Unusual and Rare Tumors of the Breast

Introduction

The rare tumors of the breast are a heterogeneous group of typically triple-negative tumors. With some notable exceptions, these tumors are low grade and are relatively indolent despite their triple-negative status and frequent basal phenotype. These tumors can be divided into those with putative salivary gland analogs and those without. The nonsalivary gland type tumors include acinic cell carcinoma (ACC), tall cell carcinoma with reversed polarity, mucinous cystadenocarcinoma (MCA), neuroendocrine carcinoma, and carcinoma with apocrine differentiation. The salivary gland type malignancies of the breast include adenoid cystic carcinoma (AdCC), secretory carcinoma, mucoepidermoid carcinoma (MEC), and polymorphous carcinoma, among others.

Rare Tumors Without Salivary Gland Analogs

Acinic Cell Carcinoma

ACC of the breast is an infiltrative malignant epithelial neoplasm composed of large polygonal cells with clear to amphophilic cytoplasm containing PAS-positive diastase-resistant zymogen granules. It typically presents as a palpable mass with no site predilection in adult women (age range 20–80 years, mean 50 years), although a single case has been identified in a man. Grossly it is a firm, solid, infiltrative nodule.

On histologic examination, ACC is an infiltrative tumor showing variable architecture ranging from microcystic to solid nests, sometimes with comedo-type necrosis. The cells have a characteristic polygonal appearance with abundant clear to amphophilic granular cytoplasm containing zymogen granules. The centrally located nucleus often exhibits a prominent nucleolus. Cellular atypia and mitotic figures are more prominent in solid areas. High-grade ductal carcinoma in situ (DCIS) may be present.

Immunophenotypically, ACCs are positive for markers of serous acinar differentiation, including amylase, lysozyme, and α-1-antichymotrypsin. S-100, EMA, and low molecular weight keratins are also consistently positive, and there is variable expression of GCDFP-15 and E-cadherin. ACCs are typically triple negative but can rarely express ER and PR. HER2 and smooth muscle actin (SMA) are consistently negative, and AR is usually negative (1 of 10 cases). ACCs have PAS-positive diastase-resistant zymogen granules.

While ACC of the breast is superficially histologically similar to ACC of the salivary gland, molecular studies show that it has more in common with typical triple-negative breast cancer (TNBC) than with salivary gland ACC. Like TNBC, these tumors have a high mutational load with complex genetic abnormalities including frequent mutations of TP53 (80%), PIK3CA (10%), KMT2D , ERBB4 , ERBB3 , NEB , BRCA1 , MTOR , CTNNB1 , INPP4B , and FGFR2 , as well as recurrent 8q gains and 5q losses. In contrast, ACCs of the salivary gland have a low mutational load and harbor recurrent t(4;9)(q13;q31) translocations involving NR4A3 that are not present in ACCs of the breast. Due to these factors, authors have decided to classify them as not having salivary gland analog, in contrast to WHO classification of tumours.

The histologic differential diagnosis for ACC includes high-grade invasive ductal carcinoma, oncocytic carcinoma, apocrine carcinoma, and secretory carcinoma. Immunohistochemical proof of serous acinar differentiation can narrow the differential, as can the presence of abundant PAS-positive diastase-resistant granules. Positivity for AR supports apocrine carcinoma over ACC. Low-grade ACC can be difficult to distinguish from secretory carcinoma, but secretory carcinoma lacks electron-dense granules by electron microscopy and has a consistent ETV6-NTRK3 fusion.

Despite its triple-negative status and molecular evidence of molecular similarities to typical triple-negative invasive ductal carcinoma, ACC has low to intermediate aggressive behavior. In the 30 reported cases in the literature with follow-up, nine patients had axillary nodal metastases, and three had distant metastases to the liver, lung, and bone, respectively, resulting in death in two cases. However, most patients had no evidence of recurrence on follow-up (6–184 months, mean 42 months). Notably, most patients also received adjuvant therapy in addition to surgery (see Fig. 25.1 ).

Tall Cell Carcinoma With Reversed Polarity

Tall cell carcinoma with reversed polarity (TCCRP) is a rare subtype of invasive breast carcinoma with tall columnar cells exhibiting reversed (apically oriented) nuclear polarity that is histologically reminiscent of the tall cell variant of papillary thyroid carcinoma. Clinically the tumor presents as a palpable or mammographic mass with no particular site predilection, typically in older adult women (ages 45–85 years, median 64 years), with a median size of 1.3 cm (range 0.6–5 cm). Lymph node metastases are rare, with >90% being N0 at presentation.

Histologically, TCCRP is a multinodular lesion with predominantly solid, and occasionally papillary or follicular, architecture infiltrating a dense stroma. The cells of this tumor are tall columnar with abundant eosinophilic cytoplasm and nuclei showing nuclear elongation, clearing, nuclear grooves, and nuclear pseudo-inclusions, strikingly similar to the tall cell variant of papillary thyroid carcinoma. The cells are often arranged in a bilayer pattern with abutting apical surfaces, with or without a slit-like lumen. Foamy histiocytes are commonly seen in the fibrovascular cores. Despite their circumscribed appearance, the nodules are not lined by myoepithelial cells, indicating an invasive process.

Immunophenotypically, TCCRPs stain strongly and diffusely for CK7, CK5/6, and CK34BE12. Calretinin staining is generally positive, either diffusely or focally. E-cadherin strongly stains the lateral membranes but not the apical or basal membranes, while MUC1 stains the apical surface. There is variable expression of GCDFP-15 and mammaglobin, with each positive in roughly 60% of tumors. GATA-3 positivity has also been reported. Roughly two-thirds of the tumors are triple negative, but about 36% weakly express ER (<10% of cells), and approximately 20% weakly express PR (<10% of cells). HER2 is consistently negative. AR is weakly positive (<10% of cells) in 32% of cases. TTF-1, thyroglobulin, chromogranin, and synaptophysin are uniformly negative. P63 is negative in >95% of cases. Interrogation for myoepithelial cells by p63, calponin, and smooth muscle myosin heavy chain is consistently negative. Ki67 index was low (<5%) in the two cases examined.

Molecular studies show a low mutational load with a mutational hotspot at residue R172 of isocitrate dehydrogenase 2 (IDH2) in >87% of TCCRPs. In the breast, this hotspot appears to be specific to TCCRP, as it has not been identified in any other breast tumor. Additional mutations in PI3K pathway genes, in particular PI3KCA , have been identified in more than two-thirds of cases.

The histologic differential includes various papillary neoplasms of the breast, including solid papillary, encapsulated papillary carcinoma, and intraductal papilloma, as well as metastatic papillary thyroid carcinoma. Fortunately this differential is readily sorted out, as none of these lesions have reversed nuclear polarity and most papillary neoplasms of the breast are strongly ER-positive. Additionally, encapsulated papillary carcinoma is CK5/6-negative, and intraductal papilloma will show myoepithelial cells when interrogated with p63 and calponin. Papillary thyroid carcinoma can readily by excluded by a TTF-1 stain. In difficult cases, molecular evaluation of the R172 mutational hotspot in IDH2 can be helpful.

TCCRP follows an indolent course. Of 42 patients for whom clinical follow-up was available (range 3–132 month, median 29 months), 94% were disease-free during the follow-up period, one had a local recurrence, and one had a bone metastasis. This was true despite the fact that two-thirds of the patients did not have adjuvant therapy after surgery (see Fig. 25.2 ).