Upsala J Med Sci 81: 189-191, 1976 Fa mi lia I Ovarian Carcinoma L. THOR, B. H . PERSSON and B. KJESSLER From the Department of Obstetrics and Gynaecology, University Hospital, Uppsala, Sweden ABSTRACT Familial aggregation of patients with ovarian carcinoma is unusual. A family with four affected members in three con- secutive generations is described. The tumors were all of the serous papillary adenocarcinoma type. The pattern of ap- pearance of the malignant disorder in the present family may he explained as the result of transmission of a dominant mutant autosomal gene. The future long term management of such a family might include prophylactic oophorectomy in certain family members, and possibly selective termina- tions of pregnancies with female fetuses in high-risk women. INTRODUCTION Familial aggregation of patients with ovarian adeno- carcinoma is unusual. Thus, only three cases with affected near relatives were observed in a study of 110 patients with ovarian cancer ( 5 ) . So far only seven families have been described, where ovarian adenocarcinoma has been present in two consecutive generations (1, 2, 3 , 4 , 6). We here describe a family with serous papillary adenocarcinoma of the ovary present in four family members belonging to three consecutive genera- tions, suggesting the transmission of a mutant domi- nant gene as a possible cause of this site-specific cancer. METHODS All affected members of the present family have been investigated and treated at the Department of Obstetrics & Gynaecology, University Hospital, Uppsala, where the first case appeared in 1925. Histopathological diagnosis were obtained by ana- lyses of pathology specimens derived from opera- tions and post mortem autopsies. FAMILY HISTORY Relevant family data and medical histories appear from the pedigree (Fig. 1) and Table I. CASE REPORTS I: 1. The patient was admitted after six months of symptoms including abdominal distension. A large pelvic mass was present. At operation, bilateral ovarian tumors with papillary projections were ob- served together with general engagement of adja- cent tissues. She died at the age of 47. 11: 2. This patient was originally seen because of a large pelvic mass, subsequently found to consist of large bilateral cysts which were radically removed. Three years later and despite cytostatic treatment, the patient died from a recurrent tumor with ascites after a short course. She died at the age of 55. 111: 3. This patient was admitted after two weeks of abdominal distension with a large pelvic mass present. Laparotomy revealed wide-spread ab- dominal carcinosis of ovarian origin. Cytostatic therapy did not prevent her death six months later at the age of 45. 111: 6. Chest symptoms of nearly one year’s dura- tion brought this patient to attention, and she was found to have pleural effusion and metastatic lung tumors. By means of fineneedle biopsy a large pel- ? I m 0 0 N o r m a l male or female 0 D i e d of o v a r i a n c a n c e r @ P r o p h y l a c t i c o o p h o r e c t o m y I N O o f f s p r i n g 7 D e c e a s e d Fig. 1. Pedigree of a family with ovarian cancer. Upsulu J Med Sci 81 190 L . Thor et al. Table I. Clinical and histopathological data on six members of a family with ovarian adenocarcinoma Age at Histopathologic first ad- diagnosis Duration until mission of the tumor Type of therapy fatal outcome I: 1 41 Papillary serous 11: 2 51 Papillary serous adenocarcinoma adenocarcinorna 111: 3 45 Papillary serous 111: 6 38 Papillary serous 111: 2 46 Normal ovarian 111: 4 41 Normal ovarian adenocarcinoma adenocarcinoma tissue tissue Operations and radia- (1) Bilateral salpingo- tion therapy oophorectorny +radia- tion therapy; (2) Cyto- static therapy therapy Operation+cytostatic Cytostatic therapy Prophylactic bilateral Prophylactic bilateral oophorectomy oophorectorny vie mass also present was found to consist of ovarian papillary adenocarcinoma. She died seven months later after several courses of cytostatic treatment at the age of 38. III:2&4. Due to the family history these two sisters demanded prophylactic oophorectomy to be performed, and their ovaries were found to be histo- logically normal. 11: 3. This 66 year old sister of 11: 2 is still healthy, and no pathological findings have been demon- strated at repeated gynecological examinations. 111: 7&8. These two daughters of 11: 3 are 45 and 41 years respectively. They are both in goodgeneral condition. Additionally IV: 8 has recently been found to be normal at gynecological examination. DISCUSSION In the present family all affected members suffered from papillary serous adenocarcinoma. This type of ovarian malignancy also seems to have been pre- vailing in the previously reported families ( 1 , 2, 3 7 4 ) . The probability of familial association of this site -specific malignancy by chance, has been re- garded as extremely remote, and other explanations must therefore be considered. The appearance of the same type of rare disorder in consecutive gene- rations suggests the possibility of transmission of a dominant autosomal gene according to the Men- delian laws of inheritance. The family patterns reported by Liber (4), Lewis & Davison (2), Li et al. (3), Lynch & Krush (6) < 1 year 31 year 6 months 7 months - - and Fraumein et al. (1) as well as in the present family are consistent with such an explanation. However, a polygenic mode of inheritance must also be considered. In other families with aggregation of affected sibs as described by McCrann et al. (7) and Fraumein et al. (I), transmission of rare recessive genes might explain the findings, though genetic transmission of the disease could not be proven. If mutant genes sometimes may be of importance in the etiology of malignant ovarian disease, they may of course differ with regard to mode of expres- sion and transmission. Li et al. (3) reported a large kindred, where a phenotypically normal male might possibly have transmitted a mutant gene, to his two daughters affected by abdominal carcinomatosis with un- known, primary site. So far there are no other re- ports on suggested male transmission of mutant genes for ovarian malignancy. Neither are there any reports on males affected with gonadal carcinoma as a result of suggested inheritance of mutant genes. The clinical management and counselling of families with several affected members must there- fore be based on thorough considerations of all family data available for each specific family. In the present kindred, the malignant ovarian dis- order has been restricted in its appearance to descendants within one of the two “female” branches of the family, i.e. in 11: 2 and her offspring, while II:3 and her progeny have so far escaped the disease. This finding is consistent with an in- heritance pattern of a dominant mutant gene, where Upsala J Med Sci 81 Familial ovarian carcinoma 191 II:3 may be a non-carrier of the mutant gene. Evidences in favor of such an interpretation are her present health condition together with her present age, which seems to be beyond the actual risk pe- riod within which the affected members of the family were taken ill. If II:3 is a non-carrier, her two healthy daughters and their progeny may be considered not to be a t risk. Regular clinical con- trols have been recommended for 111: 7 and 111: 8. Surgical intervention has for the moment not been considered necessary. In the affected family branch, 111: 2 and 111: 4 had their ovaries removed prophylactically without histological signs of malignancy. There are two female descendants, IV: 3 and IV: 5 , 8 and 17 years old respectively, who may be considered to be at considerable risk. These two females will require regular and thorough clinical controls until they have the number of children they want, when prophylactic oophorectomy may be indicated. For the long term management of the present family it must be taken into consideration that only female members have been affected, and are likely transmittors, and that, so far, there is no evidence of male transmission of the alleged mutant gene. Prenatal sex determination and selective abortion of female fetuses in future pregnancies of IV: 3 and IV:5 could therefore possibly reduce the rate of long term anguish for having in fact “affected” fe- male offspring. Should it be, that male members of the present family d o not transmit the genes for this disorder, then selective termination of pregnancies with female fetuses may in addition help to even- tually eliminate the adverse gene from this family. REFERENCES 1 . Fraumein, J. F., Jr, Grundby, G . W . , Creagan, E. T. & Everson, R. B.: Six families prone to ovarian cancer. Cancer 36: 364-369, 1975. 2 . Lewis, A. C. W. & Davison, B. C. C.: Familial ovarian cancer. Lancet II: 235-237, 1%9. 3 . Li, F. P., Rapaport, A. H . , Fraumein, J. F., Jr & Jen- sen, R. D.: Familial ovarian carcinoma, JAMA 214: 1559-1561, 1970. 4. Liber, A. F.: Ovarian cancer in mother and five daughters. Arch Parhol49: 280-290, 1950. 5 . Lynch, F. W . : A clinical review of 110 cases of ovarian carcinoma. Am J Obstet Gynec 32: 753, 1936. 6. Lynch, H. T. & Krush, A . J.: Carcinoma in the breast and ovary in three families. Surgery, Gynecology & Obstetrics 133: 644-648, 1971. 7. MacCrann, D. J . , Marchant, D. J . & Bardawil, W. A.: Ovarian carcinoma in the three teenage siblings. Ob- stet Gynecol43: 132-137, 1974. Received March 28, 1976 Address for reprints: Berndt Kjessler, M.D. Department of Obstetrics & Gynecology University Hospital S-750 14 Uppsala Sweden Upsala J Med Sci 81