—  SPECIALTY CONFERENCE  —

Breast Pathology

Case 1 - Metastatic Malignant Melanoma to the Breast

Melinda F. Lerwill, Mass General Hospital, Boston, MA





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Clinical History
83-year-old woman with a 4.5 x 3 cm hard, palpable mass in the upper outer quadrant of the right breast.


Case 1 - Slide 1
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Case 1 - Figure 1
The tumor cells demonstrate diffuse positivity for S-100.
Case 1 - Figure 2
The tumor cells demonstrate diffuse positivity for HMB-45.
Case 1 - Figure 3
The tumor cells demonstrate diffuse positivity for MART-1.
Case 1 - Figure 4
The tumor cells demonstrate focal positivity for cytokeratin AE1/3-Cam5.2

Introduction:
An 83-year-old woman was referred to our institution with a diagnosis of locally advanced breast cancer. The patient had self-palpated a right breast mass in the upper outer quadrant. Mammogram confirmed the presence of a large mass, and she underwent a core biopsy of the lesion at an outside institution. The pathological findings were interpreted as infiltrating ductal carcinoma, grade 3 of 3. The tumor was negative for ER, PR, and Her-2/neu. She was referred to our multidisciplinary breast clinic for consideration of therapeutic options.

The outside pathology slides were forwarded to our department for routine review. The requisition form gave the clinical history as "breast cancer." It was not until the case was reviewed at the multidisciplinary clinic that the pathologist became aware that the patient had a history of a malignant melanoma of the right shoulder that was excised 2 years earlier. This revelation prompted further work-up of the case.

Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
The core biopsy demonstrates a diffuse proliferation of pleomorphic epithelioid tumor cells with broad areas of necrosis. For the most part, the growth is patternless, although focal vague nesting is observed. In areas, there is a suggestion of mild spindle-shaped elongation of the tumor cells. The large, round to oval nuclei have vesicular chromatin and prominent red macronucleoli. Occasional binucleate cells and rare intranuclear pseudoinclusions are seen. The tumor cells contain abundant eosinophilic cytoplasm. Only minimal pigment is present and is easily overlooked.

The tumor cells are negative for ER, PR, and Her-2/neu. After learning of the history of melanoma, additional immunohistochemical studies were performed. These show that the tumor cells are diffusely positive for S-100, HMB-45, and MART-1, and focally positive for cytokeratin.

Differential Diagnoses:
High-grade invasive ductal carcinoma Metastatic malignant melanoma.

Final Diagnosis:
Metastatic malignant melanoma to the breast

Case Discussion:
Certainly, common things being common, a poorly-differentiated breast carcinoma is a leading consideration in this case. The diffuse growth of high-grade epithelioid tumor cells with necrosis is compatible with a breast carcinoma, particularly one with triple-negative receptor status. Only subtle findings on the H&E suggest that the diagnosis might be otherwise: loose cellular cohesion, mild spindling of some tumor cells, binucleate cells, pseudoinclusions, and focal pigment. These findings, coupled with the belatedly obtained history of melanoma, swing the diagnostic pendulum towards metastatic melanoma. In the absence of such history, a low threshold for further diagnostic testing when even subtly unusual histologic features are present is important.

In this case, subsequent immunohistochemical studies demonstrated diffuse positivity for S-100, HMB-45, and MART-1, confirming a diagnosis of metastatic malignant melanoma. It should be noted that S-100 is also positive in nearly 50% of breast carcinomas, [1] and therefore this marker is not reliable for distinguishing melanoma from breast carcinoma. HMB-45 and MART-1 are more specific markers for this purpose. Focal cytokeratin positivity was also present in this case, a recognized phenomenon in occasional melanomas, but which may be misleading if evaluated in the absence of accompanying melanoma markers. [2] Although the presence of melanin pigment strongly suggests a diagnosis of melanoma, occasional breast carcinomas that breach the skin may contain melanin pigment or even melanocytes. [3] Additionally, rare variants of metaplastic carcinoma of the breast can demonstrate melanocytic differentiation. Although regions of these tumors histologically, immunohistochemically, and ultrastructurally resemble melanoma, other areas clearly represent carcinoma. [4]

Review of the Literature/Treatment Options
The breast is a remarkably uncommon site of secondary tumor involvement. [5] Metastases to the breast can easily be misdiagnosed as primary breast carcinomas due to histologic patterns that mimic breast carcinoma and to a lack of suspicion on the part of the pathologist and clinician. When spread from contralateral breast cancers, hematologic malignancies, and solid tumors are all considered, secondary tumors of the breast account for 1.3% to 3% of breast malignancies. [6] The most common source of metastatic disease is actually the contralateral breast. When tumors of mammary origin are excluded, metastatic solid tumors account for 0.2% to 1.1% of all breast malignancies. The most common solid non-mammary malignancy to spread to the breast is melanoma, followed by pulmonary and gynecological carcinomas. Secondary breast involvement occurs most often in the setting of disseminated metastatic disease and is accordingly associated with a poor prognosis.

Metastatic melanoma to the breast is reported over a wide age range, from 13 to 84 years, with a median of 48 years. The median time interval from the diagnosis of melanoma to the development of breast metastases is 36 to 52 months, although late recurrences up to 23 years later have been reported. Approximately 30% of cases represent metastases from melanomas arising on the trunk or abdomen, 25% from the lower extremities, 24% from the upper extremities, and the remainder from miscellaneous or unknown primary locations. The most common presentation for metastatic melanoma, like that for metastases to the breast in general, is that of a solitary discrete mass in the upper outer quadrant. 23% of patients have multiple nodules. Most patients have disseminated disease by the time breast metastases are identified, and median survival is only 9 months to 1 year. [7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31]

Conclusion(s):
Metastases to the breast are rare but represent an important diagnostic pitfall. Malignant melanoma is the most common solid, non-mammary tumor to secondarily involve the breast. It can be mistaken for poorly-differentiated breast carcinoma based on histology alone. Clinical history is critical but may be unavailable or unknown. Attention to unusual histologic findings, even if focal, can help prevent misdiagnosis as a primary breast carcinoma and save the patient from unnecessary or inappropriate therapies.

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