A Family with Peutz-Jeghers Syndrome and Bilateral Breast Cancer

ELIZABETH RILEY, MD AND MICHAEL SWIFT, MD

The proband and her paternal grandmother had bilateral breast carcinoma and the Peutz-Jeghers syndrome. An ovarian sex cord tumor with annular tubules was an incidental finding when oophorectomy was performed as treatment of the proband’s premenopausal breast cancer. Because there are previous reports of breast cancer in patients with this syndrome, the Peutz-Jeghers gene may be associated with an increased risk of breast tumors.

Cancer 46:815-817, 1980.

HE AUTOSOMAL DOMINANT Peutz-Jeghers syn- T drome is characterized by skin and mucous mem- brane pigmentation and by polyps throughout the gas- trointestinal tract. There have been approximately 600 reported cases of Peutz-Jeghers syndrome. Persons with Peutz-Jeghers syndrome have an increased risk of de- veloping gastrointestinal cancer as well as benign ovar- ian, respiratory tract, and urinary tract tumors.

Case Report

The proband, 111-1, a 46-year-old white female, was diag- nosed as having the Peutz-Jeghers syndrome because of a positive family history, perioral pigmentation, and the pres- ence of jejunal polyps. In 1956 at age 24 years numerous je- junal polyps were resected prophylactically. A colonic hamartomatous polyp was removed in 1962. Barium studies and sigmoidoscopies subsequently have been normal.

In December 1973, when the patient was 41 years old, a right radical mastectomy revealed a poorly differentiated large cell adenocarcinoma of the breast with extensive lym- phatic invasion. Fibrocystic disease was also present. In August 1975, a cyst in the left breast was aspirated. It con- tained Class 111 cell changes with some papillary fronds. A large cell infiltrating ductal carcinoma with lymph node in- volvement was removed at mastectomy. A bone scan revealed increased activity in the lower cervical and right shoulder

From the Department of Medicine, Division of Medical Genetics, Biological Sciences Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

Supported by grants HD-03110 and CA-I7973 from the National Institutes of Health.

Address for reprints: Michael Swift, MD, Biological Sciences Re- search Center 220H, University of North Carolina, Chapel Hill, NC 27514.

The authors thank Nancy Goodman for obtaining the family history and medical records and Dr. Joachirn D. Geratz for reviewing the histology of the proband’s ovary and breasts.

Accepted for publication July 27, 1979.

regions, suggestive of metastatic disease. Subsequent treat- ment included bilateral oophorectomy and chemotherapy.

The right and left ovary measured 4 X 2.7 cm and 2.5 X 3 cm, respectively. Each ovary contained a hemorrhagic corpus luteum cyst. The greatest diameter of the cyst in the right ovary was 2.8 cm and that in the left ovary was 2.0 cm. Several follicular cysts 0.3-0.8 cm were also found in both ovaries. Two sections from the right ovary were reviewed. Primordial follicles, graafian follicles, corpora albicantia, and an early organizing corpus luteum were present. There was a single small sex cord tumor with annular tubules in the medulla of the right ovary (Fig. 1). No abnormalities were detected in the one section of the left ovary that was reviewed.

Family History

The diagnosis of bilateral breast cancer in the grand- mother, 1-2 (Fig. 2), of the proband was confirmed by death certificate. At the age of 48 she had a right radical mastectomy. Carcinoma of the second breast was diag- nosed one year later. She died in 1932 at the age of 51 of metastatic disease. The diagnosis of Peutz-Jeghers syn- drome is presumed because family members reported her to have perioral pigmentation and photographs ap- peared to confirm this.

The grandmother’s sister, 1-1, died in 1957 at the age of 83. A mastectomy had been performed for breast cancer in 1917. Her medical records have been de- stroyed. It is not known whether she had the Peutz- Jeghers syndrome.

The father, 11- 1, of the proband had multiple hamar- tomatous polyps removed from the descending sigmoid colon at the age of 56 years. Four years later, in 1963, total colectomy was performed because of the simul- taneous occurrence of two adenocarcinomas, one at the hepatic and the other at the splenic flexure. The diag- nosis of Peutz-Jeghers syndrome was made at this time,

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based on the presence of oral pigmentation, polyps, and a positive family history. Seven years later, in 1970 at the age of 67 years, he died as a result of metastatic pan-

I

II

0 2 6 3

Normal mole or female

Peutz-Jeghers Syndrome

Bilateral Breast Cancer

Unilateral Breast Cancer

Multiple GI Cancers

Proband

FIG. 1. Within the medulla of the ovary is a small, well- circumscribed, round tubu- lar structure made up of tall columnar cells arranged in a cribriform pattern. The nuclei are arranged in an antipodal fashion, and the spaces enclosed by the cells contain dense hyaline ma- terial.

creatic carcinoma, confirmed at autopsy. No gastro- intestinal polyps were found at this time.

111-3, the proband’s 29-year-old sister, who has peri- oral pigmentation and G.I. polyps, was diagnosed as having the Peutz-Jeghers syndrome at age 16 years.

1V- 1, the proband’s son, has perioral pigmentation and is therefore presumed to have inherited the Peutz- Jeghers gene.

Discussion

Individuals with the Peutz-Jeghers syndrome have an increased incidence of ovarian and gastrointestinal neo- plasms. Most of the evidence for the predisposition to gastrointestinal cancer among Peutz-Jeghers patients has come from case reports. The association is well supported by the early age of onset of the malignant neoplasm in many of the Peutz-Jeghers patients5 and the unusual distribution of the neoplasms in the gastro- intestinal tract. l4 The predisposition to gastrointestinal malignancy was confirmed by a Japanese study in which 102 patients with Peutz-Jeghers syndrome were fol- lowed over 12 years.ls Seventeen of the 32 deaths were due to a neoplasm, of which 12 were of the gastrointesti- nal system.

Bilateral breast cancer in a patient with Peutz-Jeghers syndrome was reported in a 45-year-old woman who was also found to have microscopic and macroscopic ovar- ian tumors. Manegold13 described a 33-year-old woman with the Peutz-Jeghers syndrome who had a carcinoma

FIG. 2 . The family pedigree. of the right breast and an intraductal papilloma in the

No. 4 PEUTZ-JEGHERS SYNDROME AND BREAST CA . Riley and Swift 817

other breast. In addition, one of the twins reported by Hutchinson in 1896 was said to have died at age 52 of cancer of the breast,lO and another patient had a papillary adenocarcinoma of the breast at age 395 as well as an ovarian tumor. Benign breast tumors have been reported in two patients with Peutz-Jeghers syndrome, each in association with ovarian tumors.2js These reports, taken together with the present family, raise the question of whether women with the Peutz-Jeghers gene are pre- disposed to breast cancer.

Based on the reports cited above and the present family, symptomatic bilateral breast cancer was present in three of the six women with the Peutz-Jeghers syn- drome and breast cancer. A symptomatic cancer in the second breast occurs in between 3- 10% of the unselected breast cancer patients.l5 The mean age of onset for the first breast cancer for women with breast cancer and the Peutz-Jeghers syndrome was 42 years, taking the age at death to be the onset age in the case where the latter was not reported. In the general population, the mean age for the diagnosis of breast cancer is 55-60 years.3 Case reports, however, tend to emphasize the unusual. An increased incidence of breast cancer or an excess of early onset or of bilateral breast cancer in women selected only for the Peutz-Jeghers gene would support the hypothesis that this gene predisposes to breast cancer.

It is well established that breast cancer occurs more frequently in female relatives of breast cancer patients than one would expect to occur by chance.12 The in- creased incidence of breast cancer was observed equally among paternal and maternal female relatives. Ander- son1 has identified families with premenopausal bilateral breast cancer in which the risk of breast cancer in female relatives appears substantially increased. The family we report may simply represent such a familial aggregation, independent of the Peutz-Jeghers gene. If so, it empha- sizes that genetic predisposition to breast cancer can be transmitted through a male, although the expression is restricted almost entirely to women.

The sisters of the proband were advised to examine their breasts regularly and to have mammography per- formed yearly. However, on the basis of 5 case reports of breast cancer and the Peutz-Jeghers syndrome we be- lieve it is premature to recommend frequent mammog- raphy for young women with the Peutz-Jeghers gene who do not have a family history of breast cancer.

The majority of ovarian tumors in women with the Peutz-Jeghers syndrome are benign.6 In particular, a rare ovarian sex cord tumor with annular tubules occurs with unusual frequency in this condition.I6 It is uncer- tain whether this rare ovarian tumor is pathognomonic of the Peutz-Jeghers syndrome. Ovarian tumors have been an incidental finding at oophorectomy,I8 as in our case, and at autopsy.I6

Because menstrual irregularities and endometrial hyperplasia have been observed in women with these

sex cord ovarian tumors, Scully16 suggested that the tumors are estrogen secreting. Estrogens have been implicated in the etiology of premenopausal breast cancer." It is possible that the development of breast cancer in patients with the Peutz-Jeghers syndrome is stimulated by estrogen production by ovarian tumors.

Peutz-Jeghers syndrome is a systemic disorder. In addition to the ovarian and gastrointestinal neoplasms, tumors have been reported to occur in the respiratorys and urinary tract^.'^ The gene for the Peutz-Jeghers syndrome may also predispose to breast tumors. Such an association may be even more difficult to establish than that of this syndrome with gastrointestinal cancer.

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