Morphology of Male Breast Carcinoma in the Evaluation of Prognosis

Path. Res. Pract. 186, 745-750 (1990)

Morphology of Male Breast Carcinoma in the Evaluation of Prognosis F. Cunha, S. Andre and J. Soares Laborat6rio de Anatomia Patol6gica, Instituto Portugues de Oncologia de Francisco Gentil, Lisboan, Portugal

SUMMARY

We studied a series of 44 consecutive cases ofmale breast carcinoma over a 14 year period in order to evaluate the clinico-pathological characteristics and the impact of some morphologic factors on prognosis. The age of the patients ranged from 38 to 84 years (mean 62 ± 10.8). All the patients presented a painless mass, associated with nipple retraction in 13 cases (29.4%), skin ulceration in 12 cases (27.2%) and nipple discharge in 6 (13.6%). Microscopically all the tumors were infiltrating ductal carcinomas, 42 being of the NOS type. A better survival was associated with low mitotic index, T 1 tumors and absence of peritumorallymphatic permeation. However, only these two parameters had statistical significance and were found to have predictive value on the prognosis of the disease. The degree of differentiation assessed according to Bloom and Richardson's classification showed no influence on prognosis. Post surgical radiotherapy did not seem to influence the outcome of the disease.

Material and Methods Introduction Male carcinoma of the breast is an uncommon disease6,7, 11, 12, 16, 17 representing only 1% of the number of female mammary carcinomas and accounting for 1 % of all malignancies found in men 7,23. The disease shows morphological and clinical similarities to the female breast carcinoma, but it predominates in older age groups and presents a worse prognosis5- 8, 11, 12, 14, 16, 17,23. Several studies have been carried out to find prognostic markers of mammary carcinoma, most of them concerning female neoplasia 2o • It is well established in the female sex that lymph node involvement, tumor size as measured in surgical specimens and histopathologic classification are the three major prognostic parameters for assessing the outcome of the disease 2,3, 10, 13, 19,20. The present study attempts to identify prognostic information of some pathologic factors in a series of 44 consecutive male breast carcinoma. © 1990 by Gustav Fischer Verlag, Stuttgart

Between 1970 and 1984, a series of44 male patients with breaSt carcinoma was treated in the Portuguese Cancer Institute (Centro de Lisboa). The prognosis of the disease was evaluated using several pathological factors. The clinical records were reviewed for age, presenting symptoms, duration and stage of the disease, therapeutic modalities and follow-up. Thirty-nine patients underwent surgery (radical mastectomy) and 24 of them received complementary radiotherapy; two were also treated with chemotherapy (Table 1). Four patients were treated with radiotherapy associated with chemotherapy only; one patient refused to receive any treatment (Table 1). The size of the tumors was measured in surgical specimens and classified accordingly into three groups: T 1 < 2 cm; 5 cm > T 2 > 2 cm; T3 > 5 cm. The axillary lymph node involvement was evaluated from the surgical specimens in 20 patients. The average number of nodes studied was 3.2 (range: 1 to 9). Two groups were considered: NO-free of lymph node metastases; N I-metastases in regional (axillary) lymph nodes. 0344-0338/90/0186-0745$3.50/0

746 . F. Cunha, S. Andre and J. Soares 20,...--------------------,

Table 1. Type of treatment Treatment

No of patients

S S+R

13 24 2 4

S+R+C R+C N Total

1

15

10

44

S = Surgery; R = Radiotherapy; C = Chemotherapy; N = No treatment.

The slides available from every case were reviewed. New sections were made whenever needed. The type of the tumor growth was classified as infiltrative and expansive. The WHO classification was used for the histological type of tumor 15 . The tumor grading was scored according to Bloom and Richardson's criteria (4) and assessed by two of us (FC, SA). The number of mitotic cells was evaluated in 10 HPF. Lymphatic involvement and venous invasion was searched for around the primary tumor. Follow-up information was obtained in all the cases. Results were expressed in percentages or in mean +/- standard deviation. Actuarial survival curves were compared by the Breslow method and differences between curves were tested with the Mantel-Haemel test. Differences were considered as significant at 5% level. For evaluating the influence of the mitotic index the patients were arbitrarily divided into two groups: low mitotic index « 5 mitosis) and high mitotic index (> 5 mitosis) and the respective survival curves were compared.

Results A series of 44 consecutive male breast carcinoma was studied during a 15 year period from 1970. The age of the patients ranged from 38 to 84 years (mean 62 ± 10.8 years) (Fig. 1). All the patients presented a palpable nodule. Other symptoms were: nipple retraction in 13 cases (29.4%), skin ulceration in 12 cases (27.2%) and nipple discharge in 6 cases (13.6%). The duration of the symptoms had varied from one week to 20 years. According to TNM classification we found, for the dimensions of the tumor, Tx (n = 1), T 1 (n = 18), T2 (n = 20) and T 3 (n = 5); for the axillary lymph node metastases Nx (n = 4), NO (N = 18); and N1 (n = 22) and for distant metastases Mx (n = 6), M 0 (n = 29) and M 1 (n = 9) (Table 2). The majority of the patients was classified as stage 1(15 cases - 34.0%) and stage II (15 cases - 34.0%). Four patients were included in stage III and nine in stage IV. One patient was unclassified (Tx NOM 0). All the tumors were histologically classified as infiltrating ductal type (42 as common pattern NOS, 1 as predominant intraductal and 1 as mucoid). Twenty-nine tumors (65.9%) showed pushing type of growth and the remaining 15 (34.1 %) had infiltrating margins.

5

o~---

20-30 30-40 40-50 50-60 60-70

70-80 80-90

Fig. 1. Age distribution.

100..------------------------,

80

60

40

n=44

20

Ol.--'-_L----'---_-'---------'--_-'----'-_...L.---l._--L------'_-'----'

o

2

3

4

5

6

7

8

9

10

II

12 13 years

Fig. 2. % Cumulative survival.

n=18

n=20

20

OL----'---_-'---------'--_-'----'-_...L---l._--'--------'-_.....L------'_-'----'

o

2

3

4

-TI

5

6

7

-+-T2

8

9

10

II

12 13 years

---*-T3

(p=0.04-TlvsT2 and p=0.021-TlvsT2/T3)

Fig. 3. Survival curves ofT 1, T 2 and T 3 tumors. One tumor was Tx.

Male Breast Carcinoma· 747 The mitotic index of the neoplasia varied from 1 to 21 mitoses per 10 HPF (Table 2). Twenty three patients were scored as grade I according to Bloom and Richardson's criteria and the remaining 20 cases as grade II. Twentyeight (63.6%) had peritumoral lymphatic invasion and seven cases (15.9%) had peritumoral venous invasion. Seven out of the 20 patients that underwent axillary lymphadenectomy had metastases (2 to 3 nodes). The patients were followed during a period of 1 month to 13 years, or until death. Thirty-one patients died because of metastatic spread of the disease and 11 are alive and well.

The overall survival was 25% at ten years. The actuarial survival curve of the tumor collective is shown in Fig. 2. Survival curves were calculated for several parameters. The cumulative survival curves for the groups with T 1, T 2 and T 3 carcinoma are shown in Fig. 3. Differences were found between T 1 and T 2 groups and between T 1 and T 2-T 3 taken together. A better prognosis of the group of tumors measuring 2 cm or less has statistical significance in comparison with T 2 tumors (p = 0.04) and T 2-T 3 tumors taken together (p = 0.021). We did not compare T 2 with T 3 groups

Table 2. Summary of the histomorphological parameters No

T

1 2 3 4 5 6 7 8 9 10

2 2 3 2 2 3 1 2 1 1 3 1 2 2 2 2 1 2 2 2 1 1 1 1 2 2 1 1 2 1 2 1 2 3 1 ? 1 1 3 2 2 1 2 1

11

12

13 14

15 16 17 18 19 20 21

22

23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44

N

M

Tumor Type

B&R

Venous Invasion

Lymphatic Invasion

d. d. d. d. d. d. d. d. d. d. dpi. d. d. d. d. d. d. d. d. d. d. d. d. d. d. d. d. d. d. d. d. d. d. d. d. d. d. d. m. d. d. d. d. d.

I

1 1 ? 0 1 1 0 1 0 1 1 0 0 0 1 1 1 0 0 0 ? 1 0 0 1 1 1 1 0 1 1 0 0 1 1 0 0 1 0 1 0

0 ? ? 0 0 1 0 ? 0 0 0 0 1 1 0 ? 0 1 1 ? 0 0 0 1 0 0 0 1 1 0 0 1 0 0 0 ? 0 0 0 0 0 0 0 0

n y n n n n n n n n n n n n n n n y y

y y y y y y y y y n y n y y y n n

Y

Y

Y

Y Y

I II I I

I I I I

II

I I I

II

I

II I I I II II II

I

II II II

I

II II

I

II II II II II

I I

I II I II

I

II

n n n n n n n y

n n y n n n n n n n n n n n n

Y

y

n n n n y n n

y y n y y n y y n n n y n y y

Mitosis (10 HPF) 3 7

14

10 3 4 4 1 1 2 2 1 4 6 4 3 1 2 2 3 6 1 4 1 3 2 1 11

18 3 6 3 4 21 1 2 6 6 1 13

10 12 1 5

Borders pus inf pus pus pus inf pus pus pus pus inf pus inf pus pus pus pus pus inf inf inf pus pus pus pus pus pus inf pus inf pus inf inf pus pus pus pus pus inf pus inf pus inf inf

B & R = Bloom and Richardson classification; d. = Infiltrating ductal carcinoma; dpi = Infiltrating ductal carcinoma with a predominant intraduct component; m. = mucinous carcinoma; pus = pushing border; inf = Infiltrating border.

748 . F. Cunha, S. Andre and J. Soares

because only five cases were included III the latter group. Figure 4 shows the survival curves of two groups of tumors: with pushing and infiltrating type of growth. The curves almost overlap and the p value is 0.987. In Fig. 5 we compared the survival of the patients with grade I and grade II tumors scored according to Bloom and Richardson's classification. The p value obtained by comparing the curves was 0.349. The evaluation of the mitotic index arbitrarily considered two groups « 5 and > 5 mitosis per 10 HPF). Its influence on survival showed (Fig. 6) difference between the groups although not statistically significant (p = 0.079). In Fig. 7 we compared the survival curves of the tumors with and without peritumoral lymphatic permeation. The difference obtained has statistical significance for a p value of 0.019. The influence of postsurgery radiotherapy as complementary treatment was evaluated by comparing the survival curves of the patients receiving radiotherapy in relation to the ones that were treated with surgery only. As shown in Fig. 8 no statistical difference was found (p = 0.509). We also compared the survival curves of the group of patients receiving radiotherapy following surgery or as single treatment and the group of patients not submitted to radiotherapy. The curves were rather coincident and the p value was 0.913.

100+--------------------,

60

60

40

n=29

n=15 20

O'-----'--"'----'----'----'---'----'----'---'-----'------''---L--'

o

2

3

-

(p=0.967)

4

5

6

Pushing margins

7

6

9

10

11

--I- infiltrating margins

12 13 years

Fig. 4. Survival curves of the groups of tumors with pushing and infiltrating margins.

n=20 40

n=23

20

Discussion Male breast neoplasia is an uncommon tumor and information concerning its prognosis is scarce. We studied clinical and pathological features of a series of 44 consecutive cases with special emphasis on the influence on survival of several parameters. The mean age of the patients was 62 years, similar to that of most of the published series6, 7, 17. All but Pannettiere's study18 confirm that male breast carcinoma is an old age pathology. The discrepancy in Pannettiere's work can be explained by the fact that it deals with a military hospital-based series. The presenting symptoms of our patients agree with other published series23 • A painless mass was the first noticeable symptom but nipple retraction and nipple discharge were also quite common. The latter complaint is believed to be a very important manifestation of malignancy in men for it is much more frequently associated with breast cancer than in women. Like Trevers et aPl we found a great variability in the duration of the symptoms. A longer duration of the complaints, namely the presence of breast lumps, may eventually be related to a preexistent gynaecomastia23 • However, we did not find this association in our material. All cases of this series were classified as ductal carcinoma. Although every histological type of carcinoma may occur in the male breast, it is generally agreed that "lobular-type" carcinoma or small cell type of carcinoma are exceedingly rare ll ,21.

O'---L-"'----'----'----'---'----'----'---'-_---'---_'---L--'

o

(p=0.349)

2

3

-

4

5

Grade I

6

7

6

9

--I- Grade II

10

II

12 13 years

Fig. 5. Survival curves of the group of tumors classified as Grade I and II (Bloom and Richardson's classification). The case classified as mucinous carcinoma was not included in these groups.

40

n=30

n=14

20

O'-----L_.L----'--_.L---L_...L----'-_--'----'_---'------'_---'------' o 2 3 4 5 6 7 6 9 10 II 12 13 (p=0.079)

-

< 5 mitosis

--I-

> 5 mitosis

year.

Fig. 6. Survival curves of the groups of tumors showing high mitotic index (> 5 mitoses per 10 HPF) and low mitotic index (~ 5 mitoses per 10 HPF).

Male Breast Carcinoma· 749 1001<---------------'----------,

60 n=16 60

40

20

OL.----'---'-------'----'-------'----'-------'---'-------'----'------'---'-------'

o

2

3

(p=O.019)

4

5

6

-

Without

7

8

--+-

With

9

10

11

12 13 years

Fig. 7. Survival curves of the group of tumors with and without lymphatic permeation.

100.._-----------------------, S+R (n=26) S (n=13)

60

R (n=30) NR (n=14)

60

40

20

OL.----'-_-'-------'--_-'-------'--_-'-------'-_-'-------'-_--'----'-_....L----J

o

2

3

-

4

S

+

5

R

6

--+-

S

7

6

-- R

9

--e-

10

II

12 13 years

NR

(p=O.509-SvsS+R and p=O.913-RvsNR)

Fig. 8. Survival curves of the groups of patients that received surgical treatment (S), surgery with radiotherapy (S + R), all patients that received radiotherapy (R) and all not treated by radiotherapy (NR).

Table 3. Five year survival: comparison between series Series

Year

%

Wainwright Treves Moss Keddie Stepheesee Classen Norris Donegan Pannettiere Present series

1927 1955 1964 1967 1969 1970 1972 1973 1974 1989

19 29.1 41 15 30 80 55

33.3

65.6 49.1

The overallS and 10 year survivals of the cases studied are similar to those reported by Crichlow7 and Norris 17 in the last two decades and are an improvement in relation to previous reports 21 ,22 (Table 3). This probably reflects a better knowledge of the biological behavior of the neoplasia and the adoption of standardized protocols of treatment 1• Concerning the potential influence of the following parameters on survival: type of growth, grade of differentiation, mitotic index, lymphatic invasion and dimensions of the tumor, all but the last two morphological markers showed no statistically significant differences. With regard to the tumor size, we found a better survival in the group of T 1 tumors in comparison to the groups of T 2 and T 3 tumors, the curves of the latter being almost coincident. This confirms other views stating that tumor dimension is a fairly important prognostic factor in breast carcinoma 12,17. However, no difference was found between T 2 and T 3 groups, contrary to what is usually reported in female breast carcinoma 3 • The anatomical difference related to the size of the gland may explain such discrepancy. As demonstrated in Fig. 4, there is a marked similarity between the survival curves of the patients with tumors presenting pushing margins vs. the ones having infiltrating limits. As Donegan 8 previously showed, the type of tumor growth in male breast neoplasia does not seem to influence the prognosis of the neoplasia. The same conclusion was found concerning the usefulness of Bloom and Richardson's grading system 4• Nowadays it is believed that this "traditional" histomorphological grading system is too subjective and inaccurate for prognostication in the individual patient9 . Our results are in accordance with Wolff's conclusions 23 and contradict Crichlow7 and Licchtyl6, who proposed that tumor grade is an important factor to predict the outcome of the disease. A better survival was observed in the group of tumors presenting a low mitotic index. However, its difference from the high mitotic index group had no statistical significance. In this respect, as expected, it fits well with the results obtained using the Bloom and Richardson's grading system since the mitotic counting is included in the scoring evaluation. Many authors claim that the main prognostic factor in male breast cancer is the axillary node neoplastic involvement 6, 14, 17,21. Due to the fact that axillary lymphadenectomy was performed in less than half of our patients, the presence of nodal metastases was accurately evaluated by microscopic documentation in only 20 patients of the present series. This number of cases does not allow definite conclusions concerning the influence of nodal positivity on survival. However, this influence may indirectly be suggested by the fact that seven out of twenty patients submitted to lymphadenectomy and showing nodal metastases died of the disease. The statistically significant difference in survival between the group with neoplastic permeation of lymphatic vessels and the one without lymphatic involvement also points to the importance of the nodal deposits in the outcome of the disease. In the majority of our patients (88.6%) radical mastectomy was the primary treatment. Complementary thera-

750 . F. Cunha, S. Andre and J. Soares

peutic modalities remain controversial in male breast cancer 23 • Donegan 8 advocates irradiation following radical surgery as an effective local therapeutic agent. The analysis of the survival of the group receiving post surgical radiotherapy in relation to the group treated with surgery only did not show any difference. However, no definite conclusions can be established as the series is too small and radiotherapy was used only in cases with locally advanced and disseminated disease.

References 1 Adami HO, Holmberg L, Malker B, Ries L (1985) Long-term survival in 406 males with breast cancer. Br J Cancer 52: 99-103 2 Alderson MR, Hamlin I, Staunton MD (1971) The relative significance of prognostic factors in breast carcinoma. Br J Cancer 25:646-656 3 Azzopardi JG (1979) Problems in Breast Pathology. James L. Bennington (Ed.) W. S. Saunders Company, London-Philadelphia-Toronto 4 Bloom HJC, Richardson WW (1957) Histological grading and prognosis in breast cancer. A study of 1409 cases of which 359 have been followed for 15 years. Br J Cancer 11: 359-377 5 Cortese AT, Cornell GN (1971) Carcinoma of the male breast. Ann Surg 173: 275-280 6 Crichlow RW (1972) Carcinoma of the male breast. Collective review. Surg Gynecol-Obstret 134: 1011-1019 7 Crichlow RW, Faplan EL, Fearney WH (1972) Male mammary cancer: an analysis of 32 cases. Ann Surg 175: 489-494 8 Donegan WL, Perez-Mesa CM (1973) Carcinoma of the male breast. A 30 year review of 28 cases. Arch Surg 106: 273-279

9 Fallenius A (1986) DNA content and prognosis in breast cancer. Ed. Fallenius A. (PhD Thesis), Stockholm 10 Fisher B, Slack NH, Bross IDJ (1969) Cancer of breast: size of neoplasm and prognosis. Cancer 24: 1071-1080 11 Giffler RF, Fay S (1976) Small cell carcinoma of the mammary gland. A tumor ressembling infiltrating lobular carcinoma. Am J Clin Pathol 66: 715-722 12 Haagensen CD (1971) Diseases of the Breast, WB Saunders Co, Philadelphia, pp. 779-792 13 HaybittleJL, Blamey RW, Elston CW,JohnsonJ, Doyte PJ, Cambell FC, Nicholson RI, Griffiths K (1982) A prognostic index in primary breast cancer. Br J Cancer 45: 361-366 14 Heller KS, Rosen PP, Schottenfeld D, Ashifari R, Kinne DW (1978) Male breast cancer: a clinico-pathologic study of 97 cases. Ann Surg 188: 60-65 15 Histological typing of breast tumors (1982) International Histological Classification of Tumors No 2, 2nd ed., World Health Organization, Geneva 16 Liechty RD, Davis J, Cleysteen J (1969) Cancer of the male breast. Forty cases. Cancer 20: 1617-1624 17 Norris HY, Taylor HB (1969) Carcinoma of the male breast. Cancer 23: 1428-1435 18 Pannettiere FY (1974) Cancer ofthe male breast. Cancer 34: 1324-1327 19 Silverberg SC, Chitale AR (1973) Assessment of significance of proportions of intraductal and infiltrating tumor growth in ductal carcinoma of the breast. Cancer 32: 830-837 20 Sobrinho-Simoes MA, Brandao A, Sousa Le F, Giesteira de Almeida A (1985) Prognostic significance of some pathologic factors in breast carcinoma. Path Res Pract 180: 185-191 211 Treves N, Holleb AI (1955) Cancer of the male breast. A report of 146 cases. Cancer 8: 1239-1250 22 Wainwright JM (1927) Carcinoma of the male breast. Arch Surg 14: 836-859 23 Wolff M, Reims MS (1981) Breast cancer in the male: clinic-pathological study of 40 patients. In: Fenoglio C, Wolff M (Eds.) Prog Surg Pathol3: 77-107

Received November 22, 1989 . Accepted in revised form January 30, 1990

Key words: Male breast cancer - Mammary carcinoma - Tumor prognosis - Ductal carcinoma - Mitotic index Dr. Jorge Soares, Servi~o de Patologia Morfol6gica, Instituto Portugues de Oncologia, Rua Prof Lima Bastos, 1093 Lisboa Codex, Portugal