Clinicopathologic and Immunophenotypic Classification of Invasive Lobular Carcinoma with Histiocytoid Features.

INTRODUCTION: Histiocytoid lobular breast carcinoma is a rare subtype of invasive lobular carcinoma characterized by relatively bland, uniform nuclei, single small eosinophilic nucleolus, and ample granular cytoplasm. These cancers are typically triple negative, show frequent androgen receptor (AR) positivity, and are therefore theorized to represent a variant of apocrine differentiation in invasive lobular carcinoma. Anecdotal evidence suggests that these tumors have excellent outcomes, though some studies suggest a variable clinical outcome. METHODS: Inclusion criteria included women with a histologic diagnosis of invasive lobular carcinoma with histiocytoid features, regardless of immunohistochemical profile, diagnosed at our institution between 2008 and 2021 with additional tissue still available for ancillary studies. We reviewed patients meeting these criteria and investigated hematoxylin and eosin-stained slides and a panel of immunohistochemical stains (estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 [HER2], AR, endothelial growth factor receptor, and keratin 5/6), as well as outcomes including survival and metastatic disease. RESULTS: Overall, 12 eligible patients were identified. The classical immunophenotype (triple negative with AR positivity) was noted in 4 out of 12 tumors. The majority of the remaining tumors (7 out of 12) showed a luminal B immunohistochemical profile, while 1 out of 12 was HER2-enriched. No patients in the cohort died from disease-related causes and 2 out of 12 presented with distant metastatic disease during their disease course. CONCLUSION: Histiocytoid lobular breast carcinoma is a morphologic variant of lobular carcinoma with apocrine features that shows a variable immunohistochemical profile and variable clinical behavior. Further subclassification and stricter diagnostic criteria may be helpful in the distinction between truly indolent tumors and those with more aggressive clinical features.

The role of PRAME and NY-ESO-1 as potential therapeutic and prognostic biomarkers in triple-negative breast carcinomas.

PRAME and NY-ESO-1 are cancer-testis antigens (CTAs) reported to be highly enriched in triple-negative breast cancers (TNBCs), against which vaccines and immunotherapies are currently being developed. This study aims to analyze PRAME and NY-ESO-1 expression in TNBCs and their correlation with clinical outcomes. This is a retrospective cohort study of TNBC patients who have undergone neoadjuvant chemotherapy. PRAME and NY-ESO-1 expression were assessed on pre-therapy biopsies as H-scores (percentage x intensity) with final H scores of 2-3 considered as positive. Association between expression and pathologic complete response (pCR), metastasis, and residual cancer burden (RCB) were assessed via logistic regression. Cox proportional hazards models were used to assess the association with progression-free survival. P-values < 0.05 were considered statistically significant. Sixty-three percent of 76 patients were positive for PRAME. In contrast, only 5 % were positive for NY-ESO-1. PRAME positivity was significantly associated with a lower likelihood of early metastatic disease (OR = 0.24, 95 % CI 0.08-0.62; P = 0.005). However, it was not significantly associated with pCR, RCB category, or progression-free survival. NY-ESO1 score was not significantly associated with early metastatic disease, pCR, RCB category, or progression-free survival. Our results suggest that PRAME positivity may be associated with a lower risk of early metastasis in TNBCs, but not with response to neoadjuvant chemotherapy or progression-free survival. The high expression of PRAME in TNBCs makes it a potential therapeutic target, while NY-ESO1 appears to be a less useful marker. However, further larger studies are needed to ascertain the utility of these markers.

Correlation of manual semi-quantitative and automated quantitative Ki-67 proliferative index with OncotypeDXTM recurrence score in invasive breast carcinoma.

BACKGROUND: Ki-67 immunohistochemistry (IHC) staining is a widely used cancer proliferation assay; however, its limitations could be improved with automated scoring. The OncotypeDXTM Recurrence Score (ORS), which primarily evaluates cancer proliferation genes, is a prognostic indicator for breast cancer chemotherapy response; however, it is more expensive and slower than Ki-67. OBJECTIVE: To compare manual Ki-67 (mKi-67) with automated Ki-67 (aKi-67) algorithm results based on manually selected Ki-67 "hot spots" in breast cancer, and correlate both with ORS. METHODS: 105 invasive breast carcinoma cases from 100 patients at our institution (2011-2013) with available ORS were evaluated. Concordance was assessed via Cohen's Kappa (κ). RESULTS: 57/105 cases showed agreement between mKi-67 and aKi-67 (κ 0.31, 95% CI 0.18-0.45), with 41 cases overestimated by aKi-67. Concordance was higher when estimated on the same image (κ 0.53, 95% CI 0.37-0.69). Concordance between mKi-67 score and ORS was fair (κ 0.27, 95% CI 0.11-0.42), and concordance between aKi-67 and ORS was poor (κ 0.10, 95% CI -0.03-0.23). CONCLUSIONS: These results highlight the limits of Ki-67 algorithms that use manual "hot spot" selection. Due to suboptimal concordance, Ki-67 is likely most useful as a complement to, rather than a surrogate for ORS, regardless of scoring method.

Clinicopathologic features of unexpectedly HER2 positive breast carcinomas: An institutional experience.

Human epidermal growth factor receptor 2 (HER2) overexpression occurs in 15-20 % of all breast carcinomas. These tumors are usually high-grade which often correlates with reduced overall survival and increased rates of recurrence. In a retrospective review, we identified 19 cases of unexpectedly HER2 positive (by immunohistochemistry and/or fluorescence in-situ hybridization) invasive breast carcinomas on core needle biopsies from a registry at Northwestern Memorial Hospital. These cases included low-grade tumors, invasive lobular carcinomas, classic type, and invasive carcinomas with special subtype features. Twelve of the tumors were histologic grade 1 and 7 were histologic grade 2. One of the grade 1 tumors had tubular features (8 %), 1 had cribriform features (8 %), 2 had mucinous features (17 %), 2 were invasive lobular carcinomas, classic type (17 %), and the rest were invasive carcinoma, no special type (50 %). The histologic grade 2 tumors included 5 invasive lobular carcinomas, classic type (71 %) and 2 invasive ductal carcinomas with mucinous features (29 %). By immunohistochemistry, 13 (65 %) were HER2 score 3+, 7 were score 2+ (35 %), and reflex fluorescence in-situ hybridization (FISH) testing showed amplification in 6 cases, with 1 equivocal case amplified on excision. Despite the HER2 positive status in the selected cases, no unique morphologic features that would indicate aggressive behavior were identified. In clinical follow up, two patients were found to have recurrences, five had lymph node metastasis, and one had distant metastasis. None of the patients with recurrent disease were treated with trastuzumab, despite their positive HER2 results. These findings support that our population of HER2 positive carcinomas showed a similar rate of lymph node metastases and recurrence as poorly-differentiated tumors, supporting HER2 positivity as a poor prognostic indicator, irrespective of morphologic features. We recommend continuing to test all breast cancers, regardless of grade or special subtype features, to provide the most comprehensive treatment and prognostic information for both clinicians and patients.