ALDRED SCOTT WARTHIN. Professor of Pathology and Director of the Pathological Laboratoru, llniversity of Michigan, Ann Arbor

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1 THE FURTHER STUDY OF A CANCER FAMILY ALDRED SCOTT WARTHIN Professor of Pathology and Director of the Pathological Laboratoru, llniversity of Michigan, Ann Arbor In the Archives of Internal Medicine, November, 1913, Vol. 12, pages , the writer reported a study of Heredity with Reference to Carcinoma based upon the cases of carcinoma examined for diagnostic purposes in the Pathological Laboratory of the University of Michigan during the period of This statistical study, the facts of which were drawn from the relatively incomplete surgical histories accompanying the operative material, revealed a surprisingly high number of cases showing in the family history a multiple occurrence of carcinoma, in some cases so striking that the use of the terms cancer family and cancer fraternity was justified. This study seemed to show that a marked susceptibility to carcinoma exists in the case of certain family generations and family groups; that this susceptibility is frequently associated with a marked susceptibility to tuberculosis, and also with lowered fertility. The multiple occurrence of carcinoma in a family generation practically always was associated with its occurrence in a preceding generation; and the family tendency was found to be more marked when carcinoma occurred in both maternal and paternal lines. Family susceptibility to carcinoma was shown particularly in the case of carcinoma of the gastrointestinal tract and the uterus. In a family showing the occurrence of carcinoma in several generations there was shown a decided tendency for the neoplasm to develop at an earlier age in successive generations, and an especial degree of malignancy was often noted in such cases. When this study was reported it met with little favor among surgical writers and particularly among those interested in propaganda for the prevention of cancer. In some of the 279

2 280 ALDRED SCOTT WARTHIN literature put out under this latter head the statement was made that there was no evidence for the existence of a familial susceptibility to cancer. It is true that at that time, there occurred in the literature very little authentic evidence favoring such a view. Since 1913, however, much has been done to give support to the view of the existence of a hereditary factor in cancer susceptibility, and the important animal investigations of Miss Slye and others gave to this clinical and pathological view a firm experimental foundation. An analysis of our knowledge on this subject was brought up to date by Wells, in the Journal of the A. M. A,, in September, 1923, Volume 81, p From the evidence so far presented Wells concludes that in animals the capacity to resist cancer behaves as a dominant character, the susceptibility as a recessive. There is evidence available which supports the inference that in man also the susceptibility to cancer behaves as an inherited recessive character. Among the cancer families reported by the writer in 1913, one (Family G) stood out as of especial significance in that it presented a fairly complete survey of a family for three generations, showing in forty-eight descendants of a cancerous grandfather seventeen descendants also cancerous. This family was of German origin and the members of the second, third and fourth generations have continued to live in Washtenaw County, Michigan, in the neighborhood of Ann Arbor. A large proportion of the operative material coming from this family has been examined by the writer in the University Pathological Laboratory, and three autopsies from it have also been performed by members of the laboratory staff. The writer had also an unusual opportunity of obtaining accurate information concerning the various lines of descent in this family from an intelligent and cooperative member of the family, who, unfortunately, fell a victim herself to a rapidly-developing carcinoma of the uterus. Just before her disease was discovered she had furnished the writer with a complete genealogical table of the family, comprising all of the descendants of the original grand-paternal settler. This is given in Chart 11. In Chart I, the original chart of the report given in 1913 is reproduced with

3 THE FURTHER STUDY OF A CANCER FAMILY 28 1 the initials of the first generation added. It was found that in that chart the age-order of the children of that generation was not accurate, and as the correct age-order is given in Chart 11, which is also initialed for the first generation, it was thought best to reproduce the original chart with the initials of the Conccr Sbmoch or Inteatine FAMILY G. No Comer in Fomlly R. 8. M. A. I E. M. Jo. CMKIr, Utvus Childbirth Aprplur lioiuw LMtm bnur Stmh LN4T LHSO LNS arc. c2w-e AIlNd Uterus Uterus bdowlo bmlovm brc. Care Cqm. Cam. slanwch Intdlrn Uterus Wnu CHART 1. Reproduction of chart from article in Archives of Internal Medicine, 1913, Volume 12, page 546, with first generation initialed for compariqon wit,h corrected chart &B given in Chart 2. first generation added so that confusion would be prevented on the part of anyone comparing the two papers. The first study was incomplete in so far as the number of descendants in the successive generations were concerned. Minor children were not included in the first chart; in Chart I1 of the present paper all the descendants in each line are included, up to the date of the final study which was made in 1918, five years after the original paper was written. The known cancer deaths

4 282 ALDRED SCOTT WARTHIN occurring since 1918 have, however, been included in this chart. No increase in the total number of individuals has occurred in this time. The original study gave 48 descendants (not including minor children) with an incidence of 17 cases of carcinoma; the present chart, including all descendants, comprises 144 descendants of the original settler, with 27 cases of carcinoma. Including the latter and his wife, out of 146 individuals 28 known cases of cancer death have occurred, an incidence of per cent. If the 58 minor children are not counted in, the proportion of cancer cases becomes 28 to 88 adult individuals who had reached even the lowest limits of the cancer age shown by this family, or a cancer-incidence of per cent. Both of these percentages fall roughly into the limits of expectancy of the inheritance of a recessive unitcharacter. The fact that the incidence when adults alone are considered is somewhat higher than such expectancy, and that the total incidence of carcinoma in this family will undoubtedly be higher when the younger members have reached adult life may be explained on the theory of combinations of unit characters derived from the intermarrying lines. It has been impossible to check up the incidence of cancer in any one of those lines. No positive case of the occurrence of cancer in any of the lines marrying into the family was known to my informant. On consulting Chart 11 it will be found that the original settler in this country died at the age of 50 of abdominal cancer, said to be either of stomach or intestine. There is a traditionary history of cancer in his forebears. His wife had a normal family history. They had ten children, five males and five females, two of the latter being twins. Five of these ten children died of cancer, three males and two daughters. From the oldest daughter, herself dying of cancer, there were nine children, six females and three males, three of the females and two of the males dying of cancer. The oldest son (Jac.) died of cancer, and of his nine children, three females died of cancer and one had been operated for cancer of uterus. His oldest daughter who died of cancer had five children, one dying of, and the other operated upon for, cancer; his second daughter,

5 THE FURTHER STUDY OF A CANCER FAMILY 283 dying of cancer, had nine children, one boy dying of cancer. The daughters B. M. and A. of the first generation showed no cancer, and no occurrence in their descendants. The sixth child Jo. died of cancer, and two of his daughters have been operated upon for carcinoma. The seventh child L. died of FAMILY G OV Int. I 3 Z(tlk) *di bdo*:: I* z 3 v t z 8L- m- k k 4rm9 o( cancer..re~ic dyirq d Cancer MKIM or, 0P.mt.d dlll linnq far =Non bncomub Mole ONon-Ccmurour Fnala. CHART 2. Corrected and completed chart of Family G. First generation is initialed for comparison with Chart 1. cancer and his oldest daughter of the same disease. The eighth son was cancer-free, but one of his daughters died of cancer. The ninth child, female, died of cancer, and of her ten children two sons and one daughter have died of cancer, and one daughter operated for the same. This daughter had nine children, of whom two sons have already died of cancer at the early age of 25 and 27 years. The member of this family cooperating in these genealogical charts was the sixth daughter of K. At the age of twenty-two she had been operated upon for a dermoid

6 284 ALDRED SCOTT WARTHIN cyst of ovary, and a polyp of the uterus. At thirty-five she died of adenocarcinoma of the uterus. In the original chart (I) the age of her oldest sister is given as 42. In the corrected chart it is given as thirty-five. This case was also diagnosed adenocarcinoma of the uterus, and the patient is still living after a complete hysterectomy. It will be seen from the chart that the ages of cancer deaths and operations in the total 28 cases of cancer occurring in this family were: 50 in the great-grandparent; 40, 43, 50, 45 and 55 in the first generation; 40, 40, 42, 45, 45, 45, 45, 40, 39, 35, 40, 45, 40, 35, 35, 28 and 37 in the second generation; and 27, 18, 30, 27 and 25 in the third. This makes an average of 37.9 years. The earlier incidence in the second and third generations is notable. It must also be borne in mind that the developnient of cancer in these individuals was, of course, earlier than the recorded death or operation. There was a marked tendency, however, for the rapid development of symptoms and for a very rapid course. In the case of the member of the family from whom the family history was obtained, repeated warnings had been given as to the significance of symptoms, and she was in frequent contact with medical men interested in the family history. Haemorrhage from the uterus developed suddenly without other symptoms; a diagnostic curettage showed advanced adenocarcinoma of the endometrium. Hysterectomy was performed in less than a week, and the uterus showed complete adenocarcinomatous infiltration of the entire wall of the body of the uterus, involving the bladder and broad ligament. The patient died of peritonitis within a few days. Still more fulminating in character was the course of the disease in the case of the three young male members of the family who presented symptoms of acute appendicitis, were operated upon for such, and on operation were found to have advanced carcinoma of the intestine with generalized metastases of mesenteric and retroperitoneal nodes, all three dying of generalized peritonitis following the operation. The first of these was autopsied by myself, the other two by Dr. C. V. Weller. It seemed a striking coincidence that these

7 THE FURTHER STUDY OF A CANCER FAMILY 285 two (first cousins), one 29 years of age, the other 27, were autopsied only twenty-four hours apart, May 24 and 25, The other cousin, 28 years of age, was autopsied on January 14, The striking features of these three deaths made a profound impression upon the local community. Since 1918 two other male cousins have succumbed to the same condition. A brief condensation of the pathological findings in the three autopsied cases follows: Autopsy U-72, Pathological Laboratory, Male, aged 28. Clinical Diagnosis : Acute appendicitis. Pathological Diagnosis : Primary mucoid adenocarciaoma of caecum. Metastases in retroperitoneal and mesenteric lymphnodes and liver. Carcinomatous infiltration of mesentery. Diffuse fibrino-purulent peritonitis. Infected laparotomy wound. Asthenic constitution. Autopsy A-63-V, Pathological Laboratory, Male, aged 30. Clinical Diagnosis : Acute appendicitis. Exploratory operation three weeks before death. Pathological Diagnosis : Primary adenocarcinoma of rectum. Metastases in retroperitoneal and mesenteric nodes. Acute fibrino-purulent peritonitis, post-operative. Asthenic constitution. Autopsy A-64-V, Pathological Laboratory, Male, aged 27. (First cousin of the preceding patient.) Was taken ill on the same day and ran an identical course, had an exploratory operation on the same day, and died one day later than his cousin. Clinical Diagnosis : Acute appendicitis. Pathological Diagnosis : Primary adenocarcinoma of the descending colon with stenosis. Metastases in prevertebral and bronchial lymphnodes. Acute generalized peritonitis following exploratory operation with colostomy. Purulent bronchopneumonia. Asthenic constitution. The 28 cases of carcinoma were distributed as to site, as follows: Gastro-intestinal Tract Uterus Ovary

8 286 ALDRED SCOTT WARTHIN Of the 15 gastro-intestinal cancers 9 were positively located in the intestine, 3 in the stomach, 2 in the abdomen (stomach or intestine?), and 1 in the liver (most probably metastatic from primary either in stomach or intestine). The one case of ovarian neoplasm was diagnosed as a papilliferous cystocarcinoma. Other points of interest in connection with this family are the apparent decrease in fertility after two generations of rather high fertility, and the associated tuberculosis. The incidence of the latter disease in the family is much higher than shown here; it was found impossible to collect accurate information about cases regarded as tuberculous, and it was, therefore, not attempted, with the exception of four cases positively known to be tuberculosis. As to other causes of death in the older non-cancerous members of the family, nothing of significance is noted. In conclusion, the further study of three generations derived from a cancerous great grandfather shows an incidence of per cent of cases of cancer in the total 146 individuals comprising the family, and an incidence of per cent of cancer in the 88 adult members of the family. These findings suggest strongly the occurrence of a recessive familial susceptibility to the development of cancer, shown in the males in the gastrointestinal tract, and in the females in the generative organs. The early average cancer age of the affected members, 37.9 years, and the tendency to sudden development and rapid course of the adenocarcinoma types occurring in the family are also notabie features.