Breast

This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2019, Case 32, and is Metaplastic carcinoma of the breast with mesenchymal differentiation.

This case is an example of metaplastic carcinoma of the breast. The tumor shows a heterogenous malignant tumor cell population composed of spindle cells and epithelioid cells with scattered osteoclast-like giant cells. Distinct areas of chondroid extracellular matrix production are evident though not clearly present in all sections. Microglandular adenosis (MGA) showing a continuum from typical to atypical to carcinoma in situ is noted in association with this tumor in many slides.

Metaplastic carcinoma is comprised of a group of histologically diverse lesions characterized by the presence of neoplastic epithelium with squamous and/or mesenchymal differentiation. The most frequently encountered mesenchymal elements include, but are not limited to, spindle, chondroid, osseous, and rhabdoid cells. The extent of involvement by metaplastic elements is variable. Ductal carcinoma in situ is frequently discovered in association with metaplastic carcinoma, followed by lobular carcinoma in situ, atypical ductal hyperplasia, and less commonly MGA.

The World Health Organization has created a descriptive classification system with 5 subtypes of metaplastic carcinoma. Multiple subtypes may be identified in the same lesion, leading to the diagnosis of a mixed metaplastic carcinoma.

1. Low-grade adenosquamous carcinoma: characterized by an infiltrative pattern of small, round, glandular structures and solid cords of epithelial cells with admixed squamous cells, pearls, and/or cysts. There is a desmoplastic, spindle-cell background and frequently a peripheral rim of chronic inflammation sometimes referred to as “cannon ball-like.”
2. Fibromatosis-like metaplastic carcinoma: composed of bland spindle cells with minimal nuclear atypia and pale eosinophilic cytoplasm, and is arranged in wavy, interlacing fascicles that infiltrate into the surrounding parenchyma. The stroma is variably collagenized with prominent chronic inflammation, especially at the periphery, with focal squamous differentiation and clusters of “plump” spindle to epithelioid cells.
3. Squamous cell carcinoma: resembles squamous cell carcinomas found at other sites and is typically a cystic lesion lined by atypical/pleomorphic squamous cells with a prominent stromal reaction and inflammatory infiltrate. Metastatic disease must be ruled out for this diagnosis to be rendered.
4. Spindle cell carcinoma: markedly cellular and composed of cohesive sheets of spindle cells with prominent nuclear atypia arranged in a mix of architectural patterns, including herringbone and storiform patterns. Small clusters of epithelioid cells or squamous differentiation may be identified.
5. Carcinoma with mesenchymal differentiation: defined by an admixture of mesenchymal/heterologous elements with a moderate to poorly differentiated carcinoma. There can a broad range of atypia present in the mesenchymal/heterologous elements, at times resembling a primary sarcoma.

Key to the diagnosis of metaplastic carcinoma is the identification of epithelial differentiation. The expression of cytokeratin is variable and commonly focal; as such, a panel of high-molecular-weight cytokeratins should be utilized such as 34BetaE12 (CK903), CK5/6, CK14, and AE1/AE3. Low-molecular-weight cytokeratins such as CK7 and CK20 are frequently negative. The myoepithelial marker p63 is expressed in >90% of metaplastic carcinomas and should be included in the diagnostic workup. GATA3 expression occurs in approximately half of metaplastic carcinomas and may be useful in the workup of metastatic lesions. Estrogen receptor, progesterone receptor and HER2 are negative in >90% of metaplastic carcinomas.

Metaplastic carcinoma has been traditionally classified within the basal-like subtype of breast carcinomas. This correlates well with the frequent triple-negative expression status and the common identification of TP53 mutations. New research utilizing microarray gene-expression profiling has shown that a subset of metaplastic carcinomas now fits best in the newly recognized claudin-low breast carcinoma subtype. This subtype exhibits low expression of several claudin genes, which are involved in cell-cell junctions, and is believed to encompass the most primitive of tumors with features that closely resemble the mammary stem cell. Carcinomas in this subgroup typically demonstrate high-grade nuclear features and a marked lymphocytic infiltrate. Numerous additional genetic alterations have been identified in varying proportions to include the loss of CDKN2A (p16) and PTEN; mutations in PIK3CA, CTNNB1, and various genes in the Wnt pathway; and the amplification of EGFR. BRCA1 mutations have been rarely identified in metaplastic carcinoma.

Metaplastic carcinoma may occur at any age, though it predominantly affects peri- and postmenopausal women. Patients typically present with a firm, non-mobile breast mass that exhibits rapid growth and large size. Treatment typically consists of surgery, chemotherapy, and radiation. Neoadjuvant therapy has been reported to have a complete pathologic response in 10% of patients, and novel therapies have been described that target the sarcomatous elements within the metaplastic carcinoma.

As a whole, metaplastic carcinoma has a lower response rate to conventional chemotherapy and has outcomes that are worse than other triple-negative breast carcinomas. Lymph node metastases tend to occur at a much lower rate, though there is an increased risk of distant metastases, predominantly to the brain, lungs, and bones. Factors that contribute to a worse prognosis include age less than 39 years, squamous cell carcinoma metastatic to lymph nodes, and skin invasion. Interestingly, studies have indicated that the fibromatosis-like and low-grade adenosquamous types have significantly better outcomes than the others.

Primary mammary sarcoma must be considered in the differential of this lesion. While rare, they do occur in the breast. Osteosarcoma, which could be considered in this case, represents 12% of mammary sarcomas, and a third show cartilaginous differentiation (chondroblastic osteosarcoma). The identification of epithelial lineage or an in situ component serves to exclude this diagnosis. GATA3, p63, and keratin staining are typically used to differentiate these from metaplastic carcinoma, as they should be negative in true sarcomas.

Nodular fasciitis is a proliferation of fibroblasts and myofibroblasts that can present as a rapidly growing breast mass in reproductive-age women. The stroma is typically myxoid to mucoid and can mimic the heterologous/mesenchymal differentiation found in metaplastic carcinoma. Nodular fasciitis is often quite mitotically active but contains little to no cytologic atypia or atypical mitotic figures. Key to the diagnosis of nodular fasciitis is negative cytokeratin expression. Molecular findings include ALK1 or USPS6 gene rearrangement, neither of which has been identified in metaplastic carcinoma.

Phyllodes tumors are notorious for mesenchymal differentiation in the malignant stromal component. Their malignant stroma can often overrun the biphasic architecture, hiding its true identity. Thorough evaluation for carcinoma in situ, intrinsic benign epithelial elements, and foci of more conventional biphasic appearance is required to exclude this entity. While the same panel of stains useful for determining epithelial differentiation is certainly helpful, several publications have shown phyllodes tumors to focally express keratins and p63. While typically less often positive in malignant phyllodes, CD34 can be expressed in phyllodes tumors but not in metaplastic carcinomas.

Pleomorphic adenoma is a benign biphasic tumor with epithelial and myoepithelial differentiation. It is extremely rare in the breast and is histologically similar to its salivary gland counterpart. The myxoid stroma and keratin-positive epithelial elements of a pleomorphic adenoma may cause it to be confused with a metaplastic carcinoma with mesenchymal differentiation. Separating the two lesions can be difficult and requires a complete and thorough histologic examination. A pleomorphic adenoma should be cytologically bland, have no necrosis or atypia, show rare mitotic figures, have non-infiltrative margins, and contain a benign epithelial component. Metaplastic carcinomas with mesenchymal differentiation arising from pleomorphic adenomas have been reported, and any lesion with features of a pleomorphic adenoma should be completely excised.

1. Which of the following is the most important factor used to distinguish metaplastic carcinoma from other spindle cell lesions of the breast?
   
   
   1. Cellular atypia
   2. Chondroid matrix production
   3. Cytokeratin expression
   4. Growth pattern
   5. Mitotic activity
2. Alteration of which gene is most frequently identified in metaplastic carcinoma of the breast?
   
   
   1. BRCA1
   2. CDH1
   3. CHEK2
   4. PTEN
   5. TP53
3. Which of the following subtypes of metaplastic carcinoma portends the best prognosis?
   
   
   1. Carcinoma with mesenchymal differentiation
   2. Fibromatosis-like metaplastic carcinoma
   3. Mixed type (spindle and squamous)
   4. Spindle cell carcinoma
   5. Squamous cell carcinoma

1. Brogi E, Hoda SA, Sayed A, Koerner FC, Rosen PP. Rosen’s Diagnosis of Breast Pathology: By Needle Core Biopsy. 4th Edition China: Wolters Kluwer/Lippincott Williams & Wilkins; 2017: 238-258.
2. Chia Y, Thike AA, Cheok PY, Yong-Zheng Chong L, Man-Kit Tse G, Tan PH. Stromal keratin expression in phyllodes tumours of the breast: a comparison with other spindle cell breast lesions. J Clin Pathol. 2012;65(4):339-347.
3. Cimino-Mathews A, Sharma R, Illei PB, Vang R, Argani P. A subset of malignant phyllodes tumors express p63 and p40: a diagnostic pitfall in breast core needle biopsies. Am J Surg Pathol. 2014;38(12):1689-1696.
4. Guerini-Rocco E, Piscuoglio S, Ng CK, et al. Microglandular adenosis associated with triple-negative breast cancer is a neoplastic lesion of triple-negative phenotype harbouring TP53 somatic mutations. J Pathol. 2016;238(5):677-688.
5. McCart Reed AE, Kalaw E, Nones K, et al. Phenotypic and molecular dissection of metaplastic breast cancer and the prognostic implications. J Pathol. 2019;247(2):214-227.
6. McKinnon E, Xiao P. Metaplastic Carcinoma of the Breast. Arch Pathol Lab Med. 2015;139(6)819-822.
7. Perou CM. Understanding and Treating Triple-Negative Breast Cancer Across the Age Spectrum: Molecular Stratification of Triple-Negative Breast Cancers, The Oncologist. 2010;15(suppl 5):39-48.
8. Reis-Filho JS, Sotiriou C, Vincent-Salomon A, et al. Metaplastic carcinoma. In: WHO Classification of Tumours Editorial Board. Breast Tumours: WHO Classification of Tumors. 5th ed. IARC Press; 2019.
9. Schnitt SJ, Collins LC. Biopsy Interpretation of the Breast. 2nd Edition China: Wolters Kluwer/Lippincott, Williams & Wilkins; 2018: p. 344-351.

Timothy Harkcom, DO
Staff Pathologist
Fort Belvoir Community Hospital
Fort Belvoir, VA 

Justin M Wells, MD, LTC MC USA, FCAP
Surgical Pathology Committee
Walter Reed National Military Medical Center
Bethesda, MD

1. Cytokeratin expression (c)
2. TP53 (e)
3. Fibromatosis-like metaplastic carcinoma (b)