, the tumors were no longer palpable. A rapid recur- rence followed, acute pleural effusion occurred and death ensued on April 14, 1921. Sarcoma of the Soft Parts (Exclusive of Neurogenic and Lympho- sarcomas. The 132 tumors included in this study were an in- 242 GEORGE T. PACK AND ROBERT G. LEFEVRE AGE AND SEX DISTRIBUTION 243 definite group comprising the so-called spindle-cell, round cell, polyhedral cell and alveolar sarcomas not included in the groups of neurogenic and lymphosarcomas. Some of them probably were of neurogenic origin. They comprised about 0.7 per cent of all admissions to the clinics, 0.8 per cent of all the malignant tumors in this series, 1.01 per cent of a11 malignant tumors in males and 0.6 per cent of all malignant tumors in females. The average age of these patients was 36 years. As with other sar- comas, there was practically a constant distribution of 6 to 13 cases for each of the 5 year age periods from birth to 70 years; this caused an incidence of occurrence which gradually increased with the advancing years to the quinquennium 65 to 69 years, when the maximal incidence was found. Forty-two patients or 31.8 per cent were under 25 years of age; this number constituted 6.58 per cent of all the malignant tumors occurring in people under 25 years of age. The youngest patient was 1-113 years of age. There were 61.4 per cent males and 38.6 per cent females. Miscellaneous Tumors of Mesoblastic Origin. (Table 14.) The desmoid tumor of the abdominal wall is a rare tumor; there were only three instances of this neoplasm at the Memorial Hospital. The six patients with angiosarcomas averaged 40 years of age; 213 of these patients were males. On the basis of the number of benign angiomas studied, we might infer that the angiosarcomas comprise 1.3 per cent of all angiomatous tumors. Excluding the uterine , of which there were 16, only 3 extra-uterine myosarcomas were found, one of the small intestine, one of the rectum and one of the roof of the mouth. The 11 cases of were almost equally dis- tributed in sex; the average age of these patients was 40 years. Many of the large group of neurogenic sarcomas had definite myxosarcomatous elements in their substances; probably these two sarcomatous types are histogenetically related. There were many instances of xanthelasma, some cases of xantho- lipoma, and numerous xanthomatous changes observed in other tumors; there were only two tumors recorded as pure primary xanthosarcomas; the average age of these patients was 46 years. There were 10 benign giant-cell tumors of tendon sheaths, of TABLE NO. 15 Tumars of Lymphoid Tissue and Allied Diseases

Age 'bW 8er Total -----0-4 5-9 10-14 15-19 -2(t24 ------25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-84 65-69 -70-74 ----75-79 80-84 85-89 Lymphosarcoma exclu- sive of tonsillsr and retroperitoneal r e - gione...... Male 3 6 10 15 27 17 26 33 28 25 27 19 5 8 1 1 251 Female 1 4 1 4 10 12 12 19 9 14 12 12 10 12 3 3 1 139 Total 17 7 14 25 39 29 45 42 42 37 39 29 17 11 3 2 1 390 Retroperitoneal Lym- pho-aarcorna...... Male 2 12 232222111 20 Female 1 21111341 1 16 Total 1 2 141343563121 36 Sarcoma Spleen ...... Total 1111 4 Thymic Tumors...... Male 4 2 3 3 2 2 7 4 4 3 2 1 37 Female 2 12 132 1 12 Total 62 4 5 2 3 10 6 4 4 2 1 49 Endothelioma-Lymph nod-...... Male 1 2 1 1112 9 Female 2 1 1111 7 Total 2 1 1 2 1 12222 16 Hodgkin'sDiseme ..... Male 1 6 5 11 22 30 31 18 17 14 19 9 11 4 1 199 Female 2 4 10 24 18 18 15 17 5 8 9 2 3 1 136 Total 1 8 9 21 46 48 49 33 34 19 27 18 13 7 2 335 Lymphatic Leukemia . . Male 23 2 2 55 4514755 21 62 Female 1 11 142 7322 24 Total123 2 3 156 8 71414 8 7 41 86 Spleno-myelogenous Leukemia...... Male 1 1246105654411 50 Female 2354514111 27 Total 1 147111410 7 9 5 5 2 1 --77 993 AGE AND SEX DISTRIBUTION 245

which 6 were in females and 4 in males; the average age of these patients was 40 years.

TUMORS OF LYMPHOID TISSUE AND ALLIED DISEASES

Lymphosarcoma No. Pereantnges General or Regional...... 376 82.09% Retroperitoneal, ...... 36 7.86% Tonsillar...... 32 6.99% Mediastinal...... - 14 3.OG% Total...... 458 100.0 % Lymphosarcoma. The lymphosarcomas of all regions consti- tuted 2.39 per cent of admissions to the clinics, 2.76 per cent of all malignant tumors, 3.67 per cent of all the malignant tumors in males and 1.93 per cent of all the malignant tumors in females. The tonsillar lymphosarcomas comprised 0.84 per cent of all the intra-oral tumors and 7.9 per cent of tumors of the tonsil; the re- maining 92.1 per cent of tonsillar tumors were carcinomas. Of the entire group, 64 per cent were males and 36 per cent were females; in the tonsillar region, 71.9 per cent of the lymphosar- comas were males. The average age of all the patients was 43 years; the average age of the retroperitoneal group was 40 years, of the mediastinal group44 years, and of the tonsillar group46 years. The greatest distribution of cases was in the age period 35 to 39 years; the maximal incidence of lymphosar- coma occurred in the age period 55 to 59 years, then gradually declined. There were 6 patients of 75 or more years of age, of whom the oldest was a man of 87 years. There were 65 patients (14.19 per cent) under 25 years of age; these included 10.19 per cent of all the patients under 25 years with malignant disease. The youngest patient was a 3 year old girl. Sarcoma of the Spleen. Symmers (146) studied 100 lympho- sarcomas and found only one of these neoplasms primary in the spleen. Practically all of the primary splenic tumors are sarco- mas or closely related tumors. There were 4 sarcomas of the spleen of which 3 were in males. The average age of these pa- tients was 39 years. 246 GEORGE T. PACK AND ROBERT Q. LEFEVRE

Thymic Tumors.--Thymomas. The 49 thymic tumors were only 0.296 per cent of all the malignant tumors. Three-fourths of these tumors were in males; we know no explanation for this disparity in sex distribution. The average age of these patients was 27 years; the females were 5 years younger than the males. Thymic tumors have long been known as neoplasms peculiar to late childhood or early adult life. The thymus undergoes physiological atrophy at this early age. Nineteen patients (38.77 per cent) were younger than 25 years; the age period 30 to 34 years contained the greatest distribution of these cases. Case Report No. 66. J. c., a 5 year old boy, had pertussis at 4-314 years. One month later his father observed large right axillary nodes, 5 cms. in diameter, and bilateral supraclavicular lymphadenopathies. He had a slight cough. A radiograph of the chest revealed a medias- tinal tumor. The red and white blood counts were normal. Treat- ment by X-irradiation was instituted with such an immediate disap- pearance of the tumors that the clinical diagnosis of thymic lympho- sarcoma was made. Six months later, the patient had pneumonia, which left no residual evidence3 in later radiographs of the chest. One year later, he remains clinically free of disease. Case Report No. 67. F. S., an 8 year old boy, was admitted on February 6, 1919, with an illness of 4 months duration. The first sign was a rapid increase in size of his tonsils. In December, 1918, a tonsillectomy was done followed by rapid enlargement of the cervical lymph nodes. In January, 1919, the enlarged cervical lymph glands were excised. These operations were done elsewhere. On admission large lymph nodes were palpated in both axillae and on both sides of his neck; the spleen extended 2 inches below and one inch to the left of the umbilicus. Sudden death followed a single treatment by external radium therapy on February 14, 1919. Necropsy showed a general lymphomatosis affecting the thymus, liver, spleen, kidney, cervical, thoracic, abdominal and subcutaneous lymph nodes. The final diag- nosis was thymic lymphocytoma and lymphemia. Primary Endothelioma of Lymph Nodes. This is a rare tumor entity; some of the so-called primary endotheliomas of lymph nodes have possibly been metastatic transitional-cell carcinomas or lymphoepitheliomas. Our 16 patients averaged 41 years of age; the females were 14 years younger than the males. AGE AND SEX DISTRIBUTION 247

Hodgkin's Disease (Malignant Lymphogranulomatosis). There were 335 patients with Hodgkin's Disease treated in this hos- pital; this number comprised 1.75 per cent of all admissions. Almost 60 per cent of these patients were males. The average age was 35 years. Forty-four per cent of these subjects were between 20 and 35 years of age. The peak of age incidence fell in the quinquennium 30 to 34 years. These facts are in agreement with the commonly accepted opinion that the malady of Hodgkin is a disease which affects principally young male adults.

Case Report No. 68. T. C., a boy aged 4 years, had a slowly growing lump on the left side of his neck. On admission one year after the onset of his disease, a tumor mass composed of confluent lymph nodes and measuring 5 X 3 inches was found on the left side of his neck. A biopsy showed Hodgkin's disease. External radium therapy caused a temporary disappearance of the lymphadenopathies. On July 29, 1922, a recurrence was observed in the left neck and the patient began to have intermittent hyperpyrexia (102' F.). On August 1, 1922, a palpable mass appeared in the upper abdomen. It waa radiosensitive. On February 1, 1923, several nodes were found in the right groin; on June 4, 1923, a new node appeared in the right upper neck. These nodes responded at first to irradiation but invariably recurred. The course of the disease was the typical Pel-Ebstein type. The patient died on September 7, 1923. Case Report No. 69. J. D. B., a girl, aged 6 years, had enlarged lymph nodes in her left axilla; a biopsy was done at another hospital; the report on the tissue was " chronic hyperplastic lymphadenitis." On admission one year later (8-16-22) there were bilateral axillary lymphadenopathies in addition to a number of enlarged, firm, discrete, movable nodes in the left supra- and infra-clavicular spaces. On August 19,1922, a biopsy was done; the report on the excised node was " Hodgkin's disease." X-irradiation only was employed; an immediate response was followed by recurrences. By November 19, 1923, the patient had ascites, anemia, fever and asthenia; there was never any evidence of mediastinal involvement. The patient died on January 28, 1924. Lymphatic Leukemia. Eighty-six patients with lymphatic leukemia were treated palliatively during this 12 year period. 17 248 GEORGE T. PACK AND ROBERT G. LEFEVRE

Of these subjects, 72 per cent were males and 28 per cent were females. Their average age was 47 years; the females were 4 years older than the males. Acute leukemia is said to be essentially a disease of infants and young adult males. In the menopausal period (40 to 50 years) women are more fre- quently affected (Warren (157)); we have not verified the un- usual frequency of acute leukemia in women at any age period. Chronic lymphatic leukemia is definitely more common in the age decade 50 to 59 years (Table 15). Case Repmt No. 70. N. W., a white girl, was born on June 12, 1920. Her growth was normal until she was 10 months old, when she had an* rexia and apparent coryza. On May 1, 1921, her tonsils were enorm- ous, the spleen was enlarged as were the superficial lymph nodes. There were ecchymoses of the oral mucous membranes. The hemo- globin percentage was 35; the red blood count was 1,864,000 per cu. mm. of blood; the white blood count was 332,500 per cu. mm.; the differential count was 99 per cent of lymphocytes and 1 per cent of polymorphonuclear leucocytes. On May 7, 1921, a transfusion was given; after this the count of white blood cells was 147,600; one week later the white blood count was 55,000 per cu. mm. of blood. Radium therapy to the lymph node areas was given; on the succeeding day the white blood count had dropped to 36,000 cells per cu. mm. of blood. The patient died on August 21, 1921. Case Repmt No. 71. S. L., a male, aged 75, developed asthenia and pain in the splenic area in October 1921. On March 28, 1922, his white blood count was 34,000 cells per cu. mm. of blood; there were 70 per cent small lymphocytes, 8 per cent large lymphocytes and 22 per cent polyrnorphonuclear leucocytes. Low voltage X-ray therapy and emanation (Radon) pack treatment were given. After treatment, on June 3, 1922, the white blood count was 12,000 cells per cu. mm. of blood; there were 82 per cent small lymphocytes and 18 per cent polyrnorphonuclear leucocytes. The patient died one year after the onset of the disease. Spleno-myelogenous Leukemia. Of the 77 cases of spleno- myelogenous leukemia treated in this institution, 65 per cent were males and 35 per cent were females. The average age of the patients was 41 years. The youngest patient, a boy aged 7 years, was the only subject under 18 years to have this disease. AGE AND SEX DISTRIBUTION 249

Ocular Tumors No. Percentage Glioma of Eye...... 29 49.15% Melanoma of Eye...... 8 13.54% Epithelioma of Cornea and Conjunctiva...... 14 23.73% Sarcoma of Iris...... 3 5.08% Leuko-sarcoma of Choroid...... 2 3.42% Carcinoma of Lachrymal Sac...... -3 5.08% Total...... 59

MISCELLANEOUS TUMORS The average age of the patients with epitheliomas of the cornea or conjunctiva was 54 years, which is 4 years younger than for patients with epitheliomas of the skin. The youngest patient was a female, aged 25 years. Two-thirds of these subjects were males. There were three instances of sarcomas of the iris; the ages of these patients varied from 12 to 73 years. The two leukosarcomas of the choroid were in males, aged 37 and 39 years. There were only three carcinomas of the lach- rymal sac, all in males aged 39 to 72 years. There were many basal-cell epitheliomas of the eyelids, but only 3 adenocarcino- mas of the tarsal glands.

Case Report No. 72. A. B., a white male baby, aged one year, had a tumor of the left upper eyelid excised at another institution. Histo- logically it was an embryonal adenocarcinoma of the eyelid. A rapid recurrence and metastases developed in the orbit, especially along the inner wall of the left orbit and in the left submaxillary node. Pallia- tive radium therapy was tried. The patient died six months later. Primary Carcinoma of the Lungs. The 102 primary carcino- mas of the lung were only 0.616 per cent of all the cancers at Memorial Hospital. Seyforth (131) found primary carcinomas to comprise 5 per cent of all cancers; Lubarsch's (93) percentage was 5.4 per cent. Carcinoma of the lung is universally more frequent in males; at the Memorial Hospital the males consti- tuted 73 per cent of 102 cases; at other institutions the same disparity in sex distribution is found, viz.: 74.2 per cent of 1087 cases (Breckwoldt (12)), 71.9 per cent of 372 cases (Alder Am Type Sex Total M 59 1&14 1519 D24 25-29 30-34 3539 -4 4549 50-54 W59 0Q-64 6560 70-74 7579 80-84 85-89 ______-__------Epithelioma-rnea and Conjunct~va...... Total 11 13122 12 14 Adeno-carcinoma-Eye- d...... To 1 2 3 Carcinoma-La~hr~mal Sac...... Total 1 1 1 3 Sarcoma Irie...... Total 1 1 1 3 Leuco-asrcoms of chor- oid of eye...... Total 2 2

Melanoma of Eye. . . . . Male 1 1 11 4 Female 11 2 4 Total 1 21112 8 Sarcoma Lung...... Total 1 2 2 2 12 1 1 12 Meaothelioma...... Total 1 2 1 1 5 kcinoma Lung...... Male 112 710 91412 7 73 1 74 Female 2 1224421442 28 Total 3 2 4 9 14 13 16 13 11 11 5 1 102 Demoid Cyst (other than ovary)...... Total 1 1 2 4 Thyroid Adenoma . . . . . Male 11412134 1 1 19 Female 4 6 10 14 21 18 14 11 11 4 4 1 1 119 Total 5 7 14 15 23 19 17 15 11 5 4 2 1 138 Thyroid Carcinoma. . . . Male 11242466641 37 Female 13 12 6 11 8 17 20 16 11 6 5 2 118 Total 1 4 I 14 10 13 12 23 26 22 15 7 5 2 155 Sarcoma Thyroid...... Total 1 11 -3 452 AGE AND SEX DISTRIBUTION 251

(2)), 81.4 per cent of 118 cases (McCrae, Funk and Jackson (99)), 80.5 per cent of 87 cases (Weller (164)), 75 per cent of 576 cases (Brunn (15)), 90 per cent of 10 cases (Fried (48)). MBnBtrier said: "There is no primary lung cancer without a previous in- flammation." Not only is the male sex more exposed in general to lung infections but the frequency of primary carcinoma of the lung in miners, glass-blowers and workers, chemists and cigar makers suggests that these infections and occupational hazards may influence the predominance of this cancer in males. At the Memorial Hospital, the primary lung cancers included only 0.924 per cent of the malignant tumors in men and 0.33 per cent of the malignant tumors in women. Lubarsch (93) found them to constitute 8 per cent of all the carcinomas in men and 2.57 per cent of all the carcinomas in women. The average age of the subjects in our series was 51 years; on the average the males were 3 years older than the females. The youngest patient was a girl aged 20 years (Case Report No. 73); only 3 patients (2.9 per cent) were under 25 years of age. The oldest subject was a male aged 81 years. Over 82 per cent of our patients were more than 40 years of age; Brunn (15) found 90 per cent over 40 years; McCrae, Funk and Jackson (99) reported 91 per cent of their patients with this disease to be older than 35 years. The quinquennium in which the greatest distribution occurred was from 50 to 54 years; the maximal incidence was in the age period 65 to 69 years, after which the incidence decreased with advancing years. When Weller (164) corrected the curve of incidence for his material for the con- stantly declining population of aged persons, its apex fell in the quinquennium from 58 to 62 years.

Case Reporl No. 73. J. P., a single Italian girl, aged 20 years, had lettcsided pneumonia in May, 1928, followed by pleural empyema. A thoracotomy was done followed by drainage, asthenia, hemoptysis and constant cough. On admission to the Memorial Hospital she weighed 10 pounds less than her normal weight. She had 3,100,000 red blood cells per cubic millimeter of blood. Near the 8th rib in the posterior axillary line was a discharging sinus from which tissue was obtained for microscopical examination. It proved to be an adeno- 252 GEORGE T. PACK AND ROBERT G. LEFEVRE carcinoma, presumably of bronchogenic origin. Pelvic examination and examination of breasts were negative. A radiograph of the chest showed a clean-cut homogenous shadow in the left lower lung. Sputum analysis was positive for tubercle bacilli, a not infrequent association with primary carcinoma of the lung. On October 17, 1928, a large fungating mass occupied the thoracotomy wound. She died in No- vember, 1928. TABLE NO. 19 Turnof the Lung No. Percentage Primary Carcinoma of Lung...... 102 85.7% Primary Sarcoma of Lung...... 12 10.1% of Pleura...... 5 - 4.2% Total...... 119 100.0% Primary Sarcoma of the Lung. The 12 sarcomas of the lung constituted 10 per cent of the primary lung tumors. They were equally divided between the sexes. The average age of the patients was 47 years, four years younger than the subjects with carcinoma of the lung. The youngest patient was a boy aged 12 years. Mesothelioma of the Pleura. (Pleural Endothelioma.) The five patients with this disease averaged 41 years of age; the youngest subject was a girl aged 18 years. Dermoid Cyst (other than Ovary). There were four dermoid cysts of extra-ovarian origin; two of these were intrathoracic tumors. Three of the four patients were women. The average age of the group was 34 years. Sarcoma of the Thgroid Gland. There were only 3 histologi- cally verified sarcomas of the thyroid gland at the Memorial Hospital and there has been some dispute about their nature, because of the spindle-cell characters of many thyroid carcinoma cells. Only 1 per cent of the thyroid tumors were sarcomas. The average age of these patients was 46 years; collective reviews of the literature on this subject indicate that most sarcomas of the thyroid occur in the fifth and sixth decades of life. One unusual and striking difference of thyroid sarcomas from those sarcomas occurring in other body regions, is the uniformly late age at which the former appear. AGE AND SEX DISTRIBUTION 253 Two of our three patients were females; Becker (1) states that both sexes are equally affected in sarcoma of the thyroid. Only 0.18 per cent of the malignant tumors in this institution were thyroid sarcomas. There is considerable disparity of opinion among authorities concerning the frequency of this disease. Kocher (80) stated that the thyroid gland is one of the chief seats of " acute " sarcoma. Per contra, Craver (29) says : "The occurrence of true sarcoma of the thyroid in man is doubtful." However, in 19 of his histologically proven cases, 17 were carcinomatous, one was a round-cell sarcoma, another was a small spindle-cell sarcoma. In 1902, Ehrhardt (40) collected 99 case reports of thyroid sarcoma together with 150 carcinomas of the same organ. This ratio does not exist in the papers of later authors. Herbst (69) reported that of 290 patients with malignant disease of the thyroid gland, seen* at the Mayo clinic between 1901 and 1921, nineteen had sarcomas. Simpson (133) examined microscopically 1449 extirpated thyroids and found only 50 carcinomas and 5 sarcomas. Speese and Brown (137) studied 426 lesions of the thyroid gland, among which carcinoma occurred 19 times and sarcoma 3 times. Bloodgood (9) found 9 carcinomas and only one sarcoma in 148 thyroid lesions, surgically removed. Limacher (90) in Berne discovered 44 sarcomas and 38 carcinomas of the thyroid gland in 7641 necropsies. For his study of malignant disease of the thyroid gland Louis B. Wilson (167) in 1921 included European and American reports to total 991 malignant epithelial tumors and 195 sarcomas. The ratio of carcinoma to sarcoma is variously given as 10 to 1, or even 4 to 1 (Tebbutt and Wood- hill (147)) ; at the Memorial Hospital the ratio seemed to be 51 to 1. TABLE NO. 20 Thyuid Tumors No. Percentage Adenornag ...... 138 46.63 % Carcinomas...... 155 52.36% Sarcomaa ...... - 3 1.01% Total...... 296 100.0 % 254 GEORGE T. PACK AND ROBERT G. LEFEVRE Thyroid Adenomas. The 138 adenomas of the thyroid glands constituted 6.68 per cent of all benign tumors. The disparity in sex distribution is well known; 86.3 per cent were females and 13.7 per cent were males. The average age of these patients was 41 years; the greatest number of cases were in the age period 35 to 39 years. The youngest patient was 15 years old. Thyroid Carcinoma. The 155 carcinomas of the thyroid gland include 0.81 per cent of all admissions to the clinic, 0.94 per cent of all the malignant tumors, 0.46 per cent of all the malignant tumors in males, and 1.38 per cent of all the malignant tumors in females. Of female subjects there was 76.1 per cent in contrast to 23.9 per cent of males, a ratio of 3.18 to 1. Lloyd F. Craver (29) of the Memorial Hospital, quotes the following sex ratios: 65 per cent 9 -35 per cent 8 (Balfour) ; 69 per cent 9 -31 per cent 8 (Wilson) ; 60 per cent 9 -40 per cent 8 (Miiller and Speese) ; 70 per cent 9 -30 per cent fl (Orcel); 63 per cent Q -37 per cent 8 (Carrel-Billard) ; 80 per cent Q - 20 per cent 8 (Delore) ; 67 per cent 9 -33 per cent 8 (Hueck). It is obvious that thyroid carcinoma is predominant in women; in benign nodular goitre (thyroid adenoma), the females out- numbered the males in proportions of 7 to 1, but this difference did not obtain for carcinomas of the thyroid gland; the natural conclusion would be that a greater proportion of male goitre cases develop cancer than do females. Breitner and Just (13) assert that 5.8 per cent of males with nodular goitres and 3.8 per cent of females with the same lesion, develop thyroid cancer. The average age of the patients with carcinoma of the thyroid gland was 53 years, which is 12 years older than the subjects with benign adenomas of the thyroid. On the average, the males were two years younger than the females. Eberts and Fitzgerald (39) report the average age for thyroid cancer to be 43 years. About 4.5 per cent of our subjects were older than 74 years, 65 per cent were over 50 years of age and 72 per cent were more than 45 years old; almost three-fourths of these people there- fore had passed the age of greatest physiological activity of the thyroid and sex glands. H. M. Clute and L. W. Smith (25) found the greatest incidence of thyroid cancer to occur in the age per- AGE AND SEX DISTRIBUTION 255 iod 50 to 65 years; at the Memorial Hospital 45.8 per cent of the patients were in this 15 year age epoch. The quinquennium of greatest age distribution was from 55 to 59 years (16.77 per cent); the greatest incidence, however, was from 85 to 89 years. The corrected incidence for the relative number of persons liv- ing during these later years, indicated that cancer of the thyroid increased in relative frequency to the 65th year of life, then grad- ually became less frequent except for two unusual instances in women of 85 years. It is conceivable that the degenerative hyperplasia of the thyroid which occurs in some middle-aged subjects, may cause existing thyroid adenomas to become carcinomatous. Five patients (3.22 per cent) were younger than 25 years; the youngest patient was a 17 year old girl (Case No. 74). Meleney (106) reported a cancer of the thyroid in a 13 year old Chinese subject. At the Memorial Hospital the 3 youngest subjects with cancer of the thyroid, who are under the care of Dr. Craver, are all clinically free of this disease. One explanation of this fact is that cancer of the thyroid may be present for many years, encapsulated with the benign adenomas from which it originates; the discovery of cancer occurs in the pathology lab- oratory following the surgical extirpation of a supposedly benign thyroid adenoma; the cancer is frequently not clinically mani- fest until it ruptures the capsule and begins to invade and in- volve the surrounding structures.

Case Report No. 74. A. B., a girl, aged 17.5 years, had a rapidly growing lump in the left lobe of her thyroid gland. On November 20, 1915, when she was 18 years of age, this tumor mass was excised at another hospital. Histologically it was an adenocarcinoma. She re- ceived prophylactic X-irradiation at the Memorial Hospital. Later she married and had one child. When seen 10 years later (1925) she was clinically free of this disease. Case Report No. 76. R. P., a white woman, aged 21, had an enlarged thyroid gland for 4 years. She had been married for 3 years. She had menorrhagia for the last two years. More recently she had com- plained of nervousness, asthenia, dyspnea, palpitation, tremor, tachy- cardia, loss of 18 pounds in weight and finally hoarseness of 4 weeks 256 GEORGE T. PACK AND ROBERT Q. LEFEVRE duration. The right lobe of the thyroid gland was enlarged; the right supraclavicular and right carotid nodes were involved. On June 18, 1920, a right partial lobectomy with removal of the lymph nodes was done; both were involved with carcinoma. The report by Dr. Ewing was: "Islands of adenocarcinoma. The cells are not large; they are acidophile, not highly atypical, nuclei not hyperchromatic. Some large vessels are filled with tumor tissue. The tumor is not the highly atypical form of thyroid carcinoma occurring in young women but it is a malignant adenocarcinoma." The post operative treatment con- sisted of external and interstitial radium therapy. When last seen, two years later, there was no clinical evidence of recurrence. Case Report No. 76. S. S., a white male, when 18 years of age, had a lump the size of a marble in the right lobe of the thyroid gland. There was a gradually asymptomatic increase in size of this mass until January, 1924, when he was 22 years of age, a partial excision was done at another hospital. Histologically it proved to be an adenocarcinoma. Dr. George Crile later performed a complete operation. He was then given prophylactic X-irradiation at the Memorial Hospital. One year later, when last seen, there was no evidence of recurrence.

THE ASCENDING SCALE OF AVERAGE AGE OCCURRENCE OF THE DIFFERENT MALIONANT NEOPLASMS In 100 regional and histologic varieties of malignant tumors observed at the Memorial ~os~ital,the ascending order of average ages at occurrence were as follows: Wilma' adeno-myoaarcoma of kidney Spinal cord tumors (34) (3) Primary carcinoma of umbilicus (35) Glioma of eye (8) Endothelioma of bone (35) Endothelial myeloma (22) Teratoma of testis (35) Sarcoma of testis (25) Sarcoma of prostate (35) EpitheIioma of middle ear (26) Sarcoma of skin (36) Glioma of brain (27) Sarcoma of soft parts (36) Sarcoma of stomach (27) Sarcoma of appendix (37) Thymoma (27) Leuco-sarcoma of choroid (38) Sarcoma of Meckel's diverticulum (28) Sarcoma of kidney (38) Bone sarcoma (30) Sarcoma of spleen (39) Myosarcoma (30) Adamantinoma (39) Sarcoma of parotid (30) Sarcoma of nasopharynx (39) Brain tumor-type unknown (32) Retroperitoneal lymphosarcoma (40) Carcinoma of appendix (32) Angiosarcoma (40) Adenocarcinoma of eyelid (33) Myxosarcoma (40) Sarcoma of ovary (33) Sarcoma of iris (40) AGE AND SEX DISTRIBUTION 257

Carcinoma of lachrymal eac (52) Liposarcoma (41) Carcinoma of vagina (52) Endothelioma of lymph nodes (41) Carcinoma of colon (53) Mesothelioma (41) Carcinoma of rectum (53) Neurogenic sarcoma (42) Carcinoma of thyroid (53) Multiple myeloma (42) Primary carcinoma of submaxillary Carcinoma of small intestine (43) gland (53) Lymphoaarcoma~xclusiveof retroperi- Carcinoma of stomach (64) toneal and tonsillar regions (43) Epithelioma of cornea and conjunctiva Adenoid cystic-epithelioma of mucous (54) membranes (43) Carcinoma of antrum and superior Sarcoma of urinary bladder (43) maxilla (54) Hypernephroma (44) Carcinoma of epiglottis (54) Myosarcoma of uterus (45) Carcinoma of penis (54) Carcinoma of ovary (45) Paget's disease of nipple (55) Xanthosarcoma (46) Carcinoma of tonail (55) Sarcoma of thyroid (46) Carcinoma of urethra (55) Lymphoaarcoma of tonsil (46) Branchiogenic carcinoma (55) Carcinoma of neeal mucosa (46) Carcinoma of body of uterus (55) Mixed tumor of salivary glands (46) Sarcoma of rectum (66) Sarcoma of vagina (46) Carcinoma of parotid gland (56) Adenocarcinoma of Bartholin's glands Carcinoma of e~ophaguu(57) (46) Carcinoma of gall-bladder (57) Sarcoma of breast (47) Carcinoma of lip (57) Sarcoma of lung (47) Carcinoma of tongue (57) Carcinoma of anue (48) Carcinoma of larynx (67) Melanoma of skin (48) Carcinoma of urinary bladder (57) Carcinoma of cervix (48) Epidermoid carcinoma of skin (58) Primary carcinoma of liver (49) Carcinoma of buccal mucosa (58) Epithelioma of pharynx and naaopharynx Carcinoma of inferior alveolus (58) (49) Endothelioma of parotid gland (59) Carcinoma of kidney (50) Sarcoma of larynx (80) Melanoma of eye (50) Carcinoma of vulva (80) Carcinoma of pancreaa (50) Basal-cell epithelioma of akin (61) Carcinoma of breast (51) Carcinoma of floor of mouth (61) Carcinoma of lung (51) Carcinoma of Proatate gland (63) In 1851, Lebert (87) published the average ages at the time of onset of the following carcinomas: cervix uteri-+ years, tongue47 years, breast-50 years, stomach-54 years, urinary bladder-55 years, large and small intestines-55 years, skin- 57 years, esophagus-60 years; the mean age for all types and regions was 51 years. Now, 78 years later we have found a surprising similarity in the average ages for these same cancers, 258 GEORGE T. PACK AND ROBERT G. LEFEVRE viz: cervix uteri48, tongue-57, breast-51, stomach-54, urinary bladder-57, small and large intestines and rectum-53, skin-58, esophagus-57; the mean age for all types and regions was 53.9 years. The only significant difference was in the case of lingual cancer, where improved oral hygiene has probably increased the latent period for cancer induction in this modern era.

THE RELATION OF CANCER TO OLD AGE AND YOUTH Swift said : "Every man desires to live long but no man would be old." One of the penalties of the attainment of old age is an increased liability to the development of cancer. Bashford (6) states that carcinoma biologically is a function incident to the decay of tissues. Jonathan Hutchinson once said: " Nor indeed is it correct to say that the degree of senility is the measure of the proneness to cancer, for it is not in conditions of advanced senile atrophy that cancer is most apt to occur, but rather, in its commencement. Sometimes it is not so much senility of the entire organism as what we may term local senility and old age of the tissues concerned." All tissues do not have the same rate of decay; some approach maturity while others approach senility. In other words each organ expresses its premature senescence in its own peculiar fashion. Such a conception affordsthe contrast between senilism and senescence. Senilism or premature old age is unequal in its manifestations; it is a pathological old age and implies that a person is as old as his oldest tissue. Senes- cence on the other hand, applies to the individual as a whole, is physiologic in its nature and may be considered as a major invo- lution (Warthin (160)). Now the premature tabescence or decay of any particular organ or tissue may conceivably result in an anatomical condition and a functional state which predispose to the development of cancer, although not necessarily so, else the brain and the kidneys would be organs with a high cancer incidence in old age. The special significance of the sudden increase in cancer incidence in late middle life is said to be more closely related to decline in reproductive activity than to the TABLE NO. 21 The Benign Tumors: The Sez Distribution. Relative Frequency. and Average Agea

Hemangioma of Skin ...... 454 Fibro-adenoma-Breast ...... 151 lntra-cystic Benign Papillomn-Breast ...... 39 Neurofibroma ...... 50 Pituitary Tumors ...... 6 Giant-cell Tumor-Bone ...... 60 Osteoma ...... 7 Adenoma-Rectum ...... 1 Lipoma ...... 89 Desmoid Tumor-Abdominal wall ...... 3 Giant-cell Tumor-Tendon Sheath ...... 10 Dermoid Cyst other than ovary ...... 4 Epulls ...... 20 Fibro-adenoma-Larynx ...... 1 Papilloma-Larynx ...... 25 Adenoma-Parotid ...... 1 Myoma-Urinary Bladder ...... 1 Papilloma-Urinary Bladder ...... 66 Papilloma-Penis ...... 2 Papilloma-Vulva ...... 4 Uterine Polyp...... 19 Adeno-myome Uterus ...... 8 Fibroid Tumor-Uterus ...... 806 Benign Ovarian Cysts including dermoid cysts 72 Thyroid adenoma ...... 138 Chondroma ...... -29 Total ...... 2, 066 260 GEORGE T. PACK AND ROBERT Q. LEFEVRE influence of senility per se. However, in castrated animals this same periodic increase of cancer is observed as occurs in animals with gonads intact. A death really due to senescence or old age in the sense of Metchnikoff, represents a breaking down or wearing out of all the organ systems of the body contemporaneously. According to the early Hindus, this should be at the age of 100 years. The assertion has been made that if any man lived long enough and were spared from other diseases, he would eventually die from cancer. However, we have observed that cancer usually does not occur in extreme old age; in fact after the complete attain- ment of the senile state, cancer in general is progressively infrequent with the important exceptions of squamous carcino- mas of the skin, penis, lip, floor of mouth, buccal mucosa and inferior alveolus and basal-cell epitheliomas of the skin which are more frequent in advanced years in ratio to the proportion of the general population living at these ages. The incidence of these particular cancers of similar histological type increases each year until the normal span of human life is reached. These cancers are usually induced by chronic irritants, therefore the passage of time may permit this phenomenon of cancer induction to take place. The belief that senescence alone is a dominating factor in cancer occurrence, is due to a misinterpretation of the facts, chiefly a failure to appreciate "age incidence" in respect to mortality in general and the normal percentages for age distri- bution (Tables 22 and 23). Cancer is not a biologic retrogres- sion, because it does not occur in all old people, as does such a lesion as arteriosclerosis. It is an accidental rather than a natu- ral step in the involution of the body. If one is permitted to theorize sufficiently to assume that a hereditary predisposition to particular cancers exists in certain individuals, an explanation is available why the cancer incidence drops off beyond a certain age. The majority of such predisposed people have conceivably reacted with cancer before they have become 65 or 70 years of age. It is at the beginning then, rather than at the terminal period of old age that the greatest cancer hazard is usually present. TABLE NO . 22 The Percenlage Occurrence of the More Common Malignant Neoplasms in the Various Quinquennial Age-petiods

04 10-14 15-19 S34 45-49 ...... Type ...... 6-9 2&24 25-29 35-39 4W 50-54 55-59 6U+4 65-69 70-74 7579 80-84 85-89 90-94 95-99 100+ EpidermoidCarcinomaSkin ..... 0.18 0 0.18 0.28 0 1.37 2.29 4.95 5.77 7.79 13.01 16.5 14.48 14.94 9.53 4.95 2.39 1.1 0.09 0.09 0.09 Basal-Cell Epithelioma--Skin ..... 0.29 0.22 0.87 1.89 3.06 3.79 8.59 10.7 12.08 14.85 14.92 12.59 8.95 4.66 2.18 0.36 Carcinoma-Breast ...... 0.08 0.23 1.92 5.11 9.99 14.42 16.64 16.0 12.58 10.66 5.86 3.94 1.92 0.49 0.15 0.04 NeurogenicSarcoma ...... 0.95 1.42 2.37 3.32 8.06 7.58 10.43 11.85 8.53 9.95 9.95 10.9 8.06 1.90 3.32 1.42 Bone Sarcoma (Osteo-andperiostesl) ...... 2.25 5.0 10.25 18.25 10.5 8.5 7.5 7.5 5.25 6.5 6.5 4.75 4.25 1.75 1.0 0.25 Carcinoma Esophagus ...... 0.24 0 2.37 4.75 11.4 21.36 24.0 17.34 13.06 4.51 0.47 0.47 Carcinoma-Stomach ...... 1.2 2.69 5.39 11.68 14.37 15.27 17.36 14.97 11.98 3.89 1.2 Carcinoma--Co Ion ...... 0.93 1.87 4.67 8.41 6.54 12.15 16.82 14.95 14.95 9.35 4.67 4.67 Carcinoma-Rectum ...... 0.13 1.85 3.05 3.58 6.09 7.55 10.86 14.04 17.48 16.03 10.86 5.96 1.85 0.66 Lymphossrcorna (allregions) ...... 0.44 1.97 1.52 3.49 6.77 9.17 7.42 11.57 10.26 11.35 10.5 10.5 6.77 4.58 2.84 0.66 0.44 0.22 Sarcom(aoftpart8)...... 7.58 5.30 6.06 4.55 8.33 9.85 8.33 8.33 4.55 9.09 6.06 9.09 0.76 6.82 3.03 2.29 MelanomaincludingE~e...... 0.93 0.93 0.46 1.39 2.77 6.01 12.5 10.18 11.11 11.11 8.79 8.34 4.63 10.18 5.09 4.17 0.46 0.46 0.46 Carcmoma-Lung ...... 2.94 1.96 3.92 8.82 13.73 12.75 15.69 12.75 10.78 10.78 4.9 0.98 Carcinoma-Thyroid ...... 0.65 2.58 0.65 9.03 6.45 8.39 7.74 14.84 16.77 14.2 9.68 4.52 3.23 1.29 Carcinoma-Lip ...... 0.17 1.36 2.72 5.43 8.15 11.54 14.77 13.92 13.58 11.04 9.68 3.91 2.72 0.51 0.51 Carcinoma (Floor of Mouth) ...... 0.37 1.46 4.74 12.77 16.79 20.44 19.0 13.5 4.01 4.38 1.82 0.37 0.37 Carcinoma-Tongue ...... 0.13 0.38 1.27 2.41 8.63 12.44 17.89 17.77 16.5 12.44 6.09 2.92 1.02 0.13 Carcinoma-Buccal Mucoea ...... 0.55 0.55 0.28 2.21 2.21 6.63 13.0 11.05 16.02 17.13 13.81 7.18 5.8 2.48 0.55 0.28 0.28 Carcinoma-Antrum and Superior Maxilla ...... 0.33 0.65 0.65 0.65 1.95 4.23 5.54 8.14 11.73 13.68 14.98 14.98 10.75 7.17 2.93 1.63 Carcinoma-Inferior Alveolus ..... 0.58 0.58 1.73 2.89 4.05 9.83 13.3 21.30 15.03 15.03 8.67 4.62 2.31 Carcinoma-Tonsil ...... 0.54 1.08 1.36 0.54 2.71 3.8 12.74 18.43 19.51 17.07 11.65 7.05 2.44 1.08 Carcinoma-Kasopharynx and Pharynx ...... 2.33 1.16 1.16 1.16 5.81 6.97 6.97 3.49 13.96 16.28 17.44 12.79 6.98 1.16 1.16 1.16 Carcinoma-Larynx ...... 0.64 1.07 1.07 3.43 5.58 10.09 18.24 17.38 18.88 13.09 6.65 2.79 1.07 Carcinoma-Parotid ...... 2.22 2.22 4.44 2.22 11.11 2.22 13.33 13.33 8.89 15.56 17.78 2.22 2.22 2.22 MixedTumors-Parotid ...... 0.81 0.81 0.81 1.61 5.65 3.23 7.26 13.71 12.1 15.32 6.45 12.1 4.03 8.06 4.03 1.61 1.61 Carcinoma-Urinary Bladder ..... 0.44 1.33 1.99 4.19 5.52 8.83 14.79 16.78 20.53 12.58 8.39 3.75 0.66 0.22 Carcinoma-Penis ...... 1.0 2.0 5.0 6.0 11.0 9.0 14.0 13.0 16.0 10.0 6.0 7.0 Teratoma Testis ...... 0.6 1.2 0.6 3.59 5.39 19.16 23.95 18.56 10.78 4.79 4.19 3.0 1.2 1.8 0.6 0.6 Carcinoma Prostate ...... 0.3 1.2 0.9 1.5 3.29 8.38 17.07 20.96 23.05 14.67 6.29 2.4 Carcinoma-Vulva ...... 0.86 0.86 2.56 6.0 11.97 10.26 16.24 15.4 16.24 12.82 5.13 0.86 0.86 Carcinoma-Vagina ...... 0.98 2.94 1.96 11.76 15.69 5.88 14.7 11.76 18.63 8.82 1.96 2.94 1.96 Carcinoma--C ervix uteri ...... 0.33 2.77 6.14 13.4 16.68 18.51 15.79 11.95 7.87 3.84 2.06 0.61 0.05 Carcinoma-Body of Uterus ...... 0.43 0.43 0 2.58 1.29 7.3 9.44 20.6 24.46 15.02 11.16 6.44 0.86 Carcinoma4vary ...... 1.86 4.97 2.49 11.18 6.21 21.12 15.53 12.42 11.8 9.32 3.1 TABLE NO. 23 The Age-Zncidem of the Afore Common Malignant Neoplasms in the Variow Quinquennial Age-Perk&, Based on the Ral~8Found at these Age Petiods, which Were Sauted by a Com- parison of the Percentage of Malignant Neoplasms at these Age-Period-s (Tab& No. 22) with the Percodage of the Ghmal Population at the Same Periods

Age lSrpe ------0-4 &Q 10-14 15-19 S24 2529 30-34 35-39 4044 45-49 50-54 55-59 Wt6( 65-69 70-74 7H9 -84 85-89 90-94 9589 100+ Stsndsrd Percentage of Actual Living Population Both Sexes. United Statea ...... 11.58 10.63 9.92 9.87 9.86 8.91 7.59 6.96 5.73 4.86 4.25 3.04 2.47 1.83 1.21 0.73 0.35 0.133 0.036 0.00s 0.0039 E~idermoid Carci- noma--Skin ...... 0.01 0.0 0.01 0.039 0.0 0.16 0.32 0.76 1.08 1.72 3.29 5.85 6.31 8.79 8.45 7.33 7.34 8.85 2.65 12.11 24.85 Bssal-cell Epitheli- omaSkin ...... 0.034 0.025 0.113 0.289 0.51 0.768 2.05 2.925 4.623 6.986 9.475 12.057 14.305 15.446 18.929 11.459 Carcinoma-Breast 0.024 0.0704 0.648 2.027 4.31 7.57 10.29 11.03 12.47 12.98 9.974 9.77 7.951 4.2023 3.374 3.29 NeurogenicSarcoma 0.33 0.55 0.98 1.39 3.38 3.52 5.68 7.04 6.16 8.46 9.69 14.86 13.34 4.30 11.33 8.08 Bone Sarcoma (Os- teoandPeriosteal) 1.15 2.79 6.14 10.98 6.32 5.67 5.87 6.39 5.44 7.93 9.09 9.30 10.23 5.68 4.9 2.04 Carcinoma Eeopha- gus ...... 0.07 0.95 2.43 6.58 14.10 22.15 19.7 20.02 10.45 1.86 1.86 Carcinoma Stomach 0.40 1.07 2.34 6.16 8.63 10.87 17.31 18.35 19.82 9.7 4.99 Carcinoma Colon . . . 0.26 0.58 1.70 3.34 3.16 6.91 10.97 13.64 16.77 14.16 10.66 17.8 Carcinoma Rectum 0.0038 0.51 0.94 1.30 2.41 3.63 6.15 9.11 15.88 17.90 16.37 13.54 7.01 5.19 Lymphoslsrcoma (AllRegions) ..... 0.143 0.6780.577 1.332 2.586 3.88 3.68 6.26 6.75 8.79 9.31 13.38 10.33 9.44 8.82 3.42 4.73 6.20 SarcomaSoftPart~ 2.81 2.14 2.62 1.98 3.63 4.75 4.72 5.14 3.41 8.03 6.13 12.88 1.32 16.04 10.75 13.56 Melanoma including Eye ...... 0.22 0.24 0.13 0.39 0.78 1.89 4.62 4.10 5.44 6.41 5.81 7.72 5.26 15.64 11.79 16.12 3.68 9.66 Carcinoma-Lung . . 0.96 0.71 1.67 4.10 7.76 8.48 11.96 13.61 14.14 19.09 13.09 4.36 Carcinoma-Thyroid 0.15 0.60 0.16 2.73 2.13 3.37 3.66 8.04 12.71 13.23 12.18 8.57 10.22 n.19 Carcinoma-Lip . . . . 0.02 0.23 0.56 1.22 2.23 3.72 5.46 7.20 8.64 9.48 12.54 8.45 12.20 5.99 21.97 Carcinoma-Floor of Mouth ...... 0.072 0.368 1.453 4.61 6.95 11.84 13.52 12.97 5.99 10.59 9.13 4.86 17.82 c. m TABLE NO. 23-cmtintced

Age Type W 5-9 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 W.54 55-59 60-64 6M9 70-74 75-79 80-84 8S89 90-94 ------___------95-99 100+ Carcinoma-Tongue 0.03 0.097 0.39 0.79 3.45 5.85 9.64 13.40 15.29 15.57 11.49 9.20 6.66 8.13 Carcinoma-Buccal Mpcosa ...... 0.058 0.058 0.033 0.305 0.33 1.21 2.80 2.73 5.52 7.27 7.91 6.20 8.33 7.42 5.09 8.04 36.68 Carcmoma-Antrurn and Superior Maxilla...... 0.07 0.16 0.16 0.16 0.54 1.38 1.97 3.52 5.97 7.98 12.23 15.04 14.57 14.65 9.99 11.53 Carcinoma- Inferior Alveolus . 0.104 0.121 0.47 0.86 1.47 4.20 6.51 14.66 12.67 17.10 14.87 13.23 13.72 Carcinoma-Tonsil . 0.1 1 0.27 0.37 0.15 0.96 1.64 6.48 10.75 15.93 17.13 15.78 14.4 8.32 7.63 Carcinoma-Naso- pharynx and Pharynx...... 0.64 0.37 0.37 0.37 2.10 2.96 3.22 1.96 9.24 12.34 18.51 16.68 12.29 3.08 5.14 10.66 Carcinoma-Larynx 0.15 0.29 0.34 1.19 2.37 5.04 10.45 13.94 18.62 17.42 13.35 9.34 7.43 Carcinoma-Parotid 0.35 0.38 0.91 0.49 3.02 0.71 4.89 6.85 5.62.13.2822.88 4.76 9.8925.90 Mixed Tumors- Parotid ...... 0.224 0.2440.261 0.523 1.836 1.162 3.065 6.310 6.772 10.092 4.868 12.782 5.23 14.13 10.65 7.10 14.73 Carcinoma-Urinary Bladder ...... 0.10 0.34 0.60 1.37 2.20 4.15 7.97 12.67 19.05 15.76 15.85 11.82 4.31 3.76 Carcinoma-Penis . 0.25 0.56 1.65 2.16 4.83 4.65 8.29 10.78 16.31 13.76 12.45 24.25 Teratoma-Testis.. 0.03 0.06 0.03 2.09 3.14 12.35 18.11 15.29 10.80 5.65 5.66 5.67 2.79 5.65 2.85 9.84 Carcinoma- Prostate...... 0.052 0.27 0.22 0.46 1.11 3.43 9.77 14.76 21.90 21.08 14.98 11.93 Carcinoma-Vulva . 0.181 0.21 0.69 1.96 4.60 4.52 10.00 11.10 16.60 19.78 13.20 4.59 12.02 Carcinoma-Vagina 0.27 0.88 0.69 4.52 7.33 3.23 9.26 10.33 20.45 12.90 4.34 10.78 14.99 Carcinoma--Cervix Uteri ...... 0.12 1.22 3.18 7.75 11.45 14.96 14.62 15.49 12.54 8.26 6.60 3.30 0.56 Carcinoma-Body of Uterus...... 0.12 0.12 0.96 0.52 3.60 5.48 13.69 22.76 17.18 17.23 14.99 3.34 Carcinoma--Ovary . 0.83 2.24 1.24 6.55 3.96 16.34 14.14 13.00 17.27 16.78 7.56 264 GEORGE T. PACK AND ROBERT G. LEFEVRE '(And so from hour to hour we ripe and ripe, and then from hour to hour we rot and rot." But just where ripening leaves off and rotting begins is a plateau of time, which varies with differ- ent people. Plato for one, said man was at his highest develop- ment at the age of 40. Because of this individual variability, the term "cancer age" should be used in the relative rather than in the absolute sense. The decennial period, 40-50 is one of abrupt transitional changes, both physical and functional, for women; men are less affected. This decennium marks the per- iod where cancer frequently makes its first tremendous increase. The decennium 55 to 65 years is the age period wherein the max- imal incidence is found for the great majority of cancers. Bashford (6) states: "The span of life of the individual is not the same as that of the separate organs and tissues which have contributed to its maintenance. Some organs and tissues early attain full development and disappear; others are only active during adult life; and others again as long as life lasts." The early involutionary period for some organs coincides with the time of greatest cancer frequency in these particular organs. As previously stated, such a cancer occurrence may not agree with the state of the individual as a whole. The specific involu- tion of a particular organ which has fulfilled its function, as the thymus (Warthin's minor involution), occurs at a relatively early age and in agreement with this we find thymomas predom- inantly in young adults. The prostate gland atrophies at a late period (the male climacteric) and of all the glandular organs it is the one involved at the oldest average age. Uterine function is dependent on the endocrinal integrity of the ovary, and so we naturally find ovarian carcinomas occurring at earlier ages than cancers of the uterus. The placenta has the shortest life of any human organ, yet at times it is subject to the develop- ment of chorionepithelioma at a time period after fertilization which corresponds to its old age stage of degeneration. At birth the placenta is a senile organ with calcareous, fibrotic, atrophic and vascular changes characteristic of old age. Its cancerous transformation is in keeping with its anatomic age. So in the instance of malignant epithelial tumors, statisticians AGE AND SEX DISTRIBUTION 265

and pathologists have frequently emphasized that the age inci- dence of the individual is the sum total of the liability to cancer of all his organs, each of which has a variable liability of its own. Although sarcomas and carcinomas both aqpear with some increasing frequency as life advances, the sarcomas do not seem to be sharply influenced by sudden involutionary changes as do the carcinomas. Possibly this is because these changes are effected in organs of specialized epithelial structure, whereas the connective tissues are simpler, less differentiated, and less prone to degenerate. However, fibrosis is concomitant with the ageing process, and if we believe in Thiersch's conception of a state of equilibrium existing between connective tissue and epithelium, we may use this theory to explain the loss of restraint upon the inherent proliferative capacity of epithelium with re- sultant cancer formation. Adami said : "As the tissues age, the highly differentiated cells tend to become structurally simpler, revert, that is to say, to a simpler type, and with this simplification of structure accom- panying atrophy there may be a greater liability for these cells to assume proliferative powers." Metchnikoff conceived of the nature of senility as atrophy alone: "On r6sum6 la senilit6 par un seul mot: atrophia." Just as senility is dependent on atrophy, so is atrophy the precursor of most carcinomas, with the exception of embryonal or teratomatous or congenital tumors, easily explainable by Cohnheim's theory. Such atrophy or senility may be physiologic, as in the thymus at puberty, and in the breast and body of uterus at the menopause, which physiologically regressive organs become sites of predilection for malignant epithelial tumors. Carcinogenic agents such as tar induce atrophy of the tissues to which they are applied, before the cancer develops. Degenerations of tissues and organs brought about by toxins, by endocrine imbalances as in thyroid and ovary, by infections as in lymphoid and myeloid tissues, by trauma as in fascia1 and osteoid tissues, by chronic irritations as in skin, cervix uteri, penis, lip, tongue, and buccal mucosa, may precede and indeed influence the development of cancer in these areas. But the onset of cancer in such instances does not 266 GEORGE T. PACK AND ROBERT Q. LEFEVRE have the same specific relationship to age as do the previously mentioned physiologic atrophies, which occur at definite per- iods in the life history of the individual. In other words, these accidental atrophies in contrast to the natural atrophies, are not related to age so much except that the passing years afford sufficient time for the causative agents to induce degenerations and possibly tissue overgrowth and even cancer. With this idea in mind, we can appreciate that old age and cancer may be incidental and concomitant in their relationship, rather than cause and specific effect respectively. In suscepti- ble persons, each year of life increases the hazards of exposure to extrinsic carcinogenic influences. The average intelligent indi- vidual avoids conscious tangible irritations, which theoretically could do great damage in a relatively short time (quantity of irritant X time factor). With imperceptible irritation, the quan- tity of unknown agent is quite small and the time interval necessary to induce cancer is inversely long, so that frequently such a period represents a considerable portion of the individual's life. The disposition of any person to cancer is seldom so strong that cancer arisea under the influence of an irritation of com- paratively short duration, unless the irritation is unusually intense. Excluding the previously mentioned organs which are uniformly subject to physiologic atrophy, we believe that the age per se of the individual is not so important as the length of time of exposure to the noxious agent. Leitch (88) has demonstrated repeatedly that if young animals and old animals are subjected simultaneously to cancer inducing substances, the results in point of time of the onset of the cancer are the same in both classes. Age then affords a longer time for the effects of the agent to be produced, whether this agent be a toxin, germ, internal secretion, or physical irritant. There are many specific examples which can serve as proof of these assertions. Bilharzia infestation usually occurs in childhood, frequently in infancy; the twenty or more ensuing yeara to young adulthood often suffices for the production of Bilharzia carcinoma of the urinary bladder in relatively young subjects. Fibiger (43) stated emphatically that "Spiroptera cancer occurred in rats which, AGE AND SEX DISTRIBUTION 267 both on the transmission of the Spiroptera and at death, were still young." X-ray cancer has been significantly common in young men; the X-rays constitute an irritant so vigorous and intense that they can induce cancer in young men with exposure over only a few years. Some important facts concerning the relation of age to cancer can be gleaned from the fields of comparative and experimental pathology, viz. : 1. "Just as the gestation period varies from 21 days to 9 months in the case of the mouse and human subjects, in accord- ance with the laws which govern their respective developments, so if there be stages in the growth of cancer, they may also be adapted to the compass of life in different animals, and be gone through more quickly for the mouse than for man" (Bashford (6)). The human at 45, the horse at 10, the dog at 8, the trout at 5 and the mouse at 2 years have all entered the presenile per- iod of cancer susceptibility; this period of relative freedom is proportionately the same among these different animals. This offers additional substantiation of the relativity of "cancer ages." 2. Goodpasture and Wislocki (58) did necropsies on 15 very old dogs. In every animal they found more than one type of tumor, an occurrence very rare in young animals. The liver and adrenal glands contained tumors in 14 of the 15 dogs. Every organ of the body in some of the dogs, had been the seat of multiple tumor formation; however, all but one tumor of this large group were benign. In conclusion these investigators state: "The character of the alterations in the same organ has been uniform in all individuals; and we are convinced that the process is fundamentally a series of cellular changes dependent upon functional involution of an organ or tissue during senes- cence." 3. In an analysis of hereditary mammary cancers in mice, Tureen and Leo Loeb (151) have observed a definite relationship between the tumor rate of incidence and the age at which the tumors occur; for instance: in strains with a high tumor inci- dence, tumors appear in the large majority of cases, at an early 268 GEORGE T. PACK AND ROBERT G. LEFEVRE age; in strains with a low tumor rate, tumors appear relatively late in life. No data are available to indicate that human off- spring of cancerous parents are prone to develop cancer at an earlier age than their progenitors. 4. In suckling albino rats, whose ages varied from one to 20 days, implants of the Sugiura rat sarcoma, during the first 14 transplantation generations, were successfully inoculated (100 per cent takes) and grew to the point of ulceration in the hosts. In adult rats one year old, the percentage of tumor takes was the same as for the sucklings, but spontaneous absorption of the tumors occurred in a large number of the animals (Sugiura (142)). 5. The age of the albino rats had very little influence on the rate of spontaneous regression of Flexner-Jobling rat carcinomas, e.g., 15 per cent of the positive transplants in each of the suck- ling, young and old rat groups were absorbed. However the rate of growth of the Flexner-Jobling rat carcinoma in young rats was greater than in old rats (Sugiura (143)). 6. Sugiura (144) studied the susceptibility of young chicks (one to 30 days old) to Rous chicken sarcoma No. 1, and observed that the transplants grew rapidly, metastasized readily and killed the chicks quickly. When he inoculated chicks with this tumor at an age of less than 8 days, they died within two weeks after the implantation, but as they grew older their power of resistance increased, e.g., the sarcoma did not kill the 21 and 30 days old chicks before 25 and 30 days respectively after tumor inoculation. The Rous chicken sarcoma grew relatively faster and metastasized more quickly in healthy growing chicks than in young adult hens (Sugiura). From these transplantation experiments, it might be suggested that the tissues of youth afford a better soil and offer less resist- ance to sarcomas than do similar adult tissues. Carcinomas on the other hand do not regress spontaneously in aged animals as do the sarcomas, but their rate of growth is slower than in young animals of the same species. Somewhat contradictory to these statements were the experiments of Freund and Ehm- iner (47) on the constitutional or humoral resistance to cancer. AGE AND SEX DISTRIBUTION 269

They measured the lytic capacity for cancer cells of the serum of various age classes of human beings from the very young to the very old, and found that the serum of an infant could be diluted from 20 to 25 times before it lost this lytic capacity, the serum of adolescents at puberty about 6 times, of adults 3 to 4 times, of the aged not at all. In old age they found the lytic capacity of the serum for cancer cells still present, but easily lost with the least dilution. If the observations of Freund and Kaminer were biologically correct and all other conditions were equal, the cancers of old age would theoretically be increasingly malignant. From our appraisal of the cancers of the extremes of life, we believe there is a definite tendency to lowered malignancy in the cancers of old age. This is most apparent in the study of the histology and clinical course of mammary and skin cancers in old people. The explanation of this phenomenon resides in certain intrinsic and extrinsic factors: intrinsic as regards the nature of the cancer itself, extrinsic with reference to its environment or the state of the host. The cancers of old age are usually well differentiated adult neoplasms, slow-growing, lacking the features of anaplaaia and exhibiting little microscopical evidence of mitosis. The natural fibrosis, concomitant with the process of ageing should inhibit or restrain the growth of cancer cells. Attention has been called to the obliteration of the lymphatics as one factor in the delayed dissemination of cancer in the aged. Lowered metabolism, diminished oxidative capacities, sluggish circulation of the blood and impaired nutrition of the host, all influence the rate of cancer growth. Ewing has said: "The cancers which pursue a rapid course in the aged, are usually ones arising from tissue rests, which have long remained quiescent, but when once excited to growth, find conditions especially favorable for un- restrained proliferation." In experimental cancers, the local area is nutritionally dis- turbed, and changes are observed in the blood vessels, notably a narrowing of the lumen. Theilhaver (148) enthusiastically attributes a causal significance to these vascular changes and maintains that as a person ages, the blood-forming organs (bone 270 GEORQE T. PACK AND ROBERT Q. LEFEVRE marrow, spleen and lymph nodes) become less active and atrophy, thus predisposing to the development of cancer in old people. Other contributing factors, he adds, are the paucity of available lymphocytes and the presence of arteriosclerosis with diminished blood supply. Warner (156) made an intensive study of the relation of arteriosclerosis to the development of carcinoma; he found definite obliterative changes in the blood vessels in 57 per cent of epidermoid carcinomas of the skin, in 79 per cent of carcinomas of the cervix uteri, in 40 per cent of non-cancerous cervices, in 58 per cent of breast cancers, in 25 per cent of breasts with chronic mastitis, in 62.5 per cent of carcinomas of the body of the uterus, in 33.3 per cent of non- malignant uteri, in 33.3 per cent of carcinomas of the prostate and in 10 per cent of benign hypertrophied prostates. In conclusion he states "that endarteritis and the anatomical changes of old age cannot be looked upon as a constant factor in the production of cancer is shown by the fact that normal vessels were present in almost half the cases." Cazalis' aphor- ism " X man is as old as his arteriesJ' is true, but to paraphrase this to say "A man is as susceptible to cancer as his arteries are oldJ' is to state an untruth. Endarteritis and cancer may con- ceivably and frequently coexist in the same old individual; the endarteritis may be partially responsible for lack of nourishment for the tumor and thereby influence its growth, but there is no evidence as yet to justify the assertion that arteriosclerotic changes are causal factors in the etiology of cancer. Paget (117) in his lectures on Surgical Pathology (1853) made a comparison of the ages at death from cancer with the death rate of living people at the same ages and concluded that "the liability to cancer seems always increasing from childhood to 80 years of age." Our data on this incidence are shown in Table 23. The thought has been frequently expressed that the progressive age distribution of cancer is especially characteristic of this disease. This is true for the post-meridian period of 45 to 65 years, but after this period the general mortality from the lethal respiratory, nervous and cardio-vascular-renal diseases in- creases far more rapidly than does the mortality rate from cancer. TABLE NO . 24 Malignant Tumors: the Average Age. the Relative Frequency and the Dislribulion According to Sez

. 0/ % Average Age of Age of %.of % of cancer % of cancer ales Femalea Age Youngat -Oldat Admuions MTzMalea in Feden Epidernloid carcinoma-Skin .... 1,091 59% 41 0/0 58 1.5 101 5.70% 6.586% 8.042% 5.223 Basal-cell carcinoma-Skin ...... 1,374 56.5% 43.5Y0 61 17 94 7.18y0 8.29470 9.691y0 6.988 Epithelioma-middle ear ...... 2 50% 50% 26 11 40 0.01% 0.012% 0.012% 0.012 Primary carcinoma-Umbilicus . . 2 100% 0 35 33 38 0.01% 0.012% 0.025% None SarcomaSkin ...... 6 83% 17% 36 21 53 0.03% 0.036% 0.062% 0.058 Carcinoma-Breast ...... 2,663 1.24% 98.7% 51 17 90 13.92% 16.076% 0.4127, 30.732 Sarcoma-Bresst ...... 18 5.5% 94.5% 47 21 85 0.09% 0.109% 0.012% 0.199 Paget's Disease-- Sipple ...... 20 0 100% 55 32 70 0.10% 0.12170 None 0.234 Spinal Cord tumors ...... 12 50% 50% 34 6 65 0.06% 0.072% 0.074% 0.070 Glioma-Brain ...... 19 68.4% 31.6% 27 2.5 66 0.10% 0.114% 0.175% 0.058 Glioma-Eye ...... 29 37.9% 62.1% 8 0.33 58 0.15% 0.175T0 0.13770 0.210 Brain Tumor-- (other than Glioma) ...... 27 70.4% 29.6% 32 3.5 59 0.14% 0.164% 0.237% 0.093 Neurogenic Sarcoma ...... 211 59.7% 40.3% 42 1.0 79 1.1 1.274% 1.573% 0.993 ChondroSarooma ...... 17 53% 47% 41 22 72 0.088% 0.103% 0.112% 0.093 Multiple Myeloma ...... 11 72.7% 27.3% 42 1.5 62 0.05% 0.06670 o.10070 0.035 Endothelisl Myeloma ...... 37 51.4% 48.6% 22 2 58 0.19% 0.223% 0.237% 0.210 Bone Sarcoma (Osteogenic- Periosteal) ...... 400 62.5% 37.5% 30 1.5 77 2.097, 2.415% 3.122% 1.753 Endothelioma-Bone ...... 11 63.6% 36.4% 35 8 84 0.05% 0.066% 0.087'30 0.047 Carc+oma-Esophsgus ...... 421 80.5% 19.5% 57 25 83 2.20% 2.542% 4.234% 0.958 CsrclnomaStomach ...... 334 69.2% 30.8% 54 25 79 1.7470 2.01670 2.8857, 1.204 SaroomaStomach ...... 2 50% 50% 27 27 28 0.01% 0.012% 0.01270 0.012 CarcinomaSmall Intestine ..... 8 62.5% 37.5% 43 25 62 0.04% 0.048% 0.062Y0 0.035 Sarcoma-Meckel's Diverticulum 1 0 100% 28 - - 0.005y0 0.006yo None 0.012 Carcinoma-Appendix ...... 6 33.3% 66.7% 32 17 61 0.037, 0.036% 0.025% 0.047 Sarcoma-Ap ndix ...... 1 0 100% 37 - 0.005% 0.006% None 0.012 carcinomaslon ...... 107 56.1Y0 43.9Y0 53 22 78 0.559% 0.646% 0.749% 0.549 Carcinoma-Rectum ...... 755 61.7% 38.3% 53 17 84 3.94'30 4.557% 5.819% 3.377 Sarcoma-Rectum ...... 1 0 100% 56 - - 0.005% 0.006% none 0.012 TABLE NO . 24.- ntinued

No' % Average Age of Age of % of Xaea Femalea Age Youngest Old& Admiseona ...... Carcinoma--Anus ...... 10 60% 40% 48 20 72 0.05% Carcinoma--Pancreaa ...... 21 71.4% 28.6% 50 24 68 0.109% Carcinoma-Gall-bladder ...... 21 19% 81% 57 40 67 0.10990 Primary Carcinoma--Liver ...... 28 71.4% 28.6% 49 22 74 0.146% Lymphosarcoma (exclusive of tonsil) ...... 390 64.4y0 35.6% 43 3.5 87 2.03% Retroperitoneal L~mphosarcoma. 36 55.67, 44.470 40 3 71 0.188% SwcomaSpleen ...... 4 75% 25% 39 30 49 0.02% Thymic Tumor-Thynoma ... 49 75.5% 24.5% 27 0.1 63 0.256% Endothelioma-Lymph Xodes ... 16 56.3% 43.7% 41 2 67 0.0870 Liposarcoma ...... 5 8070 20Y0 41 7 73 0.026LT, Sarcoma-soft parts ...... 132 61.4% 38.670 36 1.3 77 0.69% Angiosarcoma ...... 6 66.7% 33.3% 40 23 53 0.03% Myosarcoma (exclusive of uterus) 3 66.7% 33.3 % 30 12 45 0.015% 0.018% 0.025% 0.012 Myxosarcoms ...... 11 45.4% 54.6% 40 2 60 0.057% 0.06670 0.0620/, 0.070 Xanthosarcoma ...... 2 0 100% 46 41 51 0.010% 0012% 1 none / 0.023 Epitheliorna.-Co rnes and Con- lunctlva ...... 14 64.3% 35.7% 54 25 78 0.073% Adenocarcinoma~Eyelid...... 3 66.7% '0.3% 33 1 49 0.01570 Carcinoma.Lachr.wla1 Sac ..... 3 100% 0 52 39 72 0.01570 Sarcoma--Iris ...... 3 66.7% 33.3% 40 12 73 0.01570 Leuco-sarcoma-Choroid of Eye 2 100% 0 38 37 39 0.010% 0.012% 0.025% none Melanoma--General ...... 208 51.4% 48.670 48 1.3 98 1.0877, 1.256% 1.336% 1.180 Melanoma--Eye ...... 8 5070 50y0 50 30 64 0.047, 0.048% 0.050% 0.047 Sarcoma--Lung ...... 12 5070 5070 47 12 79 0.06% 0.072% 0.076% / 0.070 Mesothelioma ...... 1 5 40y0 60% 41 18 so 0.026% Carcinoma--Lung ...... 102 73% 27% 51 20 81 0.53% Carcinoma-Thyroid ...... 155 23.9% 76.1% 53 17 85 0.81Y0 Sarcoma--Thyroid ...... 3 33.3Y0 66.7% 46 30 57 0.015% Carcinoma--Lip ...... 589 94.2% 5.8% 57 24 91 3.0797, TABLE NO. 2hntinued

% No' % % Average Age of Age of % o! % of cancer % of cancer Melee Fernlea Age Youngeet Old& A~LU~SSIOIU in Malea in Femalen -- - M$umT,"t Carcinoma-Floor of Mouth. .. 274 94.9% 5.1 61 25 93 1.43% 1.654% Carcinoma-Tongue ...... 788 86.9% 13.1% 57 24 91 4.119% 4.757% Carcinoma-Buccal Mucosa. .... 362 89.570 10.570 58 10 97 1.88% 2.185% Adenoid Cystic Epithelioma Mucous Membrane...... 17 47.1Y0 52.970 43 10 66 0.088% 0.103% Carcinoma-Antrum-Superior Maxilla ...... 307 66.1% 33.8% 54 9 82 1.604% 1.853% Carcinoma-Inferior Alveolus ... 173 87.3% 12.7% 58 1.5 84 0.904% 1.044% Adamantinoma ...... 21 66.77, 33.3% 39 14 69 0.109% 0.127% Carcinoma-Tonsil ...... 369 90.8% 9.2% 55 2 81 1.92970 2.227y0 L~mphosarcoma-Tonsil ...... 32 71.9y0 28.170 46 15 74 0.167% 0.193% Epithelioma-Xasopharynx and Phar>nx ...... 86 75.6% 24.4% 49 1 84 0.449% 0.519% Sarcoma-Xasophar~nx and Pharynx ...... 20 7570 25% 39 4 70 0.104% 0.122% Primary Carcinonla-Epiglottis 32 %% 470 54 32 75 0.167% 0.19370 Carcinoma-Larynx ...... 466 91.2% 8.8% 57 22 83 2.436% 2.813% Sarcoma-Larynx ...... 3 66.77, 33.370 60 49 75 0.015% 0.018% Carcinoma-Frontal and Sphe- noid Sinuses...... 2 100% o 46 35 57 0.01070 0.012% 0.025% none Carcinoma-Nasal Septum ..... 31 64.5% 35.5% 46 9 77 0.162% 0.187% 0.250% 0.129 Carcinoma-Submaxillary Gland 11 100% 0 53 30 66 0.057% 0.066% 0.137% none Carcinoma-Parotid Gland...... 45 64.4% 35.6% 56 20 85 0.235% 0.271% Mixed Tumor-Parotid and Submaxillary ...... 124 48.4% 51.6% 46 1 83 0.648% 0.749% 0.749% 0.748 Endothelioma-Parotid...... 1 100% 0 59 - - 0.00570 0.006% 0.012% none Sarcoma-Parotid ...... 3 66.7% 33.3% 30 4 52 o.01570 0.01870 0.025% 0.012 Branchiogenic Carcinoma ...... 24 75% 25% 55 35 77 0.125% 0.145% Carcinoma-Urethra ...... 18 16.7y0 83.370 55 28 75 0.094% 0.109% Carcinoma-Bladder ...... 453 77.8% 22.276 57 20 87 2.388% 2.735% 086\0 8 $%q -00 24 (

*-fr

%Fi1 # gQ0(sbb 3%," m2 ggg am" g 10CccD $j

... : .& : !'g ;: :i:a :.$ 9 g3 534 m.2 h - 'El AGE AND SEX DISTRIBUTION 275 The normal human being lives through six distinct age epochs if his life is permitted to run its normal course of years (115). As we have previously seen, there are many malignant tumors which may occur during any or almost all of these epochs. We have attempted to isolate just those malignant tumors which seem to have a significant time relationship with each of these age periods. (1) Infancy, which extends from birth to independent nutrition and motion, usually at 10 months. Wilms' tumor or the adenomyosarcoma of the kidney is of frequent occurrence, together with ocular glioma. (2) Childhood, which usually extends to the development of the senses, and second teething at the 7th or 8th year. Glioma of the eye is the most significant malignant tumor of this period, although Wilms' tumor is frequently found. (3) Pre-sexual period, which terminates at the 13th or 14th year. This period, an intermediate stage between childhood and adulthood, is unusually free of malignant tumors. There are relatively fewer malignant tumors at this age than at any other time in life. (4) Pubertal period, which bridges the span of years from puberty, to the end of length of growth. Complete maturity of growth is usually attained by the male at 28 years of age and by the female at 24 years (Warthin). The tumors of especial frequency during this period are the endothelial myelomas, thymomas, gliosarcomas and sarcomas of the testis. Many authors include bone sarcomas (of the long bones particularly), in this bracket, but as we have previously shown, the relative age inci- dence corrected on the basis of the proportionate number of the general population living during this period, does not indicate that individuals of this age are preeminently prone to develop bone sarcomas. (5) Maturity: In the male this epoch extends to the time of sexual decline, which is an indefinite terminal; in the female it terminates at the menopause. The great host 276 GEORGE T. PACK AND ROBERT a. LEFEVRE of malignant tumors occur in this period and the early part of the succeeding age period. (6) Senescence begins with the menopause in the female and the sexual climacteric in the male; it terminates in death. The cancers of salient interest in this epoch are the basal-cell epitheliomas of the skin, the squamous cell carcinomas of the skin, lip, buccal mucosa, floor of mouth and vulva, and the carcinomas of the prostate gland. In any discussion concerning the age occurrence of tumors, it should be emphasized that the anatomic and physiologic age of the subject is of greater importance than his chronologic age. For example, certain people are old at 40 years, whereas others are functionally and anatomically well preserved at 60 years. We have observed an instance of epidermoid carcinoma of the skin originating presumably on an ectopic nipple in a sexually precocious girl, 10 years old, which would serve to illustrate this viewpoint. Case Report No. 77. R. I<., a Jewish girl, aged 10 years, observed a nodule two years previously on the skin of her chest near the scapular Iine about the level of the tenth rib. This nodule became as large as a walnut during the next two years and became quite dark in color. In September, 1928, when 9 years of age she began to menstruate. Menstruation was regular and normal; the breasts were fully de- veloped; the axillary and pubic hair were abundant; she had the normal female habitus. Her weight was 101 pounds. On April 1, 1929, the nodule was completely excised. It proved to be an' epidermoid carci- noma, Grade 11. There has been no recurrence. In a previous discussion of the behavior of transplantable tumors in experimental animals, we mentioned the rapidity of tumor growth in young tissues and suggested that the tissues of youth afford a better soil and offer less resistance to the devel- opment of malignant tumors than do similar adult tissues. This observation is in keeping with well-known biological principles. For instance, Trembley in 1744 published the results of his investigation on hydroids, or fresh water polyps, showing that a complete and equal fission would result in two complete polyps. Trembley with polyps and Spallanzani, the famous Italian AGE AND SEX DISTRIBUTION 277 naturalist, with earthworms in 1768, proved conclusively that this power of replacing a lost part is far greater in young plants and animals than in the same plants and animals at older ages. In the human animal, wounds heal more quickly in youth; all regenerative and reparative processes take place with speed and vigor; fractures of bone heal with exuberant callus formation; functional demands for compensatory hyperplasia are more readily complied with; skin-grafting is more uniformly successful and finally it is our contention that cancers of early life progress more rapidly, disseminate more frequently and recur more often after removal than do their congeners of adult life. In considering the malignant tumors of youth, particularly those of epithelial structure, two groups of tumor types present themselves for analysis : (a) Certain malignant tumors which appear at early ages, are unusual in this precocity, because they are more common in mature years or middle and later life. When compared with similar tumors in older persons, these cancers in youth are usually more rapidly growing, highly cellular, undifferentiated, anaplastic neoplasms of greater malignancy. Mitoses are fre- quently abundant and there is little fibrosis and hyalinization of the surrounding connective tissue. The history of the disease is short, the course is rapid and the mortality is high. As we have previously shown, the cancers of the breast, uterus, stomach, rectum and intra-oral cavity are attended by very bad prog- noses, when they occur in young persons. As Rankin and Broders (124) said: "The active tissues of youth, instead of resisting cancer invasion, invite its spread and the young person who is host to a malignant neoplasm has little chance for lon- gevity, regardless of the type of therapeutic measures instituted. There are at least two generally recognized exceptions to the above dictum: (1) the encapsulated adenocarcinoma of the thyroid gland and (2) the encapsulated or intra-cystic cystadeno- carcinoma of the ovary. These cancers, potentially dangerous, have a low degree of malignancy because they have attained a high degree of cellular differentiation and are restrained from dissemination by their encapsulation. TABLE NO . 25 The Malignant Tumoss of Ydand Old Age

N-- Per- P-tage N-. pep Pemntsee N-. per Per~entsgeN-. pep P-tsge ber centage Of dl ber centage dl ber of all of dl Types under under malignsnt over over malignant TYP- under %%? ovlr over -t 25 25 74 74 25 25 e,"74 74 t-ors yra . years . years . yearn . Over 74 yrs . years . under 25 years . years. Over 74 ------~~m~syears . -- years. ---Years . EpidermoidCarcinomaSkin ... 7 0.64 1.00 95 8.70 12.71 Carcinoma-Lung ...... 3 2.94 0.47 1 0.98 0.13 Basal-cell Carcinoma-Skin ..... 7 0.51 1.09 222 16.16 29.71 Carcinoma--Thyroid ...... 5 3.22 0.78 7 4.51 0.93 Epithelioma-Middle Ear ...... 1 50.00 0.15 Carcinoma-Lip ...... 1 0.17 0.15 45 7.64 6.02 SarcomaSkin ...... 2 33.33 0.31 Carcinoma-Floor of Mouth ... 19 6.93 2.54 Glandular Carcinoma-Breast .. 8 0.30 1.25 69 2.59 9.23 Carcinoma-Tongue ...... 1 0.12 0.15 32 4.06 4.28 Sarcoma-Breast ...... 1 5.55 0.15 2 11.11 0.26 Carcinoma-Buccal Mucosa .... 4 1.10 0.62 34 9.39 4.55 Brain Tumor-Type Unknoun . . 8 29.62 1.25 Adenoid cystic Epithelioma- Glioma-Bmin ...... 10 52.63 1.56 Mucous Membranes ...... 3 17.64 0.47 Glioma-- E e ...... 26 89.65 4.07 Carcinoma-Antrum and Super- S inal ~ori~umors...... 4 33.33 0.62 ior Maxilla ...... 7 2.28 1.09 14 4.56 1.87 durogenic fhrcoma ...... 34 16.11 5.32 3 1.42 0.40 Carcinoma-Inferior Alveolus .. 2 1.15 0.31 12 6.93 1.61 Chondro Sarcoma ...... 2 11.76 0.31 Adamantinoma ...... 3 14.28 0.47 Bone Sarcoma ...... 185 46.25 28.99 1 0.25 0.13 Carcinoma--Tonsil ...... 6 1.62 0.94 13 3.52 1.74 Endothelial Myeloma ...... 25 67.56 3.91 Carcinoma-Pharynx and Naso- pharynx ...... 5 5.81 0.78 2 2.32 0.26 MultipleMyeloma ...... 1 9.09 0.15 Sarcoma-Pharynx and Nsso- pharynx ...... 5 25.00 0.78 Endothelioma--Bone ...... 3 27.27 0.47 1 9.09 0.13 Carcinoma--Larynx ...... 3 0.64 0.47 18 3.86 2.41 Carcinoma-Esophagus ...... 4 0.95 0.53 Sarcoma-Larynx ...... 1 33.33 0.13 Carcinoma.4 tomach ...... 4 1.19 0.53 Carcinoma-Nasal Se turn 5 16.13 0.78 2 6.45 0.26 Carcinoma-Appendix ...... 3 50.00 0.47 Carcinoma-Parotid Eland'. '. : 1 2.22 0.15 3 6.66 0.40 Carcinoma.-Colon ...... 1 0.93 0.15 5 4.67 0.66 Mixed Tumors-Parotid and Submaxillary ...... 12 9.67 1.88 4 3.21 0.53 TABLE NO . 25 (continued)

N~~-per- Percentage N-. pep Pereentsge N~~-Per- Percentsge N~~-Per- Percentage ber centage of all b,r centage of ber centsge ber centage Of all Types under under over over -t TYP- under under over over melignsnt 25 25 74 74 25 25 74 74 t-Om under25 Over 74 Over 74 yra . years . ywa. yearn . pis. years . yean. pears . -- yeAm . -- Year- . ---.-~2~25 Ywa. Carcinoma--Rectum ...... 15 1.98 2.35 19 2.51 2.54 Sarcoma-Parotid ...... 1 33.33 0.15 Carcinoma--Anus ...... 1 10.00 0.15 Branchiogenic Carcinoma ...... 3 12.50 0.40 Carcinoma-Pancreas ...... 1 4.76 0.15 Carcinoma-Urethra ...... 1 5.55 0.13 Primary Carcinoma-Liver ..... 1 3.57 0.15 Carcinoma-Urinary Bladder ... 2 0.44 0.31 21 4.63 2.81 Lymphosercoma ...... 65 14.19 10.19 6 1.31 0.80 Carcinoma-Kidney ...... 1 5.26 0.15 Thymoma ...... 19 38.77 2.97 Adenomyosarcoma Kidney (Wh)...... 14 100.00 2.19 Endothelioma-Lymph Nodes ... 4 12.50 0.62 Hypernephroma ...... 5 10.00 0.78 1 2.00 0.13 Lipoearcoma ...... 2 40.00 0.31 carcinoma-Penis ...... 1 1.00 0.15 7 7.00 0.93 SarcomaSoft Parts ...... 42 31.81 6.58 3 2.27 0.40 Terntoma--Testis ...... 19 11.37 2.97 1 0.60 0.13 Angiosrrrcoma ...... 1 16.66 0.15 Sarcoma--Testis ...... 3 37.50 0.47 Myoearcoma-excluding uterus . 1 33.33 0.15 carcinoma-Prostate ...... 1 0.29 0.15 29 8.68 3.88 Myxoearcoma ...... 2 18.18 0.31 ~rcorna--Proatrrte...... 2 22.22 0.31 Epithelioma-fhrnea and con- Carcinoma-Vulvs ...... 8 6.83 1.07 junctiva ...... 2 14.28 0.26 Adenocsrcinoma-Eyelid ...... 1 33.33 0.15 Carcinoma-Vagina ...... 1 0.98 0.15 5 4.70 0.67 Sarcoma-Iris ...... 1 33.33 0.15 Carcinoma-Ce~ixUteri ...... 7 0.32 1.09 14 0.64 1.87 Melanoma-Skin ...... 14 6.73 2.19 12 5.77 1.61 Carcinoma-Body of Uterus .... 2 0.86 0.31 2 0.86 0.26 Sarcoma-Lung ...... 1 8.33 0.15 Myost~~~m~--Utem...... 1 6.66 0.15 Mesothelioma ...... 1 20.00 0.15 Carcinoma-4vary ...... 11 6.83 1.72 Sarcoma-Ovary ...... 1 25.00 0.15 280 QEORGE T. PACK AND ROBERT O. LDFEVRE (b) The second specified group of malignant tumors are those neoplasms which are essentially peculiar to infancy, childhood and young adulthood; they are infrequent in older people. The five most common representatives of this group are Wilms' adenomyosarcoma of the kidney, ocular glioma, teratoma testis, endothelial myeloma and thymoma. All of these tumors are cellular neoplasms, endowed with great propensity and capacity for growth. Four of these five tumors (the gliorna excluded) are among the most radiosensitive tumors, a fact dependent on the cellularity, high metabolism, anaplastic nature, mitotic activity, and other characteristics of malignant tumors occur- ring in young people. An ancient Chinese proverb states: "Before thirty, men seek disease; after 30, diseases seek men." Although this seems to be generally true for most diseases, the reverse obtains for malig- nant neoplastic disease. After age 30, many cancers are the result of the cumulative effects of chronic irritation, repeated stimulation, persistent dysfunction etc.; many of the tumors of childhood arise in connection with embryonic developmental aberrations. The congenital factor as an influence is shown by the fact that many of these tumors are of teratoid nature, some are mixed-cell in structure, some are bilateral in occurrence, others are multicentric in origin. Jonathan Hutchinson said: "Malignant disease in young persons is generally inherited." As we consider the tumors of probable inheritability, namely, cartilaginous exostoses, xeroderma pigmentosum, pigmented naevi, neurofibromatosis, multiple lipomatosis and ocular gliomas, only one, the ocular glioma, is definitely a malignant tumor, although others are potential starting-points for malig- nant degeneration. We believe that inheritance is not as im- portant a factor in the genesis of the malignant tumors of childhood as the congenital influence of misplaced, embryonal cell rests. We have previously stated that many of these mis- const~uctionsor cell groups may remain quiescent during the early periods of post-natal life, to be "activated" with the invol- utionary changes attendant on the onset of senility. The majority of the malignant teratomas of the testis and ovary AGE AND SEX DISTRIBUTION 281 develop after puberty and in the early period of sexual ma- turity. Roger Williams (165) in his book, "The Natural ," says: "One noteworthy feature about the tumors of infancy and early life is, that the localities whence they are prone to originate, are very different from those whence malig- nant tumoura commonly arise at later periods of life." For instance, the great proclivity of infants and children to malig- .nant tumors of the kidney and eye, is in marked contrast to the rarity of tumors of these regions in later life. Duzan (38) in his thesis " Du Cancer chez les Enfants," analyzed the regional distribution of 182 malignant tumors of early infancy; the fol- lowing localizations were given: eye-70, kidhey45, testis-1 1, prost ate-8, bones-5, tongue-5, brain-5, abdomen-5, lung- 4, dura mater--4, pancreas-3,liver-2, tonsil-2, rectum-2, and stomach-1. Picot (120) in his thesis "Les Tumeurs malignes des Enfants," analyzed the regional distribution of 424 malig- nant tumors of early infancy and noted the following localiza- tions: eye-100, kidney-80, bones-67, brain and membranes- 31, abdomen and pelvis-19, testis-15, liver-13, prostate-8, skin-8, intestine-7, tongue--6, and ovary--6. At the Memorial Hospital, 155 malignant tumors in patients under 10 years of age were distributed as follows: peripheral sarcomas-37, bone- 36, eye-25, kidney-18, brain and spinal cord-12, intra-oral tumors-9, thymus-8, skin+, testis4, uterus-1, and paro- tid-1. It has been said of sarcomas that they may arise at any period of life; a certain number of cases are congenital; they are quite frequent during the first five years of life, then are infrequent from ages 5 to 15 years; they increase in number with the advent of puberty and remain at a high level in each quinquennial period for many years. When percentage corrections are made for the incidence of sarcomas (exclusive of the congenital types on the basis of the proportionate number of persons living during the various age we have observed that they vary only slightly in frequency from age 15 to age 75 (Table 23). Age alone has little or no influence on the development of sarcomas; 282 QEORQE T. PACK AND ROBERT Q. LEFEVRE herein they differ in part from carcinomas. Of all the sarcomas, 26.7 per cent were in patients under 25 years of age, whereas only -1.2 per cent of the carcinomas were in subjects younger than 25 years. In other words, sarcoma is 22 times as frequent as carcinoma in young people less than 25 years of age. Burrows (20) is responsible for the "belief that the tendency for the development of sarcomas in the early life of the animal and of carcinoma in later life is to be relatedto the relative den- sity of these cells in the different periods. In the early periods of life this same mesenchyme becomes reduced in most parts of the body to cell8 widely separated by intercellular substances. At this period these cells are concentrated only in the periosteum of bone, in the membranes lining the body cavities and in the ovary. Sarcomas of later life are restricted largely therefore to these three regions. In other regions the more densely cellular masses are epithelial." The adenomyosarcomas of the kidney, nasal myxosarcomaa, neurogenic sarcomas, ocular gliomas and lymphosarcomas occur so frequently in childhood that we have not considered them sufficiently rare to justify their inclusion in case reports.

Male Period of Female Occurrence Thymoma ...... 24 Carcinoma of ovary ...... 45 I Carcinoma of cervix ...... 48 Carcinoma of lung...... 49 Thymoma ...... 29 Carcinoma of tonsil...... 50 Teratoma testis...... 35 Early Period, Carcinoma of breast...... 51 Carcinoma of thyroid...... 61 24-52 Years Carcinoma of rectum...... 51 Carcinoma of lung...... 62 Carcinoma of colon...... 52 I Carcinoma of vagina...... 52 Carcinoma of stomach...... 52 Carcinoma of larynx...... 52 Carcinoma of thyroid ...... 53 Carcinoma of breast...... 54 Carcinoma of antrum...... 53 Carcinoma of penis...... 54 Carcinoma of buccal mucoea. 54 Carcinoma of rectum...... 55 Average Period, Carcinoma of esophagus. .. .55 Carcinoma of colon...... 55 53-55 yem Carcinoma of body of uterus. 55 Carcinoma of stomach. ....55 Carcinoma of inferior alve- Carcinoma of antrum...... 55 olue ...... 65 AGE AND SEX DISTRIBUTION 283

* Carcinoma of tonsil...... 56 Carcinoma of urininary bladder...... 57 Carcinoma of urinary Carcinoma of eeophagus ....57 bladder...... 56 - Carcinoma of larynx...... 57 . Late Period, Carcinoma of tongue...... 56 Carcinoma of lip...... 57 58-59 years Carcinoma of lip...... 57 Carcinoma of tongue...... 58 Squamoua Ca. of skin...... 58 Carcinoma of buccal mucosa58 Squamous Ca. of skin...... 58 ,Ca. of inferior alveolus. ....59 Carcinoma of floor of mouth 61 Very late Basal-eel1 Ca. of skin...... 60 Basal-cell Ca. of skin...... 62 Period, Ca. of vulva...... 60 Carcinoma of prostate...... 63 00-63 years Ca. of floor of mouth...... 61

THE INFLUENCE OF SEX ON THE DISTRIBUTION OF NEOPLASTIC DISEASES Of all benign tumors, 82.14 per cent were in females and 17.86 per cent were in males. This disparity can be attributed to the large numbers of leiomyofibromas of the uterus, mammary adenofibromas and benign cystic ovarian tumors. The pre- dominance of males was evident among the following three benign tumors: papillomas of the urinary bladder, chondromas and papillomas of the larynx. The predominance of females was observed in the following six benign tumors; mammary adenofibromas, thyroid adenomas, lipomas, hemangiomas, neu- rofibromas and giant-cell tumors of bone. Of all malignant tumors in this series, only 52 per cent were in females. At first glance this figure would seem to question the generally accepted opinion of predominance in females. How- ever, we found explanation of this discrepancy in the unusually large intra-oral clinics in this hospital, wherein males were greatly in excess, and in the sex distribution of the sarcomas. Sixty per cent of the malignant connective tissue tumors were in male subjects. This too is contrary to the common idea that sarcomas which do not have the proclivity to attack the genera- tiye organs or intra-oral cavity, are about of equal frequency in the two sexes. It is true that in infancy and childhood there is little difference in the incidence of sex for the malignant tumors of this period, possibly because so many of these tumors are 284 QEORGE T. PACK AND ROBERT G. LEFEVRE congenital in origin and teratomatous or sarcomatous in structure. If we consider only the malignant epithelial tumors, then the total cancer mortality of females exceeds the cancer mortality of males at all ages from 24 to 55 years. This is by grouping all regions together, and does not apply therefore to specific cancer types, such as are found in the intra-oral group. The predomi- nance of cancer in females is very great until the decennium 45 to 55, when the maximal difference is attained, after which the frequency in males approaches and even exceeds the frequency in females during the decennium 55 to 65 years. This late tendency toward equalization of the sex ratio may be attributed to the slower decline of reproductive activity in the male sex. Although this influence of sex in relation to age incidence is most marked between the 25th and 55th year, it is interesting to note that in extreme old age, cancer is more common in women than in men; probably this is due to the fact that women have a greater expectation of life after age 75. For instance, T. E. Young found only 30 authentic centenarians in his study of longevity, of which 21 were females and 9 were males. The age incidence of cancer in men is more variable than in women. It is true that the sexes are unequally represented in the general population; this fact may tend to reduce the dis- parity of sex ratios, but even with this correction, females have a greater percentage of cancer than do males. The increased occupational and habit hazards of men have been said to be gradually erasing this difference in sex distribution. C. V. Weller (162) states that "carcinoma incidence in women runs a definite cycle which is roughly parallel to that in men, but precedes it by 5 to 10 years." We agree with this statement ex- cept that our figures indicate a constant age difference of 2-112 to 4 years for the average ages of male and female patients with the same regional and histological types of cancers; the females were younger than the males with very few excepti~ns (Table 26). The earlier age for carcinomas in general as attri- buted to women is partly due to the earlier appearance of carcinomas of the ovary, cervix, vagina and breast, and the later AGE AND SEX DISTRIBUTION 285 age for carcinomas in general as attributed to men is largely due to the late appearance of intra-oral cancers, which are so pre- dominant in men. It has been said that the uterus, ovary and breast are so frequently the site of carcinoma in young subjects because these organs attain maturity earlier than other organs and degenerate earlier. With the exception of teratoma testis, the average age of liability of males to other cancers of the urogenital tract is later than the age of liability of females. At the Memorial Hospital, 82.3 per cent of the cancers of the genitalia were in females; there were 2872 instances in females and 618 instances in males. As we have previously said, the predominance of cancer in males seems uniformly and gradually to diminish and to ap- proach the female liability as we consider the ratio of sex from the mouth through the digestive tube to the anus. The alimen- tary tract and accessory organs of digestion contained 48 per cent of all the cancers in males, and only 11.4 per cent of all cancers in females; therefore cancer of this region was four times as frequent in males as in females. The average age for males having cancer of the alimentary tract is on the average 2-1/2 to 4 years later than in females. Lazarus-Barlow's (86) tables showing the disparate average ages of males and females with identical cancers are very similar to our tables; the data appear mutually confirmatory. We believe it worth while to name in the order of their magnitude, the ten most common carcinomas in males and fe- males, respectively. Carcinomas of the stomach are not given their proper place in this table because the gastric clinic at Memorial Hospital is disproportionately small.

The Most frequent Carcinomas of Males and Females Malea Females 1. Basal-cell ca, of skin. 1. Carcinoma of breast. 2. Ca. of tongue. 2. Ca. of cervix uteri. 3. Squamous ca. of skin. 3. Basal-cell Ca. of skin. 4. Ca. of lip. 4. Squamous Ca. of skin. 5. Ca. of rectum. 5. Ca. of rectum. 6. Ca. of larynx. 6. Ca. of body of uterus. 286 GEORGE T. PACK AND ROBERT Q. LEFEVRE

7. Ca. of urinary bladder. 7. Ca. of ovary. 8. Ca. of esophagus. 8. Ca. of thyroid. 9. Ca. of tonsil. 9. Ca. of vulva. 10. Ca. of prostate. 10. Ca. of antrum. As we have previously stated, some cancers occur predomi- nantly in males, others in females (Table 24 and 28). We have summarized in two columns the chief instances wherein this predominance is characteristic of the carcinomas.

The Predominance of Carcinomas in Malee and Females Males Females 1. Ca. of floor of mouth-94.9yo 1. Ca. of breast-98.7% 2. Ca. of lip--94.2% 2. Ca. of urethra--83.3% 3. Ca. of larynx-91.2% 3. Ca. of gall-bladder-81% 4. Ca. of tonsil-90.8% 3. Ca. of thyroid-76.1% 5. Ca, of buccal mucosa-89.5% 5. Ca. of appendix-66% 6. Ca. of tongue--86.9% 7. Ca. of mophagus-80.5% 8. Ca. of urinary bladder-77.8yo 9. Ca. of lung-73% 10. Ca. of pancreas-71.4% 11. Ca. of stomach--89.2% 12. Ca. of rectum41.7% 13. Squamous Ca. of skin-59% 14. Basal-cell Ca. of akin-56.5%

SUMMARY 1. During a 12 year period, 19,129 tumors were studied at the Memorial Hospital; of these tumors, 16,565 were malignant. 2. Malignant epithelial tumors comprised 89.6 per cent of this number; 10.4 per cent were sarcomas. 3. The average age of all the patients with carcinomas was 53.9 years. The average age of all the patients with sarcomas was 38.2 years. 4. During the last 75 years, there has been no appreciable change in the average ages of occurrence of the more common malignant neoplasms. 5. The decennium 40 to 50 marks the period where cancer frequency makes its first tremendous increase. 6, Cancers developing in such organs as the breast, thymus, AGE AND SEX DISTRIBUTION 287

uterus and prostate, which undergo physiologic atrophy at defi- nite periods in the life history of the individual, have specific rela- tionships to age. The majority of the remaining malignant epithelial tumors are not related to age except that the passing years afford sufficient time for the causative agents to induce degenerations, tissue overgrowth and even cancer. 7. There was evidence to prove that chronologic age is not so important as anatomic and physiologic age as an etiological factor in cancer. 8. The fiv'e most common malignant tumars in infants and children were Wilms' adenomyosarcoma of the kidney, ocular glioma, teratoma testis, endothelial myeloma and thymoma. 9. The age incidence of certain cancers increases each year until the normal span of human life is reached. These cancers were melanomas, basal-cell epitheliomas, squamous carcinomas of the skin, carcinomas of the lip, penis, floor of mouth, buccal mucosa and inferior alveolus. 10. When percentage corrections are made for the incidence of the various sarcomas on the basis of the proportionate number of persons living during the age periods, it is seen that the in- cidence of these malignant connective tissue tumors varies only slightly from age 20 to age 80. 11. The benign papillomas of many organs always occur at younger average ages than the carcinomas of the same organ e.g., the age variance of 22 years for the larynx, 17 years for the vulva, 7 years for the urinary bladder. 12. The tumors which occurred predominantly in females were: mammary adenofibroma, lipoma, giant-cell tumor of bone, thyroid adenoma, neurofibroma, carcinomas of the breast, thyroid, urethra, appendix and gall-bladder. 13. The tumors which occurred predominantly in males were: chondroma, laryngeal papilloma, papilloma of urinary bladder, thymoma, lyrnphosarcoma, neurogenic sarcoma, bone sarcoma, multiple myeloma, hypernephroma, squamous carcinoma of skin, basal-cell epithelioma, carcinomas of lip, larynx, tonsil, tongue, buccal mucosa, esophagus, stomach, rectum, liver, pancreas and urinary bladder. 288 GEORGE T. PACK AND ROBERT G. LEFEVRE

14. There was a constant age difference of 2-112 to 4 years for the average ages of male and female patients with the same regional and histological types of cancers; the females were younger than the males. 15. The liability to epidermoid carcinomas of the skin was greatest after the age of a century was reached. 16. Thirty per cent of all malignant tumors in patients over 74 years were basal-cell epitheliomas. 17. Brain tumors were uncommon in old people; none oc- curred in patients over 70 years. Fifty per cent of the gliomas were in subjects younger than 25 years. 18. Chondrosarcoma was the only malignant connective tissue tumor which did not appear in children; the youngest patient was aged 22. 19. Giant-cell tumors of bone were the only bone tumors which occurred with greater frequency in females. Contrary to general opinion, bone sarcomas were relatively as frequent at ages 60 to 64 as at ages 15 to 19 years. 20. The average age of persons with Ewing's endothelial myeloma was 22 years; the average age of persons with multiple myeloma was 42 years. ' 21. Cancer of the alimentary tract was four times as frequent in men as in women. As the ratio of sex was considered, the major liability of the male to cancer of the alimentary tract seemed uniformly and gradu,ally to approach the female lia- bility from the mouth downward through the digestive tube. Forty-eight per cent of the cancers in males were in the alimen- tary tract and accessory organs. 22. The adenoid cystic epithelioma of mucous membranes is explained by the Durante-Cohnheim embryonal theory of tumor origin. 23. In subjects younger than 25 years, carcinoma of the tonsil was 13 times as frequent as carcinoma of the tongue. 24. At age 75, carcinoma of the larynx was 32 times as fre- quent as at age 25. For papillomas of the larynx, the male pre- ponderance was 2 to 1; for carcinomas of the larynx, the male preponderance was 10 to 1. AGE AND SEX DISTRIBUTION 289 25. There was evidence to prove the existence of a definite group of carcinomas of the nasal mucosa in children. 26. The average age of patients with carcinoma of the parotid gland was 10 years older than for patients with mixed tumors of the parotid. 27. Carcinoma of the esophagus was very rare in young people. Carcinoma of the stomach was quite infrequent in elderly people. 28. Of all cancers of the gastro-intestinal tract, carcinoma of the appendix occurred at the earliest average age, namely 32 years. 29. One of every 25 patients admitted to the hospital had carcinoma of the rectum. Epidermoid carcinoma of the anus occurred at the youngest average age, of all the regional locations of this histologic type of cancer. 30. Among 100 regional and histologic varieties of cancer, carcinoma of the prostate gland occurred in patients of the oldest average age, namely 63 years, yet the incidence for this carcinoma did not increase with advancing age. 31. Teratoma testis is essentially a disease of young men; the incidence declined rapidly after age 35. 32. Of all tumors of the female genitalia, vulvar carcinoma occurred in subjects of the oldest average age, namely 60 years. The percentage of vulvar carcinomas occurring in single women was high (16.2 per cent). 33. Carcinoma of the cervix uteri was twice as frequent after age 75 as before age 25. The percentage of carcinomas of the body of the uterus in single women was four times as great as the percentage of carcinomas of the cervix in single women. 34. The ovary was the only organ in the body wherein the benign and malignant epithelial tumors affected subjects of the same approximate age. 35. The incidence of mammary adenofibromas gradually in- creased from age 20 to age 50. These occurred in subjects who averaged 15 years younger than the patients with carcinomas of the breast. One of every 7 patients admit- ted to the hospital had mammary cancer. 290 GEORGE T. PACK AND ROBERT Q. LEFEVRE

36. Thyroid adenomas in males have a greater tendency to become carcinomatous than do the thyroid adenomas in females. 37. Tumors of the sexual organs naturally occurred at younger average ages in single than in married people, e.g., mammary and intraductal papilloma, sarcoma of the breast, teratoma testis, carcinomas of the penis, prostate, vagina, cervix, ovary and body of uterus. 38. Cancers of early life, as in breast, stomach, tongue and rectum, progress more rapidly, disseminate more frequently and recur more often after removal than do their congeners of adult life. Radiosensitivity is a property found frequently in the malignant neoplasms of youth. Fever is significantly frequent in the case of rapidly-growing malignant tumors in young people. The authors wish to express their appreciation to Professor James Ewing for his criticism and suggestions; also to Drs. Wm. S. Stone, Lloyd F. Craver, Frank E. Adair, Fred W. Stewart, Edith H. Quimby and others for their aid in the completion of this work. Miss Mary Grotty of the Department of Records was of inestimable service. REFERENCES 1. ADme, J. E.: Proc. Roy. Soc. Med., 1915-1916, 9, Sect. ObstGyn., 45. 2. ADLER:Primary Malignant Growths of the Lungs and Bronchi. 1912. 3. ANDERBAND BOBTON:Lancet, 1903, 1, 93. 4. A~~uINA~~A,A.: Rev. de Gyn. et d'Obst. (Rio de Jan.), 1925, 19, 247. 5. BALFOUR,D. C. AND HAROIB,E. H.: Amer. Jour. Med. Sci., 1927, 173, 773. 6. BASHFORD(a) First Report on , Vol. 1, pt. 2, 32. (b) Trana. Med. Soc. London, 1905, 28,6. 7. BECKER,R.: Brun'a Beitr. zur klin. Chir., 1926, 138, 76. 8. BLODCIETT,A. N.: Boston Med. and Surg. Jour., 1897, 136, 611. 9. BLOODGOOD,J. C.: Surg. Gyn. Obst., 1908, 2, 121. 10. BONNER,A.: Amer. Jour. Obst. Gyn., 1927, 14, 175. 11. BOUCHARDAND LAQUIBRE:Jour. d'Urol., 1925,20, 483. 12. BRECKWOLDT,R.: Zeitschr. I. Krebsforach., 1926, 23, 128. 13. BREITNER,B. AND JUBT,E.: Mitt. d'Grenz. Med. u. Chir., 1924, 38, 262. 14. BROWN:Lancet, Dec. 16, 1871. 15. BRUNN,H.: Arch. Surg., 1926, 12, 406. 16. BRYAN,R. C.: Surg. Gyn. Obst., 1914, 18, 545. 17. BRYANT:Diseaaes of the Breaat, 1887, 149. 18. BUCHBINDER:Amer. Jour. Med. Sci., 1925, 170, 496. 19. BUMPU~,H. C.: Surg. Gyn. Obst., 1926, 43, 150. 20. BURROWB,M. T.: Arch. Path. and Lab. Med., 1927, 4, 380. 21. BYRON,C. A. AND BIBKOFF,H. S.: Amer. Jour. Obst. Gyn., 1926, 11, 559. AGE AND SEX DISTRIBUTION

22. CHARLTON,T. J.: Arch. Int. Med., 1927, 40, 98. 23. CHEVAEEU,M.: Tumeure du Testicule, Thesis, Paris, 1908. 24. C~Y~N,E. S.: Surg. Gyn. Obst., 1928, 46, 52. 25. CLUTE,H. M., AND SMITH,L. W.: Arch. Surg., 1929, 18, 1. 26. Coum, W. G.: Boul. Soc. de Chir. de Chile, 1925, 3, 290. 27. CRAGIN,E. B.: Am. Jour. Obst., 1913, 67, 144. 28. CRAIG,W. McK., AND MACCARTY,W. C.: Annals of Surg., 1923, 77,698. 29. CRAVER,L. F.: Annals of Surg., 1925, 82, 833. 30. CRIPPB:Lancet, 1884, 2, 67. 31. CZERNY:Munch. med. Woch., 1896,43, 241. 32. DE ROUVILLE:Bull Soc. d'0bst. et Gyn. de Paris, 1912, 1, 388. 33. DEBCUME:Amer. Jour. Urol., 1915, 2, 373. 34. DOCK,G.: Amer. Jour. Med. Sci., 1897, 113, 665. 35. DOMUCCI,A.: Tumori, 1926, 12, 493. 36. DORAN,A.: Trans. Path. Soc., London, 1889, 40, 200. 37. DORRANCE,G. M., AND MCSEANE,J. K.: Annals of Surg., 1928, 88, 1007. 38. DUZAN:ThLe de Paris, 1876. 39. EBERTS,E. M., AND FITzGERALD, R. R.:Annals of Surg., 1927,86, 515. 40. EHRHARDT,0.: Beitr. z. klin. Chir., 1902, 35, 343. 41. ENGLIBH,J.: Folia Urol., 1907, 6, 37. 42. EWIN~,J. (a) Amer. Jour. Med. Sci., 1929, 177, 461. (b) Neoplastic Diseases, W. B. Saunders, Publishers. 43. FIBIGER,J.: Jour. Cancer Research, 1919, 4, 367. 44. FITZWILLIAMB,D. C. L.: The Tongue and its Diseases, Oxford Press. 45. FOWLER,L. H.: Surg. Gyn. Obst., 1926, 43, 73. 46. FOWLER,R. H.: Med. Record, 1915, 87, 730. 47. FREUND,E., AND KAMINER,G.: Biochem. Grundlag. d. Dispos f. Karzinom, Wien, J. Springer, 1925. 48. FRIED,B. M.: Arch. Int. Med., 1925, 35, 1. 49. FRIEDENWALD,J., AND ROBENTHAL,L. J.: Med. Jour. and Record, 1925,122,447. 50. FRIEDENWALD,J., ZINN, W. F., AND FELDMAN,M.: Amer. Jour. Med. Sci., 1927, 174,609. 51. GANGHOFNER,F.: Zeitschr. f. Heilk., 1888, 9, 337. 52. GARDNER,S. J., AND CUMMINB,W. T.: Calif. State Journal of Med., 1914, 12, 279. 53. GAUDY,J., AND SCHILLINOB,M.: Le Cancer, 1927,3. 54. GAYRAUD:These de doct. de Montpellier, 1911. 55. GESCHICKTER,C. F., AND COPELAND,M. M.: Arch. Surg., 1928, 16, 807. 56. GEBCHICXTER,C. F., AND COPELAND,M. M.: Arch. Surg., 1929, 19, 169. 57. GL~CKNER:Zeitschr. f. Geburtsh. u. Gyn., 1908,63, 182. 58. GOODPASTURE,E. W., AND WISMCKI,G. W.: Jour. Med. Research, 1915-1916, 28, 455. 59. GUHAM,J. M.: Edinburgh Med. Jour., 1913, 10,30. 60. GRANT,P. N.: Brit. Med. Jour., 1919, 2, 775. 61. G~oss,8. W.: Amer. Jour. Med. Sci., 1888, 95, 219. 62. GUIEEZ,J.: Bull. dlOto-rhino-laryngologieet de Bronchd)esophsgoscopie, 1925, 23, 49. 63. GURLT:Arch. f. klin. chir., 1880, 25, 420. 292 GEORGE T. PACK AND ROBERT G. LEFEVRE

64. GUSSENBAUER:Wien. med. Wochenschr., 1894, 44, 763. 65. Guss~~ow,A.: Deutsch. Chir., 1886,57,211. 66. HAMMESFAHR,C.: Zentralk. f. Chir., 1929,54,1804. 67. HAMMOND,F. C.: New York Med. Jour., 1922, 116, 14. 08. HARRIS,R. H.: Surg. Gyn. Obst., 1917, 24, 604. 69. HERBST,W. P., JR.: Annals of Surg., 1924, 79, 488. 70. HERRICK:Anna18 of Surg., 1920, 71, 168. 71. HIQQINS,C. C.: Annals of Surg., 1928, 87, 263. 72. HINES,H. H.: Lancet--Clinic, 1910, 104, 442. 73. HIRTZ,E., AND LEBN~,E.: Med. Moderne, 1896,7, 481. 74. HOFFMAN,C. S.: Amer. Jour. Obst., 1897, 36, 331. 75. HOFFMAN,F.: Mortality from Cancer throughout the World, Prudential Press. 76. HUNT,V. C., AND SIMON,H. E.: Annala of Surg., 1928, 87, 84. 77. JACKSON,C.: (a) Amer. Jour. Med. Sci., 1925, 169, 625. (b) Arch. Surg., 1926, 12, 236. 78. JACOBS,A. W.: Surg. Gyn. Obst., 1926, 43, 50. 79. KAUFMANN:Spezielle Pathologkche Anatomie, ed. 7, 1922, Vol. 1. 80. KOCHER,A.: Deutsche Zeitschr. f. Chir., 1907, 91, 197. 81. K~STER:Centralb. f. Chir., 1888, 15,372. 82. KRAUS:Nothnagel's Specielle Pathologie und Therapie, 1902, 16, 226. 83. KUTZMANN,A. A., AND GIB~ON,T. E.: Annals of Surg., 1923,78,761. 84. LANDOUZY:Bull. de la Soc. Anat. de Paris, 1872, 47, 27. 85. LAQUIERE,M., AND BOUCHARD,R.: Jour. d'Urol., 1926, 22,244. 86. LAZARUS-BARLOW,W. 8.: (a) Arch. Middlesex Hosp., 1904, 2, 128. (b) Arch. Middlesex Hoap., 1905, 5, 26. 87. LEBERT:Trait4 des mal. cancerusea, 1851. 88. LEITCH,A.: Intern. Conf. on Cancer, London, 1928,20, John Wright & Sons. 89. LENEUF,M.: Ann. d. Anat. Path., 1926, 3, 639. 90. LIMACHER:Virch. Arch., 1898, (Supplement) 161, 113. 91. LITPLE,SEELYE: Personal Communication. 92. LEOWENBER~,8. A,: Med. Jour. and Record., 1928, 127, 183. 93. LUBAB~CH,0.: Med. Klin., 1924,20,299. 94. LUNN:Trans. Path. Soc. London, 1897,48, 247. 95. MACCARTY,W. C., AND MAHLE,A. E.: Jour. Lab. and Clin. Med., 1921,6,473. 96. MACCARTY,W. C., AND MCGRATE,B. F.: Annals of Surg., 1914, 59, 675. 97. M~LE,A. E.: Surg. Gyn. Obst., 1923, 36, 385. 98. MATHIEU:Semaine Med., 1895, 15, 225. 99. McCun, T., FUNK,E. H., AND JACK~ON,C.: J. A. M. A., 1927, 89,1140. 100. MCFARLAND,J.: Amer. Jour. Med. Sci., 1911, 141, 670. 101. MCFARLAND,J.: Surgical Pathology, 1924, 499. 102. MCFARLAND,J.: Amer. Jour. Med. Sci., 1926, 172, 804. 103. MCFARLAND,J.: Surg. Gyn. Obst., 1927,45, 729. 104. MCGUFFIN,W. H.: Radiology, 1928, 10, 21. 105. MCWILLIAMB,C. A.: Amer. Jour. Med. Sci., 1908, 135, 822. 106. MELENEY,F. L.: Annala of Surg., 1922, 76,684. 107. ME~~DOZA-GUAZON,M. P.: Jour. Philippine 181. Med. Assoc., 1922,2, 169. 108. MENQERBHAUBEN:Inaugural Dim., Freiburg, 1895. 109. MERTENS,V. E.: Med. Klinik., 1927, 23, 1999. AGE AND SEX DISTRIBUTION

110. MILLIGAN,W. Sir: Practitioner, 1927, 118, 205. 111. MILNE,J. A.: Brit. Med. Jour., 1905, 2, 925. 112. MOLESWORTH,E. H.: Med. Jour. Austral., 1927, 14, 878. 113. MOORE,N.: Trans. Path. Soc. London, 1885, 36, 195. 114. MORRIS:Arch. Surg., 1927, 15, 530. 115. OERTEL,H.: Outlinea of Pathology, 1927, Renouf Co. 116. PACK,G. T.: Le Cancer, 1928, 3. 117. PAQET,J., Sir: Lectures on Surg. Path., 1853, 2, 546. 118. PAWTRIER,L. M.: Arch. Derm. and Syph., 1928, 17, 767. 119. PETERSON,R.: Surg. Gyn. Obst., 1919, 29, 544. 120. PICOT:Rev. MBd. de la Suisse romande, 1883. 121. PROWSTAND VIAN:Ann. d. mal. d. Org. g8nito-urin., 1907,25, 721. 122. P~RCKHAUER,R.: Zeitschr. f. Krebsforsch., 1928, 28, 68. 123. QUICK,D., AND CUTLER,M.: Annals of Surg., 1925, 81, 810. 124. RANKIN,F. W. AND BRODERS,A. C.: Surg. Gyn. Obst., 1928,46,660. 125. REEL,P. J. AND CEARLTON,P. H.: Annals of Surg., 1923, 77,476. 126. ROBERTSON,H. E.: Jour. Med. Research, 1916-1917,35, 131. 127. ROLAND,M. M.: South. Med. Jour., 1927,20,794. 128. SCHEFFER:Jahrb. f. Kinderheilk., 1880, 15,425. 129. SCHMIDT,R.: Boa. Neubild. d. Bauchorg. Wien., 1911 (quoted by Ewing). 130. SELINQER,J.: Annals Of Surg., 1929, 89, 276. 131. SEYFARTH,C.: Deutsche med. Wochnschr., 1924,50,1497. 132. SHERMAN,J.: Amer. Jour. Med. Sci., 1928, 175, 79. 133. SIMPSON,W. M.: Annals Clin. Med., 1926, 4, 643. 134. SMITH,G. V. S., SMITHWICK,R. H., AND ROOERB,H., JR.: Amer. Jour. Obst. and Gyn., 1928, 15, 637. 135. SMITH,R. R., AND TORQERSON,W. R.: Surg. Gyn. Obst., 1926,43,328. 136. SMITHIES,F.: J. A. M. A., 1914, 63, 1839. 137. SPEESE,J. AND BROWN,H. P.: Annals of Surg., 1921, 74, 684. 138. STEFFEN,A.: Die Malignen Geachwulste im Kindersalter, Stuttgart, 1905. 139. STEPHEN,L. F.: Indian Med. Gaz., 1920,55,220. 140. STERN:Deutsche med. Wochnschr., 1892, 18, 494. 141. STINSON,J. W.: Surg. Gyn. Obst., 1928, 36, 180. 142. SWQIWRA,K.: Jour. Cancer Res., 1928, 12, 143. 143. SWQIWRA,K., AND B~DICT,S. R.: Jour. Cancer Res., 1926, 10, 194. 144. SWQIWRA,K.: Jour. Cancer Rea., 1926, 10, 481. 145. Swa~wu,K.: Jour. Cancer Res., 1924, 8, 376. 146. SYMMERB,D.: Amer. Jour. Med. Sci., 1927, 174, 9. 147. TEBBWTT,A. H., AND WOODHILL,V. R.: Med. Jour. Austral., 1927, 1,353. 148. THEILHABER,A.: Surg. Gyn. Obst., 1914, 19, 650. 149. THOMBON,ST. C.: Diseases of Nose and Throat, 3d Edit., D. Appleton, 1916. 150. TBCHOP.:Zentralb. f. Gyn., 1897, 21, 59. 151. TUREEN,L. L., AND LOEB,L.: Jour. Cancer Res., 1929, 13, 1. 152. VINS~N,P. P.: Amer. Jour. Med. Sci., 1923,166, 402. 153. VONWOHLENDORF, A. L.: Arch. f. klin. chir., 1921, 115, 741. 154. WAINWRIGHT,J. M.: Atlantic Med. Jour., 1925, 28, 419. 155. WALLQREN:Upsala Lakaref. Forh., 1920, 25, 113. 156. WARNER,F.: Surg. Gyn. Obst., 1916, 23, 413. 294 QEORGE T. PACK AND ROBERT Q. LEFEVRE

157. WARREN,S. L.: Amer. Jour. Med. Sci., 1929, 178, 490. 158. WARTH~N,A. s.: Arch. Int. Med., 1915, 15, 444. 159. WARTHIN,A. 8.:Bull. New York Acad. Med., 1928,4, No. 10. 160. WARTHIN,A. S.: Old Age: The Major Involution, P. Hoeber, Inc., 1929. 161. WELCH:Proc. Boston Soc. for Med. Improvement, Vol. 5, 109. 162. WELLER,C. V.: Arch. Int. Med., 1913, 12, 539. 183. WELLW, C. V.: Arch. Int. Med., 1913, 11,314. 104. WELLER,C. V.: Arch. Path. and Lab. Med., 1929, 7, 478. 165. WILUAMB,W. R.: The Natural History of Cancer. 166. WILLIAMB,W. R.: Lancet, 1897, 1, 1194. 167. WILBON,L. B.: Annals of Surg., 1921,74, 129. 168. YOUNG,H. H.: Practice of Urology, Vol. 1,609, 1926, W. B. Saundem Co.