Acta path. microbiol. scand. Section A.81,3, 3.59-365, 1973

MALE BREAST CANCER 4. Gynecomastia in Patients with Breast Cancer

OLE SCHEIKE and JAKOB VISFELDT

The Radium Center. Copenhagen and Institute of Pathology, Frederiksberg Hospital Copenhagen, Denma,rk

In order to elucidate the question of whrther or not gynecomastia is a premalignant state, a Danish series comprising 265 cases of male breast cancer was reviewed with rega,rd to a previous history of gynecomastia and the finding of clinical gynecomastia on admission. Furthermore, prepara,tians from 187 cases of the same series were assessed with a view to the presence of histolo'gically verified gynecomastia. I n 10 patients there was a history of pynecomastia; only one patient presented clinical gynecomastia on admission. In 79 cases there wa,s sufficient breast tissue for a histological study; this revealed gynecomastia in 21 cases, 6 of which were of florid type (type I ) and 15 of quiescent fibrous type (type 11). In 2 cases ducts with severe atypia of the epithelium were found, but in spite of investiga- tions of serial sections no transition into invasive growth was revealed. It is concluded that the following features seem to support the theory that gynecomastia, may be a premalignant state: A. the finding of severe atypia of the epithelium in the ducts in concurrent gyneco- mastia and breast cancer; B. lower mean age in cases of breast cancer with concurrent gynecomastia; C. the higher ratio of male to female breast cancer and the low mean age of the male patients in an area with a high frequency of gynecomastia; D. heavily increased frequency of breast cancer in patients with the Klinefelter syndrome.

The possible association be tween gynecomas- tia and breast cancer has been discussed in almost all reports on series of male breast cancer, and several series give information about anamnestic, objective and histological gynecomastia. Hence, Norris & Taylor found gynecomastia in 5 per cent of 108 patients (1 1) . Out of the 40 patients reported on by Liechty ( 7 ) , 7 had gynecomastia. Sinner (15) found 5 cases in 27 patients. Huggins & T a y - lor (4) reported only one case of gynecomas- tia among 75 patients, and Holleb et al. ( 3 ) found only 2 cases among 198 patients.

In order to elucidate the question of whet-

Received 6.i.73 Accepted 6.i.73 Requests for reprints should be addressed to Ole

Scheike, Radium Center, Strandboulevarden 49, 2 100, Copenhagen, Denmark.

her or not gynecomastia is a premalignant state, a comprehensive Danish series of cases of breast cancer was reviewed with regard to the presence of gynecomastia.

M A T E R I A L S A N D M E T H O D S

With the aid of the Danish Cancer Registry, 265 male patients with breast cancer were traced for the period 1 January 1943 to 1 July 1972 from all over Denmark. Histological preparations from 187 cases of male breast cancer were re-assessed (17 ) . Oest- radio1 metabolism was investigated in 19 patients ( 1 3 ) .

In connection with the clinical and histological review of these 265 cases, examination for the pre- sence of gynecomastia was made. This consisted in a survey of a ) anamnestic gynecomastia; b) clinical gynecomastia on admission; and c ) histologically verified gynecomastia based on preparations from the 187 cases of male breast cancer.

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R E S U L T S

Anamnestic Gynecomastia In 10 patients there was a history of homo-

lateral gynecomastia. In 5 of the cases the con- dition was bilateral. Three of the 10 patients had gynecomastia during puberty and in two of the cases it was irreversible. Two patients had had reversible gynecomastia during adult life. In the remaining 5 patients, who all had had gynecomastia as adults, operation or bio- psy had been carried out from 5% to 16 years prior to establishment of the cancer diagnosis. In four of the cases the histological prepara- tions were available and were reviewed. The histological diagnoses were : mastitis, gyneco- mastia type I, gynecomastia type I with mas- titis, gynecomastia type I with pmnounced proliferation of the epithelium.

Clinical Gynecomastia on Admission Only one patient had palpable gynecomas-

tia on admission. This was bilateral gyneco- mastia associated with clinically verified can- cer in the left breast. The patient is also regi- stered under “anamnestic gynecomastia”.

Histological Gynecomastia In 79 of the 187 cases there was sufficient

breast tissue for a more exact histological eva- luation. In 21 of these 79 cases, there were histological signs of gynecomastia, i.e., 6 of type I and 15 of type 11, cf. the discussion.

D I S C U S S I O N

Anamnestic Gynecomastia According to the case reports, 10 of our

patients presented a history of gynecomastia; of these 3 had gynecomastia during puberty.

In many studies on male breast cancer, anamnestic gynecomastia is included among the number of cases of gynecomastia. Apart from the usual inaccuracy pertaining to a- namnestic data, a history of gynecomastia is only slightly relevant in the assessment of the condition as a possible premalignant state, gyncomastia being fairly frequent in the nor-

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ma1 population. Hence, Nydick (12) found clinical gynecomastia in 65 per cent of normal boys of the age of 14 years. Gynecomastia. among adults is far from rare, the maximum frequency occuring at the age of 50 years (16) -(cf. Fig. 7) .

Clinical Gynecomastia on Admission According to the case records, only one of

our patients had clinical gynecomastia on ad- mission. Histologically verified gynecomastia is, however, not always associated with en- larged breasts. Hence, Williams ( 18) found enlargement of the breasts in only 4 out of 178 cases with histological gynecomastia.

Histological Gynecomastia The histological criteria for gynecomastia

vary somewhat from one author to another. Williams (18) used two types of gynecomas- tia, types I and 11, and in the present study this classification has been adopted.

Type I (florid type), Figs. 1, 2, is characte- rized by an increased number of ducts with irregular lumen, in some cases showing pseu- dolobule formation (Fig. 5 ) . Proliferation of the epithelium is present, defined as three or more layers of cells, sometimes with budding or small papillae. Around the ducts cuffs are found, consisting of characteristic, light, very loose connective tissue stroma, usually con- taining a few round cells, in some cases eosinophilic granulocytes. These cuffs are fairly well demarcated from the “interlobu- lar” connective tissue. This is increased in volume and consists of dense collagen tissue with varying fibroblastic proliferation.

Type I1 (quiescent fibrous type), Figs. 3,4, shows a slightly increased number of ducts

Figs. 2-2. Gynecomastia type I ; florid type. Ducts with irregular outline, epithelial proliferation and periductal cuffs of loose connective tissue. x 120.

Figs. 3-4. Gynecomastia, Type 11; quiescent, fibro- us type. Duct with ectasia and irregular outline. No epithelial proliferation, no cuffs. Dense, fibrous interlobular stroma. x 30.

TABLE 1. Histological Findings in 21 Cases of Gynecomastia Associated with Mammary Cancer

- 1 2 3 4 5 6 7 a 9

10 1 1 12 13 14 15 16 17

19 i a

20 21

71 + + + + + + + + I 63 + + + + + + + I 59 + + + + I1 50 + + + + I1 39 + + + IT 46 + + + + + + I 63 + + + I1 56 + + + + I1 63 + + + I1 58 + + + + + + I 68 + + + + + + I1 72 + + + + + + + I1 40 + + + + + I1 36 + + + + I1 49 + + + + I1 56 + + + + + + + ( + ) I 47 + + + + I1 59 + + + + + + ( + ) + I 80 + + + + + + I1 48 + + + + I1 41 + + ( + ) + + + I1

with irregular lumen and often slight ectasia. Little or no proliferation of the epithelium is present, and seldom budding and small pa- pillae. Normally no cuffs are seen; the inter- lobular tissue extends as far as to the basement membrane. The stroma is increased in vo- lume, often with hyalininzation and without pronounced fibroblastic proliferation.

The most important historlogical findings in the 21 cases of gynecomastia in our series are shown in Table 1.

Ductal proliferation is difficult to assess. There is both a qualitative element (pseu- dolobule formation) and a quantitative ele- ment. A reliable definiiition of the number of lobules must require examination of the entire breast, and this we were unable to do. How- ever, we estimated that there was an increased number of ducts in all cases, but often to a modest extent in type 11. Cuffs of loose con- nective tissue is the predominant feature in type I, and it was registered in all cases of type I and in one case of type 11. Prolifera-

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tion of the epithelium is characteristic pri- marily in 'type I, but may occur in type 11. An increased quantity of interlobular stroma is found in all cases; hyalinization was present mainly in type 11, although, in a single case, we observed a small hyalinized area in a type I. Apocrine glands are said to be a fairly fre- quent finding in gynecomastia (18); we found this in a total of three cases.

The table and the above comments show that we are unable to establish any definite criteria for a differentiation between types I and 11. The histological characteristics of the two types overlap to a certain extent, which also appears from the report by Nicolis et al. ( 10). Consequently, the classification into types I and I1 is based on a collective evalua- tion of the histological findings.

Our cases are distributed into 6 (29 per cent) of type I and 15 (71 per cent) of type 11. This corresponds fairly well to the distri- bution in Williams' series ( 18), which inclu- ded 21 per cent of type I and 79 per cent of type I1 out of 178 autopsy cases with histo-

F i g . 5. Gynecomastia, type I. Pseudolobule formation. x 30.

Fig. 6. Gynecomastia, type I. Severe atypia of ductal epithelium. x 480.

logical gynecomastia. As regards the frequen- cy of histological gynecomastia there was suf- ficient breast tissue for evaluation in only 79 cases of the 187 cases of male breast cancer which form our basic material. We found histological gynecomastia in 21 of these cases, corresponding to 27 per cent. By examining breast tissue from 447 consecutive autopsy cases, Williams found histological gynecomas- tia in 178 cases, corresponding to 40 per cent. The difference in the incidence of histological gynecomastia in the two series may perhaps be explained by the more limited quantity of breast tissue available in our sections.

More recent studies (10) indicate that there is a relationship between the histological type of gynecomastia and the duration of the condition. Hence, it was found that the florid type I occurs most frequently among fresh

cases, and that type 11, the fibrous type, is most frequent in cases with a long history of the disease (10).

Our series included two cases of gyneco- mastia type 11, in which histological prepara- tions of tissue taken 16 years and 6 years pre- viously, showed gynecomastia of type I. Alt- hough there are only two cases, these Seems to substantiate the theory of a relationship between the histological type and the dura- tion of the condition.

Histological Gynecomastia and Focal Beginning of Cancer

The transition from gynecomastia to car- cinoma is thought by several authors (2,6, 8 ) to have been proved histologically. However, this demonstration is extremely difficult, if the criterion is invasive growth of epithelium

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- & lf40 21-30 3-0 41-50 51-60 bl-70 7t-60

Fig. 7. Age distribution of males with gynecomastia and breast cancer. Reproduced by permission of Pro- fessor Carlo Sirtori, Milan, and Cancer ( 16).

from the ducts into areas with gynecomastia. The probability of a transition can be sup- ported by demonstration of ducts with epithe- lium showing carcinoma in situ ( 9 ) . In two of our cases we found ducts with abnormal epithelium in the gynecomastia co-existing with breast cancer (Fig. 6 ) . In spite of ex- amination of serial sections, we were unable to demonstrate direct transition into invasive growth.

Senescent Gynecomastia in Male Breast Cancer

I t is well known that gynecomastia has two incidence maxima, one in puberty, and the other between the ages of 50-60 years (12, 16). Sirtori found a maximum incidence of gynecomastia at the age of 55, and a maxi- mum incidence of breast cancer at 65 years of age (cf. Fig. 7 ) . In our series of male breast cancer comprising 265 cases, the average age was 64.8 years. In the 21 cases with concur- rent histological gynecomastia, the average age was 55.4 years, which is significantly lower (P < 0.01).

In Egypt, a remarkably high ratio of male to female breast cancer of about 1 to 15 was

found (1 ) . At the same time there is a high incidence of gynecomastia. The average age for the diagnosis of male breast cancer in that country is 41 years. Hence, the same tendency seems to apply as that found in our series: early development of breast cancer in asso- ciation with gynecomastia, indicating a p s - sible etiological relationship between gyneco- mastia and breast cancer.

Gynecomastia and Breast Cancer in Cases of the Klinefelter Syndrome

Gynecomastia is a cardinal symptom in the Klinefelter syndrome (5 ) . On the basis of literary studies and our own series, we found an incidence of breast cancer in the Klinefel- ter syndrome of about 20 times the incidence of breast cancer in normal males (14). This is a further indication of a possible etiological relationship between gynecomastia and breast cancer.

C O N C L U S I O N

It must be concluded that none of the features reviewed would prove the existence of an

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etiological relationship between gynecomastia and breast cancer.

However, certain facts appear to support the theory that gynecomastia may be a pre- malignant state. Among these the following should be emphasized: A. the finding of scv- ere atypia of ductal epithelium in certain cases with concurrent gynecomastia and breast cancer; B. the lower mean age in cases of breast cancer with concurrent gynecomas- tia; C. the higher ratio of male to female breast cancer and the low mean age of the male patients in an area with a high frequen- cy of gynecomastia; D. the heavily increased frequency of breast cancer in patients with the Klinefelter syndrome, where gynecomastia is a cardinal symptom.

The work was supported by a grant from the National Anti-Cancer League.

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