Molecular Profiling of KIT/PDGFRA-Mutant and Wild-Type Gastrointestinal Stromal Tumors (GISTs) with Clinicopathological Correlation: An 18-Year Experience at a Tertiary Center in Kuwait.

In gastrointestinal stromal tumors (GISTs), identifying prototypical mutations in the KIT/PDGFRA oncogenes, or in rare alternate genes, is essential for prognostication and predicting response to tyrosine kinase inhibitors. Conversely, wild-type GISTs (WT-GIST), which lack known mutations, have limited treatment options. Data on the mutational landscape of GISTs and their impact on disease progression are very limited in Kuwait. Using a targeted next-generation sequencing panel, we investigated the spectrum and frequency of KIT, PDGFRA, and RAS-pathway-related mutations in 95 out of 200 GISTs diagnosed at Kuwait Cancer Center from 2005 to 2023 and assessed their correlation with clinicopathological parameters. Among the 200 tumors (median age 55 years; 15-91), 54% originated in the stomach, 33% in the small bowel, 7% in the colorectum, 1.5% in the peritoneum, and 4.5% had an unknown primary site. Of the 95 molecularly profiled cases, 88% had a mutation: KIT (61%), PDGFRA (25%), NF1 (2%), and one NTRK1 rearrangement. Ten WT-GISTs were identified (stomach = 6, small bowel = 2, and colorectum = 2). WT-GISTs tended to be smaller (median 4.0 cm; 0.5-8.0) (p = 0.018), with mitosis ≤5/5 mm2, and were of lower risk (p = 0.019). KIT mutations were an adverse indicator of disease progression (p = 0.049), while wild-type status did not significantly impact progression (p = 0.934). The genetic landscape in this cohort mirrors that of global studies, but regional collaborations are needed to correlate outcomes with genetic variants.

Clinicopathological analysis of BRAF and non-BRAF MAPK pathway-altered gliomas in paediatric and adult patients: a single-institution study of 40 patients.

AIMS: Mitogen-activated protein kinase (MAPK) pathway alteration is a major oncogenic driver in paediatric low-grade gliomas (LGG) and some adult gliomas, encompassing BRAF (most common) and non-BRAF alterations. The aim was to determine the frequency, molecular spectrum and clinicopathological features of MAPK-altered gliomas in paediatric and adult patients at our neuropathology site in Kuwait. METHODS: We retrospectively searched the data of molecularly sequenced gliomas between 2018 and 2023 for MAPK alterations, revised the pathology in view of the 2021 WHO classification and evaluated the clinicopathological data for possible correlations. RESULTS: Of 272 gliomas, 40 (15%) harboured a MAPK pathway alteration in 19 paediatric (median 9.6 years; 1.2-17.6) and 21 adult patients (median 37 years; 18.9-89.2), comprising 42% and 9% of paediatric and adult cases, respectively. Pilocytic astrocytoma and glioblastoma were the most frequent diagnoses in children (47%) and adults (43%), respectively. BRAF V600E (n=17, 43%) showed a wide distribution across age groups, locations and pathological diagnoses while KIAA1549::BRAF fusion (n=8, 20%) was spatially and histologically restricted to cerebellar paediatric LGGs. Non-V600E variants and BRAF amplifications accompanied other molecular aberrations in high-grade tumours. Non-BRAF MAPK alterations (n=8) included mutations and gene fusions involving FGFR1, NTRK2, NF1, ROS1 and MYB. Fusions included KANK1::NTRK2, GOPC::ROS1 (both infant hemispheric gliomas), FGFR1::TACC1 (diffuse LGG), MYB::QKI (angiocentric glioma) and BCR::NTRK2 (glioblastoma). Paradoxical H3 K27M/MAPK co-mutations were observed in two LGGs. CONCLUSION: The study provided insights into MAPK-altered gliomas in Kuwait highlighting the differences among paediatric and adult patients and providing a framework for planning therapeutic polices.

A new paradigm for epidermal growth factor receptor expression exists in PTC and NIFTP regulated by microRNAs.

Intoduction: Identification of molecular alterations associated with tumor behavior is necessary to guide clinical management. The 2022 WHO classification has organized the thyroid follicular cell-derived neoplasms into benign, low-risk and high-risk neoplasms, and emphasized the value of biomarkers that may provide differential diagnostic and prognostic information to avoid overtreatment of low risk neoplasms. This work aims to study the epidermal growth factor receptor (EGFR) expression, functional and spatial dynamics in relation to specific miRNAs alterations in papillary thyroid cancer (PTC) and in non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) considered as models of high-risk and low-risk thyroid tumors respectively. Methods: Primary thyroid cultured cells were used for miRNA gain/loss of function and luciferase reporter assays. Paraffin embedded tissues were used for real time PCR, immuno-fluorescence stain and confocal microscopy experiments. Results: Our results showed that in PTC, EGFR mRNA is reduced as an effect of miR-146b-5p upregulation. The EGF expression is low and the ERK pathway is inhibited. The EGFR protein high cytoplasmic expression and colocalization with the endosomal/exosomal markers, ALIX and CD63, suggest the occurrence of stress-induced EGFR internalization, accumulation in endosomal vesicles and secretion via exosomes. In NIFTP EGFR transcription is increased in association with downregulation of miR-7-5p and the EGFR/ERK pathway is active indicating dependence on the canonical EGFR pathway for growth. Conclusion: Downregulation of transcript level along with cytoplasmic accumulation of undegraded protein is a new pattern of EGFR regulation associated with malignancy in thyroid. Further research is needed to elucidate the intracellular trafficking defects responsible for this specific EGFR dynamic in PTC.

Evaluation of the Oncomine Comprehensive Assay v3 panel for the detection of 1p/19q codeletion in oligodendroglial tumours.

AIMS: Accurate assessment of 1p/19q codeletion status in diffuse gliomas is of paramount importance for diagnostic, prognostic and predictive purposes. While targeted next generation sequencing (NGS) has been widely implemented for glioma molecular profiling, its role in detecting structural chromosomal variants is less well established, requiring supplementary informatic tools for robust detection. Herein, we evaluated a commercially available amplicon-based targeted NGS panel (Oncomine Comprehensive Assay v3) for the detection of 1p/19q losses in glioma tissues using an Ion Torrent platform and the standard built-in NGS data analysis pipeline solely. METHODS: Using as little as 20 ng of DNA from formalin-fixed paraffin-embedded tissues, we analysed 25 previously characterised gliomas for multi-locus copy number losses (CNLs) on 1p and 19q, including 11 oligodendrogliomas (ODG) and 14 non-oligodendroglial (non-ODG) controls. Fluorescence in-situ hybridisation (FISH) was used as a reference standard. RESULTS: The software confidently detected combined contiguous 1p/19q CNLs in 11/11 ODGs (100% sensitivity), using a copy number cut-off of ≤1.5 and a minimum of 10 amplicons covering the regions. Only partial non-specific losses were identified in non-ODGs (100% specificity). Copy number averages of ODG and non-ODG groups were significantly different (p<0.001). NGS was concordant with FISH and was superior to it in distinguishing partial from contiguous losses indicative of whole-arm chromosomal deletion. CONCLUSIONS: This commercial NGS panel, along with the standard Ion Torrent algorithm, accurately detected 1p/19q losses in ODG samples, obviating the need for specialised custom-made informatic analyses. This can easily be incorporated into routine glioma workflow as an alternative to FISH.

Intestinal LMNA::NTRK1-fused spindle cell neoplasm with S100 and CD34 coexpression: a new case.

Recurrent fusions involving neurotrophin tyrosine receptor kinase (NTRK) genes have been increasingly recognised in spindle cell tumours of somatic soft tissues due to the widespread use of RNA-based sequencing techniques. This heterogeneous group of neoplasms is included as an emerging entity in the current WHO Classification of Soft Tissue and Bone Tumors A subset of these tumours, associated with NTRK1 fusions, displays a distinctive phenotype in the form of monomorphic cytomorphology, patternless arrangement, perivascular and stromal hyalinisation, and CD34+/S100+/SOX10- immunoprofile. Gastrointestinal tract counterparts have been recently described with emphasis on distinction from KIT/PDGFRA/BRAF/RAS wild-type gastrointestinal stromal tumours (GIST). Here, we present a recently encountered intestinal spindle cell neoplasm harbouring an LMNA::NTRK1 gene fusion in a woman in her early 20s, which was initially thought to represent a GIST or a solitary fibrous tumour. Awareness of this emerging tumour type in the gastrointestinal tract is important due to treatment implications.

Giant cell-rich solitary fibrous tumour of the lacrimal gland with prominent angiomatoid cystic changes and an underlying NAB2ex3-STAT6ex18 fusion.

Giant cell-rich solitary fibrous tumour (GCR-SFT) is a rare variant of SFT with a predilection for the orbital region. Despite its hypervascularity, extensive angiomatoid cystic changes are unusual in GCR-SFT and may pose a diagnostic challenge. A 47-year-old man presented with a right eye proptosis and a protruding tumour of several years' duration with recently accelerated tumour growth. MRI revealed a cystic-solid heterogeneous mass arising from the lacrimal gland and displacing the globe. A subtotal excision of the mass was performed due to unanticipated hypervascularity and intraoperative bleeding. Pathologically, a vascular neoplasm was initially suspected. The diagnosis of GCR-SFT was made following careful evaluation and demonstration of CD34 and STAT6 expression. Molecular studies revealed a pathognomonic but rare NAB2ex3-STAT6ex18 fusion variant as well as a TP53 mutation suggestive of aggressive phenotype. The patient had a complete resolution of the proptosis but the clinical picture remains guarded due to incomplete resection.

Interpretable multimodal deep learning for real-time pan-tissue pan-disease pathology search on social media.

Pathologists are responsible for rapidly providing a diagnosis on critical health issues. Challenging cases benefit from additional opinions of pathologist colleagues. In addition to on-site colleagues, there is an active worldwide community of pathologists on social media for complementary opinions. Such access to pathologists worldwide has the capacity to improve diagnostic accuracy and generate broader consensus on next steps in patient care. From Twitter we curate 13,626 images from 6,351 tweets from 25 pathologists from 13 countries. We supplement the Twitter data with 113,161 images from 1,074,484 PubMed articles. We develop machine learning and deep learning models to (i) accurately identify histopathology stains, (ii) discriminate between tissues, and (iii) differentiate disease states. Area Under Receiver Operating Characteristic (AUROC) is 0.805-0.996 for these tasks. We repurpose the disease classifier to search for similar disease states given an image and clinical covariates. We report precision@k = 1 = 0.7618 ± 0.0018 (chance 0.397 ± 0.004, mean ±stdev ). The classifiers find that texture and tissue are important clinico-visual features of disease. Deep features trained only on natural images (e.g., cats and dogs) substantially improved search performance, while pathology-specific deep features and cell nuclei features further improved search to a lesser extent. We implement a social media bot (@pathobot on Twitter) to use the trained classifiers to aid pathologists in obtaining real-time feedback on challenging cases. If a social media post containing pathology text and images mentions the bot, the bot generates quantitative predictions of disease state (normal/artifact/infection/injury/nontumor, preneoplastic/benign/low-grade-malignant-potential, or malignant) and lists similar cases across social media and PubMed. Our project has become a globally distributed expert system that facilitates pathological diagnosis and brings expertise to underserved regions or hospitals with less expertise in a particular disease. This is the first pan-tissue pan-disease (i.e., from infection to malignancy) method for prediction and search on social media, and the first pathology study prospectively tested in public on social media. We will share data through http://pathobotology.org . We expect our project to cultivate a more connected world of physicians and improve patient care worldwide.

The stress-activated protein kinase pathway and the expression of stanniocalcin-1 are regulated by miR-146b-5p in papillary thyroid carcinogenesis.

Papillary thyroid cancer (PTC) is the most common type of thyroid cancer. Deciphering the pathophysiological mechanisms that contribute to PTC development is essential to the discovery of optimal diagnostic and therapeutic approaches. MiR-146b-5p has been identified as a cancer-associated microRNA highly up-regulated in PTC. This study explores the hypothesis that miR-146b-5p contributes to papillary thyroid carcinogenesis through regulation of cell signaling pathways in a manner that overcomes the cellular growth suppressive events and provides survival advantage. The effect of miR-146b-5p inhibition on major cancer related signaling pathways and expression of Stanniocalcin-1 (STC1), an emerging molecule associated with stress response and carcinogenesis, was tested in cultured primary thyroid cells using luciferase reporter assays, quantitative real-time PCR, immunofluorescence staining, and flow cytometry. Our results demonstrated that miR-146b-5p inhibits the JNK/AP1 pathway activity and down-regulates the expression of STC-1 in thyroid-cultured cells and in thyroid tissue samples. In the presence of miR-146b-5p, PTC cells were resistant to cell death in response to oxidative stress. This is a novel report that miR-146b-5p directly targets STC1 and regulates the activity of JNK/AP1 pathway. Considering the importance of the JNK/AP1 pathway and STC1 in mediating many physiological and pathological processes like apoptosis, stress response and cellular metabolism, a biological regulator of these pathways would have a great scientific and clinical significance.

Down-regulation of the human major histocompatibility complex class I chain-related gene A (MICA) and its receptor is mediated by microRNA-146b-5p and is a potential mechanism of immunoediting in papillary thyroid carcinoma.

Immune escape is one of the main reasons for the rapid progression of cancer and the poor efficacy of immunotherapy. Papillary thyroid cancer (PTC) is usually accompanied by intra-tumoral lymphocytic infiltration. The mechanisms regulating this tumor associated immune response or its evasion are not well understood. The major histocompatibility complex class I chain-related proteins A (MICA) and its receptor the natural killer group 2 member D (NKG2D) are major executers of the anti-tumor defense. This work aimed to study the expression and regulation of MICA-NKG2D and its association with the lymphocytic infiltration and miRNAs in PTC. Expression of MICA and NKG2D in thyroid tissues, and in cultured primary thyroid cancer cells and lymphocytes transfected with miR-146b-5p inhibitor/mimic was tested by RT-PCR. Results were confirmed by immunofluorescence staining and confocal microscopy. MICA is expressed in malignant and benign thyroid tissues with no association with aggressive behavior. Expression of MICA and NKG2D in PTC is concomitant with the presence of tumor associated lymphocytic response and is regulated by miR-146b-5p. MiR-146b-5p indirectly downregulates NKG2D expression in cancer cells and in lymphocytes. Overexpression of miR-146b-5p in PTC down-regulates MICA expression possibly to reduce the immunogenicity of the tumor cells. Targeting of the MICA-NKG2D axis by miR-146b-5p might be one of the ways adopted by thyroid cancer cells to aid the tumor in evading the immune response. The importance of our findings resides in the potential therapeutic use of MICA, NKG2D and miRNA-146b-5p as targets or modulators to enable the immune response against cancer.

Interpreting a Diagnosis of Atypical Squamous Cells of Undetermined Significance in Cervical Cytology and its Association with Human Papillomavirus: A retrospective analysis of 180 cases in Kuwait.

OBJECTIVES: Atypical squamous cells of undetermined significance (ASC-US) represent a diagnostic challenge during cervical cytology. This study aimed to review and identify high-risk human papillomavirus (HR-HPV) genotypes among previously diagnosed ASC-US cases in Kuwait. METHODS: This retrospective study analysed 180 cases diagnosed as ASC-US between June 2017 and May 2018 at the Mubarak Al-Kabeer Hospital, Kuwait. Cervical specimens were assayed to determine the presence of HR-HPV DNA; subsequently, positive cases underwent genotyping and were categorised into three groups (HPV 16, HPV 18/45 and other HR-HPV types). RESULTS: In total, ASC-US was confirmed in only 105 cases (58.3%), with the remaining cases reclassified as negative for intraepithelial lesions or malignancy (NILM; 32.2%) and epithelial cell abnormalities (ECA; 9.4%). Of these, HR-HPV DNA was present in 20 ASC-US (19%), one NILM (1.7%) and six ECA (35.3%) cases. There were 62 Kuwaiti and 43 non-Kuwaiti women with confirmed ASC-US; of these, three (4.8%), six (9.7%) and four (6.5%) Kuwaitis and one (2.3%), one (2.3%) and five (11.6%) non-Kuwaitis had HPV 16, both HPV 16 and 18/45 and other HR-HPV genotypes, respectively. Of those with HR-HPV DNA, the NILM case had the HPV 18/45 genotype, while the six ECA cases had the HPV 16 (n = 1), both HPV 16 and 18/45 (n = 1) and other HR-HPV (n = 4) genotypes. CONCLUSION: Overall, HR-HPV DNA was present in 19% of ASC-US cases compared to 1.7% of NILM cases initially misdiagnosed as ASC-US. Re-review of cervical cytology diagnoses may reduce unnecessary costs associated with HR-HPV genotyping.

Efficacy and safety of crizotinib in patients with anaplastic lymphoma kinase-positive advanced-stage non-small-cell lung cancer.

INTRODUCTION: Lung cancer is the leading cause of cancer mortality worldwide, despite advances in management, especially with targeted agents and immunotherapy. Numerous oncogenes have been identified that control the growth of these malignancies. Anaplastic lymphoma kinase (ALK) is a tyrosine kinase that develops distorted functioning as a result of chromosomal rearrangement. Crizotinib, a tyrosine kinase inhibitor (TKI), was approved by the Food and Drug Administration (FDA) in 2011 for the treatment of advanced ALK-positive non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: In this chart review, we compiled data from two cancer hospitals in Kuwait and Saudi Arabia which were collected from patients with advanced NSCLC treated between January 2013 and September 2017 with crizotinib after diagnosed with ALK-positive disease. Crizotinib 250 mg BID was given orally with/without food intake. We assessed overall survival (OS), objective response rate (ORR), progression-free survival (PFS), duration of the response, and dose reduction/cessation. RESULTS: De-identified data from 38 subjects were compiled. Their median age was 53 years, 65.8% were male, the 1-year OS was 88%, and the PFS was 16.5 months. Two cases (5.3%) had a complete response (CR), while 17 (44.7%) had a partial response (PR). Side effects of grade III/IV occurred, including elevated transaminase levels, diarrhea, and prolonged QT intervals, in 8% patients, with dose reduction in six patients (15.8%). CONCLUSION: In NSCLC, crizotinib is a viable treatment option with good response and tolerable toxicity for patients with ALK-positive advanced disease.

ALK Is a Specific Diagnostic Marker for Inflammatory Myofibroblastic Tumor of the Uterus.

Inflammatory myofibroblastic tumor (IMT) is a myofibroblastic/fibroblastic neoplasm of intermediate malignant potential. It is frequently characterized by genetic fusion of ALK with a variety of partner genes, which results in the activated ALK signaling pathway that can be targeted with kinase inhibitors. IMTs can occur in the gynecologic tract, with the uterus (corpus and cervix) being the most frequent site. Recent studies suggest that IMTs in the gynecologic tract are underrecognized, and a low-threshold for performing ALK immunohistochemistry has been proposed. The aim of this study was to evaluate the specificity of ALK immunohistochemistry for IMTs among uterine mesenchymal and mixed epithelial/mesenchymal tumors. We performed ALK immunohistochemistry on 14 molecularly confirmed uterine IMTs and 260 other uterine pure mesenchymal and mixed epithelial/mesenchymal tumors. Cases showing any positive cytoplasmic and/or membranous staining of the tumor cells were considered to be ALK positive. All 14 IMTs were confirmed to harbor ALK genetic fusion by RNA sequencing, and ALK immunostaining in the form of granular cytoplasmic positivity with paranuclear accentuation was observed in all 14 cases. ALK was negative (complete absence of staining) in all the other pure mesenchymal tumors and in all mixed epithelial/mesenchymal tumors examined. Our findings show that ALK is a highly specific diagnostic immunohistochemical marker for ALK fusion in uterine mesenchymal tumors. In the work-up of uterine mesenchymal tumors, particularly smooth muscle tumors showing myxoid stromal changes, a diagnosis of IMT should be strongly considered if ALK positivity is observed.

Discriminatory miRNAs for the Management of Papillary Thyroid Carcinoma and Noninvasive Follicular Thyroid Neoplasms with Papillary-Like Nuclear Features.

BACKGROUND: Papillary thyroid carcinoma (PTC) variants have several overlapping clinical and pathological features. The World Health Organization recently published a new classification of thyroid tumors containing significant revisions. Encapsulated papillary thyroid carcinoma (EPTC) has been recognized as a distinctive variant of PTC. The noninvasive encapsulated follicular variant of PTC has been reclassified as noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP). Different neoplasms are associated with different outcomes and require different clinical management. The objective of this study was to explore the miRNA expression patterns specific for classic PTC (cPTC), EPTC, follicular variant of PTC, and NIFTP in order to identify biomarkers of diagnostic and prognostic utility aiming for better clinical decisions. METHODS: The expression of 84 miRNAs was determined by quantitative real-time polymerase chain reaction in 113 thyroid tissues of PTC (classic, encapsulated, and follicular), NIFTP, and hyperplasia lesions. Expression of the same miRNAs was tested in pre- and postoperative whole-blood samples. RESULTS: Several miRNAs were differentially expressed in the different groups. Expression profile of miRNAs in the tissue was similarly reflected in the circulation. Receiver operating characteristic curve analysis showed that miR-7-5p, miR-222-3p, and miR-146b-5p can discriminate between the different groups with high sensitivity and specificity. Downregulation of miR-144-3p, miR-15a-5p, miR-20a-5p, miR-32-5p miR-142-5p, miR-143-3p, and miR-20b-5p is associated with aggressive behavior in cPTC. Circulating miR-146b-5p, miR-222-3p, miR-155-5p, and miR-378a-3p are potential diagnostic and follow up biomarkers for PTC. CONCLUSION: Downregulation of miR-7-5p discriminates NIFTP from hyperplasia. Upregulation of miR-222-3p discriminates follicular variant of PTC from NIFTP. High levels of miR-146b-5p distinctively characterize cPTC. These miRNAs are useful biomarkers in the diagnosis of PTC and NIFTP, and help to avoid unnecessary thyroidectomy and improve clinical management.

Imaging of rare appendicular non-acral soft-tissue chondromas in adults with histopathologic correlation.

Background Soft-tissue chondroma (STC) is a rare benign soft tissue tumor that arises primarily in acral extra-skeletal locations. Occasionally, STCs may arise in more proximal non-acral locations, accompanied by non-classic features that label them as indeterminate lesions and pose diagnostic challenge for both radiologists and pathologists alike. Purpose To explicate the potential of diagnostic imaging in the identification and characterization of appendicular non-acral STCs with emphasis on their morphologic magnetic resonance imaging (MRI) enhancement. Material and Methods Our clinical database records were searched for patients with histologically proven primary soft-tissue chondroid lesions over a five-year period. Two musculoskeletal (MSK) trained radiologists evaluated the imaging studies and an MSK pathologist revised the pathological findings. Results The study included six cases of appendicular non-acral STCs (mean age = 40.5 years). The mean size of the tumors was 5.6 cm, with four localized to the knee region, one in the thigh, and one in the sternoclavicular region. All cases showed high signal intensity matrix with low-signal intensity septa on T2-weighted MRI and post-contrast marginal/septal enhancement. The lesions were lobulated and lacked host tissue reaction except for one showing subjacent mild soft-tissue edema. Histologically, the cases lacked overt features of malignancy although one was originally misdiagnosed as chondrosarcoma. Conclusion Non-acral STCs are benign cartilaginous tumors that may pose a diagnostic challenge, both radiologically and pathologically. Collaborative imaging and pathologic workup is needed for better characterization of non-aggression of these lesions, and to avoid diagnostic pitfalls and unnecessary radical resections.

Metastatic non-small cell lung carcinoma a mimic of primary breast carcinoma-case series and literature review.

Metastatic tumors to the breast are rare but constitute a major diagnostic dilemma. Of these, non-mammary carcinomatous metastases to the breast are particularly challenging and, without a clinical history, may be extremely difficult to distinguish from primary breast carcinoma (PBC). We specifically studied metastatic tumors of pulmonary origin, as the lung is one of the major primary sites for carcinomatous metastasis to breast. Sixteen metastatic lung tumors to the breast were identified in our archives between 1996 and 2017 including 12 non-small cell lung carcinomas (NSCLC), one large-cell neuroendocrine, one atypical carcinoid, and two small-cell carcinomas. Adenocarcinoma was the most frequent amongst the NSCLCs (11/14). We retrieved the clinical information of these cases and reviewed the pathological characteristics to provide practical tools for pathologists to aid in their identification. Even in the absence of a clinical history of lung cancer, metastatic pulmonary adenocarcinoma to the breast should be considered in at least one of the following scenarios: (1) single or multiple well-circumscribed lesions of the breast that lack an in situ component and that are accompanied by distant metastases but negative axillary lymph nodes, (2) breast tumors that are triple negative yet not high-grade, or (3) breast tumors presenting as stage 4 disease and/or having an unusually aggressive clinical course on standard breast therapy. Accurate and timely diagnosis of these tumors is mandatory because of treatment and prognostic implications.

BCOR is a robust diagnostic immunohistochemical marker of genetically diverse high-grade endometrial stromal sarcoma, including tumors exhibiting variant morphology.

Recognition of high-grade endometrial stromal sarcoma is important because of its aggressive clinical behavior. Morphologic features of YWHAE-NUTM2 high-grade endometrial stromal sarcoma may overlap with other uterine sarcoma types. BCOR immunoexpression was studied in these tumors and their morphologic mimics to assess its diagnostic utility. BCOR immunohistochemical staining was performed on archival tissue from 28 high-grade endometrial stromal sarcomas with classic morphology (20 YWHAE-NUTM2, 5 ZC3H7B-BCOR, 3 BCOR-ZC3H7B), 3 high-grade endometrial stromal sarcomas with unusual morphology and unknown gene rearrangement status, 66 low-grade endometrial stromal sarcomas, 21 endometrial stromal nodules, 38 uterine leiomyosarcomas, and 19 uterine leiomyomas. Intensity of nuclear staining and percentage of positive tumor cells were recorded. Strong diffuse nuclear BCOR staining (defined as >95% of tumor cells) was seen in the round cell component of all 20 (100%) classic YWHAE-NUTM2 high-grade endometrial stromal sarcomas and the 3 unusual high-grade endometrial stromal sarcomas which prompted FISH studies confirming YWHAE rearrangement in 2 tumors. Genomic PCR confirmed the presence of BCOR exon 16 internal tandem duplication in the third case. Diffuse BCOR staining was strong in three and weak in one BCOR-rearranged high-grade endometrial stromal sarcoma while absent in the remaining four BCOR-rearranged tumors. BCOR staining was weakly positive in <5% of tumor cells in 4 of 66 (6%) low-grade endometrial stromal sarcomas and 1 of 18 (6%) endometrial stromal nodules and weakly to moderately positive in <5-40% of tumor cells in 6 of 31 (19%) leiomyosarcomas. No BCOR staining was seen in the remaining low-grade endometrial stromal sarcomas, endometrial stromal nodules, leiomyosarcomas, or any of the leiomyomas. BCOR immunohistochemical staining is a highly sensitive marker for YWHAE-NUTM2 high-grade endometrial stromal sarcoma with both classic and unusual morphology and identifies a subset of high-grade endometrial stromal sarcoma with BCOR alterations, including BCOR rearrangement and internal tandem duplication.

ETV6-NTRK3 Is Expressed in a Subset of ALK-Negative Inflammatory Myofibroblastic Tumors.

Inflammatory myofibroblastic tumor (IMT) is a genetically heterogenous tumor of the viscera and soft tissues, with multiple molecular features having been demonstrated in this tumor type. About 50% of cases harbor an anaplastic lymphoma kinase (ALK) gene rearrangement, and recent studies have described novel fusions involving the ROS1 and PDGFRß genes in a subset of ALK-negative cases. However, the molecular features of the remaining subset of cases are not yet defined. We report a case of a large, highly aggressive IMT of the lung in a 17-year-old girl. This case was molecularly characterized through whole-genome and transcriptome sequencing. Subsequently, we investigated a cohort of 15 ALK-negative IMTs of various anatomic sites. All cases were screened using fluorescence in situ hybridization (FISH) for rearrangement of the ETV6 locus and with reverse transcription polymerase chain reaction (RT-PCR) for the ETV6-NTRK3 fusion transcript. Whole-genome and transcriptome sequencing revealed an ETV6-NTRK3 fusion transcript in our index case. This was confirmed by FISH studies for ETV6 gene rearrangement, as well as by RT-PCR. In addition, 2 additional cases in our cohort demonstrated ETV6 rearrangement by FISH. The presence of ETV6-NTRK3 fusion transcript was demonstrated by RT-PCR in one of these additional cases. In summary, we demonstrate the expression of the ETV6-NTRK3 fusion oncogene in a small subset of IMTs, lending further support to the role of oncogenic tyrosine kinases in the pathophysiology of this tumor type. Our data also further expand the growing spectrum of tumor types expressing the ETV6-NTRK3 fusion.

Colonic mucosubmucosal elongated polyp: report of a series of 14 cases and review of the literature.

AIMS: Most colorectal polyps can be reliably assigned to one of the known polyp categories, but a subset of polyps named colonic mucosubmucosal elongated polyps (CMSEPs) do not fall into any of these categories. First described in the Japanese literature, CMSEPs seem to be under-recognized in the Western literature. The aims of this study were to describe the clinicopathological features of 14 CMSEPs, discuss potential pathogenetic mechanisms, and increase awareness of this entity among pathologists. METHODS AND RESULTS: Fourteen pedunculated colorectal polyps that met the histopathological criteria for CMSEP (as described by Matake et al. and Alizart et al.) were assessed (12 males and two females; mean age 59.7 years). Five polyps were located in the sigmoid colon, four in the rectum, two in the descending colon, and three in the colon not otherwise specified. Nine of 14 polyps were discovered incidentally: two of nine on routine screening colonoscopy, two of nine on surveillance colonoscopy for inflammatory bowel disease (IBD), and five of nine upon surgical intervention for carcinoma or IBD. None coexisted with diverticular disease. The polyps were long and slender, varied from 5 to 30 mm in length (mean 15.9 mm), and showed a normal-looking colonic mucosal layer and underlying loose submucosa with thick-walled and congested blood vessels and lymphatics. CONCLUSIONS: CMSEPs show subtle but distinctive pathological features, and occur in normal and diseased colons. Pathologists need to be aware of this entity, to avoid confusion with other more commonly encountered colorectal polyps. With increasing colon cancer screening programmes and surveillance colonoscopy, it is likely that CMSEPs will be encountered more often.

The Bethesda System for Reporting Thyroid Fine-Needle Aspiration Cytology: A Kuwaiti Experience - A Cytohistopathological Study of 374 Cases.

INTRODUCTION: The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) identifies 6 diagnostic categories in which the risk of malignancy increases respectively. The aim of our study was to assess TBSRTC reporting in our hospital and to evaluate its specificity based on cytohistological correlation. METHODS: A histological diagnosis was available in 374 (110 males and 264 females) out of 7,809 thyroid aspirates examined at Mubarak Al-Kabeer Hospital, Kuwait, from 2004 to 2012. The aspirates were classified in accordance with TBSRTC. RESULTS: Thyroid aspirates were classified as nondiagnostic (n = 18; 4.8%), benign (n = 114; 30.5%); atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS; n = 59; 15.8%), follicular neoplasm/suspicious for follicular neoplasm (FN/SFN; n = 17; 4.5%), suspicious for malignancy (SM; n = 80; 21.4%), or malignant (n = 86; 23.0%). In 75 of 86 malignant cases, a papillary carcinoma was detected. There were 3 (1.6%) false-positive aspirates and the sensitivity, specificity, negative predictive value, and positive predictive value were 91.0, 61.9, 84.2, and 75.3%, respectively. CONCLUSIONS: Our results are fairly comparable to those of various previous studies in the SM, AUS/FLUS, and SFN categories. The higher rates observed in the nondiagnostic and benign categories were possibly due to limited guided aspirations and a lack of on-site evaluation for all cases.

Endometrial stromal tumours revisited: an update based on the 2014 WHO classification.

Endometrial stromal tumours (EST) are rare tumours of endometrial stromal origin that account for less than 2% of all uterine tumours. Recent cytogenetic and molecular advances in this area have improved our understanding of ESTs and helped refine their classification into more meaningful categories. Accordingly, the newly released 2014 WHO classification system recognises four categories: endometrial stromal nodule (ESN), low-grade endometrial stromal sarcoma (LGESS), high-grade endometrial stromal sarcoma (HGESS) and undifferentiated uterine sarcoma (UUS). At the molecular level, these tumours may demonstrate a relatively simple karyotype with a defining chromosomal rearrangement (as in the majority of ESNs, LGESSs and YWHAE-rearranged HGESS) or demonstrate complex cytogenetic aberrations lacking specific rearrangements (as in UUSs). Herein we provide an update on this topic aimed at the practicing pathologist.