Rare subtypes of triple negative breast cancer: Current understanding and future directions

Abstract

Rare subtypes of triple-negative breast cancers (TNBC) are a heterogenous group of tumors, comprising 5-10% of all TNBCs. Despite accounting for an absolute number of cases in aggregate approaching that of other less common, but well studied solid tumors, rare subtypes of triple-negative disease remain understudied. Low prevalence, diagnostic challenges and overlapping diagnoses have hindered consistent categorization of these breast cancers. Here we review epidemiology, histology and clinical and molecular characteristics of metaplastic, triple-negative lobular, apocrine, adenoid cystic, secretory and high-grade neuroendocrine TNBCs. Medullary pattern invasive ductal carcinoma no special type, which until recently was a considered a distinct subtype, is also discussed. With this background, we review how applying biological principals often applied to study TNBC no special type could improve our understanding of rare TNBCs. These could include the utilization of targeted molecular approaches or disease agnostic tools such as tumor mutational burden or germline mutation-directed treatments. Burgeoning data also suggest that pathologic response to neoadjuvant therapy and circulating tumor DNA have value in understanding rare subtypes of TNBC. Finally, we discuss a framework for advancing disease-specific knowledge in this space. While the conduct of randomized trials in rare TNBC subtypes has been challenging, re-envisioning trial design and technologic tools may offer new opportunities. These include embedding rare TNBC subtypes in umbrella studies of rare tumors, retrospective review of contemporary trials, prospective identification of patients with rare TNBC subtypes entering on clinical trials and querying big data for outcomes of patients with rare breast tumors.

Fig. 1. Incidence estimates of uncommon solid tumors and rare triple negative breast cancer subtypes.

Solid tumors other than breast shown in blue. Rare subtypes of breast cancer shown in pink. Incidence is per 100,000 women/year in the United States (seer.cancer.gov/statfacts/)^,,. Light pink on top metaplastic breast cancer represents the possible extent of this tumor type which is likely underrepresented in databases due to diagnostic challenges and overlapping diagnosis codes^,,. (In comparison, the incidence of all breast cancer is 126.9/100,000 women/year in the United States.).

Fig. 2. Invasive ductal carcinoma of no special type - medullary pattern.

Morphologic features include high grade histology, syncytial architecture with no glandular structures, pushing margins, and prominent tumor infiltrating lymphocytes. (The term “syncytial growth” refers to a growth pattern characterized by broad, confluent bands of tumor cells more than five cells thick, often with indistinct cell borders). Previously, described as “medullary carcinoma”, “atypical medullary carcinoma”, or “carcinoma with medullary features”, it is no longer classified as a special histologic subtype of invasive carcinoma according to the current WHO Classification. It is rather considered part of the spectrum of invasive carcinoma no special type, representing one end of the spectrum of the tumor infiltrating lymphocyte rich invasive carcinomas. H&E stain. Magnification 200x.

Fig. 3. Metaplastic carcinoma.

A heterogeneous group of invasive carcinomas characterized by squamous or mesenchymal differentiation. a Matrix producing subtype, with chondroid matrix. b Spindle cell carcinoma, with high grade spindle cells. The neoplastic cells are positive for high molecular weight cytokeratin by immunohistochemistry (not shown). c Squamous cell carcinoma, showing squamous differentiation. H&E stain. Magnification 200x.

Fig. 4. Triple negative invasive lobular carcinoma.

Invasive lobular carcinoma, classic type, with discohesive neoplastic cells arranged in single file growth pattern invading the stroma. H&E stain. Magnification 200x. The picture insert demonstrates the absence of immunoreactivity for estrogen receptor (ER) in this tumor.

Fig. 5. Breast cancer intrinsic subtypes in TNBC no special type and triple negative invasive lobular carcinoma.

Portions of intrinsic molecular subtypes observed in TNBC no special type shown in blue and portions of subtypes observed in triple-negative invasive lobular carcinoma shown in orange. TNBC Triple negative breast cancer, NST No special type, ILC Invasive lobular carcinoma, HER2 Human epidermal growth factor receptor 2.

Fig. 6. Carcinoma with apocrine differentiation.

The neoplastic cells have abundant eosinophilic cytoplasm, enlarged nuclei with prominent nucleoli. The tumor cells are often positive for androgen receptor (AR). H&E stain. Magnification 200x.

Fig. 7. Adenoid cystic carcinoma.

An example of classic adenoid cystic carcinoma, composed of epithelial and myoepithelial neoplastic cells, arranged in cribriform growth patterns. Pseudolumina are filled with basement membrane material. H&E stain. Magnification 200x.

Fig. 8. Secretory carcinoma.

The tumor cells have abundant intracytoplasmic vacuoles and extracellular secretions. H&E stain. Magnification 200x.

Fig. 9. Small cell carcinoma.

High grade carcinoma exhibiting neuroendocrine morphology with hyperchromatic cells, high N:C ratio, and scant cytoplasm. Immunohistochemical stains show the tumor cells are positive for cytokeratin, neuroendocrine markers (synaptophysin, chromogranin), negative for TTF-1, with high Ki67 proliferation index (>90%) and loss of RB protein expression (not shown). Magnification 200x.