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The most common metastatic tumors in the breast are from contralateral breast primaries, but these are excluded in most series and are not discussed here. Breast metastases from extramammary malignant neoplasms are uncommon and account for up to 3% of all breast malignancies, although their incidence at autopsy is greater than 6%. The rarity of metastatic disease from an extramammary location is due to the characteristics of breast tissue. In addition, hormonal status may play a role in metastatic disease to the breast since the occurrence of breast metastasis increases in pubescent, lactating, and pregnant females. Most metastases to the breast from extramammary malignancies occur in women, whereas only 5% to 8% occur in men.
The most common extramammary solid tumor that metastasizes to the breast is the hematopoietic neoplasm. However, breast involvement of a hematopoietic neoplasm usually occurs as a result of systemic involvement; most reviews and books do not include them under metastatic disease to the breast from an extramammary location.
Excluding hematopoietic tumors, the most common site of metastatic disease in the breast is the skin and the most common type of tumor is malignant melanoma, followed by lung carcinomas, ovarian carcinomas, genitourinary carcinomas, gastrointestinal (GI) carcinomas, and soft tissue sarcomas.
Less common sites and types of tumors that have been reported to be metastatic to the breast include osteosarcomas, thyroid neoplasms, cervical/vaginal or endometrial carcinomas, skin squamous cell carcinoma, Merkel cell carcinoma, ocular melanoma, thymus and heart tumors, mesothelioma, tongue malignancy, choriocarcinoma, adenoid cystic carcinoma, and neuroblastomas ( Table 35.1 ).
Type of Metastatic Disease of the breast | Frequency (%) |
---|---|
Pulmonary carcinoma | 16 |
Gynecological carcinoma | 15 |
Genitourinary carcinoma | 12 |
Gastrointestinal carcinoma | 9 |
Head and neck carcinoma | 4 |
Other carcinoma | <1 |
Melanoma | 27 |
Neuroendocrine tumor | 10 |
Sarcoma | 7 |
Other noncarcinoma | <1 |
Moreover, previous studies of metastatic disease to the breast have revealed discordance in prevalence among individual reports, which is probably due to the difference in ethnicity of the patient population and location of these studies. For example, gastric carcinoma followed by thyroid carcinoma are the most common metastatic tumors to the breast in Korean women, whereas melanoma followed by lung carcinoma are the most common metastatic tumors in Australian women. In men, the prostate is the most common primary site of metastatic tumors in the male breast, with a 5% incidence, followed by lung carcinoma. However, one-fourth of the men with prostatic carcinoma had microscopic breast involvement of the tumor at autopsy. In children, rhabdomyosarcoma is the most common malignant tumor that metastasizes to the breast.
Metastatic tumors in the breast are difficult to diagnose, especially when they are the first manifestation of an occult extramammary malignancy. Breast metastasis is the initial presentation of extramammary occult malignant neoplasms in approximately 25% of patients. The most common sites of the occult carcinomas include the lung (particularly small cell carcinoma), followed by the kidney, stomach, intestine (carcinoid), ovary, uterine cervix, and thyroid gland. Moreover, even in patients with a history of extramammary malignancy presenting with a single breast mass, a second primary breast lesion is always considered more probable than a metastasis.
The majority of cases of metastatic extramammary malignancy in the breast have a known history of primary tumor. Vaughan and colleagues and others have reported an average interval of 50 to 60 months between the initial diagnosis of primary malignancy and the development of a metastasis to the breast.
Breast metastasis shows a female predominance, mostly in the reproductive age group (30–45 years). The upper outer quadrant is the one most commonly involved. Some studies have reported that the right breast is more frequently involved than the left. In contrast, others have reported that the left side is more frequently affected than the right. Bilateral involvement is not uncommon. Metastases to the breast can be multiple and bilateral with axillary lymph node involvement, features often seen in primary tumors. Enlarged axillary lymph nodes are encountered in about 40% of cases. The frequency of axillary lymph node involvement tends to be higher in series that include malignant lymphomas. Involvement of axillary lymph nodes by metastatic carcinoma in the breast is a manifestation of systemic spread and signifies a poor prognosis.
Clinically, regardless of the origin, metastatic lesions in the breast present as rapidly growing painless swellings or masses. Rarely, pain and nipple discharge are reported. In contrast, patients with primary breast carcinoma are usually asymptomatic and identified during screening examination. Metastatic carcinomas to the breast are relatively well-circumscribed and freely mobile masses, often misinterpreted as a benign breast lesion such as a fibroadenoma. Unlike primary tumors, the masses are superficially located without skin involvement. A preceding history of extramammary carcinoma can be helpful in suspecting a mass being metastatic in origin.
Metastatic carcinoma to the breast may produce clinical signs mimicking inflammatory breast cancer; patients present with a swollen, erythematous breast with diffuse skin thickening. A punch biopsy of the skin of the breast demonstrating intralymphatic carcinoma cells is generally regarded as confirmatory for inflammatory breast cancer. This phenomenon has been reported in neoplasms metastatic from ovarian origin, gastric carcinomas, rarely from squamous cell carcinoma of the tonsil, and lung and pancreatic adenocarcinoma.
The most common mammographic appearance is a rounded mass with well-defined or slightly irregular margins that lack microcalcifications and are therefore indistinguishable from benign lesions such as fibroadenomas. Multiple or bilateral tumors are seen in a minority of cases. Ultrasound typically shows a hypoechoic mass, which is sometimes heterogeneous or poorly defined. It has been suggested that lack of tumor-associated acoustic shadowing is a characteristic ultrasonographic feature of metastatic tumors in the breast.
The absence of microcalcifications is considered a characteristic feature of metastatic lesions to the breast. McCrea and colleagues even suggested that the presence of recognizable calcification in a mass on a mammogram virtually excludes metastatic disease to the breast. However, microcalcifications can be seen in metastatic ovarian serous carcinoma, and rarely in other metastatic malignancies such as hepatocellular carcinoma, gastric carcinoma, renal cell carcinoma, and medullary thyroid carcinoma.
Recognizing a breast tumor as being metastatic is crucial for appropriate treatment and prognosis because a delay in diagnosis or a misdiagnosis of a metastatic tumor often causes worse outcomes. Patients with metastatic disease in the breast rarely benefit from surgical management. In addition, systemic chemotherapy regimens are significantly different among metastatic diseases, and between metastatic disease and primary breast cancer. Most patients with metastatic disease to the breast have a poor prognosis; however, better survival is well recognized in some patients after receiving appropriate effective treatment.
The diagnosis can be particularly challenging for pathologists when core needle biopsy (CNB) is performed owing to the relatively limited amount of tissue available for microscopic examination and additional ancillary studies. To date, there are no reliable or specific clinical or radiological tests that can predict a tumor being metastatic rather than being a primary lesion. However, several features may suggest the presence of metastasis to the breast, such as a well-circumscribed tumor with multiple satellite foci, unusual histological features, tumors surrounded by normal ducts and lobules with little or no hyperplasia, the absence of an in situ carcinoma component, and the presence of many lymphatic tumor emboli.
The diagnosis of a metastatic tumor in the breast should be considered in patients with known extramammary malignancy and whenever the morphology does not correspond to the typical histological patterns of primary breast tumors. Comparison of primary breast tumors and metastatic lesions in the breast is very important in establishing a correct diagnosis of metastasis.
IHC plays a crucial role in the accurate identification of metastatic lesions. Breast cancer is typically positive for cytokeratin-7 (CK7), negative for CK20, and positive for low molecular weight CK (LMWCK), CAM5.2, and epithelial membrane antigen (EMA). S100 is expressed in 50% and carcinoembryonic antigen (CEA) in 30% of breast carcinomas. Diffuse and strong expression of estrogen receptors (ER) is largely restricted to carcinomas of the breast, endometrium, and ovary. Occasionally, tumors from other sites may express ER, but usually it is weak and focal.
Several breast origin markers are currently available, including gross cystic disease fluid protein-15 (GCDFP-15), mammaglobin, and GATA3. GCDFP-15 and mammaglobin are relatively specific for breast primary, but are not sensitive, especially in triple-negative breast carcinoma (31% positive for mammaglobin and 25% positive for GCDFP-15). In addition, up to 15% of lung carcinomas can express GCDFP-15. GATA3 is most widely used for making a diagnosis of breast primary due to its higher sensitivity and nuclear staining. GATA3 is positive in more than 90% of ER+ breast carcinomas, but positive in only 50% to 70% of triple-negative breast carcinomas. GATA3 is also positive in lymphocytes, urothelial carcinomas, squamous cell carcinomas, and mesotheliomas, with labeling in a few percentage of pancreatobiliary adenocarcinomas, cholangiocarcinomas, and lung adenocarcinomas. Recently, trichorhinophalangeal syndrome type 1 (TRPS1) was shown to have very promising results in labeling breast carcinomas sensitively and specifically, with positive staining in 98% of ER+ breast carcinomas, 87% of human epidermal growth factor receptor 2 (HER2) positive breast carcinomas, 86% of metaplastic breast carcinomas, and 86% of nonmetaplastic triple-negative breast carcinomas. In addition, TRPS1 showed no or little expression in urothelial carcinomas, lung adenocarcinoma, pancreatic adenocarcinoma, and others.
In patients without a known history of a malignancy, the workup for a breast metastasis should generally follow the path of workups for a tumor of unknown origin. Because of the fact that the most common secondary breast tumors are lymphoma and melanoma, an initial panel of markers should be directed to exclude these malignancies. Expression of CK7 and CK20 is considered to be most helpful in identifying the origin of an adenocarcinoma. By combining the results of CK7/20, ER/progesterone receptor (PgR), and site-specific markers such as thyroid transcription factor-1 (TTF-1), CDX2, PAX-8, and prostate-specific antigen (PSA), most metastatic carcinomas to the breast can be properly classified. In pathological practice, a panel of antibodies should be selected on the basis of each patient’s history and gender as well as the frequency of possible primaries.
Melanoma metastases to the breast account for 1.2% of all malignant melanomas. Patients are usually premenopausal and have primary skin lesions on the upper body. Ravdel and colleagues reviewed 27 patients with breast metastatic melanoma, and all the patients had a history of primary cutaneous melanoma involving the upper body. Metastatic melanoma presenting as a breast mass may be difficult to recognize if the primary lesion is occult. In addition, malignant melanoma can mimic adenocarcinoma and may overlap with mammary carcinoma on histological features and clinical presentation. Useful morphological clues to the diagnosis are cytoplasmic pigment and prominent intranuclear inclusions ( Fig. 35.1 ). The negativity for CKs and hormone receptors (HR) in the tumor cells should provide an IHC clue to the diagnosis. S100 is the most sensitive IHC marker for melanoma, but it is not specific, because it can also be expressed in breast cancers and other malignancies. Homatropine methylbromide-45 (HMB45), Melan-A, and microphthalmia transcription factor are all less sensitive, being present in about 70% of melanomas, but are more specific than S100. Uncommonly, melanoma may show aberrant expression of low molecular weight CKs CAM5.2, EMA, and CD68. SOX10, a transcription factor, is expressed in melanocytes and Schwann cells, and hence it is a very useful marker for melanoma. Up to 95% of metastatic and 98% of desmoplastic melanoma cases are positive for SOX10, making it a valuable addition to the panel of IHC stains for melanocytic differentiation ( Fig. 35.1 ). However, up to 40% of primary breast carcinomas, predominantly triple-negative, basal-like, and metaplastic carcinomas, can also show SOX10 expression, but these primary breast tumors are usually positive for Ks.
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