Is ultrasound-guided fine needle aspiration biopsy of axillary lymph nodes a viable alternative to sentinel lymph node biopsy?

BACKGROUND: Axillary lymph node (ALN) ultrasound-guided fine needle aspiration biopsy (US-FNAB), a minimally invasive procedure, may be used for the preoperative evaluation of ALN status of breast cancer patients. Despite the relative ease of use and low cost, paucity of comparative studies and variation in the reported sensitivity of FNAB preclude its clinical utility in evaluation of ALNs. This study aims to determine the accuracy of US-FNAB in detecting metastasis in ALN pre-operatively and to assess US-FNAB as a viable alternative to sentinel lymph node (SLN) excision. METHODS: The 228 consecutive ALN US-FNABs with subsequent histologic follow up performed from 2005 to 2020 in patients with breast carcinoma were retrospectively evaluated. FNAB results were correlated with histologic diagnosis. Sensitivity, specificity, accuracy, and risk of malignancy of FNAB were calculated. RESULTS: 157/228 (69%) FNABs were concordant with histology, 37/228 (16%) discordant. Positive FNAB findings correlated with primary tumor size, grade, number of metastatic lymph nodes and size of metastases. FNAB with negative diagnosis carried a 22% risk of malignancy, atypical 43%, suspicious 80%, and positive a 100% risk of malignancy (100% positive predictive value [PPV]). The sensitivity and specificity were 78% and 95% respectively; accuracy was 77%. SLN biopsy was avoided in all 82 (36%) cases with positive FNAB results. CONCLUSION: Negative FNAB result does not exclude metastatic carcinoma. With 100% PPV, full ALN dissection and/or neoadjuvant chemotherapy can be safely planned after a positive FNAB result, avoiding SLN biopsy, reducing management costs and shortening time interval to definitive therapy.

TROP-2, 5hmC, and IDH1 Expression in Anaplastic Thyroid Carcinoma.

BACKGROUND: Anaplastic thyroid carcinoma (ATC), a highly aggressive malignancy, has no effective treatment to date. Trophoblast cell-surface antigen 2 (TROP-2), a transmembrane glycoprotein, has been suggested to be a promising novel target for sacituzumab govitecan, an antibody-drug conjugate. 5-Hydroxymethylcytosine (5hmC) has a role in tumor suppression and promoting modification. Additionally, isocitrate dehydrogenase 1 (IDH1) mutations are strongly associated with increased overall survival in gliomas and worse prognosis in leukemias. This study attempts to evaluate the immunoexpression of TROP-2, 5hmC, and IDH1 in ATCs and to determine their potential impact in targeted therapy. METHODS: Twenty-four ATCs were retrieved, with 9 cases that occurred de novo and 15 cases derived from either papillary thyroid carcinoma (PTC) or follicular thyroid carcinoma (FTC). Sections were immunostained with TROP-2, 5hmC, and IDH1 antibodies, and evaluated using the QuPath program. The t tests were performed using SPSS software. RESULTS: TROP-2 was detected in 12 ATCs with 9 cases demonstrating a high expression and in all PTC components, and absent in all FTC components of secondary ATCs. 5hmC expression was moderately reduced in PTC and FTC components and markedly reduced in ATC. The entire cohort showed a total absence of IDH1. CONCLUSIONS: Increased TROP-2 immunoexpression in some ATCs supports that these patients may potentially benefit from an antibody-drug conjugate therapy targeting TROP-2. Markedly reduced 5hmC expression suggests that 5hmC may be used as potential therapeutic targets for ATC. The total lack of IDH1 R132H mutation by immunostain indicates that it has no prognostic and therapeutic value in ATC.

Androgen receptor positive triple negative breast cancer: Clinicopathologic, prognostic, and predictive features.

INTRODUCTION: Overexpression of the androgen receptor (AR) characterizes a distinct molecular subset of triple negative breast carcinomas (TNBC). The role of AR as a prognostic/predictive biomarker in TNBC is controversial, but increasing evidence suggests that this subset may respond to therapeutic agents targeting AR. Evaluation of AR has not been standardized, and criteria for selection of patients for antiandrogen therapy remain controversial. In this study we determine the appropriate threshold of AR immunoreactivity to define AR positive (AR+) TNBC, describe the clinicopathologic features of AR+ TNBC, and discuss the utility of AR positivity as a prognostic and predictive marker in TNBC. MATERIALS AND METHODS: 135 invasive TNBC processed in accordance with ASCO/CAP guidelines, were immunostained for AR. Clinicopathologic features of AR+ TNBC were analyzed and compared to AR negative (AR-) TNBC. Patients' age, tumor size, tumor grade, lymph node status, proliferation rate, immunopositivity for EGFR, CK5/6, Ki-67, and disease free survival (DFS) were evaluated statistically. RESULTS: A 1% cutpoint was confirmed as the appropriate threshold for AR positivity. Using this cutpoint 41% of 135 TNBC were AR+. AR+ TNBC occurred in older women, were larger, had lower mean proliferation rate and increased incidence of axillary metastasis than AR- TNBC. 76% of TNBC with apocrine morphology were AR+. A subset of AR+TNBC expressed basal markers (EGFR and CK5/6). A prognostic model was created. SUMMARY: AR identifies a heterogeneous group of TNBC. Additional evaluation of EGFR expression allowed us to stratify TNBCs into 3 risk groups with significant differences in DFS and therapeutic implications: low-risk (AR+ EGFR-) which represents the LAR molecular subtype with the best prognosis and may benefit the most from anti-androgen therapies; high-risk (AR- EGFR+) which represents the basal molecular subtype with the worst prognosis and may benefit the most from chemotherapy regimens; intermediate-risk (AR+EGFR+ and AR-EGFR-) TNBC with an intermediate prognosis. Prospective trials are required to further validate this prognostic and predictive grouping.

Stratification of Prognosis of Triple-Negative Breast Cancer Patients Using Combinatorial Biomarkers.

BACKGROUND: Triple-negative breast cancer (TNBC) is highly diverse group of cancers, and generally considered an aggressive disease associated with poor survival. Stratification of TNBC is highly desired for both prognosis and treatment decisions to identify patients who may benefit from less aggressive therapy. METHODS: This study retrieved 192 consecutive non-metastasis TNBC patients who had undergone a resection of a primary tumor from 2008 to 2012. All samples were negative for ER, PR, and HER2/neu. Disease-free-survival (DFS) and overall-survival (OS) were evaluated for expression of immunohistochemical biomarkers (P53, Ki-67, CK5/6 and EGFR), as well as clinicopathological variables including age, tumor size, grade, lymph node status, pathologic tumor and nodal stages. The cutoff values of the basal biomarkers, EGFR and CK5/6, were estimated by time-dependent ROC curves. The prognostic values of combinatorial variables were identified by univariate and multivariate Cox analysis. Patients were stratified into different risk groups based on expression status of identified prognostic variables. RESULTS: Median age was 57 years (range, 28-92 years). Patients' tumor stage and nodal stage were significantly associated with OS and DFS. EGFR and CK5/6 were significant prognostic variables at cutoff points of 15% (p = 0.001, AUC = 0.723), and 50% (p = 0.006, AUC = 0.675), respectively. Multivariate Cox analysis identified five significant variables: EGFR (p = 0.016), CK5/6 (p = 0.018), Ki-67 (p = 0.048), tumor stage (p = 0.010), and nodal stage (p = 0.003). Patients were stratified into low basal (EGFR≤15% and CK5/6≤50%) and high basal (EGFR>15% and/or CK5/6>50%) expression groups. In the low basal expression group, patients with low expressions of Ki-67, low tumor and nodal stage had significantly better survival than those with high expressions/stages of three variables, log-rank p = 0.015 (100% vs 68% at 50 months). In the high basal expression group, patient with high basal expression of both biomarkers (EGFR >15% and CK5/6 >50%) had worse survival (mean DFS = 25 months, 41.7% event rate) than those patient with high expression of either one marker (mean DFS = 34 months, 25.5% event rate). CONCLUSIONS: Immunoexpression of basal biomarkers, EGFR and CK5/6, is useful in predicting survival of TNBC patients. Integrated with Ki-67, tumor and nodal stages, combinatorial biomarker analysis provides a feasible clinical solution to stratify patient risks and help clinical decision-making with respect to selecting the appropriate therapies for individual patients.

Clinicopathological significance of HER2/neu genetic heterogeneity in HER2/neu non-amplified invasive breast carcinomas and its concurrent axillary metastasis.

BACKGROUND: HER2/neu (HER2) is a significant prognostic marker for breast carcinomas. Recently, new guidelines defining HER2 genetic heterogeneity (GH) were published by the College of American Pathologists. AIMS: To determine the prevalence of HER2 GH as defined in primary invasive breast carcinoma, to determine its relationship with prognostic variables and to investigate its impact on concurrent axillary metastasis. METHODS: 235 consecutive infiltrating breast carcinomas were evaluated for GH (defined as presence of 5-50% of neoplastic cells with HER2/CEP17 ratio >2.2) using fluorescence in situ hybridisation. Pathological features of carcinomas with GH were compared with those lacking GH. GH was also evaluated in a subset of 37 paired primary carcinomas and its concurrent axillary nodal metastases using dual in situ hybridisation. RESULTS: HER2 GH was noted in 27% of HER2 negative breast carcinomas. These carcinomas demonstrated aggressive characteristics (larger size, higher grade and greater incidence of lymph node metastasis) in comparison with HER2 negative cases without GH. Higher levels of GH were associated with the equivocal HER2 status. GH was maintained in the concurrent lymph node metastases with some variations; however, two cases with clusters of HER2 amplified cells in the primary carcinoma showed HER2 amplification in the nodal metastasis. CONCLUSIONS: HER2 GH is present in 27% of breast carcinomas, portends an aggressive phenotype and contributes to the equivocal HER2 status. Evaluation of the HER2 status in nodal metastasis of select primary carcinomas with GH may be beneficial before treatment selection.

Intraductal papillary lesions of the breast: clinical and pathological correlation.

Papillary lesions of the breast range from a spectrum of benign intraductal papillomas with and without atypia to papillary carcinoma. Distinction between benign and malignant lesions on core needle biopsy (CNB) is difficult without surgical excision. We examined if clinical findings in patients with benign intraductal papillomas (IP) on CNB correlate with pathology at surgical excision. Between 1998 and 2011, 103 patients were identified with a papillary lesion on CNB. Clinical variables were studied to determine if there was clinical correlation with pathological outcomes at final surgical excision. Of the 103 patients, 59 (57%) patients had IP on initial CNB and were included in our analysis. On final pathology, 17 (29%) of these were upstaged to intraductal papilloma with atypia and six (10%) were found to have carcinoma. A clinically palpable mass was the only significant predictor of upstaging to malignancy (P<0.05). No radiographic findings were found to be significant predictors of pathological upstaging. In conclusion, surgical excision is still recommended for benign papillary lesions diagnosed on CNB because the correlation with clinical and radiological findings does not assure benign pathology.