Predictive value of breast magnetic resonance imaging in detecting mammographically occult contralateral breast cancer: Can we target women more likely to have contralateral breast cancer?

BACKGROUND AND OBJECTIVES: Preoperative breast magnetic resonance imaging (B-MRI) staging in newly diagnosed breast cancer increases detection of synchronous contralateral findings, but may result in false-positive outcomes. This study objective was to identify women more likely of having mammographically occult, MRI detected contralateral breast cancer (CBC). METHODS: We performed a retrospective review of patients who had preoperative B-MRI prior to surgery from 2010 to 2015 and collected patient imaging and clinicopathologic data. Multivariate logistic regression was used to identify predictors of CBC. RESULTS: MRI resulted in contralateral findings in 201 of 1894 patients (10.6%). Overall 3.2% (60 of 1894) had synchronous CBC detected on B-MRI. The majority of CBCs (n = 60) were stage 0 or IA (85.0%), hormone receptor positive (94.9%), human epidermal growth factor receptor 2 (HER2/neu) negative (89.7%), and low/intermediate pathological grade (87.2%). Women more likely to have CBC were older (P < .001), had lobular index cancer (P = .03), and estrogen receptor (ER)+ (P = .027) or progesterone receptor (PR)+ (P = .002) tumors. On multivariate analysis (receiver operating characteristic curve area = 0.75), PR + status (P = .022), and older age (P = .004) were predictive of CBC. CONCLUSIONS: Preoperative MRI is most effective in detecting early stage, hormone receptor-positive CBC in older women.

Clinicopathologic analysis of a large series of microinvasive breast cancers.

Clinical management of microinvasive breast cancer (Tmic) remains controversial. Although metastases are infrequent in Tmic carcinoma patients, surgical treatment typically includes lymph node sampling. The objective of this study was to determine the rate and predictors of lymph node metastases, recurrence, and survival in a large series of Tmic breast carcinomas. Consecutive cases of Tmic were identified within our health care system from 2001 to 2015. We reviewed results of lymph node sampling and other pathologic factors including hormone receptor/HER2 status, associated in situ tumor size/grade, margin status, number of invasive foci, surgical/adjuvant therapies, and recurrence/survival outcomes. In this cohort, 294 Tmic cases were identified with mean follow-up of 4.6 years. Of 260 patients who underwent axillary staging, lymph node metastases were identified in 1.5% (all of which were ductal type). All Tmic cases with positive lymph node metastases had associated DCIS with size > 5 cm (5.3-8.5 cm) compared to a median DCIS tumor size of 2.5 cm (0.2-19.0 cm) for the entire cohort. No lymph node metastases were seen with microinvasive lobular carcinoma. During the follow-up period, there were no regional/distant recurrences or breast cancer-associated deaths in a mean follow-up period of 4.6 years. Two patients developed subsequent ipsilateral breast cancer (DCIS) in a different quadrant than the original Tmic. Clinical behavior of microinvasive breast cancer in this series is similar to DCIS. Lymph node metastases are uncommon and were only seen with ductal type microinvasive carcinoma. Our data suggest limited benefit for routine node sampling and support management of Tmic similar to DCIS, particularly for patients with DCIS < 5 cm in size.

HER2 Testing Characteristics Can Predict Residual Cancer Burden following Neoadjuvant Chemotherapy in HER2-Positive Breast Cancer.

OBJECTIVES: The response to HER2-targeted neoadjuvant chemotherapy (NAC) in HER2-positive (+) breast cancer can be quantified using residual cancer burden (RCB) pathologic evaluation to predict relapse free/overall survival. However, more information is needed to characterize the relationship between patterns of HER2 testing results and response to NAC. We evaluated clinicopathologic characteristics associated with RCB categories in HER2+ patients who underwent HER2-directed NAC. METHODS: A retrospective chart review was conducted with Stage I-III HER2+ breast cancer cases following NAC and surgical resection. HER2 immunohistochemistry (IHC) staining and fluorescence in situ hybridization (FISH), histologic/clinical characteristics, hormone receptor status, and RCB scores (RCB-0, RCB-I, RCB-II, and RCB-III) were evaluated. RESULTS: 64/151 (42.4%) patients with HER2+ disease had pathologic complete response (pCR). Tumors with suboptimal response (RCB-II and RCB-III) were more likely to demonstrate less than 100% HER2 IHC 3+ staining (p < 0.0001), lower HER2 FISH copies (p < 0.0001), and lower HER2/CEP17 ratios (p = 0.0015) compared to RCB-I and RCB-II responses. Estrogen receptor classification using ≥10% versus ≥1% staining showed greater association with higher RCB categories. CONCLUSIONS: HER2+ characteristics show differing response to therapy despite all being categorized as positive; tumors with less than 100% IHC 3+ staining, lower HER2 FISH copies, and lower HER2/CEP17 ratios resulted in higher RCB scores.

HER2 Testing: Insights From Pathologists' Perspective on Technically Challenging HER2 FISH Cases.

OBJECTIVE: College of American Pathologists and the American Society of Clinical Oncology guidelines provide straightforward criteria for HER2 interpretation in breast carcinomas; however, a subset of cases present unusual diagnostic dilemmas. MATERIALS AND METHODS: Ten challenging HER2 fluorescence in situ hybridization (FISH) cases were selected for analysis. The study included a variety of problematic cases such as those with discordant immunohistochemistry (IHC) and FISH results, cases with high intratumoral variability in HER2 copy number, a case with a highly amplified clone in 5% to 10% of the tumor sample, and a case with tumor cells containing tightly clumped HER2 signals. Six high volume HER2 FISH laboratories performed and interpreted HER2 FISH (adding HER2 IHC if necessary). Interpretation strategies were discussed. RESULTS: There was 100% concordance between laboratories in 4/10 cases. Tumors with increased intratumoral variability (tumors with high variability in HER2 copy number per cell but which otherwise do not fulfill College of American Pathologists and the American Society of Clinical Oncology criteria for heterogeneity) exhibited 100% concordance in 3/4 cases, but 1 case had only 50% agreement. Low positive HER2 cases (group 1 cases with <6 average HER2 copies/cell) had 1 laboratory disagreeing with the majority in 4/4 cases, and this was the only category with discordance between IHC and FISH methodologies. All laboratories identified the case with heterogeneity and interpreted it as positive. Five of the 6 laboratories interpreted the case with tightly clustered HER2 signals as positive. CONCLUSIONS: This study offers specific observations and interpretation strategies that laboratories can use when confronted with difficult HER 2 cases. It then highlights communication strategies a laboratory may use to discuss these unusual HER2 results with the clinical team.

Effects of Germline Pathogenic Variants, Cancer Subtypes, Tumor-related Characteristics, and Pregnancy-associated Diagnosis on Outcomes.

BACKGROUND: Although breast cancer (BC) is uncommon in women age ≤ 35 years, women in this age group may have more aggressive cancer subtypes and high-risk pathogenic variants (HRPVs). Higher recurrence and mortality rates in young patients may be related to differences in tumor biology, pathologic mutation status, or treatment. The purpose of this study was to evaluate germline mutation status and other factors that affect recurrence-free survival (RFS) and overall survival (OS) in young women with BC. MATERIALS AND METHODS: This was a retrospective study of women diagnosed with BC at age ≤ 35 years at Allina Health System from 2000 through 2017 (n = 306). Information was collected on germline mutation status, tumor characteristics (grade, hormone receptor, and human epidermal growth factor receptor 2), molecular subtype, pregnancy-associated cancers, and treatment. Survival analyses using Kaplan-Meier curves were conducted for RFS and OS. RESULTS: With mean follow-up of 6.5 years, OS was 87.0% for invasive cancers, RFS was 84.7%; 69% obtained genetic testing, and 26.9% had HRPVs. There were no differences in RFS or OS between patients with HRPV versus unknown/low/moderate risk variants. Recurrence analysis showed increased recurrence rates in luminal B-like cancers followed by triple negative and human epidermal growth factor receptor 2-positive cancers (P = .041). Pregnancy-associated BC diagnoses, angiolymphatic invasion, and tumor stage were associated with reduced OS. In spite of young age at diagnosis, nearly one-third of patients did not receive germline genetic testing. CONCLUSIONS: Similar survival patterns were found between women with HRPV versus no known mutations. Luminal B-like subtype, pregnancy-associated BC, angiolymphatic invasion, and cancer stage were associated with reduced OS.

Utility of Oncotype DX Risk Assessment in Patients With Invasive Lobular Carcinoma.

INTRODUCTION/BACKGROUND: Oncotype DX (Genomic Health, Redwood City, CA) uses reverse transcriptase polymerase chain reaction analysis to measure tumor gene expression for determining recurrence risk (RR) and guiding chemotherapy decisions for breast cancer patients. Invasive lobular carcinoma (ILC) is a histologic subtype that has not been the focus of prior studies validating Oncotype DX. The study purpose was to develop a model using histologic tumor characteristics to predict uniformly low Oncotype DX Recurrence Scores (RS) in ILC. PATIENTS AND METHODS: ILC cases in our pathology database with Oncotype DX testing were identified. Histologic tumor characteristics, immunohistochemical (IHC) of estrogen receptor (ER)/progesterone receptor (PgR) percent, HER2, E-cadherin expression, and Ki-67 levels were obtained for cases. Discriminant analysis was used to test the hypothesis that tumors classified as lower/higher risk based on Oncotype DX RS would differ significantly on a linear combination of variables. RESULTS: From 2006 - 2014, 158 cases of ILC having Oncotype DX testing were identified; 90 low risk (RS < 18), 66 intermediate risk (RS 18 - 30) and 2 high risk (RS > 30). Discriminant analysis showed that PgR% followed by Ki-67 provided the greatest contribution to discern low versus elevated RS. A subset of 57 cases (∼36%) with predicted probabilities > 86% for either low or high RS yielded 96.5% correct classification, 92.3% sensitivity, and 97.7% specificity. CONCLUSION: Our analytical model may be useful in predicting lower RR in patients with ILC. If validated, this provides a faster and less expensive alternative to Oncotype DX testing in certain patients with ILC.

Surgical Outcomes of Lobular Neoplasia Diagnosed in Core Biopsy: Prospective Study of 316 Cases.

BACKGROUND: Management recommendations for lobular neoplasia (LN) including lobular carcinoma-in-situ (LCIS) and atypical lobular hyperplasia (ALH) diagnosed in core biopsies (CB) are controversial. Our aim was to prospectively identify a subset of patients who do not require subsequent surgical excision (SE). PATIENTS AND METHODS: All patients diagnosed with LN on CB were enrolled and referred for SE. Cases with coexistent ductal carcinoma-in-situ or invasive carcinoma were excluded. Cases with coexistent ductal atypia (LN-DA) and LCIS variants (LN-V) were separated from pure classic LN (LN-C). Dedicated breast pathologists and radiologists reviewed cases with careful imaging/pathology correlation. RESULTS: Of 13,772 total percutaneous breast CB procedures, 302 of 370 patients diagnosed with LN underwent SE. Upgrade to carcinoma was present in 3.5% (8/228) LN-C, 26.7% LN-V (4/15), and 28.3% LN-DA (15/53). Calcifications were the imaging target for 180 (79%) of 228 LN-C cases; 7 were associated with upgrade (3.9%). Upgrades were rare for mass lesions (1/32) and magnetic resonance imaging-targeted lesions (0/14). Upgrades were similar for ALH and LCIS (3.4% vs. 4.5%). During postsurgical follow-up (mean, 34.5 months), 6.5% LN-C patients developed carcinoma in either breast. CONCLUSION: Although LN with nonclassic morphology or with associated ductal atypia requires SE, this can be avoided in LN-C diagnosed on CB targeting calcifications when careful imaging/pathology correlation is applied. Until larger numbers are studied, excising LN-C diagnosed as masses or magnetic resonance imaging-detected lesions may be prudent. Regardless of their selection for surgical management, LN patients need close surveillance in view of their long-term risk of breast cancer.

Interpretive Diagnostic Error Reduction in Surgical Pathology and Cytology: Guideline From the College of American Pathologists Pathology and Laboratory Quality Center and the Association of Directors of Anatomic and Surgical Pathology.

CONTEXT: Additional reviews of diagnostic surgical and cytology cases have been shown to detect diagnostic discrepancies. OBJECTIVE: To develop, through a systematic review of the literature, recommendations for the review of pathology cases to detect or prevent interpretive diagnostic errors. DESIGN: The College of American Pathologists Pathology and Laboratory Quality Center in association with the Association of Directors of Anatomic and Surgical Pathology convened an expert panel to develop an evidence-based guideline to help define the role of case reviews in surgical pathology and cytology. A literature search was conducted to gather data on the review of cases in surgical pathology and cytology. RESULTS: The panel drafted 5 recommendations, with strong agreement from open comment period participants ranging from 87% to 93%. The recommendations are: (1) anatomic pathologists should develop procedures for the review of selected pathology cases to detect disagreements and potential interpretive errors; (2) anatomic pathologists should perform case reviews in a timely manner to avoid having a negative impact on patient care; (3) anatomic pathologists should have documented case review procedures that are relevant to their practice setting; (4) anatomic pathologists should continuously monitor and document the results of case reviews; and (5) if pathology case reviews show poor agreement within a defined case type, anatomic pathologists should take steps to improve agreement. CONCLUSIONS: Evidence exists that case reviews detect errors; therefore, the expert panel recommends that anatomic pathologists develop procedures for the review of pathology cases to detect disagreements and potential interpretive errors, in order to improve the quality of patient care.

HER2 assessment by immunohistochemical analysis and fluorescence in situ hybridization: comparison of HercepTest and PathVysion commercial assays.

We determined HER2 protein overexpression by immunohistochemical analysis and HER2 gene amplification by fluorescence in situ hybridization (FISH) in 215 formalin-fixed, paraffin-embedded breast tumors. Pathologist concordance for immunohistochemical scoring, and HER2 status concordance, as determined by immunohistochemistry and FISH, were high for immunohistochemical 3+, 1+, and 0 tumors but poor for 2+ tumors. Consensus immunohistochemical scores correlated with absolute and chromosome 17 (CEPI 7)-corrected HER2 gene copy number Among HER2-nonamplified tumors, the immunohistochemical score and mean absolute chromosome 17 (CEP17) copy number were weakly correlated. Seventeen tumors were HER2-amplified using absolute HER2 gene criteria but nonamplified when corrected for chromosome 17 polysomy (8 of these were immunohistochemical 2+). Assessment of benign epithelium within the immunohistochemical slides revealed either no staining or basolateral membrane staining, suggesting normal HER2 protein expression. Twenty tumors showing similar basolateral HER2 immunostaining were all low-moderate grade, tubule-forming, and HER2-nonamplified (17) or borderline amplified (3). Additional studies relating changes in HER2 gene content due to amplification or chromosome 17 polysomy and HER2 protein expression may be helpful to pathologists who interpret HER2 immnuohistochemical slides. Breast tumors scored at 2+ should be analyzed by FISH, preferably using a dual-probe FISH assay capable of distinguishing HER2 gene amplification from chromosome 17 polysomy.

Choroidal biopsy of a patient with AIDS and systemic tuberculosis: a clinicopathologic case report.

PURPOSE: To report a case of Mycobacterium tuberculosis choroidal granuloma confirmed by the presence of acid-fast bacilli seen on subretinal biopsy of the choroidal lesion. METHODS: Observational case report. A 54-year-old woman with AIDS and systemic tuberculosis reported decreased vision in the right eye for 2 months duration. RESULTS: Subretinal biopsy showed granulomatous inflammation, and acid-fast bacilli were identified on the acid-fast bacilli stain. CONCLUSION: In cases of presumed tuberculosis choroidal granuloma not initially responsive to tuberculosis therapy, biopsy of the choroidal mass can be beneficial to confirm the diagnosis and guide treatment.

Pathologic evaluation of axillary dissection specimens following unexpected identification of tumor within sentinel lymph nodes.

CONTEXT: Axillary lymph node dissection has been the standard of care after identification of a positive sentinel lymph node for breast cancer patients. OBJECTIVE: To determine the likelihood of non-sentinel lymph node involvement for patients with negative sentinel node by frozen section, who are subsequently found to have tumor cells in the sentinel node by permanent section levels and/or cytokeratin immunohistochemistry. DESIGN: One hundred three patients with invasive breast cancer exhibiting negative frozen section evaluation of their sentinel node, but later found to have isolated tumor cells (n  =  46), micrometastasis (n  =  46), or metastases (n  =  11) in their sentinel node by permanent sections or immunohistochemistry, were enrolled in this prospective cohort study and underwent completion axillary dissection. RESULTS: Six of 46 patients (13%) with isolated tumor cells in their sentinel node, 15 of 46 patients (33%) with micrometastasis in their sentinel node, and 2 of 11 patients (18%) with metastasis in their sentinel node had additional findings in the nonsentinel nodes. These findings resulted in a pathologic stage change in 2 patients. Predictors of positive nonsentinel nodes were 2 or more positive sentinel nodes (P  =  .002), sentinel nodes with micrometastasis versus isolated tumor cells (P  =  .03), and those with angiolymphatic invasion (P  =  .04). CONCLUSIONS: Our findings lend support to axillary node dissection for patients with micrometastasis or metastasis in their sentinel nodes. However, studies with clinical follow-up are needed to determine whether axillary node dissection is necessary for patients with isolated tumor cells in sentinel nodes.