Neuroendocrine and squamous cell phenotypes of NUT carcinoma are potential diagnostic pitfalls that discriminating it from mimickers, such as small cell and squamous cell carcinoma.

INTRODUCTION: NUT carcinoma is a rare cancer associated with a poor prognosis. Because of its rarity, its diagnosis is challenging and is usually made by excluding other diagnoses. Immunohistochemical analysis is a reliable technique that contributes to a correct diagnosis, but overestimating the expression of neuroendocrine (NE) markers may result in an incorrect diagnosis. In this study, we established the immunohistochemical phenotypes of NUT carcinoma compared with tumors that mimic its phenotype to identify potential diagnostic pitfalls. METHODS: Eight cases of NUT carcinoma were examined along with eight basaloid squamous cell carcinomas and thirteen cases of small cell carcinoma using an immunohistochemical panel consisting of various antibodies. RESULTS: Of the eight NUT carcinomas, three patients had a smoking history. All the cases examined for INSM1 were positive (6/6, 100%), although the staining was somewhat weak. Among the NE markers, synaptophysin was variably positive in two NUT carcinomas (2/6, 33%); however, all cases were negative for ASCL1, chromogranin A, and CD56. Moreover, the squamous cell markers, p40 and CK5/6, were weakly expressed in 4/6 (67%) and 3/6 (50%) of the NUT carcinomas, respectively. CONCLUSIONS: For tumors with an ambiguous morphology, applying the neuroendocrine phenotype of NUT carcinoma may be misleading; particularly, when distinguishing it from small-cell carcinoma. Similarly, null or weak expression of squamous cell markers may be observed in NUT carcinoma, but this differs from squamous cell carcinoma, which consistently demonstrates strong positivity for squamous cell markers.

KDM2B-Rearranged Soft Tissue Sarcomas Expand the Concept of BCOR-Associated Sarcoma.

Sarcomas with BCOR genetic alterations (BCOR-associated sarcomas) represent a recently recognized family of soft tissue and bone tumors characterized by BCOR fusion, BCOR internal tandem duplication, or YWHAE::NUTM2B fusion. Histologically, the tumors demonstrate oval to spindle cell proliferation in a variably vascular stroma and overexpression of BCOR and SATB2. Herein, we describe 3 soft tissue sarcomas with KDM2B fusions that phenotypically and epigenetically match BCOR-associated sarcomas. The cases included 1 infant, 1 adolescent, and 1 older patient. All tumors showed histologic findings indistinguishable from those of BCOR-associated sarcomas and were originally diagnosed as such based on the phenotype. However, none of the tumors had BCOR or YWHAE genetic alterations. Instead, targeted RNA sequencing identified in-frame KDM2B::NUTM2B, KDM2B::CREBBP, and KDM2B::DUX4 fusions. KDM2B fusions were validated using reverse-transcription PCR, Sanger sequencing, and in situ hybridization assays. Genome-wide DNA methylation analysis matched all 3 tumors with BCOR-associated sarcomas using the Deutsches Krebsforschungszentrum (DKFZ) classifier and t-distributed stochastic neighbor embedding analysis. One localized tumor showed a flat genome-wide copy number profile, and the patient remained disease-free after treatment. The other tumors showed multiple copy number alterations, including MDM2/CDK4 amplification and/or CDKN2A/B loss, and both tumors metastasized, leading to the patient's death in one of the cases. When tested using KDM2B immunohistochemistry, all 3 KDM2B-rearranged sarcomas showed diffuse strong staining, and all 13 sarcomas with BCOR genetic alterations also demonstrated diffuse, strong, or weak staining. By contrast, among 72 mimicking tumors, only a subset of synovial sarcomas showed focal or diffuse weak KDM2B expression. In conclusion, our study suggests that KDM2B-rearranged soft tissue sarcomas belong to the BCOR-associated sarcoma family and expand its molecular spectrum. This may be related to the known molecular relationship between KDM2B and BCOR in the polycomb repressive complex 1.1. Immunohistochemical analysis of KDM2B is a potentially valuable diagnostic tool for BCOR-associated sarcomas, including those with KDM2B rearrangement.

Spectrum of Histopathological, Immunohistochemical, Molecular and Radiological Features in 12 Cases of BCOR::CCNB3-positive Sarcomas With Literature Review.

Introduction BCOR::CCNB3-positive undifferentiated sarcomas are rare. Herein, we present clinicopathological features including immunohistochemical and molecular data, along with the radiological profile of 12 such tumors. Methods Tumors were tested for BCOR::CCNB3 fusion by reverse transcription polymerase chain reaction (RT-PCR) technique. Eight tumors were tested for EWSR1 and three for SS18 gene rearrangements by fluorescence in situ hybridization, and two for SS18::SSX fusion by fragment analysis. Results Ten of 12 patients were male with ages ranging between 4 and 17 years (median = 13, average = 14.4). Nine tumors occurred in bones and three in soft tissues (median size = 8 cm). Four of five tumors within the appendicular bones were metadiaphyseal and appeared as permeative lesions, invariably associated with cortical thickening. Three tumors displayed mineralization. Histopathologically, the tumors comprised round to epithelioid cells with round to oval to spindle-shaped nuclei, mostly diffusely arranged in a myxoid stroma with intervening thin-walled vessels. Immunohistochemically, tumor cells were positive for BCOR (10/11), SATB2 (8/9), TLE1 (5/6), cyclinD1 (4/4), and EMA (3/8). All tumors revealed BCOR::CCNB3 fusion transcript. Nine patients underwent neoadjuvant chemotherapy, including five who underwent surgical resection, with two patients, who received adjuvant radiation therapy. A single patient, each, underwent palliative chemotherapy and palliative radiotherapy, respectively. Four patients developed pulmonary metastasis and three developed local recurrences. Four patients were alive-with-disease and two were free-of-disease. Conclusions It is crucial to identify BCOR::CCNB3 fusion-positive sarcomas, given significant treatment-associated implications. Certain clinicoradiological, histopathological features, absent EWSR1 rearrangement and BCOR, SATB2, and TLE1 immunoexpression are useful for triaging these tumors for molecular testing. A review of the literature on these ultra-rare tumors, including their diagnostic mimics is presented.

Clinical relevance of BCOR internal tandem duplication and TP53 aberration in clear cell sarcoma of the kidney.

Clear cell sarcoma of the kidney (CCSK) is the second most common pediatric renal malignancy, characterized by BCOR internal tandem duplication (ITD), YWHAE rearrangement, BCOR-CCNB3 fusion, and lack of other consistent structural alteration. We accidentally identified TP53 deletion in CCSK, which was often associated with adverse clinical outcomes. In this study, we assessed the incidence as well as the clinical relevance of these molecules in CCSK patients. BCOR ITD, YWHAE rearrangement, BCOR-CCNB3 fusion and TP53 status were examined by polymerase chain reaction, fluorescence in situ hybridization, or Sanger sequencing in a cohort of 39 patients with CCSK. Among them, 34 cases (87.18%) had BCOR ITD, 1 (2.56%) had YWHAE rearrangement, and 1 (2.56%) had BCOR-CCNB3 gene fusion. The remaining 3 (7.69%) harbored none of these aberrations. BCOR ITD, YWHAE rearrangement and BCOR-CCNB3 were mutually exclusive. Furthermore, 25.64% of the cohort acquired TP53 aberration (10/39, 3 with both copy number deletion and point mutation, 6 with deletion only, and 1 with mutation only), all of which were associated with BCOR ITD. Patients with or without BCOR ITD or TP53 aberration did not differ in demographic characteristics such as sex, onset age, or tumor stage at diagnosis. However, the overall survival rates and progression-free survival rates of BCOR ITD or TP53 deletion groups showed obvious downward trends, albeit not all reaching statistical significance. Patients with both BCOR ITD and TP53 deletion had the poorest prognosis.

CNS tumor with BCOR internal tandem duplication: Clinicopathologic, molecular characteristics and prognosis factors.

The central nervous system tumor with BCOR internal tandem duplication (CNS tumor with BCOR ITD) is a recently identified rare tumor entity, the complete morphologic characteristic, genetic alteration, classification, clinical outcomes and optimal treatment for this tumor entity have not been fully clarified. Here, two new cases of CNS tumor with BCOR ITD were reported and the clinicopathologic, molecular characteristics, and prognosis were analyzed through reviewing of the reported literature. The histological features included a clear border with adjacent brain parenchyma, an extensively microcystic background, and the cells with round to oval nuclei containing delicate chromatin, ependymoma-like perivascular pseudorosettes, and palisading necrosis. Immunohistochemical features showed strong and diffuse positive expression for BCOR, scattered positive expression for OLIG2, and negative expression for GFAP, Syn, and EMA. PCR and direct DNA sequencing analysis identified exon 15 ITD of the BCOR gene in both cases. Interestingly, both cases revealed two duplication segments, which had not been reported in the literature. A review of the literature shows that CNS tumor with BCOR ITD has a poor prognosis with a median survival of 1.7 years; surgical gross total resection is a good prognostic factor. A combination of radiation treatment and chemotherapy, while trending towards significance, does not reach statistical significance. On the contrary, the OS is not associated with age, gender, and tumor location. In conclusion, CNS tumor with BCOR ITD is a rare tumor entity with characteristic morphologic and molecular features and a poor prognosis. The optimal treatment strategies need further studies.

TRIB3 Is Highly Expressed in the Adipose Tissue of Obese Patients and Is Associated With Insulin Resistance.

CONTEXT: The upregulation of TRIB3 (Tribbles homolog 3), a stress-inducible gene encoding a pseudokinase, has been implicated in the development of insulin resistance in the skeletal muscle and liver of patients with obesity and type 2 diabetes. However, there is little information regarding TRIB3 expression in human adipose tissue. OBJECTIVE: To investigate whether TRIB3 expression is dysregulated in human adipose tissue in the context of obesity and type 2 diabetes and whether TRIB3 expression in adipose tissues is associated with insulin resistance. METHODS: We measured metabolic parameters and TRIB3 expression in abdominal subcutaneous and visceral adipose tissue in obese (with or without type 2 diabetes) and normal-weight women. Regulation of TRIB3 expression was studied in human adipocytes. RESULTS: TRIB3 expression in both fat depots was higher in patients with obesity and/or type 2 diabetes; in addition, the expression level was significantly associated with insulin resistance. Incubating adipocytes under conditions mimicking the microenvironment of obese adipose tissue, including increased endoplasmic reticulum (ER) stress, induced TRIB3 expression. In human adipocytes, the overexpression of TRIB3 impaired insulin-stimulated protein kinase B (AKT) phosphorylation and caused dysregulation of the transcription of genes encoding bioactive molecules released from adipocytes, such as proinflammatory cytokines, adiponectin, and leptin. Pioglitazone, an insulin-sensitizing agent, reduced both these effects of TRIB3 and the ER stressor-induced expression of TRB3. CONCLUSION: Our data indicate that TRIB3 expression in adipose tissue is enhanced in patients with obesity and suggest that increased TRIB3 dysregulates adipocyte function, which may contribute to the development of insulin resistance.

18F-FDG PET cannot predict expression of clinically relevant histopathological biomarkers in head and neck squamous cell carcinoma: a meta-analysis.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is a common cancer. Positron emission tomography (PET) with 18F-fluorodeoxyglucose (18F-FDG) is a widely used imaging modality in HNSCC. PURPOSE: To provide evident data about associations between 18F-FDG PET and histopathology in HNSCC. MATERIAL AND METHODS: The MEDLINE database was screened for associations between maximum standard uptake values (SUVmax) derived from 18F-FDG PET and histopathological features in HNSCC up to May 2020. Only papers containing correlation coefficients between SUVmax and histopathology were acquired. Overall, 23 publications were collected. RESULTS: The following correlations were calculated: KI 67: 12 studies (345 patients), pooled correlation coefficient (PCC): 0.23 (95% confidence interval [CI] 0.06-0.40); hypoxia-inducible factor-1α: eight studies (240 patients), PCC: 0.24 (95% CI 0.06-0.42); microvessel density: three studies (64 patients), PCC: 0.33 (95% CI 0.02-0.65); vascular endothelial growth factor: two studies (59 cases), PCC: 0.27 (95% CI 0.02-0.51); tumor suppressor protein p53: four studies (159 patients), PCC: 0.05 (95% CI -0.41 to 0.51); epidermal growth factor receptor: two studies (124 patients), PCC: 0.21 (95% CI 0.05-0.37); tumor cell count: three studies (67 patients), PCC: 0.18 (95% CI -0.06 to 0.42); tumor cell apoptosis: two studies (40 patients), PCC: 0.07 (95% CI = -0.85 to 0.99); B-cell lymphoma-2 protein: two studies (118 patients); PCC: 0.04 (95% CI -0.65 to 0.74); glucose-transporter 1: 10 studies (317 patients), PCC: 0.20 (95% CI 0.10-0.30). CONCLUSION: SUVmax derived from 18F-FDG PET cannot reflect relevant histopathological features in HNSCC.

Prognostic association of starvation-induced gene expression in head and neck cancer.

Autophagy-related genes (ARGs) have been implicated in the initiation and progression of malignant tumor promotion. To investigate the dynamics of expression of genes, including ARGs, head and neck squamous cell carcinoma (HNSCC) cells were placed under serum-free conditions to induce growth retardation and autophagy, and these starved cells were subjected to transcriptome analysis. Among the 21 starvation-induced genes (SIGs) located in the autophagy, cell proliferation, and survival signaling pathways, we identified SIGs that showed prominent up-regulation or down-regulation in vitro. These included AGR2, BST2, CALR, CD22, DDIT3, FOXA2, HSPA5, PIWIL4, PYCR1, SGK3, and TRIB3. The Cancer Genome Atlas (TCGA) database of HNSCC patients was used to examine the expression of up-regulated genes, and CALR, HSPA5, and TRIB3 were found to be highly expressed relative to solid normal tissue in cancer and the survival rate was reduced in patients with high expression. Protein-protein interaction analysis demonstrated the formation of a dense network of these genes. Cox regression analysis revealed that high expression of CALR, HSPA5, and TRIB3 was associated with poor prognosis in patients with TCGA-HNSCC. Therefore, these SIGs up-regulated under serum starvation may be molecular prognostic markers in HNSCC patients.

B-cell lymphoma/leukaemia 11B (BCL11B) expression status helps distinguish early T-cell precursor acute lymphoblastic leukaemia/lymphoma (ETP-ALL/LBL) from other subtypes of T-cell ALL/LBL.

B-cell lymphoma/leukaemia 11B (BCL11B) is an essential transcription factor for T-cell lineage commitment and maturation. We investigated BCL11B expression by immunohistochemistry in T-lymphoblastic leukaemia/lymphoma (T-ALL/LBL) (n = 115). The majority (83%) of early T-cell precursor T-ALL/LBL (ETP-ALL) cases showed negative BCL11B expression, while most (84%) of non-ETP-ALL/LBL were positive for BCL11B. A simplified three-marker [BCL11B, cluster of differentiation 5 (CD5), CD13] immunophenotypic score discriminated reliably between ETP-ALL and non-ETP-ALL/LBL. In ETP-ALL, patients with positive BCL11B expression had a better overall survival than those with negative BCL11B (P = 0·009). In summary, BCL11B is a valuable marker for T-ALL/LBL subtyping and serves as a potential prognostic marker in patients with ETP-ALL.

Expression of insulinoma-associated protein 1 in non-small cell lung cancers: a diagnostic pitfall for neuroendocrine tumors.

Insulinoma-associated protein 1 (INSM1) has been reported as a highly sensitive and specific marker of neuroendocrine tumors. INSM1 expression has also been reported, although uncommonly, in non-neuroendocrine tumors. This study aimed to elucidate potential nonspecific INSM1 expression in non-small cell non-neuroendocrine lung cancers (NSCNELCs), especially in squamous cell carcinomas (SqCCs) with basaloid features to avoid diagnostic pitfalls. Tissue microarrays (TMAs) were constructed for 324 NSCNELCs, including 196 adenocarcinomas (AdCs), 86 SqCCs, and 42 other NSCNELCs. In addition, 38 whole-tissue sections of SqCCs with basaloid features were examined. INSM1 immunostain was semiquantitively evaluated based on the percentage of nuclear staining in tumor cells, categorized as negative, focal (<10% tumor cells), and positive (>10% tumor cells). Among 324 TMAs, 6.2% (20/324) were positive for INSM1, 4.9% (16/324) were focal, and 88.9% (289/34) were negative. Of 196 AdCs, 5.1% (10/196) were positive for INSM1, 4.7% (9/196) were focal, and 90.3% (177/196) were negative. Of 86 SqCCs, 9.3% (8/86) were positive for INSM1, 5.8% (5/86) were focal, and 84.9% (73/86) were negative. Of the remaining 42 NSCNELCs, 4.8% (2/42) were positive for INSM1, 4.8% (2/42) were focal, and 90.4% (38/44) were negative. Among 38 cases of whole-tissue sections of SqCCs with basaloid features, 15.8% (6/38) were positive for INSM1, 18.4% (7/38) were focal, and 65.8% (25/38) were negative. Our study demonstrates that INSM1 is expressed in a significant subset of NSCNELCs, suggesting caution in interpreting INSM1 staining, especially with limited samples. INSM1 should not be used as a stand-alone neuroendocrine marker in differentiating primary lung tumors.

Cytological features of BCOR-CCNB3 sarcoma: Comparison with Ewing sarcoma and synovial sarcoma.

INTRODUCTION: BCOR-CCNB3 sarcoma (BCS) is one of the histological types classified as an undifferentiated small round cell sarcoma of bone and soft tissue. This sarcoma frequently develops in males under 20 years of age. Histologically, a delicate capillary network has been reported as a conspicuous finding. In this study, the cytological findings of BCS were observed in two cases of primary lesions and one case of a lung metastatic lesion. The cytological findings of BCS were compared with its histological mimics, and the characteristic findings of BCS were examined. METHODS: Three cases of BCS were studied, and a cytological comparison was performed with 8 cases of Ewing sarcoma (ES) and 10 cases of synovial sarcoma (SS; monophasic type: 7 cases, biphasic type: 2 cases, poorly differentiated: 1 case). RESULTS: In all BCS cases, small clusters with thin and delicate vascular cores and tiny vascular fragments were conspicuous. In ES and SS cases, although small clusters with vascular cores were observed, the vascular cores were thicker than in BCS, and no tiny vascular fragments appeared in most cases. Cytomorphological differences of tumour cells were also observed among BCS, ES, and SS. Predominantly rounded nuclei with fine chromatin and inconspicuous nucleoli can be cytological clues for BCS. CONCLUSIONS: BCS shows characteristic cytological findings that make the diagnosis of BCS more likely than that of ES and SS. Cytological evaluation is a useful tool for appropriate differential diagnosis that leads to a more accurate final diagnosis and rapid treatment.

Usefulness of SS18-SSX antibody as a diagnostic marker for pulmonary metastatic synovial sarcoma.

BACKGROUND: The novel SS18-SSX fusion-specific antibody is reported to have high sensitivity and specificity for the diagnosis of primary synovial sarcoma (SS), which often metastasizes to the lung. Thus far, no study has validated the diagnostic efficacy of SS18-SSX antibody for pulmonary metastatic SS. Therefore, we aimed to investigate the usefulness of the SS18-SSX antibody in the diagnosis of pulmonary metastatic SS. METHODS: We evaluated the immunohistochemistry of SS18-SSX fusion-specific antibody (E9X9V) in 10 pulmonary metastatic SS cases and the corresponding five primary sites (four limbs and one mediastinum) in five patients, for whom SS was already diagnosed and confirmed by fluorescence in-situ hybridization in the metastatic and primary sites, and in 93 clinical and histologic mimics including 49 non-SS, pulmonary metastatic sarcomas, 39 primary lung cancers, and five intrathoracic solitary fibrotic tumors. All specimens were surgically resected at Shinshu University Hospital during 2001-2019. For primary and metastatic SS, we also evaluated SS18-SSX immunohistochemistry using needle biopsy and touch imprint cytology specimens from the primary site. RESULTS: SS18-SSX staining was diffusely-strongly positive in all 10 pulmonary metastatic SS cases and the corresponding five primary sites; whereas, it was negative in all 93 clinical and histologic mimics (100% sensitivity and 100% specificity). Further, SS18-SSX staining was also sufficiently positive in the biopsy and cytology specimens. CONCLUSIONS: Immunohistochemistry of the SS18-SSX fusion-specific antibody is useful for the differential diagnosis of pulmonary metastatic SS in clinical practice. This simple and reliable method has the potential to replace traditional genomic tests. However, further studies are warranted in this regard.

A limited panel of INSM1 and LEF1 immunostains accurately distinguishes between pancreatic neuroendocrine tumor and solid pseudopapillary neoplasm.

Solid pseudopapillary neoplasm (SPN) and well differentiated pancreatic neuroendocrine tumor (PNET) can show significant cytomorphological overlap. In this study, we evaluated the role of INSM1 and LEF1 immunohistochemical stains in distinguishing between these two tumors. 22 SPN and 25 PNET surgically resected cases were stained for both INSM1 and LEF1. All the 22 cases of SPN showed strong and diffuse nuclear staining for LEF1 (in >95 % of tumor cells), while all 25 PNET were negative for LEF1. All 25 PNET cases were positive for INSM1 (moderate to strong intensity nuclear staining in >50 % of the tumor cells), while all 22 cases of SPN were negative for INSM1. The results of our study show that a limited panel comprising of INSM1 and LEF1 immunostains accurately distinguishes between SPN and PNET.

BCOR gene alterations in hematologic diseases.

The BCL6 corepressor (BCOR) is a transcription factor involved in the control of embryogenesis, mesenchymal stem cells function, hematopoiesis, and lymphoid development. Recurrent somatic clonal mutations of the BCOR gene and its homolog BCORL1 have been detected in several hematologic malignancies and aplastic anemia. They are scattered across the whole gene length and mostly represent frameshifts (deletions, insertions), nonsense, and missence mutations. These disruptive events lead to the loss of full-length BCOR protein and to the lack or low expression of a truncated form of the protein, both consistent with the tumor suppressor role of BCOR.BCOR and BCORL1 mutations are similar to those causing 2 rare X-linked diseases: oculofaciocardiodental (OFCD) and Shukla-Vernon syndromes, respectively. Here, we focus on the structure and function of normal BCOR and BCORL1 in normal hematopoietic and lymphoid tissues and review the frequency and clinical significance of the mutations of these genes in malignant and nonmalignant hematologic diseases. Moreover, we discuss the importance of mouse models to better understand the role of Bcor loss, alone and combined with alterations of other genes (eg, Dnmt3a and Tet2), in promoting hematologic malignancies and in providing a useful platform for the development of new targeted therapies.

Application of INSM1 in Diagnosis and Grading of Laryngeal Neuroendocrine Carcinoma.

OBJECTIVE: Chromogranin (CHG), synaptophysin (Syn), and CD56 are generally used in a panel to support diagnoses of laryngeal neuroendocrine carcinomas (NECs). However, the absence of expression of these markers does not completely exclude the diagnosis. INSM1 is a novel marker that is considered sufficiently sensitive and specific for NE differentiation. The aim of this study is not only to detect its sensitivity and specificity, but also to evaluate its application in grading for laryngeal NECs. METHODS: The clinicopathological characteristics of the 25 cases with laryngeal NECs were retrospectively analyzed. The expressions of INSM1, CHG, Syn, and CD56 were detected by immunohistochemistry. RESULTS: Of the 25 laryngeal NECs, INSM1 had higher sensitivity (92%) than Syn (84%), CHG (76%) and CD56 (76%). The average H scores of INSM1, CD56, Syn, and CHG were 160, 37.5, 300, 300 for well-differentiated neuroendocrine carcinoma (WD-NEC); 190, 149, 209, 215 for moderately differentiated neuroendocrine carcinoma (MD-NEC); 251, 208, 104, 25 for poorly differentiated neuroendocrine carcinoma with small cell (SCNEC); 109, 160, 98, 26 for large cell types (LCNEC), respectively. Of these 98 non-neuroendocrine tumors, INSM1 expression was seen in nine (9%) tumors, all were squamous cell carcinoma. And INSM1 staining was generally focal. CONCLUSION: INSM1 has high sensitivity and specificity in diagnosis of laryngeal NECs. For grading laryngeal NECs, Syn and CHG showed significant advantages in the diagnosis of WD-NEC and MD-NEC, whereas INSM1 and CD56 showed greater diagnostic value in the diagnosis of SCNEC and LCNEC, especially in SCNEC. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E2662-E2668, 2021.

High-grade neuroepithelial tumor with BCL6 corepressor-alteration presenting pathological and radiological calcification: A case report.

A 5-year-old girl presented with headache and vomiting. Head computed tomography and magnetic resonance imaging showed a right frontal lobe tumor with marked calcification. The patient underwent resection surgery with suspicion of anaplastic ependymoma, and the tumor was gross totally removed. Pathological examination revealed areas of dense tumor cells with a high nucleocytoplasmic ratio and myxoid areas consisting of tumor cells with a round-shaped nucleus and eosinophilic cytoplasm. Perivascular pseudorosette, necrosis, circumscribed growth, and microcalcification were also observed. Immunohistochemistry demonstrated negative staining for glial fibrillary protein and epithelial membrane antigen. Diagnosis of a high-grade neuroepithelial tumor (HGNET) with BCL6 corepressor (BCOR) alteration was made based on pathological findings and internal tandem duplication in the exon 15 of BCOR. Although calcification on radiological and pathological examination is not typical, it would be essential to recognize that calcification could appear in HGNET-BCOR.

Diagnostic Utility of INSM1 in Medullary Thyroid Carcinoma.

Insulinoma-associated protein 1 (INSM1) is shown to be an excellent marker for neuroendocrine differentiation. However, the diagnostic utility of INSM1 in medullary thyroid carcinoma (MTC) has not yet been extensively investigated. INSM1 staining was performed on 21 MTCs, 7 MTC mimickers (including 3 papillary carcinomas, 2 poorly differentiated carcinomas, 1 follicular adenoma, and 1 nodular plasma cell hyperplasia), and 3 cases of C-cell hyperplasia. INSM1 staining of these cases was compared with the traditional MTC markers including calcitonin (CT), monoclonal carcinoembryonic antigen (mCEA), chromogranin A (CgA), and synaptophysin (Syn). The H-score was generated using the QuPath program, an open-source image analysis software. All 21 MTC cases and 3 C-cell hyperplasia cases were positive for all markers. The MTC mimickers were entirely negative for INSM1. INSM1 and Syn displayed, more consistently, high expression with minimal variability than CgA that showed a wide range of expression with significant variability. mCEA and CT exhibited mostly a high expression with some variability. Being a nuclear stain, interpretation was easier with INSM1 compared to other cytoplasmic markers. INSM1 is an excellent marker for neuroendocrine differentiation, entirely applicable in the diagnosis of MTC and C-cell hyperplasia with high sensitivity and specificity. In comparison with the traditional MTC markers, INSM1 is unique in the crisp nuclear staining pattern with a consistent, diffuse, and strong expression. INSM1 can be potentially combined with CT or mCEA as a dual stain, especially when the lesional tissue is limited for a panel of immunostains.

Timing, number, and type of sexual partners associated with risk of oropharyngeal cancer.

BACKGROUND: Case-control studies from the early 2000s demonstrated that human papillomavirus-related oropharyngeal cancer (HPV-OPC) is a distinct entity associated with number of oral sex partners. Using contemporary data, we investigated novel risk factors (sexual debut behaviors, exposure intensity, and relationship dynamics) and serological markers on odds of HPV-OPC. METHODS: HPV-OPC patients and frequency-matched controls were enrolled in a multicenter study from 2013 to 2018. Participants completed a behavioral survey. Characteristics were compared using a chi-square test for categorical variables and a t test for continuous variables. Adjusted odds ratios (aOR) were calculated using logistic regression. RESULTS: A total of 163 HPV-OPC patients and 345 controls were included. Lifetime number of oral sex partners was associated with significantly increased odds of HPV-OPC (>10 partners: odds ratio [OR], 4.3 [95% CI, 2.8-6.7]). After adjustment for number of oral sex partners and smoking, younger age at first oral sex (<18 vs >20 years: aOR, 1.8 [95% CI, 1.1-3.2]) and oral sex intensity (>5 sex-years: aOR, 2.8 [95% CI, 1.1-7.5]) remained associated with significantly increased odds of HPV-OPC. Type of sexual partner such as older partners when a case was younger (OR, 1.7 [95% CI, 1.1-2.6]) or having a partner who had extramarital sex (OR, 1.6 [95% CI, 1.1-2.4]) was associated with HPV-OPC. Seropositivity for antibodies to HPV16 E6 (OR, 286 [95% CI, 122-670]) and any HPV16 E protein (E1, E2, E6, E7; OR, 163 [95% CI, 70-378]) was associated with increased odds of HPV-OPC. CONCLUSION: Number of oral sex partners remains a strong risk factor for HPV-OPC; however, timing and intensity of oral sex are novel independent risk factors. These behaviors suggest additional nuances of how and why some individuals develop HPV-OPC.

Nuclear Insulinoma-Associated Protein 1 Expression as a Marker of Neuroendocrine Differentiation in Neoplasms of the Breast.

Insulinoma-associated protein-1 (INSM1), a transcription factor encoded by the insulinoma associated-1 gene, is a second-generation biomarker of neuroendocrine differentiation. Its sensitivity and specificity in comparison with chromogranin-A and synaptophysin have been extensively validated in several organs, but evidence regarding its expression in mammary neoplasms is limited. In this study, INSM1 immunohistochemistry was validated in a cohort of 22 mammary neoplasms, enriched with special type breast carcinomas with known neuroendocrine differentiation as determined by immunohistochemistry for synaptophysin and chromogranin-A. Subsequently, INSM1 expression was evaluated in a consecutive series of 66 invasive breast cancer biopsies. In the validation cohort, 14 tumors were synaptophysin-positive, of which all but one showed INSM1 immunoreactivity. Eight tumors were synaptophysin-negative, of which 3 showed focal nuclear INSM1 expression. Six tumors were chromogranin-A-positive, of which one was INSM1-negative. When compared with synaptophysin, INSM1 seems more sensitive but less specific than chromogranin-A. In the biopsy cohort, only one invasive carcinoma of no special type showed substantial INSM1 immunoreactivity (ie, 25% of the tumor cells). Three more cases showed 1% nuclear INSM1 staining. We conclude that neuroendocrine differentiation in invasive breast carcinoma of no special type is a rare finding. Immunohistochemical biomarkers, comprising INSM1 as well as the first-generation biomarkers chromogranin-A and synaptophysin, are useful to distinguish neuroendocrine differentiation in breast neoplasms. The identification of neuroendocrine differentiation can be helpful to establish the diagnosis of special type breast carcinomas such as solid papillary carcinoma.

The panel of syntaxin 1 and insulinoma-associated protein 1 outperforms classic neuroendocrine markers in pulmonary neuroendocrine neoplasms.

Syntaxin-1 (STX1) is a recently described highly sensitive and specific neuroendocrine marker. We evaluated the applicability of STX1 as an immunohistochemical marker in pulmonary neuroendocrine neoplasms (NENs). We compared STX1 with established neuroendocrine markers, including insulinoma-associated protein 1 (INSM1). Typical carcinoids (n = 33), atypical carcinoids (n = 7), small cell lung carcinomas ([SCLCs] n = 30), and large cell neuroendocrine lung carcinomas (n = 17) were immunostained using tissue microarray for STX1, chromogranin A, synaptophysin, CD56, and INSM1. Eighty-four of eighty-seven (96.5%) NENs showed STX1 positivity. Carcinoids and LCNECs typically presented a combined strong membranous and weak cytoplasmic staining pattern; cytoplasmic expression was predominately observed in SCLCs. The sensitivity of STX1 was 90% in SCLCs and 100% in typical carcinoids, atypical carcinoids, and large cell neuroendocrine lung carcinomas. The overall sensitivity of STX1 in pulmonary NENs was 96.6%, and the sensitivity of the other markers was as follows: chromogranin A (85.2%), synaptophysin (85.2%), CD56 (92.9%), and INSM1 (97.7%). STX1 was found to be an excellent neuroendocrine marker of pulmonary NENs, with sensitivity and specificity surpassing that of classic markers. We propose a panel of STX1 and INSM1 for the routine immunohistochemical workup of pulmonary NENs.