Pathological measurement and staging of residual breast cancer after neoadjuvant chemotherapy.

AIMS: The 8th Edition of the American Joint Committee on Cancer Staging System (yAJCC) excludes treatment-related fibrosis from the measurement of residual tumour after neoadjuvant chemotherapy (NAC) for breast cancer. The impact of the 8th Ed. yAJCC on post-NAC pathologic staging was examined in 188 breast cancer specimens from 183 patients with measurable residual tumour. METHODS: Tumour size, ypT, and ypN categories were reassessed with the current yACC criteria and compared to the original pathology reports. Histological patterns of response in the breast were categorised as concentric or scattered. RESULTS: The reassessed breast tumour size or ypT category differed from the original report in 101 (53.7%) cases. Changes in the ypT and/or ypN category resulted in downstaging of 45/185 (24.3%). A smaller reassessed tumour size or lower ypT category occurred more often in hormone receptor-positive/HER2-negative (HR+/HER2-) (68.3%) and HER2-positive (HER2+) tumours (74.0%) than triple-negative breast cancer (TNBC) (37.5%) (P < 0.001). A scattered pattern of response was more frequent in HR+/HER2- (54.9%) and HER2+ (66.0%) tumours than TNBC (35.7%) (P = 0.006). Changes in size, ypT, or multifocality based on the 8th Ed. yAJCC criteria were more frequent in tumours with a scattered pattern of response (P < 0.001). CONCLUSION: Strict adherence to yAJCC criteria for measurement of the residual breast tumour after NAC resulted in smaller tumour size, lower ypT category, lower yAJCC stage, and more frequent classification of residual tumour as multifocal. Downstaging based on 8th Ed. yAJCC criteria was associated with tumour subtype and histological pattern of response.

Pleomorphic Invasive Lobular Carcinoma of the Breast With Extracellular Mucin and HER2 Amplification.

Invasive lobular carcinoma with extracellular mucin is an uncommon pattern of invasive breast carcinoma. The 5th Edition of the World Health Organization Classification of Breast Tumors states that it is unknown whether these tumors are a subtype of mucinous carcinoma or invasive lobular carcinoma. Invasive lobular carcinoma with extracellular mucin frequently presents as a palpable mass and may be more likely to be grade 2 to 3 and HER2-positive than classic invasive lobular carcinoma. This case of pleomorphic invasive lobular carcinoma with extracellular mucin was detected by imaging only and was HER2-amplified, suggesting that a subset of these tumors may be clinically occult with an aggressive phenotype. Invasive lobular carcinoma with extracellular mucin is infrequently encountered and awareness of this entity is helpful in avoiding misdiagnosis.

Clinicopathologic features of breast cancer reclassified as HER2-amplified by fluorescence in situ hybridization with alternative chromosome 17 probes.

OBJECTIVE: Dual probe fluorescence in situ hybridization (FISH) assays for determination of human epidermal growth factor receptor 2 (HER2) gene amplification in breast cancer provide a ratio of HER2 to chromosome 17. The ratio may be skewed by copy number alterations (CNA) in the control locus for chromosome 17 (CEP17). We analyzed the impact of alternative chromosome 17 control probes on HER2 status in a series of breast cancers with an emphasis on patients reclassified as amplified. METHODS: Breast cancer patients with equivocal HER2 immunohistochemistry (2+) and equivocal FISH with CEP17 were included. Reclassification of HER2 status was assessed with alternative chromosome 17 control probes (LIS1 and RARA). RESULTS: A total of 40 unique patients with 46 specimens reflexed to alternative chromosome 17 probe testing were identified. The majority (>80%) of patients had pT1-2, hormone receptor-positive tumors with an intermediate or high combined histologic grade. There were 34/46 (73.9%) specimens reclassified as amplified with alternative probes, corresponding to 29/40 (72.5%) patients. Of the patients reclassified as amplified with alternative probes, 34.5% (10/29) received HER2-targeted therapy. CONCLUSION: In this series, the majority of breast cancers tested with alternative chromosome 17 control probes under the 2013 ASCO/CAP Guidelines were converted to HER2-amplified. The treatment data and the clinicopathologic profile of the tumors suggest that most of these patients will neither receive nor benefit from HER2-targeted therapy. The findings support the recommendation in the 2018 ASCO/CAP HER2 Guidelines to discontinue the use of alternative chromosome 17 probes.

MRI-guided core needle biopsy of the breast: Radiology-pathology correlation and impact on clinical management.

OBJECTIVE: Breast MRI is used to screen high-risk patients and determine extent of disease in breast cancer (BC) patients. The goal of this study was to determine the pathologic correlates of breast MRI abnormalities biopsied under MRI guidance. METHODS: We retrospectively identified 101 MRI-guided core needle biopsies (CNB) of the breast from 79 women over a 4-year period. MRI-detected lesions biopsied with ultrasound or stereotactic guidance were excluded. MRI studies and pathology were reviewed by breast radiologists and pathologists. RESULTS: Of the 79 patients, 72 (91%) had a history of prior (n = 13) or concurrent (n = 59) BC. There were 101 MRI abnormalities: 60 (59%) with non-mass enhancement (NME) and 41 (41%) with mass enhancement. Pathology was benign in 83/101 (82%), including in the majority of NME lesions (43/60, 72%). The most common benign findings were: fibrocystic changes (FCC) (49%), sclerosing lesions (13%), and fibroadenoma (FA) (9%). There were 18 (18%) malignant diagnoses: 8 (44%) invasive lobular carcinoma (ILC), 7 (39%) ductal carcinoma in situ (DCIS), and 3 (17%) invasive ductal carcinoma (IDC). Of the 18 malignant diagnoses, 16 (89%) occurred in 14 unique patients with concurrent BC. Based on the malignant MRI-guided CNB, 6 (46%) of these patients had additional (sentinel lymph node biopsy or contralateral breast surgery) or more extensive (wider lumpectomy) surgery. CONCLUSION: In this series, most MRI-guided CNB of the breast were benign. The vast majority of malignant diagnoses occurred in patients with concurrent BC and frequently resulted in changes in clinical management.

The LI-RADS Version 2018 MRI Treatment Response Algorithm: Evaluation of Ablated Hepatocellular Carcinoma.

Background The Liver Imaging Reporting and Data System (LI-RADS) treatment response algorithm (TRA) is used to assess presumed hepatocellular carcinoma (HCC) after local-regional therapy, but its performance has not been extensively assessed. Purpose To assess the performance of LI-RADS version 2018 TRA in the evaluation of HCC after ablation. Materials and Methods In this retrospective study, patients who underwent ablation therapy for presumed HCC followed by liver transplantation between January 2011 and December 2015 at a single tertiary care center were identified. Lesions were categorized as completely (100%) or incompletely (≤99%) necrotic based on transplant histology. Three radiologists assessed pre- and posttreatment MRI findings using LI-RADS version 2018 and the TRA, respectively. Interreader agreement was assessed by using the Fleiss κ test. Performance characteristics for predicting necrosis category based on LI-RADS treatment response (LR-TR) category (viable or nonviable) were calculated by using generalized mixed-effects models to account for clustering by subject. Results A total of 36 patients (mean age, 58 years ± 5 [standard deviation]; 32 men) with 53 lesions was included. Interreader agreement for pretreatment LI-RADS category was 0.40 (95% confidence interval [CI]: 0.15, 0.67; P < .01) and was lower than the interreader agreement for TRA category (κ = 0.71; 95% CI: 0.59, 0.84; P < .01). After accounting for clustering by subject, sensitivity of tumor necrosis across readers ranged from 40% to 77%, and specificity ranged from 85% to 97% when LR-TR equivocal assessments were treated as nonviable. When LR-TR equivocal assessments were treated as viable, sensitivity of tumor necrosis across readers ranged from 81% to 87%, and specificity ranged from 81% to 85% across readers. Six (11%) of 53 treated lesions were LR-TR equivocal by consensus, with most (five of six) incompletely necrotic at histopathology. Conclusion The Liver Imaging Reporting and Data System treatment response algorithm can be used to predict viable or nonviable hepatocellular carcinoma after ablation. Most ablated lesions rated as treatment response equivocal were incompletely necrotic at histopathology. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Do and Mendiratta-Lala in this issue.

Ductal Carcinoma In Situ Simultaneously Involving the Breast and Epithelial Inclusions in an Ipsilateral Axillary Lymph Node.

Benign cystic epithelial inclusions with squamous, glandular, or Müllerian phenotypes are known to occur in the axillary lymph nodes of patients with benign and malignant breast disease. Careful evaluation of hematoxylin and eosin-stained slides and correlation with the histologic findings in the ipsilateral breast are paramount in evaluation of suspected benign inclusions. In this case of ductal carcinoma in situ (DCIS) of the breast in a 73-year-old woman, DCIS also involved epithelial inclusions in an ipsilateral axillary lymph node. The recognition of these benign epithelial elements, and awareness that they can be involved by DCIS, is crucial to avoid the overdiagnosis of metastatic carcinoma.

Doing more with less: New markers for sarcoma diagnosis and their applicability to cytology specimens.

Sarcomas are a rare and extremely diverse set of neoplasms that are often a challenge to diagnose for pathologists. For a number of reasons, primary diagnosis of soft tissue neoplasms is increasingly being performed on small biopsy specimens including fine needle aspiration (FNA) and core needle biopsy (CNB). In the last several years, there has been a significant increase in our understanding of the molecular pathogenesis of this group of tumors. New insights into the genetic mechanisms of tumor formation have been exploited to create a new generation of diagnostic markers that are accessible to most laboratories. This review describes a number of new ancillary markers, and how they can facilitate accurate diagnosis of soft tissue neoplasms on FNA/CNB.

Needle biopsy of mesenchymal lesions of the head and neck: Evolving concepts and new strategies for diagnosis.

Sarcomas are a rare and heterogeneous group of neoplasms that can be a significant diagnostic challenge in routine practice. Recent advances in the understanding of molecular mechanisms underlying oncogenesis have led to an array of novel diagnostic tools. Here we review several sarcomas of the head and neck region, focusing on neoplasms with new molecular findings and highlighting novel diagnostic tools.

Lymphovascular space invasion in microcystic elongated and fragmented (MELF)-pattern well-differentiated endometrioid adenocarcinoma is associated with a higher rate of lymph node metastasis.

The microcystic elongated and fragmented (MELF) pattern of myoinvasion is a feature of some well-differentiated endometrial endometrioid adenocarcinomas that has been associated with poor prognosis. The myoinvasion in MELF-pattern tumors can be subtle and lead to underestimation of the depth of myometrial invasion resulting in tumor understaging; the presence of lymphvascular space invasion (LVSI) and lymph node metastasis in MELF-pattern tumors can also be subtle and lead to tumor understaging. To investigate the association of MELF-pattern invasion and lymph node metastasis, we reviewed a series of well-differentiated endometrioid adenocarcinomas and correlated the presence of MELF-pattern myoinvasion and LVSI with lymph node metastasis. Cases of T1 stage well-differentiated endometrioid adenocarcinomas with LVSI and a concurrent lymph node dissection were identified from departmental files. Hematoxylin and eosin-stained slides from the hysterectomy specimen and lymph nodes were reviewed for the presence of MELF-pattern myoinvasion, LVSI, and nodal metastasis. MELF-pattern myoinvasion was identified at least focally in 36% of cases. The pattern of LVSI differed between cases with MELF-pattern invasion and conventional-type invasion, as did the pattern of nodal metastasis. A statistically significantly higher rate of lymph node metastasis was present in cases with MELF-pattern invasion than in cases with conventional invasion, and the rate stratified with the proportion of MELF-pattern adenocarcinomas. MELF-pattern cases carry an increased rate of lymph node metastasis even within the subset of endometrioid tumors with LVSI, which has implications in routine clinical practice as it signals the importance of recognizing MELF-pattern myoinvasion.

The chromosome Y-linked testis-specific protein locus TSPY1 is characteristically present in gonadoblastoma.

Gonadoblastoma is a rare gonadal neoplasm that occurs almost exclusively in individuals who are phenotypically females. Most cases develop in women who have an abnormal karyotype in which at least a portion of the centromeric region of the short arm of chromosome Y is present, a region often referred to as the GBY locus. Of the several genes present in the GBY locus, the TSPY1 gene (which encodes testis-specific protein, a protein thought to have a role in cell cycle regulation) appears to be the most likely to have a critical role in the pathogenesis of gonadoblastoma. To evaluate the association of TSPY1 with the tumor, we developed an interphase fluorescent in situ hybridization assay that uses probes that target the region of the GBY locus that contains TSPY1 and a commercially available chromosome X CEP probe. Using this set of probes in a dual-color approach, we evaluated 6 cases of gonadoblastoma identified from our files and found that both TSPY1 and chromosome X were present in 5 (84%) of 6 cases; in these 5 cases, the adjacent nonneoplastic gonadal parenchyma showed the same genotype as the tumor. Of 6 cases, 1 (16%) showed no evidence of TSPY1; in this case, which occurred in a gravida 2 para 2 woman, 2 X chromosomes were present in the nonneoplastic ovary, the gonadoblastoma, and associated dysgerminoma and granulosa cell tumors. From a basic science perspective, our data demonstrate that the TSPY1 gene is present in most gonadoblastomas, supporting the hypothesized role for TSPY1 in gonadoblastoma tumorigenesis; the lack of TSPY1 in a fertile woman suggests that other loci can, however, substitute for TSPY1 in the development of the tumor. From a clinical perspective, our data show that interphase fluorescence in situ hybridization targeting TSPY1 is a straightforward approach that can be used in the evaluation of Y-associated intersex disorders in women who develop gonadoblastoma.

A structural basis for the acute effects of HIV protease inhibitors on GLUT4 intrinsic activity.

Human immunodeficiency virus (HIV) protease inhibitors (PIs) act as reversible noncompetitive inhibitors of GLUT4 with binding affinities in the low micromolar range and are known to contribute to alterations in glucose homeostasis during treatment of HIV infection. As aspartyl protease inhibitors, these compounds all possess a core peptidomimetic structure together with flanking hydrophobic moieties. To determine the molecular basis for GLUT4 inhibition, a family of related oligopeptides containing structural elements found in PIs was screened for their ability to inhibit 2-deoxyglucose transport in primary rat adipocytes. The peptide oxybenzylcarbonyl-His-Phe-Phe-O-ethyl ester (zHFFe) was identified as a potent inhibitor of zero-trans glucose flux with a K(i) of 26 mum. Similar to PIs, transport inhibition by this peptide was acute, noncompetitive, and reversible. Within a Xenopus oocyte expression system, zHFFe acutely and reversibly inhibited GLUT4-mediated glucose uptake, whereas GLUT1 activity was unaffected at concentrations as high as 1 mm. The related photoactivatable peptide zHFF-p-benzoylphenylalanine-[(125)I]Tyr-O-ethyl ester selectively labeled GLUT4 in rat adipocytes and indinavir effectively protected against photolabeling. Furthermore, GLUT4 bound to a peptide affinity column containing the zHFF sequence and was eluted by indinavir. These data establish a structural basis for PI effects on GLUT4 activity and support the direct binding of PIs to the transport protein as the mechanism for acute inhibition of insulin-stimulated glucose uptake.