Mucinous colon carcinoma in a black family

Mucinous Colon Carcinoma in a Black Family David T. Purtilo, Glenn W. Geelhoed, Frederick P. Li, James P.S. Yang, Wendy A. Thurber, John Darrah, and Christine Cassel

Carcinoma of the large bowel developed in an autosomal dominant pattern in 13 members of a black-American family. Seven members were affected prior to initial ascertainment of the family in 1976. Thereafter, the remaining six were affected while 0.2 cases were expected (p <0.001). Median age at diagnosis of colon cancer was 39 years (range, 22-62 years) in this family, compared with 65 years among black-Americans, in general. Histologic review of surgical specimens from six patients and medical record data for a seventh patient showed mucinous adenacarcinoma of the colon, an uncommon histolagic variant. Studies of several family members a decade ago had revealed no biologic markers of cancer suscepti[~ility.

ABSTRACT:

INTRODUCTION C o l o r e c t a l c a n c e r is the s e c o n d m o s t c o m m o n i n t e r n a l m a l i g n a n c y in the U n i t e d States [1]. T h e c a n c e r aggregates in f a m i l i e s w i t h an i n h e r i t e d s u s c e p t i b i l i t y , as s e e n in G a r d n e r ' s s y n d r o m e , f a m i l i a l p o l y p o s i s coli, T u r c o t ' s s y n d r o m e , a n d f a m i l i a l ade n o c a r c i n o m a of the c o l o n [2, 3]. T h i s r e p o r t d e s c r i b e s 13 m e m b e r s of a b l a c k family w i t h an a u t o s o m a l d o m i n a n t pattern of c o l o n cancer, chiefly m u c i n o u s a d e n o carcinoma.

MATERIALS AND METHODS T h e f a m i l y was first a s c e r t a i n e d in 1976, w h e n a 28-year-old b l a c k p a t i e n t w i t h renal cell c a r c i n o m a r e p o r t e d that m u l t i p l e r e l a t i v e s h a d c o l o n cancer. W i t h inf o r m e d c o n s e n t , f a m i l y m e m b e r s w e r e i n t e r v i e w e d and a v a i l a b l e m e d i c a l a n d vital records w e r e c o m p i l e d . P a t h o l o g y slides on six p a t i e n t s w i t h c o l o n c a n c e r (I-6; II3, 4, 5; II1-1, 5) w e r e r e v i e w e d by o n e of us (D. T. P.) a n d by an i n d e p e n d e n t rev i e w e r (Dr. S a m u e l Cohen). M u c i n o u s a d e n o c a r c i n o m a w a s d i a g n o s e d w h e n m o r e

From the Department of Pathology and Microbiology, Pediatrics, and the Eppley Institute for Research in Cancer and Allied Diseases (D. T. P.), University of Nebraska Medical Center, Omaha, NE; the Depart-

ment of Surgery (G. W. G.), George Washington University Medical Center, Washington, DC; the Clinical Studies Section (F. P. L., W. A. T.), National Cancer Institute at Dana-Farber Cancer Institute, Boston, MA; the Departments of Pathology and Medicine (J. P. S. Y., J. D.), St. Vincent Hospital, Worcester, MA; and the Department of Medicine (C. C.), University of Chicago, Chicago IL.

Address requests for reprints to Dr. David T. Purtilo, Department of Pathology and Microbiology, University of Nebraska Medical Center, 42nd and Dewey Ave., Omaha, NE 68105. Received November 1, 1985; accepted December 9, 1985.

11 © 1987 Elsevier Science Publishing Co., Inc. 52 Vanderbilt Ave., New York, NY 10017

Cancer Genet Cytogenet 24:11-15(1987) 0165-4608/87/$03.50

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D.T. Purtilo et al. than 50% of the tumor was composed of small aggregates or single cells surrounded by abundant mucinous material. Family members were offered a physical examination, sigmoidoscopy, Giemsabanded karyotypes of their peripheral blood leukocytes, and serum assays of carcinoembryonic antigen, alpha-fetoprotein, and human chorionic gonadotropin. Seven of them accepted and were evaluated in 1976. The aggregate findings failed to establish familial susceptibility to colon cancer. A preliminary report of the family was made by us [4] and other investigators reported one case in detail [5]. Subsequently, the family members have been followed through contact with individual patients and their personal physicians. During the last decade, the number of colon cancers observed in the family was compared with that expected on the basis of colon cancer incidence rates among U.S. blacks. The expected figure between 1976 and 1985 was derived by applying appropriate race-and age-specific colon cancer rates to the 94 adult members of generations I, II, and III [1].

RESULTS Thirteen members of this black-American family (seven women and six men), were documented to have colon cancer (Fig. 1). Prior to 1976, the diagnosis of colon cancer was confirmed in seven of these cases (I-1, 2, 6; II-4, 5, 6, 14); excluded from consideration were seven other unconfirmed cases in distant relatives. Thereafter, six additional family members developed colon cancer, whereas, 0.2 cases were expected (p <0.001). Those affected in the last decade were III-1 in 1979, II-3 in 1980, II-22 in 1983, II-23 in 1983, III-5 in 1984, and II-7 in 1985. Median age at diagnosis of colon cancer in the 13 patients was 39 years (range, 22-62 years), in contrast with 65 years in U.S. blacks, in general [1]. None of the family members had polyposis coli, and only one (III-1) had a villous adenoma. The primary site of cancer was the right colon in five patients, transverse colon in three patients, sigmoid colon in one, and was unspecified in the remaining patients. Review of avail-

Figure 1

Pedigreeof the black family with colon cancer. O

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Colon Cancer in a Black Family

13

able histopathology for six of the 13 patients showed mucinous adenocarcinoma (Fig. 2). In a seventh patient (I-2), the autopsy report indicated metastatic mucinous adenocarcinoma of the colon. The frequency of primary cancers of other sites in family members did not appear excessive. Individual patients had endometrial adenocarcinoma (I-4, age 47 years}, leiomyosarcoma of the uterus (II-5, age 36), renal cell carcinoma (II-7, age 28), urinary bladder cancer (II-15, age 42), oral squamous cell carcinoma (II-13, age 47), and glioblastoma (I-5, age 65). In 1976, sigmoidoscopic examinations of six asymptomatic family members had not revealed polyps or tumors. Serum levels of alpha-fetoprotein and human chorionic gonadotropin were normal. However, two individuals had slightly elevated carcinoembryonic antigen (CEA) levels (7.0 ng/ml and 8.4 ng/ml; normal, <5 ng/ml) attributed to cigarette smoking or liver disease; one of them has died of a glioblastoma (I-5} and the other of sarcoidosis. Karyotypes of four family members, including the patient with renal cell carcinoma, showed no abnormalities. There was no family history of cosanguinous marriages or unusual toxic environmental exposures. DISCUSSION Carcinoma of the large bowel was documented in 13 relatives, six of whom were affected in the last decade. Colon cancers were also reported in additional members of earlier generations but their medical records were not available for review. The neoplasm developed in both men and women at unusually early ages (median, 39 years) in a pattern consistent with autosomal dominant transmission.

Figure 2 Representative photomicrograph of a mucinous adenocarcinoma of the colon of a family member. Tumor cells are seen within mucinous material. {Hematoxylin and eosin, × 250]

14

D . T . Purtilo et al. Familial colon cancer has often been reported in whites, but rarely in blacks. A u t o s o m a l d o m i n a n t l y transmitted p o l y p o s i s coli and solitary p o l y p s are predisposing lesions in some kindreds. In others w i t h no identifiable precursor disorders, inherited susceptibility needs to be distinguished from chance association of the n e o p l a s m w i t h i n a large family [6, 7]. W h e n initially ascertained in 1976, the pattern of m u c i n o u s a d e n o c a r c i n o m a among young adults in m u l t i p l e generations of this family suggested autosomal d o m i n a n t inheritance. This hypothesis was confirmed by subsequent d e v e l o p m e n t of colon cancer in six a d d i t i o n a l family members (0.2 cases expected), four of w h o m (II-3, 7; III-1, 5) had an affected parent. At least seven patients in the family d e v e l o p e d m u c i n o u s a d e n o c a r c i n o m a of the large bowel, a variant that accounts for a p p r o x i m a t e l y 15% of bowel cancers in the United States [1]. This histologic diagnosis is based on the n u m b e r and distribution of acini that secrete lakes of m u c u s in the t u m o r mass, though specific diagnostic criteria a p p e a r to differ among pathologists [8]. M u c i n o u s a d e n o c a r c i n o m a reporte d l y comprises a higher fraction of colorectal cancers among black-Africans and among all c h i l d r e n in the U.S. [9, 10]. In one series of 893 patients with colorectal cancer, 31% of the patients with m u c i n o u s a d e n o c a r c i n o m a s also had a villous adenoma, w h i c h was found in only one of our patients [8]. In that series, a high p r o p o r t i o n of m u c i n o u s a d e n o c a r c i n o m a s arose in the right and transverse colon (68%). These are also the most c o m m o n sites of familial colon cancers, w h i c h s h o u l d be e x a m i n e d for the m u c i n o u s variant [11]. Laboratory studies of several family members in 1976 failed to detect markers of cancer susceptibility, and to predict the striking cancer excess on follow-up. However, autosomal d o m i n a n t inheritance portends the d e v e l o p m e n t of a d d i t i o n a l colon cancers in this family, particularly among descendants of patients, I-1, I-2, I-3, and I-5. Surviving family members need closer surveillance for early cancer diagnosis through p e r i o d i c e x a m i n a t i o n s of the large bowel. Recently, potential biological markers of colon cancer susceptibility have been reported for assays such as ornithine decarboxylase levels in colonic mucosa and m e t h i o n i n e d e p e n d e n c e of cultured fibroblasts [12, 13]. If confirmed, these findings can be a p p l i e d to select members of our colon cancer family for more intensive surveillance. The authors thank Dr. Samuel Cohen for review of pathology slides and David Marchetto for assistance in data collection. W. A. T. is a recipient of the Amy Potter Memorial Fellowship.

REFERENCES

1. Young JL Jr, Percy CL, Asire AJ, Eds. {1981): Third National Cancer Survey: Incidence Data. DHEW, National Cancer Institute Monograph 57. Publication no. (NIHI 81-2330). Washington, DC, Government Printing Office. 2. Murphy EA, Krush AJ (1980): Familial polyposis coll. Prog Med Genet 4:59-101. 3. Erbe RW (1970): Inherited gastrointestinal-polyposis syndromes. N Engl J Med 294:11011104. 4. Purtilo DT, Yang JPS, Darrah J (1977): Autosomal Dominant Colon Adenocarcinoma Syndrome. Lab Investig 30:349. 5. Budd DC, Fink DL (1982): Autosomal dominant mucoid colon carcinoma: A study of a case and a kindred. Am Surg 48:180-183. 6. Burt RW, Bishop DT, Cannon LA, Dowdle MA, Lee RG, Skolnick MH (1985): Dominant inheritance of adenomatous colonic polyps and colorectal cancer. N Engl J Med 312:15401543. 7. Boland CR, Troncale FJ (1984): Familial colonic cancer without antecedent polyposis. Ann Intern Med 100:700-701.

Colon Cancer in a Black Family

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8. Symonds DA, Vickery AL Jr (1976): Mucinous carcinoma of the colon and rectum. Cancer 37:1891-1900. 9. Edington GM, Easmon CO (1967): Incidence of cancer of the alimentary tract in Accra, Ghana, and Ibadan, Western Nigeria. In: Tumors of the Alimentary Tract in Africans, JF Murray Jr, ed. National Cancer Institute Monograph 25. Washington, DC, U.S. Printing Office, pp. 17-27. 10. Chabalko JJ, Fraumeni JF Jr (1976): Colorectal cancer in children: Epidemiologic aspects. Dis Colon Rectum 18:1-3. 11. Lynch PM, Lynch HT, Harris RE (1977): Hereditary proximal colonic cancer. Dis Colon Rectum 20:661-668. 12. Luk GD, Baylin SB (1984): Ornithine decarboxylase as a biologic marker in familial coIonic polyposis. N Engl J Med 311:80-83. 13. Mikol YB, Lipkin M (1984): Methionine dependence in skin fibroblasts of humans affected with familial colon cancer or Gardner's syndrome. J Natl Cancer Inst 72:19-22.