A Brief Overview of the WHO Classification of Breast Tumors, 4th Edition, Focusing on Issues and Updates from the 3rd Edition

Special Subtypes of Invasive Breast Carcinoma

The most common specific subtypes include invasive lobular, tubular, cribriform, metaplastic, apocrine, mucinous, papillary, and micropapillary carcinoma, as well as carcinoma with medullary, neuroendocrine, and salivary gland/skin adnexal type features. These specific tumor types are defined by their morphology, but are also linked to particular clinical, epidemiological, and molecular features.

With invasive lobular carcinoma (ILC), variants such as solid, alveolar, pleomorphic, tubulolobular, and mixed variants are recognized and related to differences in prognosis when compared to ILC of classic type. Among pleomorphic lobular carcinomas, apocrine, histiocytic, or signet-ring cell differentiation can be observed. Tumor grading of ILC is advocated, with the majority (approximately 76%) of classic ILCs being grade 2 in the Nottingham histological grading system, and ILC of grade 3 comprising mostly a solid and pleomorphic subtype [3, 4]. Immunostaining with E-cadherin can help in distinguishing ILC from NST carcinomas, but as about 15% of ILCs also express E-cadherin (e.g. the tubulolobular variant), positive E-cadherin immunostaining should not be used to reclassify an ILC as an NST carcinoma.

Carcinomas with medullary features are an overlapping group of tumors with more or less ‘medullary’ appearance, and are described in a separate chapter of the new WHO classification. The authors advocate abandoning the terms medullary carcinoma, atypical medullary carcinoma and invasive carcinoma NST with medullary features, and recommend using the term carcinoma with medullary features for this group of tumors because of the overlapping morphological and immunohistological features and low interobserver reproducibility. The relatively good outcome of carcinomas with medullary features is attributed to the presence of a prominent lympho-plasmocytic infiltrate [5], and the presence of a B cell/plasma cell metagene in these tumors [6]. Carcinomas with medullary features are more common in patients with BRCA1 germ-line mutations.

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Metaplastic carcinoma represents a group of unrelated invasive breast cancers displaying differentiation of the tumor cells into squamous or mesenchymal-looking elements. This includes, but is not limited to, spindle, chondroid, osseous, and rhabdomyoid cells, and these elements may be mixed with carcinoma of usual type. Depending on their cellular features, metaplastic carcinomas may be either low-grade tumors (e.g. low-grade adenosquamous carcinoma or low-grade spindle cell carcinoma), or high-grade tumors (e.g. high-grade squamous cell carcinoma, or high-grade spindle cell carcinoma). Because of the heterogeneity of this group of tumors, a descriptive classification is advocated. As a group, metaplastic carcinomas typically are triple-negative tumors, but have worse prognosis than other forms of triple-negative breast cancers [7].

Carcinomas with apocrine differentiation mostly comprise tumors that are otherwise of no specific type; however, apocrine differentiation is also seen in special-type carcinomas, such as lobular, micropapillary, papillary, and medullary tumors [8]. The use of the term apocrine carcinoma is, therefore, discouraged, and tumors with apocrine differentiation should be classified according to their primary invasive type. These tumors are frequently negative for estrogen and progesterone receptors, and mostly, but not always, show androgen receptor expression and/or HER2 positivity [9]. Therefore, histologically defined apocrine differentiation overlaps with, but is not identical to, the molecular apocrine subtype of breast cancer [10].

Adenoid cystic carcinoma is the most frequently encountered salivary-type tumor of the breast and is, in the great majority of cases, a low-grade malignant tumor [11]. Recently, a recurrent chromosomal translocation t(6;9)(q22–23;p23–24), which leads to the formation of the MYB–NFIB fusion gene, has been described in adenoid cystic carcinoma [12]. Like other salivary-type tumors of the breast, it rarely spreads to the regional lymph nodes. Its characteristic histological and immunohistological features clearly distinguish this tumor from other types of invasive breast cancers. Variants, such as the solid variant with basaloid features, should be recognized, but a special grading system of adenoid cystic carcinoma has no practical value.

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Mucinous carcinomas and carcinomas with signet-ring cell differentiation are described together in the new WHO classification. Carcinomas with signet-ring cell differentiation are listed among the invasive breast carcinomas (table ​(table1),1), but are not regarded to represent a tumor type of its own. Rather, signet-ring cell differentiation may be observed either with invasive lobular carcinomas (mostly), where it is 1 pattern seen with the pleomorphic variant or with invasive carcinomas NST, and, rarely, also with high-grade mucinous carcinomas that otherwise show predominantly extracellular mucin production. No specific prognosis is believed to be associated with signet-ring cell differentiation.

Invasive mucinous carcinoma of the breast characteristically has a luminal mucinous A molecular subtype [10], but mucinous carcinomas presenting with large cell clusters as hypercellular or type B mucinous carcinomas [13] show a gene expression pattern that is similar to that of neuroendocrine carcinomas [14]. Prognostically, pure mucinous carcinomas have an excellent prognosis, but the outcome for mixed mucinous carcinomas is similar to NST tumors [15].

Invasive papillary carcinoma of the breast is regarded as a specially differentiated adenocarcinoma of the breast with papillary morphology, but otherwise no distinguishing clinical, genetic, or prognostic features. Invasive micropapillary carcinoma is a luminal-type breast cancer with a propensity for lymphovascular invasion and regional lymph-node metastasis. The possible relationship of this feature with an impaired prognosis for the patient remains to be determined; 1 report, however, has confirmed this association [19].

Exceptionally rare tumor types and variants include secretory carcinoma of the breast – a tumor with a distinctive genetic translocation occurring in young patients. Oncocytic carcinoma resembles oncocytic tumors of the kidney and thyroid. Other rare tumor types include polymorphous carcinoma, sebaceous carcinoma of the breast, lipid-rich carcinoma, glycogen-rich clear cell carcinoma, and acinic cell carcinoma.


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