9

FAMILIAL MALE BREAST CANCER FREDERICK P. LI RICHARD B. EVERSON F. JACK FISHMAN JOSEPH FRAUMENI, JR. RICHARD E. WILSON DAVID STOUT HENRY J. NORRIS

Epidemiology Branch, National Cancer Institute, Bethesda, Maryland; Institute for Steroid Research, Montefiore Hospital and Medical Center, Bronx, New York; Peter Bent Brigham Hospital and Sidney Farber Cancer Center, Boston, Massachusetts; Eugene Leland Memorial Hospital, Riverdale, Maryland; and Armed Forces Institute of Pathology, Washington, D.C., U.S.A.

Infiltrating ductal carcinoma of the breast occurred in a total of six men from two families. In one family specimens from three men who had prophylactic mastectomies revealed focal intraductal hyperplasia, suggesting a familial tendency toward proliferation of mammary-duct epithelium. In the other family, benign and malignant breast lesions also developed in several women. Preliminary data suggest elevated urinary œstrogen excretion in three men from these families, implicating a defect in oestrogen production or metabolism in the pathogenesis of male breast neoplasms.

FAMILY A

FAMILY B I

Summary

Introduction A FAMILIAL tendency for breast cancer is well recognised among women.1-3We describe here the occurrence of male breast cancer (M.B.C.) in two families reported by clinicians to the Epidemiology Branch of the National Cancer Institute, and laboratory studies employed in an effort to clarify aetiological mechanisms.

- MALE WITH BREAST CANCER

FEMALE WITH

FIBROCYSTIC DISEASE DECEASED

TONGUE CANCER TEN PERSONS, EITHER SEX

O

 STILLBORN

PROBAND PROBAND

p

PROPHYLACTIC

MASTECTOMY

LABORATORY

STUDIES PERFORMED

Fig. 1—Family pedigrees. FAMILY A

Affected Families shown in fig. 1. Breast cancer depedigrees in three brothers (family A) and in a man, his veloped and uncle father, paternal (family B). Illnesses and causes of death in the two families were identified by correspondence with relatives, and by examination of hospital records, death certificates, pathology reports, and histology specimens. Available family members were contacted and one man with breast cancer and eight other members of the two families volunteered to donate blood and urine specimens for biochemical studies. No consanguinity, unusual occupations, exposures to toxic materials, or disorders known to predispose to M.B.c. were found in these families. Histological specimens of the primary tumour were available for case 1-5; all had typical infiltrating ductal carcinoma. Case 1 also showed histological evidence of mild, inactive gynæcomastia. The

5. 6. 7. 8. 9.

are

Case 1.—In 1973 the proband (II-6), a 78-year-old retired engineer, discovered a mass in his right breast. Biopsy revealed carcinoma (fig. 2) and a modified radical mastectomy was performed. The patient is well at age 80 years. Case 2.-The proband’s brother (11-4), a retired 68-year-old general practitioner, developed a 3x44 cm carcinoma in the right breast in 1958. It was treated successfully with simple mastectomy and radiotherapy. His past medical history in-

Fias, I., Dombi, E., Wenhardt, E., Horvath, I. ibid. 1973, i, 1519. Pole, J. R. G., Barr, W., Willoughby, M. L. N. ibid. 1974, i, 1051. Fraser, I. D , Bennett, M. O., Bothamley, J. E. Br. J. Hœmat. 1974, 28, 147. Cotton, R., Sobey, D. F. Vox Sang. 1973, 24, 181. Coombs, R. R. A., Mourant, A. E., Race, R. R. Br. J. exp. Path. 1945, 26,

255. 10. Liley, A. W. Am. J. Obstet. Gynec. 1961, 82, 1359. 11. Knox, E. G., Fairweather, D. V. I., Walker, W. Clin. Sci. 1965, 28, 147. 12. Fraser, I. D., Tovey, G. H. J. Obstet. Gynœc. Br. Commonw. 1972, 79, 981. 13. Walker, W., Murray, S. Br. med. J. 1956, 1, 187. 14. Fraser, I. D., Tovey, G. H. Clins Hœmat. (in the press) 15. Holt, E. M., Boyd, I. E., Dewhurst, C. J., Murray, J., Maylor, C. H., Smitham, J. H. Br. med. J. 1973, iii, 39.

Fig. 2-Photomicrograph family A (case 1, II-6).

Haematoxytin

of mastectomy

and eosin stain

specimen

(reduced by

a

from

third from

proband

x 80).

of

10 eluded episodes of posterior urethritis and chronic osteoarthritis treated with hydrocortisone. Death at age 74 was attributed to arteriosclerotic cardiovascular disease. No necropsy was

performed.

Case 3.-Another brother (11-5), a 62-year-old typesetter, underwent radical mastectomy for carcinoma of the left breast in 1955. He died of congestive heart-failure at age 73 without recurrence



of cancer.

a left radical mastectomy and postoperative radiotherapy for infiltrating ductal carcinoma (fig. 3). A subsequent prophylactic right subcutaneous mastectomy revealed focal intraductal hyperplasia with an irregular stratification of ductal epithelium that some pathologists regarded as dysplastic (fig. 4). At the age 51 he is free of cancer.

ney, had

Necropsy was not performed.

The parents and two sisters of the proband died of atherosclerotic heart-disease. Correspondence with family members on the paternal line in Germany revealed that an aunt and nine of fifteen first and second cousins had cancer, including four women with breast cancer. One daughter (111-7) of the proband has biopsyproven fibrocystic disease and fibroadenoma of the breast, and a second (III-8) has clinical and mammographic evidence of fibrocystic disease; their maternal grandmother and maternal great-aunt had breast cancer.

FAMILY B

Case 4.-In 1970 the

proband (m-3),

a

47-year-old

attor-

Fig. 5-Photomicrograph of prophylactic mastectomy specimen from younger son (IV-3) of proband of family B.

Haematoxytin and eosin stain (reduced by a third from x 90).

Fig. 3-Photomicrograph family B (case 4, m-3).

of mastectomy

specimen from proband

of

Haematoxytin and eosin stain (reduced by a third from x 100)

Fig. 4-Photomicrograph of prophylactic mastectomy specimen proband of family B (case 4, m-3).

Hzmatoxytin and eosin stain (reduced by a third from x 130).

from

Fig. 6--Photomicrographs of prophylactic mastectomy specimen from elder son (IV -2) of proband of family B. Hæmatoxylin and eosin stain (reduced by a third from a, x 195; b,

;

x 180). e

11 ENDOGENOUS URINARY OESTROGEN GLUCURONIDE EXCRETION IN MALE BREAST-CANCER FAMILY MEMBERS AND CONTROLS

Oestrogen excretion in four female family members (A 111-5-8) showed no abnormal pattern. Urinary 17-ketosteroid, ketogenic steroids, and fourteen individual neutral steroid metabolites measured by liquid chromatography for case 1 and three family members (A ui-4-6) normal. Serum from case 1 and eight family members (noted by an asterisk on fig. 1) showed essentially normal values for the following: oestrone, oestradiol, testosterone, dihydrotestosterone, luteinising hormone, follicle-stimulating hormone, prolactin, and quantitative were

’Patient in disease-free interval.

tFamily member. Nineteen healthy

men.

g/24hr.

Case 5.-In 1963 the

proband’s 67-year-old

father

(tut-2),

salesman, had a 4 x5 cm carcinoma excised at left radical

a

mas-

tectomy. Nineteen of twenty-four lymph-nodes contained tumour. Eight months later he developed a pleural effusion and metastases in the left chest wall. Orchiectomy was performed but he died postoperatively from pulmonary oedema. Necropsy was not conducted. Case 6.-The

proband’s 59-year-old paternal uncle (11-3), office worker, had a left radical mastectomy in 1959 for breast cancer. Recurrence four years later was treated with orchiectomy and oestrogens, and later with hypophysectomy. He died at age 66 years; no necropsy was performed. an

Two sons (iv-2, 3) of the proband underwent prophylactic bilateral subcutaneous mastectomies in 1974 at ages 26 and 23 years. In the younger son histopathological examination showed mild hyperplasia of one duct with an irregular stratification of the ductal epithelium (fig. 5). Tissue from the elder son revealed prominent breast stroma and ducts suggesting old inactive gynaecomastia and slight intraductal hyperplasia (fig. 6). This tissue was considered to be mildly dysplastic by some observers. The brother (ni-1) of the proband developed squamous-cell carcinoma of the tongue treated by radiotherapy and surgery. Cancer was reported in the maternal grandmother of the proband, but the primary site is unknown. A maternal aunt had cervical cancer. Twelve other family members (n-4-13, tit-2, 4) died before age

30, most during infancy.

The

Laboratory Studies accompanying table presents the

levels of endoin excreted a 24-hour urine collection genous oestrogens case 1 and three male members (A n-6) by family (A tn-4, B iv-2, 3). Since no simultaneous controls were obtained, values were compared with available data representing twice the 12-hour urinary excretion of nineteen healthy men aged 38-63 years. In all instances the oestrogens were measured by radioimmunoassay following hydrolysis with p-glucuronidase. Although these groups differ in age and collection period, the excretion of oestrone, cestradiol, and oestriol was distinctly elevated in case 1 and two male members of M.B.C. families, with values falling outside the range observed among the healthy men. In the third male family member (B iv-2) low creatinine and ketosteroid values suggested an in-

complete sample.

immunoglobulins. Chromosomal analysis of peripheral blood leucocytes showed no abnormality in the proband (11-6) or four offspring (uni-4, 6-8) of breast-cancer patients in family A. In family B the proband (111-3) had aneuploidy in 2 of 9 cells, probably an effect of radiotherapy at the time of the analysis. Chromosomal patterns in his two sons (iv-2, 3) were normal when examined by standard techniques and acetic-saline-Giemsa banding. Discussion The six men with carcinoma of the breast from two families had typical infiltrating ductal carcinomas. In one family, mild intraductal hyperplasia was identified in tissue prophylactically removed from the contralateral breast of the proband and from both breasts of his two sons. This finding suggests a familial tendency toward proliferation of ductal epithelium that may predispose to

malignancy.

Familial M.B.c. has been rarely recognised in the past. In a series of fifty-three patients with M.B.C., the tumour was noted in two pairs of sibs;4 one sibship probably included two men in family A (it-4, 5) while the second consisted of a patient who reported an affected brother in Greece. Recently breast cancer was reported in two brothers, one of whom had prostatic cancer.s The lack of reports of familial M.B.C. may reflect the low incidence of M.B.C. If the familial risk were equivalent to that for female breast cancer (approximately three-fold) only 1 familial case of M.B.c. would occur in about every 600 M.B.C. cases. A significant familial risk accounting for few cases numerically might thus remain unrecognised.

family A an aggregation of breast cancer was reported among female cousins, and fibrocystic disease developed in two daughters of the proband-suggesting that familial susceptibility to breast cancer may occur regardless of sex. Case series add some support to this suggestion. Combining five series of M.B.C. cases with mention of family histories, eleven patients out of a hundred and twenty (9%) had a mother or sister with the disease.6-1o In reports not indicating the nature of the familial relationship, five patients out of fifty-one (10%) had affected female relatives."-’3 These percentages seem higher than expected, but may have been raised by a tendency to report positive family histories or lowered by incomplete ascertainment. In comparison, more carefully conducted surveys of female breast cancer have shown that approximately 15% of patients In

but 5% of controls have affected mothers or sisters.3 14 The possibility that familial susceptibility to breast cancer may involve factors common to both sexes is intriguing, but confirmation will require further study. Several disorders may predispose to M.B.C. In the

12 Klinefelter

syndrome

the

excess

risk of

M.B.C.

is about

20-fold." The reported association with gynxcomas-

PHARYNGEAL LECITHIN/SPHINGOMYELIN RATIOS IN NEWBORN INFANTS

tia16-18 is difficult to assess because of the high frequency of this condition in the general population and variable diagnostic criteria.19-21 Other risk factors have been

suggested: radiation,4 22 exogenous

Familial male breast cancer.

9 FAMILIAL MALE BREAST CANCER FREDERICK P. LI RICHARD B. EVERSON F. JACK FISHMAN JOSEPH FRAUMENI, JR. RICHARD E. WILSON DAVID STOUT HENRY J. NORRIS...
642KB Sizes 0 Downloads 0 Views