Male breast cancer

Background

This is very rare, unlike its female counterpart. It is usually a disease of the elderly. Detailed epidemiologic studies are few but there is a general impression that it is an aggressive disease compared to female breast cancer, secondary to lesser amount of breast tissue in the male breast. However, when these tumors are compared to female tumors of similar size, grade, and lymph nodes, the prognosis is similar. It may ulcerate the overlying skin and invade the chest wall. If metastasis occurs, it generally follows the same patterns as female breast cancer. About 50% of the time, there is metastasis to regional lymph nodes at the time of initial diagnosis. About 70% of these tumors are positive for estrogen and progesterone receptors. Paget's disease of the nipple is more common in men than in women, usually presenting with an underlying mass and axillary lymph node metastasis.

Mutations within the BRCA2 gene are associated with an increased breast cancer risk. Klinefelter's syndrome is also a risk factor, just as it is for gynecomastia.

OUTLINE

Epidemiology

Disease Associations

Pathogenesis

Laboratory/Radiologic/
Other Diagnostic Testing

Gross Appearance and Clinical Variants

Histopathological Features and Variants

Special Stains/
Immunohistochemistry/
Electron Microscopy

Differential Diagnosis

Prognosis

Treatment

Commonly Used Terms

Internet Links

EPIDEMIOLOGY CHARACTERIZATION

Risk factors for male breast cancer--a case-control study from Scandinavia.

Ewertz M, Holmberg L, Tretli S, Pedersen BV, Kristensen A.

Danish Cancer Society, Division for Cancer Epidemiology, Copenhagen, Denmark.

Acta Oncol 2001;40(4):467-71 Abstract quote

We report a population-based case-control study on risk factors for male breast cancer. Data on a broad range of previously suggested risk factors were collected in a set of Scandinavian breast cancer cases and matched controls.

Incident cases (n = 282) with histologically verified carcinomas of the breast were identified from notification to the cancer registries of Denmark, Norway and Sweden over a 4-year period 1987-1991 and of these cases, 156 men could be approached and responded.

Controls were identified through national central population registers and were matched individually for country, sex and year of birth. Controls with a diagnosis of breast cancer were excluded; 468 of 780 controls responded. Data on risk factors were collected by self-administered questionnaires mailed to the cases between land 2 years after diagnosis and to controls during the same period.

The findings were compatible with an increased risk associated with family history of breast cancer (odds ratio (OR) = 3.3, 95% confidence interval (CI) 2.0-5.6), obesity 10 years before diagnosis (OR = 2.1, 95% CI 1.0-4.5) for BMI > 30, diabetes (OR = 2.6, 95% CI 1.3-5.3) and the use of digoxin and methyldopa (OR = 2.0 and 2.1, respectively).

The association with family history of breast cancer has been repeated in several studies, while the relation to anthropometric measures has been equivocal. We could not substantiate some associations seen in other studies; namely those with high education, fertility, marital status, testicular injury, liver disease and religion. The detailed questions about gynaecomastia indicated that many cases reported signs of breast cancer as a gynaecomastia. This type of misunderstanding may explain the strong association with gynaecomastia seen in other studies. Several patients died before contact.

Thus, risk factors related to a more aggressive male breast cancer or related to high risk of dying (e.g. liver cirrhosis, heavy smoking) may have been missed.

DISEASE ASSOCIATIONS CHARACTERIZATION

PITUITARY ADENOMA

t Pituitary prolactin-secreting macroadenoma combined with bilateral breast cancer in a 45-year-old male.

Forloni F, Giovilli M, Pecis C, Bortolani E, Preziosi A, Barzaghi ME, Corti D, Beck-Peccoz P.

Department of Medicine, Treviglio/Caravaggio Hospital, Italy.

J Endocrinol Invest 2001 Jun;24(6):454-9 Abstract quote

We describe an unusual case of bilateral breast cancer synchronous with pituitary macroprolactinoma in a young male. Up to date, only very few of such cases have been described worldwide and to our knowledge this is the first one in which both breast cancer and pituitary macroadenoma have been found together at the time of presentation.

A 45-year-old male was diagnosed as having a pituitary macroprolactinoma and bilateral breast cancer on the basis of hypogonadism (testosterone 2.9 pmol/l) with very high levels of prolactin (33,100 U/l), typical neuroradiologic finding of a pituitary macroadenoma, marked bilateral gynecomastia with mammographic pattern highly suspected for cancer and subsequent hystological confirmation. Bilateral mastectomy was performed and medical therapy with bromocriptine 10 mg/day was started. After 2-year follow-up the patient is disease-free. Hormonal, neuroradiological and oncological patterns are all negative or markedly improved.

We stress the importance of prolactin for its possible biological effects on breast cancer induction or growth. Moreover in any case of hyperprolactinemia we suggest a mammographic examination and, in the case of breast cancer, at least a baseline hormonal profile.

PATHOGENESIS CHARACTERIZATION

BRCA1 AND BRCA2

Mutation analysis of BRCA1 and BRCA2 in a male breast cancer population.

Friedman LS, Gayther SA, Kurosaki T, Gordon D, Noble B, Casey G, Ponder BA, Anton-Culver H.

CRC Human Cancer Genetics Research Group, Addenbroke's Hospital, University of Cambridge, United Kingdom.

Am J Hum Genet 1997 Feb;60(2):313-9 Abstract quote

A population-based series of 54 male breast cancer cases from Southern California were analyzed for germ-line mutations in the inherited breast/ovarian cancer genes,

BRCA1 and BRCA2. Nine (17%) of the patients had a family history of breast and/or ovarian cancer in at least one first-degree relative. A further seven (13%) of the patients reported breast/ovarian cancer in at least one second-degree relative and in no first-degree relatives. No germ-line BRCA1 mutations were found. Two male breast cancer patients (4% of the total) were found to carry novel truncating mutations in the BRCA2 gene.

Only one of the two male breast cancer patients carrying a BRCA2 mutation had a family history of cancer, with one case of ovarian cancer in a first-degree relative. The remaining eight cases (89%) of male breast cancer with a family history of breast/ovarian cancer in first-degree relatives remain unaccounted for by mutations in either the BRCA1 gene or the BRCA2 gene.

High frequency of germ-line BRCA2 mutations among Hungarian male breast cancer patients without family history.

Csokay B, Udvarhelyi N, Sulyok Z, Besznyak I, Ramus S, Ponder B, Olah E.

Department of Molecular Biology, National Institute of Oncology, Budapest, Hungary.

Cancer Res 1999 Mar 1;59(5):995-8 Abstract quote

To determine the contribution of BRCA1 and BRCA2 mutations to the pathogenesis of male breast cancer in Hungary, the country with the highest male breast cancer mortality rates in continental Europe, a series of 18 male breast cancer patients and three patients with gynecomastia was analyzed for germ-line mutations in both BRCA1 and BRCA2.

Although no germ-line BRCA1 mutation was observed, 6 of the 18 male breast cancer cases (33%) carried truncating mutations in the BRCA2 gene. Unexpectedly, none of them reported a family history for breast/ovarian cancer. Four of six truncating mutations were novel, and two mutations were recurrent. Four patients (22%) had a family history of breast/ovarian cancer in at least one first- or second-degree relative; however, no BRCA2 mutation was identified among them. No mutation was identified in either of the genes in the gynecomastias.

These results provide evidence for a strong genetic component of male breast cancer in Hungary.

Mutation analysis of BRCA1 and BRCA2 in Turkish cancer families: a novel mutation BRCA2 3414del4 found in male breast cancer.

Balci A, Huusko P, Paakkonen K, Launonen V, Uner A, Ekmekci A, Winqvist R.

Department of Medical Biology and Genetics, Faculty of Medicine, Gazi University, Ankara, Turkey.

Eur J Cancer 1999 May;35(5):707-10 Abstract quote

Since the identification of the BRCA1 and BRCA2 breast-ovarian cancer susceptibility genes, mutation analyses have been carried out in different populations.

Here we screened 15 Turkish breast and breast-ovarian cancer families for mutations in both genes by conformation-sensitive gel electrophoresis (CSGE) and the protein truncation test (PTT), followed by DNA sequencing. Three families included a male breast cancer case, one without family history. Three germline mutations were identified, two in BRCA1 and one in BRCA2. The two BRCA1 mutations, 5382insC and 5622C-->T, were found in breast-ovarian cancer families.

The BRCA2 3414delTCAG is a novel mutation detected in a site-specific breast cancer family that included 1 case of male breast cancer. These first results of Turkish families show that the frequency of germline BRCA1 or BRCA2 mutations appears to be high in families with at least 3 breast and/or ovarian cancer cases.

CHROMOSOMAL ABNORMALITIES

Chromosome banding analysis of gynecomastias and breast carcinomas in men.

Teixeira MR, Pandis N, Dietrich CU, Reed W, Andersen J, Qvist H, Heim S.

Department of Genetics, The Norwegian Radium Hospital and Institute for Cancer Research, Oslo.

Genes Chromosomes Cancer 1998 Sep;23(1):16-20 Abstract quote

Male breast cancer is 100 times less frequent than its female counterpart and accounts for less than 1% of all cancers in men. Although men with breast cancer also often have gynecomastia, it is still unknown whether gynecomastia per se predisposes the male breast to malignant disease.

We describe the cytogenetic analysis of three gynecomastias and four breast cancers in men. No chromosome abnormalities were detected in two cases of gynecomastia, with no other concomitant breast disease. The third gynecomastia sample, taken from a site where a breast carcinoma had previously been removed, had a t(2;11)(p24;p13) as the sole chromosome change; this is the first time that an abnormal karyotype has been described in gynecomastia. All four cancers had clonal chromosome abnormalities. Several cytogenetically unrelated clones were found in the breast tumor and in a metastasis from case 1. In the carcinoma of case 2, a single abnormal clone was found, characterized by loss of the Y chromosome, monosomy 17, and a deletion of the long arm of chromosome 18. In the carcinoma of case 3, a clone with loss of the Y chromosome as the sole change dominated, accompanied by the gain of an X chromosome in a subclone. In the lymph node metastasis examined from case 4, a single clone carrying trisomies for chromosomes 5 and 16 was detected.

Our findings, especially when collated with data on the six karyotypically abnormal breast carcinomas in men described previously, indicate that gain of the X chromosome, gain of chromosome 5, loss of the Y chromosome, loss of chromosome 17, and del(18)(q21) are nonrandom abnormalities in male breast carcinomas.

ERBB2

Evaluation of ERBB2 Gene Status and Chromosome 17 Anomalies in Male Breast Cancer.

Fonseca RR,
Tomas AR,
Andre S,
Soares J.

Servico de Anatomia Patologica, Instituto Portugues de Oncologia de Lisboa de Francisco Gentil E.P.E., Portugal.

Am J Surg Pathol. 2006 Oct;30(10):1292-8 Abstract quote

Male breast cancer (MBC) is an uncommon neoplasm that shares several biologic characteristics with its female counterpart. In the latter, abnormalities in the expression and/or copy number of the ERBB2 gene are present in 10% to 30% of invasive carcinoma and behave as poor prognostic markers. ERBB2 abnormalities have also been reported in MBC, yet at lower frequency, but their prognostic significance remains controversial. Furthermore, no study has addressed the impact of chromosome 17 abnormalities in MBC survival. In this study, the ERBB2-gene status (overexpression and amplification) and chromosome 17 numerical abnormalities were investigated in a series of 50 archival cases of MBC.

The results, together with patient's age, histologic grade, pathologic stage, and estrogen receptor status were correlated with overall survival. ERBB2-protein overexpression was present in 7 cases (14%), ERBB2-gene amplification in 4 (8%), and aneuploidy of chromosome 17 in 12 cases (33.3%). The pathologic stage, ERBB2 overexpression and ERBB2 amplification were significantly correlated with overall survival (P=0.002, 0.016, and 0.009, respectively). No correlation was observed between chromosome 17 aneuploidy and overall survival.

Therefore, despite their low incidence in MBC, expression abnormalities of ERBB2 behave, together with the pathologic stage of the tumor, as predictors of overall survival, akin to what has been reported for its female counterpart.

GROSS APPEARANCE/
CLINICAL VARIANTS CHARACTERIZATION

General Histopathology is similar to female breast

VARIANTS

COLLISION TUMOR

Metastatic Prostatic Adenocarcinoma Within a Primary Solid Papillary Carcinoma of the Male Breast Application of Immunohistochemisty to a Unique Collision Tumor

Sunati Sahoo, MD, Roberta E. Smith, DO, Joseph L. Potz, MD, and Paul P. Rosen, MD

From the Department of Pathology, New York Presbyterian Hospital, Weill Medical College, New York, NY (Drs Sahoo and Rosen); the Department of Pathology, Holy Redeemer Hospital and Medical Center, Meadowbrook, Pa (Dr Smith); and Abington Hematology Oncology Associates, Inc, Abington, Pa (Dr Potz).

Arch Pathol Lab Med 2001;125:1101�1103. Abstract quote

We report the case of a 78-year-old man who developed a breast mass 12 months after hormonal therapy for palliation of prostatic adenocarcinoma.

On histologic and immunohistochemical examination, the breast tumor revealed a unique collision tumor composed of metastatic prostatic adenocarcinoma and solid papillary breast carcinoma.

HISTOPATHOLOGY CHARACTERIZATION

GENERAL Similar to female breast cancer histopathology

SPECIAL STAINS/
IMMUNOHISTO-CHEMISTRY CHARACTERIZATION

PSA

Immunohistochemical localization of prostate-specific antigen in ductal epithelium of male breast. Potential diagnostic pitfall in patients with gynecomastia.

Gatalica Z, Norris BA, Kovatich AJ.

Division of Surgical Pathology, John Sealy Hospital, University of Texas Medical Branch, Galveston 77555-0588, USA.

Appl Immunohistochem Mol Morphol 2000 Jun;8(2):158-61 Abstract quote

Enlargement of the male breast is frequently encountered in the course of adjuvant antiandrogen therapy for advanced prostate carcinoma. The clinical differential diagnosis in this setting includes hormonal imbalance-induced gynecomastia, primary breast carcinoma, and metastasis of prostatic carcinoma. Biopsy of the lesion with the identification of prostate-specific antigen (PSA) plays an important role in establishing the correct diagnosis. Recent studies showed that female mammary epithelium may be a significant source of PSA, but its expression in male breasts has not been sufficiently studied.

We found that normal and hyperplastic duct epithelium in gynecomastia exhibited focal, strong (+3) PSA immunoreactivity in 5 of 18 cases (28%). In contrast, no PSA reactivity was found in eight cases of male breast carcinoma. No reactivity was seen with antiprostatic acid phosphatase (PsAP) antibody, in either benign or malignant epithelium.

Frequent expression of PSA in gynecomastia may, in an appropriate clinical setting, cause confusion with metastatic prostatic carcinoma. The lack of immunoreactivity for PsAP in male breast epithelium indicates its usefulness in the differential diagnosis.

DIFFERENTIAL DIAGNOSIS CHARACTERIZATION

MERKEL CELL CARCINOMA

Primary male neuroendocrine adenocarcinoma involving the nipple simulating Merkel cell carcinoma – a diagnostic pitfall

Mecca P, Busam K.

J Cutan Pathol 2008; 35: 207–211. Abstract quote

Male breast cancer is a rare entity accounting for < 1% of all breast cancer cases in the United States, but with a rate that has been rising over the last 25 years. Nipple skin/subcutaneous tumors in men are even rarer. Likewise, true neuroendocrine carcinoma of the breast, defined as > 50% of tumor cells staining for either chromogranin or synaptophysin, is not a common entity, usually occurring in older women.

We present the case of a 70-year-old man with a slowly growing nipple mass that had enlarged over the previous 1.5 years. The histology consisted of nests, trabeculae and sheets of basaloid cells with rare abortive gland formation and a pushing edge. The case was originally misdiagnosed as a Merkel cell carcinoma, based largely on histologic morphology. Strong staining for synaptophysin (in greater than 50% of cells), CD56, keratins AE1 : AE3 and Cam 5.2, as well as estrogen receptor and progesterone receptor was noted. Myoepithelial cells within in situ areas were identified using stains for calponin and 4A4, supporting a primary mammary duct origin. Additionally, a substantial portion of cells stained for Gross Cystic Disease Fluid Protein-15 (GCDFP-15), confirming some overlap with sweat duct differentiation.

To the best of our knowledge, although reported in the male breast, no case of primary nipple neuroendocrine carcinoma in a male patient has been reported in the literature. The gender of the patient and association with the skin of the chest wall probably contributed to the original misdiagnosis of Merkel cell carcinoma in this patient.

TREATMENT AND PROGNOSIS CHARACTERIZATION

PROGNOSIS

GENERAL

Male breast carcinoma: a review of 229 patients who presented to the Princess Margaret Hospital during 40 years: 1955-1996.

Goss PE, Reid C, Pintilie M, Lim R, Miller N.

Department of Medical Oncology and Hematology, The Princess Margaret Hospital, Toronto, Ontario, Canada.

Cancer 1999 Feb 1;85(3):629-39 Abstract quote

BACKGROUND: A single-institution review of clinical presentation, treatment, and outcome of male breast carcinoma was conducted.

METHODS: Data obtained by chart review of 229 cases were analyzed with respect to clinical presentation, treatment choice, significant prognostic factors, and survival. The patients were analyzed both as a single cohort and as four cohorts grouped according to decade of diagnosis.

RESULTS: Presentation occurred at a median age of 63 years, most often with a self-detected lump. Pathology consisted of subtypes similar to those of female breast carcinoma. The majority of tumors were larger than 2 cm in greatest dimension. Lymph node status, hormone receptors, and histologic and nuclear grade were underreported. Primary, adjuvant, and advanced disease treatment practices were reviewed over time. The 5-year disease free survival (DFS), overall survival (OS), and local control were 47%, 53%, and 91%, respectively. No difference in outcome by decade of diagnosis was observed. Negative lymph nodes and adjuvant hormone treatment predicted for better DFS and OS. Younger age and Stage 0 also predicted for better OS.

CONCLUSIONS: Compared with data from female breast carcinoma patients, 5-year OS for this series was low; however, when these patients were separated by lymph node status, survival was similar for those with axillary lymph node metastases. Despite a change in standard primary surgical treatment and an increased use of chemotherapy and hormone therapy over the study period, no difference in outcome was observed among these males. In the absence of prospective, randomized clinical trials, collection of comprehensive data on the presentation and management of male breast carcinoma may help to optimize clinical care.

Male Breast Carcinoma: Correlation of ER, PR, Ki-67, Her2-Neu, and p53 with Treatment and Survival, a Study of 65 Cases.

Wang-Rodriguez J, Cross K, Gallagher S, Djahanban M, Armstrong JM, Wiedner N, Shapiro DH.

Department of Pathology, University of California, San Diego (JWR, NW, KC) and Pathology and Laboratory Medicine Services, VA San Diego Healthcare System (JWR, MD, JA), San Diego, California.
Mod Pathol 2002 Aug;15(8):853-61 Abstract quote
Male breast cancer is rare, and experience of it in any single institution is limited. Our current understanding regarding its biology, natural history, and treatment strategies has been extrapolated from its female counterpart.

The aim of this study is to evaluate the expression patterns of estrogen receptor (ER), progesterone receptor (PR), MiB1 (Ki67), Her-2/neu (c-erbB2), and p53 and to correlate them with the prognosis, presentation, staging, management, and survival/outcome in male breast carcinoma identified through the Veterans Administration nationwide cancer registry. Sixty-five cases of male breast cancer were reviewed for classification. Tumor blocks were requested from each institution for immunohistochemical staining and evaluation of ER, PR, p53, Her2-neu, and MiB1. Seventeen age- and disease-matched male veteran patients with breast gynecomastia were used as controls. Traditional prognostic data were collected for comparison with female breast cancers (i.e., age, lymph node status, clinical staging, tumor size, histological grade, and disease-free and overall survival). Male breast carcinoma had worse disease-free survival than controls (P =.03).

The clinical stage regardless of tumor size or lymph node metastasis was the single most significant prognostic factor (P <.0001). ER-positive patients appeared to have a better survival than did ER-negative patients (P =.03, univariate; P not significant in multivariate) and did not benefit from treatment with tamoxifen (P =.0027, univariate; P =.42, multivariate). MiB1 and PR expressions did not correlate with treatment or survival, and p53 was associated with shorter disease free survival (P =.07, univariate; P =.047, multivariate). Stage for stage, Her2-neu was associated with shorter disease-free survival (P <.0001) and correlated with positive lymph nodes (P =.08). Surgery alone versus surgery with adjuvant treatments (chemotherapy, radiotherapy, tamoxifen, or combination) did not show any survival difference. Adjuvant therapy seemed to be associated with worse outcome.

In the Veterans Administration hospital setting, the clinical stage and the expressions of p53 and Her2-neu in male breast carcinoma may be prognostically useful markers in guiding future treatment in prospective studies, whereas ER, PR, and MiB1 expressions are of limited value.

FAMILY HISTORY

Localized male breast carcinoma and family history. An analysis of 142 patients.

Hill A, Yagmur Y, Tran KN, Bolton JS, Robson M, Borgen PI.

Breast Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

Cancer 1999 Sep 1;86(5):821-5 Abstract quote

BACKGROUND: Male breast carcinoma is rare; therefore, the effect of family history on the course of the disease has not been well described. Germ-line mutations in breast carcinoma susceptibility genes, particularly BRCA2, are associated with an increased risk of male breast carcinoma. The authors sought to correlate significant family history with clinical phenotype in males with breast carcinoma.

METHODS: One hundred forty-two men with breast carcinoma were treated at Memorial Sloan-Kettering Cancer Center or the Ochsner Clinic from 1973 to 1994. The authors reviewed the effect imparted by a family history of breast carcinoma on the duration of symptoms, the age at diagnosis, and the survival of men with this disease.

RESULTS: Fifteen percent of male breast carcinoma patients had a first-degree relative with the disease. Fifty-eight years was the mean age at diagnosis for those with a family history, compared with 61 years for those without (P = not significant [NS]). The mean duration of symptoms was 23 months for those with a family history, compared with 22 months for those without. Three of 22 patients (13.6%) with a family history, compared with 11 of 90 patients (12%) without a family history, had Stage III disease (P = NS) at presentation. The overall 5-year and 10-year survival rates were 86% and 64%. Survival was not affected by family history. Lymph node positivity reduced 5-year and 10-year survival rates to 73% and 50% (P = 0.0004).

CONCLUSIONS: For men with breast carcinoma, the presence of a family history did not affect the age at presentation, the duration of symptoms, the stage of disease at presentation, or the overall survival. In multivariate analysis, the most powerful predictor of outcome for these men was the status of the axillary lymph nodes.

PEPSINOGEN C

Expression of pepsinogen C in gynecomastias and male breast carcinomas.

Serra Diaz C, Vizoso F, Rodriguez JC, Merino AM, Gonzalez LO, Baltasar A, Perez-Vazquez MT, Medrano J.

Servicio de Cirugia General, Hospital Virgen de los Lirios, Poligono de Caramanxel s/n, 03804 Alcoy, Spain.

World J Surg 1999 May;23(5):439-45 Abstract quote

Pepsinogen C is a proteolytic enzyme involved in the digestion of proteins in the stomach; it is also synthesized by a significant percentage of female breast carcinomas. In addition, it has been demonstrated that pepsinogen C is one of the few proteins induced by androgens in breast carcinoma cells.

Here we evaluate the expression of pepsinogen C by immunoperoxidase staining in normal breast tissue from 3 male patients, 15 gynecomastia tissues, 2 male in situ breast carcinomas, and 68 male invasive breast carcinomas. Pepsinogen C immunostaining values were quantified in male breast tumors using the HSCORE system, which considers both the intensity and the percentage of cells staining at each intensity. The results indicated positive immunohistochemical staining for pepsinogen C in all gynecomastia tissues, the two in situ ductal carcinomas, and 52 of 68 invasive breast carcinomas (76.4%).

The three normal breast tissues analyzed showed negative staining for pepsinogen C, whereas invasive tumors showed clear differences among them with regard to the intensity and percentage of staining cells. In addition, pepsinogen C scores were significantly higher in well-differentiated (grade I, 188.7) and moderately differentiated (grade II, 145.8) tumors than in poorly differentiated (grade III, 98.5) tumors (p = 0. 032). Similarly, significant differences in pepsinogen C content were found between estrogen receptor (ER)-positive tumors and ER-negative tumors (158.5 vs. 44.3, respectively; p = 0.009). Patients with pepsinogen C-positive tumors reached longer relapse-free and overall survival periods than did those with tumors with negative staining, but no statistical differences were observed between survival curves calculated for these two groups of patients.

This results demonstrate expression of pepsinogen C by gynecomastias and by a high percentage of male breast carcinomas and may indicate an important role of pepsinogen C in the pathophysiology of male breast diseases.

Macpherson and Pincus. Clinical Diagnosis and Management by Laboratory Methods. Twentyfirst Edition. WB Saunders. 2006.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fifth Edition. Mosby Elesevier 2008

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PATHOGENESIS	CHARACTERIZATION
BRCA1 AND BRCA2
Mutation analysis of BRCA1 and BRCA2 in a male breast cancer population. Friedman LS, Gayther SA, Kurosaki T, Gordon D, Noble B, Casey G, Ponder BA, Anton-Culver H. CRC Human Cancer Genetics Research Group, Addenbroke's Hospital, University of Cambridge, United Kingdom.	Am J Hum Genet 1997 Feb;60(2):313-9 Abstract quote A population-based series of 54 male breast cancer cases from Southern California were analyzed for germ-line mutations in the inherited breast/ovarian cancer genes, BRCA1 and BRCA2. Nine (17%) of the patients had a family history of breast and/or ovarian cancer in at least one first-degree relative. A further seven (13%) of the patients reported breast/ovarian cancer in at least one second-degree relative and in no first-degree relatives. No germ-line BRCA1 mutations were found. Two male breast cancer patients (4% of the total) were found to carry novel truncating mutations in the BRCA2 gene. Only one of the two male breast cancer patients carrying a BRCA2 mutation had a family history of cancer, with one case of ovarian cancer in a first-degree relative. The remaining eight cases (89%) of male breast cancer with a family history of breast/ovarian cancer in first-degree relatives remain unaccounted for by mutations in either the BRCA1 gene or the BRCA2 gene.
High frequency of germ-line BRCA2 mutations among Hungarian male breast cancer patients without family history. Csokay B, Udvarhelyi N, Sulyok Z, Besznyak I, Ramus S, Ponder B, Olah E. Department of Molecular Biology, National Institute of Oncology, Budapest, Hungary.	Cancer Res 1999 Mar 1;59(5):995-8 Abstract quote To determine the contribution of BRCA1 and BRCA2 mutations to the pathogenesis of male breast cancer in Hungary, the country with the highest male breast cancer mortality rates in continental Europe, a series of 18 male breast cancer patients and three patients with gynecomastia was analyzed for germ-line mutations in both BRCA1 and BRCA2. Although no germ-line BRCA1 mutation was observed, 6 of the 18 male breast cancer cases (33%) carried truncating mutations in the BRCA2 gene. Unexpectedly, none of them reported a family history for breast/ovarian cancer. Four of six truncating mutations were novel, and two mutations were recurrent. Four patients (22%) had a family history of breast/ovarian cancer in at least one first- or second-degree relative; however, no BRCA2 mutation was identified among them. No mutation was identified in either of the genes in the gynecomastias. These results provide evidence for a strong genetic component of male breast cancer in Hungary.
Mutation analysis of BRCA1 and BRCA2 in Turkish cancer families: a novel mutation BRCA2 3414del4 found in male breast cancer. Balci A, Huusko P, Paakkonen K, Launonen V, Uner A, Ekmekci A, Winqvist R. Department of Medical Biology and Genetics, Faculty of Medicine, Gazi University, Ankara, Turkey.	Eur J Cancer 1999 May;35(5):707-10 Abstract quote Since the identification of the BRCA1 and BRCA2 breast-ovarian cancer susceptibility genes, mutation analyses have been carried out in different populations. Here we screened 15 Turkish breast and breast-ovarian cancer families for mutations in both genes by conformation-sensitive gel electrophoresis (CSGE) and the protein truncation test (PTT), followed by DNA sequencing. Three families included a male breast cancer case, one without family history. Three germline mutations were identified, two in BRCA1 and one in BRCA2. The two BRCA1 mutations, 5382insC and 5622C-->T, were found in breast-ovarian cancer families. The BRCA2 3414delTCAG is a novel mutation detected in a site-specific breast cancer family that included 1 case of male breast cancer. These first results of Turkish families show that the frequency of germline BRCA1 or BRCA2 mutations appears to be high in families with at least 3 breast and/or ovarian cancer cases.
CHROMOSOMAL ABNORMALITIES
Chromosome banding analysis of gynecomastias and breast carcinomas in men. Teixeira MR, Pandis N, Dietrich CU, Reed W, Andersen J, Qvist H, Heim S. Department of Genetics, The Norwegian Radium Hospital and Institute for Cancer Research, Oslo.	Genes Chromosomes Cancer 1998 Sep;23(1):16-20 Abstract quote Male breast cancer is 100 times less frequent than its female counterpart and accounts for less than 1% of all cancers in men. Although men with breast cancer also often have gynecomastia, it is still unknown whether gynecomastia per se predisposes the male breast to malignant disease. We describe the cytogenetic analysis of three gynecomastias and four breast cancers in men. No chromosome abnormalities were detected in two cases of gynecomastia, with no other concomitant breast disease. The third gynecomastia sample, taken from a site where a breast carcinoma had previously been removed, had a t(2;11)(p24;p13) as the sole chromosome change; this is the first time that an abnormal karyotype has been described in gynecomastia. All four cancers had clonal chromosome abnormalities. Several cytogenetically unrelated clones were found in the breast tumor and in a metastasis from case 1. In the carcinoma of case 2, a single abnormal clone was found, characterized by loss of the Y chromosome, monosomy 17, and a deletion of the long arm of chromosome 18. In the carcinoma of case 3, a clone with loss of the Y chromosome as the sole change dominated, accompanied by the gain of an X chromosome in a subclone. In the lymph node metastasis examined from case 4, a single clone carrying trisomies for chromosomes 5 and 16 was detected. Our findings, especially when collated with data on the six karyotypically abnormal breast carcinomas in men described previously, indicate that gain of the X chromosome, gain of chromosome 5, loss of the Y chromosome, loss of chromosome 17, and del(18)(q21) are nonrandom abnormalities in male breast carcinomas.
ERBB2
Evaluation of ERBB2 Gene Status and Chromosome 17 Anomalies in Male Breast Cancer. Fonseca RR, Tomas AR, Andre S, Soares J. Servico de Anatomia Patologica, Instituto Portugues de Oncologia de Lisboa de Francisco Gentil E.P.E., Portugal.	Am J Surg Pathol. 2006 Oct;30(10):1292-8 Abstract quote Male breast cancer (MBC) is an uncommon neoplasm that shares several biologic characteristics with its female counterpart. In the latter, abnormalities in the expression and/or copy number of the ERBB2 gene are present in 10% to 30% of invasive carcinoma and behave as poor prognostic markers. ERBB2 abnormalities have also been reported in MBC, yet at lower frequency, but their prognostic significance remains controversial. Furthermore, no study has addressed the impact of chromosome 17 abnormalities in MBC survival. In this study, the ERBB2-gene status (overexpression and amplification) and chromosome 17 numerical abnormalities were investigated in a series of 50 archival cases of MBC. The results, together with patient's age, histologic grade, pathologic stage, and estrogen receptor status were correlated with overall survival. ERBB2-protein overexpression was present in 7 cases (14%), ERBB2-gene amplification in 4 (8%), and aneuploidy of chromosome 17 in 12 cases (33.3%). The pathologic stage, ERBB2 overexpression and ERBB2 amplification were significantly correlated with overall survival (P=0.002, 0.016, and 0.009, respectively). No correlation was observed between chromosome 17 aneuploidy and overall survival. Therefore, despite their low incidence in MBC, expression abnormalities of ERBB2 behave, together with the pathologic stage of the tumor, as predictors of overall survival, akin to what has been reported for its female counterpart.

TREATMENT AND PROGNOSIS	CHARACTERIZATION
PROGNOSIS
GENERAL
Male breast carcinoma: a review of 229 patients who presented to the Princess Margaret Hospital during 40 years: 1955-1996. Goss PE, Reid C, Pintilie M, Lim R, Miller N. Department of Medical Oncology and Hematology, The Princess Margaret Hospital, Toronto, Ontario, Canada.	Cancer 1999 Feb 1;85(3):629-39 Abstract quote BACKGROUND: A single-institution review of clinical presentation, treatment, and outcome of male breast carcinoma was conducted. METHODS: Data obtained by chart review of 229 cases were analyzed with respect to clinical presentation, treatment choice, significant prognostic factors, and survival. The patients were analyzed both as a single cohort and as four cohorts grouped according to decade of diagnosis. RESULTS: Presentation occurred at a median age of 63 years, most often with a self-detected lump. Pathology consisted of subtypes similar to those of female breast carcinoma. The majority of tumors were larger than 2 cm in greatest dimension. Lymph node status, hormone receptors, and histologic and nuclear grade were underreported. Primary, adjuvant, and advanced disease treatment practices were reviewed over time. The 5-year disease free survival (DFS), overall survival (OS), and local control were 47%, 53%, and 91%, respectively. No difference in outcome by decade of diagnosis was observed. Negative lymph nodes and adjuvant hormone treatment predicted for better DFS and OS. Younger age and Stage 0 also predicted for better OS. CONCLUSIONS: Compared with data from female breast carcinoma patients, 5-year OS for this series was low; however, when these patients were separated by lymph node status, survival was similar for those with axillary lymph node metastases. Despite a change in standard primary surgical treatment and an increased use of chemotherapy and hormone therapy over the study period, no difference in outcome was observed among these males. In the absence of prospective, randomized clinical trials, collection of comprehensive data on the presentation and management of male breast carcinoma may help to optimize clinical care.
Male Breast Carcinoma: Correlation of ER, PR, Ki-67, Her2-Neu, and p53 with Treatment and Survival, a Study of 65 Cases. Wang-Rodriguez J, Cross K, Gallagher S, Djahanban M, Armstrong JM, Wiedner N, Shapiro DH. Department of Pathology, University of California, San Diego (JWR, NW, KC) and Pathology and Laboratory Medicine Services, VA San Diego Healthcare System (JWR, MD, JA), San Diego, California.	Mod Pathol 2002 Aug;15(8):853-61 Abstract quote Male breast cancer is rare, and experience of it in any single institution is limited. Our current understanding regarding its biology, natural history, and treatment strategies has been extrapolated from its female counterpart. The aim of this study is to evaluate the expression patterns of estrogen receptor (ER), progesterone receptor (PR), MiB1 (Ki67), Her-2/neu (c-erbB2), and p53 and to correlate them with the prognosis, presentation, staging, management, and survival/outcome in male breast carcinoma identified through the Veterans Administration nationwide cancer registry. Sixty-five cases of male breast cancer were reviewed for classification. Tumor blocks were requested from each institution for immunohistochemical staining and evaluation of ER, PR, p53, Her2-neu, and MiB1. Seventeen age- and disease-matched male veteran patients with breast gynecomastia were used as controls. Traditional prognostic data were collected for comparison with female breast cancers (i.e., age, lymph node status, clinical staging, tumor size, histological grade, and disease-free and overall survival). Male breast carcinoma had worse disease-free survival than controls (P =.03). The clinical stage regardless of tumor size or lymph node metastasis was the single most significant prognostic factor (P <.0001). ER-positive patients appeared to have a better survival than did ER-negative patients (P =.03, univariate; P not significant in multivariate) and did not benefit from treatment with tamoxifen (P =.0027, univariate; P =.42, multivariate). MiB1 and PR expressions did not correlate with treatment or survival, and p53 was associated with shorter disease free survival (P =.07, univariate; P =.047, multivariate). Stage for stage, Her2-neu was associated with shorter disease-free survival (P <.0001) and correlated with positive lymph nodes (P =.08). Surgery alone versus surgery with adjuvant treatments (chemotherapy, radiotherapy, tamoxifen, or combination) did not show any survival difference. Adjuvant therapy seemed to be associated with worse outcome. In the Veterans Administration hospital setting, the clinical stage and the expressions of p53 and Her2-neu in male breast carcinoma may be prognostically useful markers in guiding future treatment in prospective studies, whereas ER, PR, and MiB1 expressions are of limited value.
FAMILY HISTORY
Localized male breast carcinoma and family history. An analysis of 142 patients. Hill A, Yagmur Y, Tran KN, Bolton JS, Robson M, Borgen PI. Breast Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.	Cancer 1999 Sep 1;86(5):821-5 Abstract quote BACKGROUND: Male breast carcinoma is rare; therefore, the effect of family history on the course of the disease has not been well described. Germ-line mutations in breast carcinoma susceptibility genes, particularly BRCA2, are associated with an increased risk of male breast carcinoma. The authors sought to correlate significant family history with clinical phenotype in males with breast carcinoma. METHODS: One hundred forty-two men with breast carcinoma were treated at Memorial Sloan-Kettering Cancer Center or the Ochsner Clinic from 1973 to 1994. The authors reviewed the effect imparted by a family history of breast carcinoma on the duration of symptoms, the age at diagnosis, and the survival of men with this disease. RESULTS: Fifteen percent of male breast carcinoma patients had a first-degree relative with the disease. Fifty-eight years was the mean age at diagnosis for those with a family history, compared with 61 years for those without (P = not significant [NS]). The mean duration of symptoms was 23 months for those with a family history, compared with 22 months for those without. Three of 22 patients (13.6%) with a family history, compared with 11 of 90 patients (12%) without a family history, had Stage III disease (P = NS) at presentation. The overall 5-year and 10-year survival rates were 86% and 64%. Survival was not affected by family history. Lymph node positivity reduced 5-year and 10-year survival rates to 73% and 50% (P = 0.0004). CONCLUSIONS: For men with breast carcinoma, the presence of a family history did not affect the age at presentation, the duration of symptoms, the stage of disease at presentation, or the overall survival. In multivariate analysis, the most powerful predictor of outcome for these men was the status of the axillary lymph nodes.
PEPSINOGEN C
Expression of pepsinogen C in gynecomastias and male breast carcinomas. Serra Diaz C, Vizoso F, Rodriguez JC, Merino AM, Gonzalez LO, Baltasar A, Perez-Vazquez MT, Medrano J. Servicio de Cirugia General, Hospital Virgen de los Lirios, Poligono de Caramanxel s/n, 03804 Alcoy, Spain.	World J Surg 1999 May;23(5):439-45 Abstract quote Pepsinogen C is a proteolytic enzyme involved in the digestion of proteins in the stomach; it is also synthesized by a significant percentage of female breast carcinomas. In addition, it has been demonstrated that pepsinogen C is one of the few proteins induced by androgens in breast carcinoma cells. Here we evaluate the expression of pepsinogen C by immunoperoxidase staining in normal breast tissue from 3 male patients, 15 gynecomastia tissues, 2 male in situ breast carcinomas, and 68 male invasive breast carcinomas. Pepsinogen C immunostaining values were quantified in male breast tumors using the HSCORE system, which considers both the intensity and the percentage of cells staining at each intensity. The results indicated positive immunohistochemical staining for pepsinogen C in all gynecomastia tissues, the two in situ ductal carcinomas, and 52 of 68 invasive breast carcinomas (76.4%). The three normal breast tissues analyzed showed negative staining for pepsinogen C, whereas invasive tumors showed clear differences among them with regard to the intensity and percentage of staining cells. In addition, pepsinogen C scores were significantly higher in well-differentiated (grade I, 188.7) and moderately differentiated (grade II, 145.8) tumors than in poorly differentiated (grade III, 98.5) tumors (p = 0. 032). Similarly, significant differences in pepsinogen C content were found between estrogen receptor (ER)-positive tumors and ER-negative tumors (158.5 vs. 44.3, respectively; p = 0.009). Patients with pepsinogen C-positive tumors reached longer relapse-free and overall survival periods than did those with tumors with negative staining, but no statistical differences were observed between survival curves calculated for these two groups of patients. This results demonstrate expression of pepsinogen C by gynecomastias and by a high percentage of male breast carcinomas and may indicate an important role of pepsinogen C in the pathophysiology of male breast diseases.

Epidemiology
Disease Associations
Pathogenesis
Laboratory/Radiologic/ Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/ Immunohistochemistry/ Electron Microscopy
Differential Diagnosis
Prognosis
Treatment
Commonly Used Terms
Internet Links

GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
General	Histopathology is similar to female breast
VARIANTS
COLLISION TUMOR
Metastatic Prostatic Adenocarcinoma Within a Primary Solid Papillary Carcinoma of the Male Breast Application of Immunohistochemisty to a Unique Collision Tumor Sunati Sahoo, MD, Roberta E. Smith, DO, Joseph L. Potz, MD, and Paul P. Rosen, MD From the Department of Pathology, New York Presbyterian Hospital, Weill Medical College, New York, NY (Drs Sahoo and Rosen); the Department of Pathology, Holy Redeemer Hospital and Medical Center, Meadowbrook, Pa (Dr Smith); and Abington Hematology Oncology Associates, Inc, Abington, Pa (Dr Potz).	Arch Pathol Lab Med 2001;125:1101�1103. Abstract quote We report the case of a 78-year-old man who developed a breast mass 12 months after hormonal therapy for palliation of prostatic adenocarcinoma. On histologic and immunohistochemical examination, the breast tumor revealed a unique collision tumor composed of metastatic prostatic adenocarcinoma and solid papillary breast carcinoma.

HISTOPATHOLOGY	CHARACTERIZATION
GENERAL	Similar to female breast cancer histopathology

DIFFERENTIAL DIAGNOSIS	CHARACTERIZATION
MERKEL CELL CARCINOMA
Primary male neuroendocrine adenocarcinoma involving the nipple simulating Merkel cell carcinoma – a diagnostic pitfall Mecca P, Busam K.	J Cutan Pathol 2008; 35: 207–211. Abstract quote Male breast cancer is a rare entity accounting for < 1% of all breast cancer cases in the United States, but with a rate that has been rising over the last 25 years. Nipple skin/subcutaneous tumors in men are even rarer. Likewise, true neuroendocrine carcinoma of the breast, defined as > 50% of tumor cells staining for either chromogranin or synaptophysin, is not a common entity, usually occurring in older women. We present the case of a 70-year-old man with a slowly growing nipple mass that had enlarged over the previous 1.5 years. The histology consisted of nests, trabeculae and sheets of basaloid cells with rare abortive gland formation and a pushing edge. The case was originally misdiagnosed as a Merkel cell carcinoma, based largely on histologic morphology. Strong staining for synaptophysin (in greater than 50% of cells), CD56, keratins AE1 : AE3 and Cam 5.2, as well as estrogen receptor and progesterone receptor was noted. Myoepithelial cells within in situ areas were identified using stains for calponin and 4A4, supporting a primary mammary duct origin. Additionally, a substantial portion of cells stained for Gross Cystic Disease Fluid Protein-15 (GCDFP-15), confirming some overlap with sweat duct differentiation. To the best of our knowledge, although reported in the male breast, no case of primary nipple neuroendocrine carcinoma in a male patient has been reported in the literature. The gender of the patient and association with the skin of the chest wall probably contributed to the original misdiagnosis of Merkel cell carcinoma in this patient.