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.

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.

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.

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.

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.

Immunohistochemical survey of mismatch repair protein expression in uterine sarcomas and carcinosarcomas.

Uterine sarcomas and carcinosarcomas are an aggressive group of uterine malignancies. The frequency of mismatch repair (MMR) protein loss by immunohistochemical evaluation has not been comprehensively characterized in this group of tumors; hence, the appropriateness of applying an immunohistochemical panel to screen for Lynch syndrome in these tumors remains unclear. We examined for the immunohistochemical loss of 4 MMR proteins (MLH1, MSH2, MSH6, and PMS2) in a series of 67 uterine carcinosarcomas and 51 uterine sarcomas (20 leiomyosarcomas, 11 adenosarcomas, 9 low-grade endometrial stromal sarcomas, 8 high-grade endometrial stromal sarcomas/undifferentiated endometrial sarcomas, and 3 rhabdomyosarcomas) at our institution. Four of the 67 (6.0%) carcinosarcomas demonstrated abnormal MMR protein expression. Two tumors showed concurrent loss of MLH1 and PMS2 in both the carcinomatous and sarcomatous components. One tumor showed the loss of only PMS2 in both components. The remaining tumor showed an isolated loss of MLH1 and PMS2 in only the small cell carcinoma component, whereas the non-small-cell carcinoma and sarcoma components demonstrated normal staining patterns for MMR proteins. Two of 20 leiomyosarcomas (10%) showed the loss of MMR proteins: one with loss of PMS2 and the other with loss of MSH2 and MSH6. All other uterine sarcoma types examined showed intact MMR protein expression. These observations provide a basis for MMR protein screening in uterine carcinosarcomas and leiomyosarcomas but not in other types of uterine mesenchymal or mixed epithelial/mesenchymal malignancies.

Gender-associated genomic differences in colorectal cancer: clinical insight from feminization of male cancer cells.

Gender-related differences in colorectal cancer (CRC) are not fully understood. Recent studies have shown that CRC arising in females are significantly associated with CpG island methylator phenotype (CIMP-high). Using array comparative genomic hybridization, we analyzed a cohort of 116 CRCs (57 males, 59 females) for chromosomal copy number aberrations (CNA) and found that CRC in females had significantly higher numbers of gains involving chromosome arms 1q21.2-q21.3, 4q13.2, 6p21.1 and 16p11.2 and copy number losses of chromosome arm 11q25 compared to males. Interestingly, a subset of male CRCs (46%) exhibited a "feminization" phenomenon in the form of gains of X chromosomes (or an arm of X) and/or losses of the Y chromosome. Feminization of cancer cells was significantly associated with microsatellite-stable CRCs (p-value 0.003) and wild-type BRAF gene status (p-value 0.009). No significant association with other clinicopathological parameters was identified including disease-free survival. In summary, our data show that some CNAs in CRC may be gender specific and that male cancers characterized by feminization may constitute a specific subset of CRCs that warrants further investigation.

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.

Endometrial sarcomas: an immunohistochemical and JAZF1 re-arrangement study in low-grade and undifferentiated tumors.

The current World Health Organization classification divides endometrial sarcomas into low-grade endometrial stromal sarcoma and undifferentiated endometrial sarcoma. Recent studies suggest undifferentiated endometrial sarcoma is a heterogeneous group and a subgroup with uniform nuclei is more akin to low-grade endometrial stromal sarcoma in terms of morphologic, immunohistochemical and genetic features. We classified endometrial sarcomas treated at our institution from 1998 to 2011 into low-grade endometrial stromal sarcoma and undifferentiated endometrial sarcoma, the latter being further categorized into a group with either uniform or pleomorphic nuclei. Morphological features, immunoprofile and fluorescence in situ hybridization rearrangements of JAZF1 and PHF1 genes were correlated with tumor category and outcome. A total of 40 cases were evaluated comprising 23 low-grade endometrial stromal sarcomas, 10 undifferentiated endometrial sarcomas with nuclear uniformity and 7 undifferentiated endometrial sarcomas with nuclear pleomorphism. Low-grade endometrial stromal sarcomas were more often estrogen and progesterone receptor positive (83%) compared with undifferentiated endometrial sarcoma with nuclear uniformity (10%) or with nuclear pleomorphism (0%) (P<0.001). Positivity for p53 was restricted to undifferentiated endometrial sarcomas with more frequent expression in the group with nuclear pleomorphism (57%) than with nuclear uniformity (10%) (P=0.06). Ki-67 proliferation index in >10% of tumor cells more frequent in undifferentiated endometrial sarcoma than low-grade endometrial stromal sarcoma (P=<0.001). JAZF1 rearrangement was detected in 32% of low-grade endometrial stromal sarcomas and in none of the undifferentiated sarcomas. Rearrangement of PHF1 was found in two patients, one with JAZF1-PHF1 fusion. There were no significant differences in clinical behavior between undifferentiated endometrial sarcoma with nuclear uniformity versus nuclear pleomorphism. In conclusion, we found undifferentiated endometrial sarcoma subtypes and low-grade endometrial stromal sarcoma have distinct immunohistochemical and cytogentic profiles. Our data do not show any difference in clinical behavior between subgroups in undifferentiated sarcomas.

Stage II to IV low-grade serous carcinoma of the ovary is associated with a poor prognosis: a clinicopathologic study of 32 patients from a population-based tumor registry.

Low-grade serous carcinoma (LGSC) of the ovary has only recently been recognized as a disease entity distinct from the more common high-grade serous carcinoma (HGSC). When confined to the ovary, LGSC is associated with a very favorable prognosis, and chemotherapy is typically not recommended. There is little available information on the prognosis of patients with LGSC with extraovarian spread, from population-based tumor registries where there has been full pathology review. Thirty-two cases of Stage II to IV ovarian LGSC were identified in the Cheryl Brown Ovarian Cancer Outcomes Unit (1984-2000). In 19 cases, blocks were available and immunostaining for p53, p16, Ki-67, WT1, and E-cadherin was performed. Expression of these markers was then compared with a series of >400 cases of HGSC from the outcomes unit. LGSCs presented at Stage II in 10/32 cases, Stage III in 21/32 cases, and Stage IV in 1/32 cases. On follow-up, most patients died of disease, with <30% survival at 10 years. Compared with HGSCs, the LGSCs were significantly less likely to express p16 at high levels, or to show abnormal p53 expression (P=0.049 and <0.0001, respectively). Ki-67 staining indices were lower in the LGSCs (P<0.0001). There were no significant differences between LGSCs and HGSCs with respect to expression of WT1 and E-cadherin (P=0.27 and 0.62, respectively). This population-based series of LGSC with extraovarian spread at presentation had an unfavorable prognosis, similar to that of HGSC. As previously reported, LGSC shows lower tumor proliferation and fewer p53 abnormalities than in HGSC.

Low-grade adenosquamous carcinoma of the breast: imaging and histopathologic characteristics of this rare disease.

Low-grade adenosquamous carcinoma is a rare histologic subtype of breast carcinoma that has a variable mammographic and sonographic appearance, which overlaps with both benign and malignant neoplasms. Because of its lack of unique imaging features, a diagnosis of low-grade adenosquamous carcinoma is based on histopathology. The recognition of this entity is an important consideration in the differential diagnosis of breast masses and carries implications for prognosis, which is more favorable than other types of breast carcinoma.

Bacterial profile and antibiotic selection for pediatric appendicitis: A retrospective cohort study.

Objective: The objective of this study was to identify the predominant bacteria cultured from the surface of removed appendices in pediatric patients with acute appendicitis and determine the appropriate choice of antibiotics for preoperative and postoperative management. Methods: A 2-year retrospective cohort study was conducted at Mediclinic Parkview Hospital, Dubai, UAE. Patients under 14 years of age with diagnosed acute appendicitis who underwent laparoscopic appendectomy were included. Swab cultures, along with demographic, laboratory, and pathology data, were analyzed. Results: Out of the 56 enrolled patients, 27 (48 %) exhibited bacterial growth on swab cultures, while 29 (52 %) showed no bacterial growth. Escherichia coli (E. coli) was the predominant isolated bacteria, present in 23/27 patients (85 %). Seven patients had co-infections involving E. coli and other bacteria, with Pseudomonas being the second most common bacteria identified in 7/27 patients (25 %). Antibiotic sensitivity testing indicated that 85 % of the isolated bacteria were sensitive to Gentamicin, 63 % to Amoxicillin/Clavulanic acid, 59 % to Trimethoprim + Sulfamethoxazole, and 27 % to Cefazolin. Conclusion: E. coli was the most prevalent bacteria identified on swabs taken from inflamed appendices in pediatric patients. Amoxicillin/Clavulanic acid was determined to be an appropriate choice for preoperative prophylaxis. This study provides valuable insights for guiding the management of pediatric appendicitis and facilitating the appropriate and judicious use of antibiotics.

Bacteroides fragilis Acute Hematogenous Osteomyelitis in a Young Female with Sickle Cell Disease.

Patients with sickle cell disease are at increased risk for multiple infections including osteomyelitis. The most reported causative organisms are Salmonella spp. and Staphylococcus aureus. Anaerobic infections including Bacteroides fragilis are not commonly seen. Here, we report the first case of a 28-year-old female patient with sickle cell disease and acute hematogenous Bacteroides fragilis tibial osteomyelitis. Diagnosis was made by isolating the organism from blood and tibial fluid cultures. The patient was successfully managed with a course of intravenous followed by oral antibiotics and percutaneous drainage of collection and responded well. This case report will shed light on the importance of Bacteroides fragilis as a causative organism for osteomyelitis in sickle cell disease patients, thereby affecting the management of these patients.

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.

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.

Transitional cell carcinoma of the ovary is related to high-grade serous carcinoma and is distinct from malignant brenner tumor.

Transitional cell tumors of the ovary include benign, borderline (atypically proliferating), and malignant Brenner tumors (BT), as well as transitional cell carcinoma (TCC). Some TCCs could conceivably be examples of malignant BT where the benign component has been overgrown. Our objectives were: (A) compare the immunophenotypes of BT and TCC and (B) examine a large cohort of ovarian carcinomas for cases with the immunophenotype of BT and transitional features but lacking a benign BT component. Seven BTs (3 benign, 3 borderline/atypically proliferating, 1 malignant) and 7 TCCs were stained for WT1, ER, p53, and p16(INK4a). The BTs were negative for WT1, p53 overexpression, ER (except for weak positivity in 1), and negative or weakly positive for p16(INK4a). In contrast, the TCCs stained as follows: 4/6 positive for WT1, 5/7 positive for ER, 2/7 strongly positive for p16(INK4a), and 6/7 showed abnormal p53, an immunophenotype resembling that of high-grade serous carcinoma. A database of 500 cases of ovarian carcinoma was searched and 116 showed an immunoprofile characteristic of BT: WT1 negative, ER negative, p16(INK4a) or weak positive, p53 negative (77 clear cell carcinoma, 14 endometrioid carcinoma, 12 mucinous carcinoma, 8 high-grade serous carcinoma). None of these tumors showed transitional features on review, indicating that if examples of malignant BT where there has been overgrowth of benign BT components exist, they are rare. Our results suggest that BT and TCC are unrelated, and should not be combined for classification purposes.

Malignant degeneration of a lumbar osteochondroma into a chondrosarcoma which mimicked a large retropertioneal mass.

We report a case of a lumbar spinal osteochondroma that transformed into a large chondrosarcoma in a 39-year-old male who presented with an abdominal mass and back pain. This mass was also associated with a fracture of the stalk, which on cross-sectional imaging mimicked a mass of retroperitoneal origin. The diagnosis of chondrosarcoma transforming from a lumbar osteochondroma became apparent when comparison was made with previous studies.

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.

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.