Metastatic melanoma presenting as an isolated breast tumor: a study of 20 cases with emphasis on several primary mimickers.
MATERIALS AND METHODS
All cases of malignant melanoma metastatic to the breast were retrieved from the Department of Pathology files where the authors are affiliated as well as from the authors' own consultation files. Most cases (16 of 20) were submitted by community hospital laboratories or individual pathology laboratories, either for consultation due to unusual tumor characteristics or for standard predictive/prognostic immunohistochemical assays, including hormone receptors and human epidermal growth factor receptor 2 (HER2/neu) status assessments. Case inclusion criteria included (1) mammary tumors presenting as isolated lesions and (2) availability of adequate paraffin tissue material for immunohistochemical studies. Excluded from this study were cases involving breast tumors associated with systemic metastases of melanoma and tumors related to a primary cutaneous lesion of the skin overlying the breast. Data pertaining to preoperative radiologic findings were reviewed when available. Follow-up information was also requested from the referring or submitting physicians. A panel of commercially available antibodies was applied to formalin-fixed, paraffin-embedded tissue sections (Table 1). Nearly all cases were tested for S100 protein, gp100 (HMB-45), Melan-A, and for cytokeratin staining. Additional assays with antibodies, including estrogen receptor, progesterone receptor, HER2/neu, desmin, smooth muscle actin, p63 protein, CD34, and vimentin, were performed on the basis of preliminary interpretation by the submitting pathologist.
Pertinent clinical features are summarized in Table 2. The study includes 17 women and 3 men ranging in age from 27 to 91 years (median, 47.5 years). Tissue specimens were obtained by core needle biopsy (6 cases), excisional biopsy (13 cases), and radical mastectomy (1 case). The radical mastectomy was performed after diagnosis on needle aspiration cytology. All patients presented with palpable tumors. Precise details of preoperative radiologic findings were available in 3 cases only (patients 1, 2, and 19) for which mammographic films revealed a suspicious (R4) roundish opacity. In case 19, microcalcifications were noticed. In 2 patients, sentinel and axillary lymph node dissection was performed. Of 20 patients, history of malignant melanoma could be retrieved or presumed for 19 patients; however, precise details of the primary tumor characteristics were available only for 3 patients. The first patient underwent surgery of the toe for a pT2N0(sn) malignant melanoma, 2 years before metastasis to the breast. The second patient had a history of abdominal skin melanoma, pT2N1(sn). The third patient had a history of choroid melanoma 6 years before presenting with an isolated 1.6-cm breast tumor. Follow-up data were available for only 5 patients. Two patients are alive (cases 1 and 2), 1 with clinical evidence of metastatic disease (case 2). Two patients had clinical evidence of brain and distant metastases (cases 5 and 16). One patient died of metastases 2 years after diagnosis (case 19).
Macroscopic and Histopathologic Features
Macroscopic information was available in 4 cases. Tumors appeared bulky, with pushing margins often displaying hemorrhagic areas or brownish discoloration of the cut surface. Microscopically, 13 tumors featured prevalent epithelioid or mixed epithelioid/spindle cell morphology. Sheets of large, discohesive polygonal cells with eosinophilic cytoplasm and vesicular nuclei, usually with prominent nucleoli, predominated in these cases. In some cases, optically clear spaces within the cytoplasm, pushing the nuclei to the periphery, were pronounced focally, giving the impression of rudimentary acinar/glandular differentiation (Figure 1, A). Mitotic activity was generally brisk (Figure 1, B). Other microscopic features, which may be seen in MM, included pseudopalisading arrangement (Figure 1, C) or atypical spindle cells growing in a hemorrhagic background with aneurysm-like spaces and admixed with osteoclast-like giant cells (Figure 1, D). Regressive changes with areas of tumor necrosis were often seen, and when prominent, the tumor acquired a cavitated appearance (Figure 2, A). In these particular cases, viable cells were clustered around vascular cores, imparting a vague papillary configuration to the tumor growth (Figure 2, B). Heavy melanin pigment deposits were seen in only 2 cases (Figure 3). In 1 case, there was a pronounced retrograde colonization of breast duct units (Figure 4). In addition to the epithelioid and mixed epithelioid/spindle morphology, more distinct microscopic patterns were recognized in 7 cases. In 2 of these cases, the tissue sections showed a distinctive micronodular growth pattern with a concomitant, brisk inflammatory infiltrate. A vague syncytial arrangement of tumor cells, closely juxtaposed with less discernible cytoplasmic membranes, could be focally recognized in these cases (Figure 5). A fine, dustlike pigment was focally seen. One tumor was entirely composed of small to intermediate-sized cells, often with indented or lobated nuclei, which raised an initial suspicion of lymphoma. The tumor cells diffusely percolated the mammary fat and exhibited a scant to moderate amount of eosinophilic and granular cytoplasm (Figure 6, A and B). A different tumor revealed exclusively spindle, mesenchymal-like cells. In this tumor, fascicles of spindle cells grew within a loose ground substance and featured prominent cytoplasmic vacuolization and vague nuclear scalloping (Figure 7, A and B). In another case, spindled myoid cells arranged in fascicles were observed (Figure 8, A and B). The nonneo-plastic breast tissue, in all cases but 2, was unremarkable. These 2 cases showed microscopic evidence of lobular carcinoma in situ (case 1) and ductal carcinoma in situ with microcalcifications (case 19).
Results of Immunohistochemistry
All tested cases were positive for Melan-A (Figure 9, A), S100 protein (Figure 9, A [inset]), and HMB-45 (Figure 9, B through D) (Table 1). Results for all other tested markers, including cytokeratin stains (Figure 9, B [inset]), CD45, ER, PR, HER2/neu, p63, and desmin, were negative (Figure 9, C [inset]).
Malignant melanoma is one of the most prevalent neoplastic conditions worldwide. Common metastatic sites include lymph node, liver, lung, and brain, although virtually any organ can be involved. Metastatic tumors to the breast are rare with an incidence of 0.5% to 2% of all breast malignancies. (15) Melanoma is one of the most common solid tumors metastasizing to the breast. (16) Young women seem to be more often affected, (13) perhaps because of a physiologically increased vascularization of mammary tissue. (15) Recognition of MM generally is prompted by several microscopic clues such as epithelioid or spindle cell morphology; cell discohesion; eosinophilic cytoplasm with fine, dustlike or coarse, granular pigment; and vesicular nuclei with inclusion-like macronucleoli. Thus, in the appropriate clinical context, the diagnosis of MM can be rendered with a relative degree of confidence, on the basis of either tissue sections or aspiration cytology smears. (17-19) Nonetheless, a number of clinical and pathologic features may be the source of interpretive errors, resulting in inappropriate treatment, which have potentially detrimental consequences for patients. These errors may also have serious medicolegal implications for pathologists. The matter may further be compounded in cases of MM presenting as isolated tumors of the mammary gland, especially when the medical history is noncontributory or when patients or the treating physicians neglect to convey a previous history of melanoma. It is also important to remember that malignant melanoma can metastasize many years after a primary lesion has been removed, lag times as long as 10 years have been reported. (7) Adding to the diagnostic complexity is the paucity of previously published series. Although MM to the breast is well investigated from the clinical point of view, pathologic studies are found only in general reference sources, (20,21) and published research in specialized pathology journals is scant. In addition, studies specifically addressing the various microscopic features of these lesions and their potential implications are underreported.
In our series, the age range was relatively broad, with a slight preponderance of premenopausal patients (9 of 17) and a median age of 47.5 years. Three patients were men. Most cases had been submitted for a second diagnostic opinion, for the assessment of estrogen receptor and progesterone receptor, or for "unusual" high-grade breast cancer.
Most of the cases in our series were characterized by proliferating epithelioid or mixed epithelioid and spindle cell tumors, suggestive of poorly differentiated, high-grade metaplastic carcinoma. These findings are similar to previously published observations of MM to the breast. (12,16) Tumors with macroscopic information available were described as fairly delimited, with pushing borders, in contrast to the irregular margins often seen in invasive carcinoma of breast. On retrospective review, few microscopic features of melanoma were seen in this group, including cell discohesion, eosinophilic cytoplasm, and inclusion-like nucleoli. Melanin pigment within tumor cells was an obvious clue to the diagnosis of MM; however, this particular feature was seen in only 2 cases. Less frequently, the epithelioid cells were associated with prominent cytoplasmic vacuolization, suggesting mucin production and/or glandular differentiation. Tumor necrosis was noticed in most cases, and when extensive, it was often associated with pseudocyst formation with remnants of viable neoplastic cells growing around fibrovascular cores. The latter feature led to an initial diagnosis of high-grade intracystic papillary carcinoma in 1 case. This interpretation was rendered on a core-needle biopsy specimen in a community hospital, and the patient was treated with a quadrant excisional biopsy. A sentinel lymph node biopsy was also performed, and results were negative for the presence of tumor cells. In one case within this group, tumor cells were associated with a prominent hemorrhagic background featuring benign multinucleated osteoclast-like cells mimicking infiltrating carcinoma. In another case, the neoplastic proliferation filled preexisting duct units, simulating lobular cancerization by ductal carcinoma.
Although poorly differentiated carcinoma was the main pathologic condition simulated by most of our cases, a phenotypic tumor diversity, documented in an additional 7 cases, substantially expanded the spectrum of differential diagnosis. Two cases exhibited a micronodular growth pattern with syncytia formation and confluent neoplastic cells with poorly defined cytoplasmic membranes; large, clear nuclei; and a brisk lymphoplasmacytic infiltrate. These cases were histologically reminiscent of medullary carcinoma. In 2 cases, packed tumor cells diffusely infiltrated the breast adipose tissue, often with fine tentacle-like cords. In one of these cases, the tumor cells were small, exhibiting irregularly lobated nuclei, and relatively scant cytoplasm. These cases were originally suspected to be primary, high-grade malignant lymphoma. Another distinct pattern documented featured vacuolated cells scattered within a loose, myxoid-like background. These changes imparted a lipoblast-like resemblance, giving the impression of an atypical lipomatous tumor or a liposarcoma. Palisading of tumor cells suggested peripheral nerve sheath derivation in 1 case. Finally, in 1 case, the tumor cells grew in distinctive fascicles intersecting at right angles and featuring spindle cells with myoid qualities, resembling leiomyosarcoma.
The differential diagnosis of MM to the breast, therefore, includes a number of malignant diseases. Based on conventional morphology, the microscopic interpretation may be hampered by several drawbacks, including similarity of MM cells to those often seen in any poorly differentiated
breast carcinoma. It has been suggested that cases of breast MM are fairly circumscribed and lack tissue microcalcifications. (13) In addition, desmoplastic changes or concomitant in situ carcinomas are not seen in breast MM, in contrast to most primary breast carcinomas. However, these criteria are usually difficult to apply in limited tissue material such as core-needle biopsy specimens. Furthermore, in one of our cases, we documented foci of microcalcifications associated with a low-grade ductal carcinoma in situ adjacent to MM (case 19). Immunohistochemical stains, in these tumors, showed positivity for S100 protein, HMB-45, and Melan-A, whereas antibodies against other antigens such as cytokeratins, CD45, desmin, estrogen receptor, and progesterone receptor, were nonreactive. A negative result for cytokeratin staining should, therefore, raise the index of suspicion for MM. It is important to be mindful, however, that cytokeratin reactivity has been reported in melanoma (2) and that antibodies with a classically positive profile in melanoma, including S100, may have a variable sensitivity or a negative profile altogether. In essence, the results of immunohistochemical markers should be taken into consideration, along with the clinical and morphologic findings, when diagnosing MM.
In addition to MM, several pigmented lesions have been described in the breast, including ductal carcinoma showing aberrant melanocytic differentiation. These cases are reported in the literature as "melanotic carcinoma," 22-25 pigmented mammary Paget disease, (26,27) and blue nevi of the mammary gland proper. (28) Some cases with pigments are merely breast carcinomas that have phagocytized melanin from the adjacent skin. (21)
Nonetheless, the differential diagnosis of MM to the breast is a rather complex task. Poorly differentiated breast carcinoma is the utmost condition that probably deserves greatest consideration, yet it is just one of the mimickers to be ruled out. In fact, data from our series indicate that MM can simulate other malignant tumors including lymphoma, leiomyosarcoma, liposarcoma, and medullary carcinoma. Medullary carcinoma may be considered by virtue of the syncytial growth pattern of tumor cells and the lymphoplasmacellular infiltrate within the background. Noteworthy, primary lymphoma is rare but not exceptional in the breast, with a broad spectrum of clinical and microscopic presentations (29,30) including anaplastic large cell lymphoma, a well-known mimicker of epithelioid tumors such as carcinoma and melanoma. (31) Primary leiomyosarcoma in the breast is rarely, but not exceptionally, reported. (32,33) Immunostaining for muscle markers proves useful in these cases, but it should be remembered that desmin may only show focal positivity in leiomyosarcoma of the breast. Furthermore, muscle actin antibodies have a low specificity, since these antibodies can show positivity in myofibroblastic lesions. In addition, positivity for S100 protein has also been reported in cases of primary leiomyosarcoma of the breast. (34,35) Finally, in the case of MM with lipoblast-like cells, strong and diffuse positivity for S100 protein, HMB-45, and Melan-A was considered adequate evidence of its metastatic origin.
In practical terms, data from this study suggest that a broad spectrum of malignant tumors should be considered in the differential diagnosis of MM to the breast. Although epithelioid and spindle cell metaplastic carcinomas are the most important conditions to rule out, other malignant tumors can be closely mimicked. Clues to the correct interpretation include a discohesive cell population with high-grade nuclear features, vesicular nuclei, prominent nucleoli, and eosinophilic cytoplasm. The lack of an in situ component or dystrophic calcifications may further raise the index of suspicion; yet, in 2 of our cases, there was microscopic evidence of in situ neoplasia (either ductal or lobular) and microcalcifications. The latter was demonstrated on mammography, reinforcing the clinical impression of a primary breast tumor. As we have observed in the series reported herein, the application of immunohistochemistry is a critical diagnostic step. In fact, tumor cell immunoreactivity for S100 protein, Melan-A, and HMB-45, along with no expression for cytokeratin staining, proved useful in differentiating MM from other malignant tumors, including breast carcinoma, lymphoma, and leiomyosarcoma. However, certain positive results, especially for S100 protein, should be interpreted with caution and always in the proper clinicopathologic context. Nonetheless, in selected breast tumors featuring poorly differentiated histologic appearance, which may closely mimic a triple-negative invasive carcinoma, an extended immunohistochemistry panel may prove useful especially if an in situ component is absent. A thorough clinical history remains the best approach to avoid misdiagnosis, which may result in inappropriate patient treatment. Limited follow-up information in our series precludes drawing any conclusion regarding the prognostic significance of MM to the breast; however, on the basis of the data available, the clinical course is unfavorable, as otherwise suggested by published clinical studies. (6,7,14,36)
In conclusion, we reported 20 cases of MM to the breast presenting as isolated tumors and simulating a broad spectrum of primary malignant breast tumors, including poorly differentiated invasive carcinoma, high-grade lymphoma, medullary carcinoma, and tumors of mammary stromal tissue, such as leiomyosarcoma and liposarcoma, thus expanding the spectrum of differential diagnoses of MM. The present series illustrates that MM to the breast may pose diagnostic challenges and that clinicopathologic correlation is the most crucial step toward correct interpretation and appropriate clinical management.
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Carlos E. Bacchi, MD, PhD; Sheila C. Wludarski, MD; Abiy B. Ambaye, MD; Janez Lamovec, MD; Tiziana Salviato, MD; Giovanni Falconieri, MD
Accepted for publication April 13, 2012.
From Consultoria em Patologia, Botucatu, SP, Brazil (Drs Bacchi and Wludarski); the Department of Pathology, University of Vermont College of Medicine, Burlington (Dr Ambaye); the Department of Pathology, Institute of Oncology, Ljubljana, Slovenia (Dr Lamovec); the Department of Pathology, Pordenone General Hospital, Pordenone, Italy (Dr Salviato); and the Department of Pathology, General Hospital S. Maria della Misericordia, Udine, Italy (Dr Falconieri).
The authors have no relevant financial interest in the products or companies described in this article.
Reprints: Giovanni Falconieri, MD, Department of Pathology, General University Hospital "S. Maria della Misericordia," I 33100 Udine, Italy (e-mail: Falconieri.Giovanni@aoud.sanita.fvg.it).
Table 1. Panel of Antibodies Applied to Paraffin Sections of Tumors Antigen Clone or Antibody Dilution S100 protein S100, polyclonal 1:1400 HMB-45 gp100 1:400 Melan-A A103 1:50 p53 protein DO-7 1:250 Cytokeratins AE1/AE3 1:900 Estrogen receptor ERSP1 1:1200 Progesterone receptor PGR636 1:1600 HER2/neu SP3 1:300 p63 protein A4A 1:4000 Desmin DE-R-11 1:50 Cytokeratin 5/6 D5/16B4 1:100 Smooth muscle actin 1A4 1:600 CD34 QBEnd 1:800 CD45 LCA 1:200 EMA E29 1:2000 MDM2 IF2 1:1600 CD30 BerH2 1:900 Myeloperoxidase MPO-7 1:10000 CD99 O13 1:800 NGFR NGFR 1:800 GCDFP-15 23A3 1:1200 Antigen Manufacturers S100 protein Dako, Carpinteria, California HMB-45 Dako, Carpinteria, California Melan-A Dako, Carpinteria, California p53 protein Dako, Carpinteria, California Cytokeratins Thermo Fisher Scientific, Fremont, California Estrogen receptor Thermo Fisher Scientific, Fremont, California Progesterone receptor Dako, Carpinteria, California HER2/neu Thermo Fisher Scientific, Fremont, California p63 protein Thermo Fisher Scientific, Fremont, California Desmin Leica Microsystems, Newcastle Upon Tyne, United Kingdom Cytokeratin 5/6 Dako, Carpinteria, California Smooth muscle actin Dako, Carpinteria, California CD34 Dako, Carpinteria, California CD45 Dako, Carpinteria, California EMA Dako, Carpinteria, California MDM2 Invitrogen, Carlsbad, California CD30 Dako, Carpinteria, California Myeloperoxidase Dako, Carpinteria, California CD99 Dako, Carpinteria, California NGFR Dako, Carpinteria, California GCDFP-15 Abcam, Cambridge, Massachusetts Antigen No. of Cases Tested S100 protein 20 HMB-45 20 Melan-A 19 p53 protein 3 Cytokeratins 20 Estrogen receptor 8 Progesterone receptor 6 HER2/neu 5 p63 protein 5 Desmin 3 Cytokeratin 5/6 3 Smooth muscle actin 3 CD34 3 CD45 2 EMA 2 MDM2 2 CD30 1 Myeloperoxidase 1 CD99 1 NGFR 1 GCDFP-15 1 Abbreviations: EMA, epithelial membrane antigen; GCDFP/15, gross cystic disease fluid protein 15; HER2/neu, human epidermal growth factor receptor 2; MDM2, murine double minute gene 2; NGFR, nerve growth factor receptor. Table 2. Summary of the Clinical and Salient Microscopic Features of the Case Series, Including the Diagnosis Proffered in 16 Cases Submitted for a Second Opinion Case Age, Type of No. y/Sex Specimen Laterality 1 49/F QB + SLN biopsy Right 2 50/F Radical mastectomy Right 3 87/F Lumpectomy Right 4 43/F Lumpectomy Right 5 39/F Lumpectomy Right 6 53/M CNB Right 7 33/F Lumpectomy Right 8 43/F Lumpectomy Left 9 45/F CNB Unknown 10 91/F Lumpectomy Right 11 27/F CNB Right 12 38/F CNB Right 13 40/F Lumpectomy Left 14 57/M Lumpectomy Unknown 15 43/F Lumpectomy Right 16 46/F Lumpectomy Unknown 17 69/M Lumpectomy Unknown 18 57/F CNB Left 19 52/F QB + SLN biopsy Left 20 76/F CNB Right Case No. Microscopic Features Initial Proffered Diagnosis 1 Fronds of poorly Papillary adenocarcinoma differentiated cells abutting within pseudocystic spaces 2 Epithelioid tumor cells Poorly differentiated carcinoma 3 Sheets of poorly Malignant lymphoma differentiated malignant 4 Epithelioid and spindle Poorly differentiated carcinoma cell tumor cells 5 Epithelioid tumor cells Poorly differentiated carcinoma 6 Epithelioid tumor cells Poorly differentiated carcinoma 7 Epithelioid tumor cells Poorly differentiated carcinoma 8 Epithelioid tumor cells Poorly differentiated carcinoma 9 Vacuolated, lipoblast-like Liposarcoma cells within a loose stroma 10 Multinodular tumor with Medullary carcinoma neoplastic cells within a background rich with inflammatory cells 11 Epithelioid and spindle Poorly differentiated, possibly tumor cells sarcomatoid carcinoma 12 Micronodular tumor with Medullary carcinoma inflammation; polygonal and cohesive cells. Presence of dustlike pigment. 13 Finely infiltrating Malignant lymphoma, malignant cells percolating granulocytic sarcoma fat 14 Spindle and osteoclast-like Metaplastic carcinoma with giant cells. Aneurysm-like osteoclast-like giant cells; spaces. spindle cell sarcoma 15 Epithelioid and spindle cell Poorly differentiated, possibly tumor cells sarcomatoid carcinoma 16 Highly necrotic neoplasm Sarcomatoid carcinoma; with palisading cell malignant schwannoma arrangement 17 Epithelioid and spindle Poorly differentiated, possibly cell tumor cells sarcomatoid carcinoma 18 Epithelioid and spindle Metastatic melanoma tumor cells 19 Epithelioid and spindle Metastatic melanoma tumor cells 20 Epithelioid and spindle Metastatic melanoma tumor cells Abbreviations: CNB, core/needle biopsy; QB, quadrant biopsy/ quadrantectomy; SLN, sentinel lymph node.
Please note: Illustration(s) are not available due to copyright restrictions.