Malignant melanotic Xp11 neoplasms exhibit a clinicopathologic spectrum and gene expression profiling akin to alveolar soft part sarcoma: a proposal for reclassification.

The classification of the distinct group of mesenchymal neoplasms, first described as 'Xp11 translocation perivascular epithelioid cell tumor (PEComa)' and for which the term 'melanotic Xp11 neoplasm' or 'Xp11 neoplasm with melanocytic differentiation' has recently been proposed, remains challenging and controversial. We collected 27 melanotic Xp11 neoplasms, the largest series to date, for a comprehensive evaluation. Fourteen of the cases, together with eight alveolar soft part sarcomas (ASPS), nine conventional PEComas and a control group of seven normal tissues were submitted to RNA sequencing. Follow-up available in 22 patients showed 5-year overall survival and 5-year disease-free survival of 47.6 and 35.7%, respectively, which were similar to ASPS and significantly worse than conventional PEComa. Univariate analysis of location (occurring in the kidney versus not kidney), infiltrative growth pattern, nuclear pleomorphism, mitotic activity ≥2/50 high-power fields (HPF), necrosis and lymphovascular invasion were found to be associated with overall survival and/or disease-free survival. Multivariate analysis identified that location was the only factor found to independently correlate with disease-free survival. More importantly, RNA sequencing-based clustering analysis segregated melanotic Xp11 neoplasm and ASPS from other tumors, including conventional PEComa and Xp11 translocation renal cell carcinoma, and formed a compact cluster representative of the largely similar expression signature. Here we clearly define the true biologic nature of melanotic Xp11 neoplasms which are distinctive malignant mesenchymal tumors, rather than simply PEComa variants with occasionally unpredictable behavior. Meanwhile, melanotic Xp11 neoplasm and ASPS more likely represent phenotypic variants of the same entity, which is distinct from conventional PEComa and Xp11 translocation renal cell carcinoma. Based on these important findings, melanotic Xp11 neoplasm might be reclassified into a distinctive entity together with ASPS, independent from PEComa, in future revisions of the current WHO categories of tumors of soft tissue and bone for the improved reclassification. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

MS1, a direct target of MS188, regulates the expression of key sporophytic pollen coat protein genes in Arabidopsis.

Sporophytic pollen coat proteins (sPCPs) derived from the anther tapetum are deposited into pollen wall cavities and function in pollen-stigma interactions, pollen hydration, and environmental protection. In Arabidopsis, 13 highly abundant proteins have been identified in pollen coat, including seven major glycine-rich proteins GRP14, 16, 17, 18, 19, 20, and GRP-oleosin; two caleosin-related family proteins (AT1G23240 and AT1G23250); three lipase proteins EXL4, EXL5 and EXL6, and ATA27/BGLU20. Here, we show that GRP14, 17, 18, 19, and EXL4 and EXL6 fused with green fluorescent protein (GFP) are translated in the tapetum and then accumulate in the anther locule following tapetum degeneration. The expression of these sPCPs is dependent on two essential tapetum transcription factors, MALE STERILE188 (MS188) and MALE STERILITY 1 (MS1). The majority of sPCP genes are up-regulated within 30 h after MS1 induction and could be restored by MS1 expression driven by the MS188 promoter in ms188, indicating that MS1 is sufficient to activate their expression; however, additional MS1 downstream factors appear to be required for high-level sPCP expression. Our ChIP, in vivo transactivation assay, and EMSA data indicate that MS188 directly activates MS1. Together, these results reveal a regulatory cascade whereby outer pollen wall formation is regulated by MS188 followed by synthesis of sPCPs controlled by MS1.

Ethylene signaling is critical for synergid cell functional specification and pollen tube attraction.

ETHYLENE INSENSITIVE 3 (EIN3) is a key regulator of ethylene signaling, and EIN3-BINDING F-BOX1 (EBF1) and EBF2 are responsible for EIN3 degradation. Previous reports have shown that the ebf1 ebf2 double homozygous mutant cannot be identified. In this study, the genetic analysis revealed that the ebf1 ebf2 female gametophyte is defective. The pollination experiment showed that ebf1 ebf2 ovules failed to attract pollen tubes. In female gametophyte/ovule, the synergid cell is responsible for pollen tube attraction. Observation of the pEIN3::EIN3-GFP transgenic lines showed that EIN3 signal was over-accumulated at the micropylar end of ebf1 ebf2 female gametophyte. The overexpression of stabilized EIN3 in synergid cell led to the defect of pollen tube guidance. These results suggested that the over-accumulated EIN3 in ebf1 ebf2 synergid cell blocks its pollen tube attraction which leads to the failure of ebf1 ebf2 homozygous plant. We identified that EIN3 directly activated the expression of a sugar transporter, SENESCENCE-ASSOCIATED GENE29 (SAG29/SWEET15). Overexpression of SAG29 in synergid cells blocked pollen tube attraction, suggesting that SAG29 might play a role in ethylene signaling to repel pollen tube entry. Taken together, our study reveals that strict control of ethylene signaling is critical for the synergid cell function during plant reproduction.

RNA sequencing of Xp11 translocation-associated cancers reveals novel gene fusions and distinctive clinicopathologic correlations.

Both Xp11 translocation renal cell carcinomas and the corresponding mesenchymal neoplasms are characterized by a variety of gene fusions involving TFE3. It has been known that tumors with different gene fusions may have different clinicopathologic features; however, further in-depth investigations of subtyping Xp11 translocation-associated cancers are needed in order to explore more meaningful clinicopathologic correlations. A total of 22 unusual cases of Xp11 translocation-associated cancers were selected for the current study; 20 cases were further analyzed by RNA sequencing to explore their TFE3 gene fusion partners. RNA sequencing identified 17 of 20 cases (85%) with TFE3-associated gene fusions, including 4 ASPSCR1/ASPL-TFE3, 3 PRCC-TFE3, 3 SFPQ/PSF-TFE3, 1 NONO-TFE3, 4 MED15-TFE3, 1 MATR3-TFE3, and 1 FUBP1-TFE3. The results have been verified by fusion fluorescence in situ hybridization (FISH) assays or reverse transcriptase polymerase chain reaction (RT-PCR). The remaining 2 cases with specific pathologic features highly suggestive of MED15-TFE3 renal cell carcinoma were identified by fusion FISH assay. We provide the detailed morphologic and immunophenotypic description of the MED15-TFE3 renal cell carcinomas, which frequently demonstrate extensively cystic architecture, similar to multilocular cystic renal neoplasm of low malignant potential, and expressed cathepsin K and melanotic biomarker Melan A. This is the first time to correlate the MED15-TFE3 renal cell carcinoma with specific clinicopathologic features. We also report the first case of the corresponding mesenchymal neoplasm with MED15-TFE3 gene fusion. Additional novel TFE3 gene fusion partners, MATR3 and FUBP1, were identified. Cases with ASPSCR1-TFE3, SFPQ-TFE3, PRCC-TFE3, and NONO-TFE3 gene fusion showed a wide variability in morphologic features, including invasive tubulopapillary pattern simulating collecting duct carcinoma, extensive calcification and ossification, and overlapping and high columnar cells with nuclear grooves mimicking tall cell variant of papillary thyroid carcinoma. Furthermore, we respectively evaluated the ability of TFE3 immunohistochemistry, TFE3 FISH, RT-PCR, and RNA sequencing to subclassify Xp11 translocation-associated cancers. In summary, our study expands the list of TFE3 gene fusion partners and the clinicopathologic features of Xp11 translocation-associated cancers, and highlights the importance of subtyping Xp11 translocation-associated cancers combining morphology, immunohistochemistry, and multiple molecular techniques.

The transcription factors MS188 and AMS form a complex to activate the expression of CYP703A2 for sporopollenin biosynthesis in Arabidopsis thaliana.

The sexine layer of pollen grain is mainly composed of sporopollenins. The sporophytic secretory tapetum is required for the biosynthesis of sporopollenin. Although several enzymes involved in sporopollenin biosynthesis have been reported, the regulatory mechanism of these enzymes in tapetal layer remains elusive. ABORTED MICROSPORES (AMS) and MALE STERILE 188/MYB103/MYB80 (MS188/MYB103/MYB80) are two tapetal cell-specific transcription factors required for pollen wall formation. AMS functions upstream of MS188. Here we report that AMS and MS188 target the CYP703A2 gene, which is involved in sporopollenin biosynthesis. We found that AMS and MS188 were localized in tapetum while CYP703A2 was localized in both tapetum and locule. Chromatin immunoprecipitation (ChIP) showed that MS188 directly bound to the promoter of CYP703A2 and luciferase-inducible assay showed that MS188 activated the expression of CYP703A2. Yeast two-hybrid and electrophoretic mobility shift assays (EMSAs) further demonstrated that MS188 complexed with AMS. The expression of CYP703A2 could be partially restored by the elevated levels of MS188 in the ams mutant. Therefore, our data reveal that MS188 coordinates with AMS to activate CYP703A2 in sporopollenin biosynthesis of plant tapetum.

Xp11.2 translocation renal cell carcinoma with NONO-TFE3 gene fusion: morphology, prognosis, and potential pitfall in detecting TFE3 gene rearrangement.

Xp11 translocation renal cell carcinomas are characterized by several different translocations involving the TFE3 gene. Tumors with different specific gene fusions may have different clinicopathological manifestations. Fewer than 10 renal cell carcinoma cases with NONO-TFE3 have been described. Here we examined eight additional cases of this rare tumor using clinicopathological, immunohistochemical, and molecular analyses. The male-to-female ratio of our study cohort was 1:1, and the median age was 30 years. The most distinctive feature of the tumors was that they exhibited glandular/tubular or papillary architecture that was lined with small-to-medium cuboidal to high columnar cells with indistinct cell borders and an abundantly clear or flocculent eosinophilic cytoplasm. The nuclei were oriented toward the luminal surface and were round and uniform in shape, which resulted in the appearance of secretory endometrioid subnuclear vacuolization. The distinct glandular/tubular or papillary architecture was often accompanied by sheets of epithelial cells that presented a biphasic pattern. Immunohistochemically, all eight cases demonstrated moderate (2+) or strong (3+) positive staining for TFE3, CD10, RCC marker, and PAX-8. None of the tumors were immunoreactive for CK7, Cathepsin K, Melan-A, HMB45, Ksp-cadherin, Vimentin, CA9, 34ßE12 or CD117. NONO-TFE3 fusion transcripts were identified in six cases by RT-PCR. All eight cases showed equivocal split signals with a distance of nearly 2 signal diameters and sometimes had false-negative results. Furthermore, we developed a fluorescence in situ hybridization (FISH) assay to serve as an adjunct diagnostic tool for the detection of the NONO-TFE3 fusion gene and used this method to detect the fusion gene in all eight cases. Long-term follow-up (range, 10-102 months) was available for 7 patients. All 7 patients were alive with no evidence of recurrent disease or disease progression after their initial resection. This report adds to the known data regarding NONO-TFE3 renal cell carcinoma.

Understanding the molecular pathogenesis and prognostics of bladder cancer: an overview.

The knowledge of cellular mechanisms in malignances of the bladder has grown exponentially. Molecular technologies have led to the discovery of the molecular pathways distinguishing low-and high-grade urothelial neoplasms. This trend portends the future in which the classification and diagnosis of the bladder tumors through morphologic analysis will be supported by molecular information correlating with prognosis and targeted therapy. This article outlines tumor molecular pathology of bladder cancer with an emphasis on several promising candidate biomarkers that may soon make their transition to the realm of clinical management of bladder cancer.

DYT1 directly regulates the expression of TDF1 for tapetum development and pollen wall formation in Arabidopsis.

The tapetum plays a critical role during the development and maturation of microspores. DYSFUNCTIONAL TAPETUM 1 (DYT1) is essential for early tapetal development. Here, we determined that the promoter region (-550 to -463 bp) contains indispensable cis-elements for DYT1 expression. Although DYT1 transcripts can be detected in both meiocytes and tapetal cells, localization of DYT1-GFP demonstrated that DYT1 is strictly located in tapetal cells during microsporogenesis. Chromatin immunoprecipitation (ChIP) analysis revealed that DYT1 directly binds the promoter region of Defective in Tapetal Development and Function 1 (TDF1), a transcription factor essential for tapetum development. When TDF1 driven by the DYT1 promoter is expressed in a dyt1 mutant, the expression of the transcription factors AMS, MS188/MYB80, TEK and MS1 and the pollen wall-related genes are restored. Although the pollen wall is not formed and the microspores are ruptured, DIOC2 staining showed that fatty acids, the precursors of the pollen wall, were synthesized in the transgenic lines. These results indicate that DYT1 regulates the expression of AMS, MS188/MYB80, TEK and MS1 for pollen wall formation, primarily via TDF1.

Recurrent Tuberous Sclerosis Complex/Mammalian Target of Rapamycin Mutations Define Primary Renal Hemangioblastoma as a Unique Entity Distinct From Its Central Nervous System Counterpart.

ABSTRACT: Renal hemangioblastoma (HB) is a rare subset of HBs arising outside of the central nervous system (CNS), with its molecular drivers remaining entirely unknown. There were no significant alterations detected in previous studies, including von Hippel-Lindau gene alterations, which are commonly associated with CNS-HB. This study aimed to determine the real molecular identity of renal HB and better understand its relationship with CNS-HB. A cohort of 10 renal HBs was submitted for next-generation sequencing technology. As a control, 5 classic CNS-HBs were similarly analyzed. Based on the molecular results, glycoprotein nonmetastatic B (GPNMB) immunohistochemistry was further performed in the cases of renal HB and CNS-HB. Mutational analysis demonstrated that all 10 renal HBs harbored somatic mutations in tuberous sclerosis complex 1 ( TSC1 , 5 cases), TSC2 (3 cases), and mammalian target of rapamycin (2 cases), with the majority classified as pathogenic or likely pathogenic. The CNS-HB cohort uniformly demonstrated somatic mutations in the von Hippel-Lindau gene. GPNMB was strong and diffuse in all 10 renal HBs and completely negative in CNS-HBs, reinforcing the molecular findings. Our study reveals a specific molecular hallmark in renal HB, characterized by recurrent TSC/mammalian target of rapamycin mutations, which defines it as a unique entity distinct from CNS-HB. This molecular finding potentially expands the therapeutic options for patients with renal HB. GPNMB can be considered for inclusion in immunohistochemical panels to improve renal HB identification.

Upregulation of caveolin-1 and SR-B1 in mice with non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is one of the most frequent causes of liver diseases, with markedly increased prevalence. However, its mechanisms are not clear. The present study was undertaken to illustrate the role of caveolin-1 (cav1) and the scavenger receptor class B type 1 (SR-B1) in NAFLD. METHODS: Adult male C57BL/6 mice were fed with a normal diet or high fat and cholesterol (HFC) diet for 14 weeks. The mice were sacrificed to collect plasma and harvest the liver; their plasma lipid concentration was measured. Hepatic cav1 and SR-B1 mRNA and protein expression were determined by real-time quantitative polymerase chain reaction (qPCR) and Western blotting, respectively. In order to study cav1 and SR-B1 distribution and change in hepatocytes, immunohistochemical analysis was performed. RESULTS: HFC diet increased plasma lipids, induced NAFLD and increased the liver/body weight ratio. Compared to the control mice (n=6), the mRNA and protein levels of cav1 and SR-B1 in liver tissue of the NAFLD mice (n=12) increased significantly (cav1 mRNA: 1.536+/-0.226 vs 0.980+/-0.272, P<0.05; protein: 0.643+/-0.240 vs 0.100+/-0.130, P<0.01; SR-B1 mRNA: 1.377+/-0.125 vs 0.956+/-0.151, P<0.01; protein: 2.156+/-0.507 vs 0.211+/-0.211, P<0.01). Furthermore, both cav1 and SR-B1 immunoreactivity increased and their distribution was also changed, mainly in the plasma membrane of hepatocytes, cytoplasm and membrane of lipid droplets and around. CONCLUSION: NAFLD is associated with increased concentration of plasma lipids and upregulation of hepatic cav1 and SR-B1 gene and protein expressions, which indicate that cav1 and SR-B1 might play crucial roles in the pathogenesis of NAFLD.

Molecular and clinical features of papillary thyroid cancer in adult patients with a non-classical phenotype.

Purpose: Genotyping is fundamental in papillary thyroid cancer (PTC) and helps to enhance diagnosis and prognosis and determine appropriate treatments. The phenotype-genotype association in PTC was previously studied, with BRAF V600E characterizing classic PTC and tall-cell PTC and RAS mutations characterizing follicular-variant PTC. In clinic, some non-classical histological subtypes of PTC were also identified, however, their genotype remains unclear. In this study, we collected samples of these non-classical PTC after the exclusion of classic phenotypes and examined their phenotypes, genotype and the relationship between phenotype and genotype. Methods: We screened out non-classical PTC by excluding classical PTC from 1,059 different thyroid samples, and a total of 24 cases was obtained and described from the morphological features, which is rare in differentiated PTC. DNA/RNA sequencing was performed using 18 available samples to describe the genetic features. Results: PTC with the non-classical phenotype were characterized cuboidal to low columnar tumor cells with subtle nuclear features of PTC and without discernible nuclear elongation, concurrently with dense microfollicles, delicate papillae or solid nodules with delicate fibrovascular cores. They were associated with lymphatic vessel invasion (P<0.001) but not with a worse prognosis (P=0.791). Gene fusions were identified in 14 of 18 (77.8%) cases, including eight fusions of NTRK and six fusions of RET. The high percentage of fusions in this papillary thyroid cancer subgroup suggested a correlation of gene fusions with the phenotype that does not belong to the BRAF V600E-mutant or RAS-mutant group. Conclusions: Our study retrospectively screened a large cohort of different thyroid tissue samples, and presented the histopathological and genetic features of a non-classical phenotype of PTC from 24 patients. It may contribute to diagnose in PTC, and patients of these non-classical phenotype may benefit from targeted therapy, compared to a natural patient cohort without selection.

Expert Consensus on Pathological Diagnosis of Intrahepatic Cholangiocarcinoma (2022 version).

Intrahepatic cholangiocarcinoma (iCCA) can originate from the large bile duct group (segment bile ducts and area bile ducts), small bile duct group (septal bile ducts and interlobular bile ducts), and terminal bile duct group (bile ductules and canals of Hering) of the intrahepatic biliary tree, which can be histopathological corresponding to large duct type iCCA, small duct type iCCA and iCCA with ductal plate malformation pattern, and cholangiolocarcinoma, respectively. The challenge in pathological diagnosis of above subtypes of iCCA falls in the distinction of cellular morphologies, tissue structures, growth patterns, invasive behaviors, immunophenotypes, molecular mutations, and surgical prognoses. For these reasons, this expert consensus provides nine recommendations as a reference for standardizing and refining the diagnosis of pathological subtypes of iCCA, mainly based on the 5th edition of the World Health Organization Classification of Tumours of the Digestive System.

Solitary fibrous tumor of the liver: a case report.

Hepatic solitary fibrous tumor (SFT) is a rare tumor originating from the mesenchyme. Here we report a new case of SFT in the liver and review the clinical presentation, radiological and operative findings, diagnosis, treatment, and outcome. The patient was a 59-year-old man who presented with progressive fatigue for 3 months and an abdominal mass for 3 days. On laboratory tests, no abnormality was detected except that abdominal ultrasonography revealed a 9.0 × 6.2 cm hypoechogenic mass in the left lobe of the liver. A computed tomographic scan confirmed a hypodense lesion in the left lobe of the liver. The patient underwent left hepatectomy. SFT was diagnosed on the basis of histopathological findings. The patient was free from all symptoms and had no signs of local recurrence after 24 months' follow up.

[Expression of GADD153 in follicular tumors of thyroid and comparison with CK19, Galectin-3 and HBME-1].

OBJECTIVE: To study immunohistochemical expression of GADD153 and assess its usefulness as markers in the differential diagnoses in follicular tumors of the thyroid. METHODS: Immunohistochemical staining was performed on formalin-fixed paraffin-embedded tissue of 34 cases of follicular thyroid adenomas (FTA), 46 cases of follicular thyroid carcinomas (FTC), 29 cases of follicular variant papillary carcinomas (FVPC). RESULTS: (1) GADD153 was expressed in cell nucleus with positive or strong positive expression in FTC, and no or weak expression in FTA and FVPC. The positive expressions of GADD153 were present in 38 of 46(82.6%) in FTC, 11 of 34(32.4%) in FTA and three of 29(10.3%) in FVPC, the positive expression rate in FTC was obviously higher than that in FTA and in FVPC, the differences were statistically significant (χ² = 20.80 and 37.48; P < 0.01). (2) CK19, Galectin-3 (Gal-3) and HBME-1 were all expressed in the cytoplasm, the positive expressions of CK19, Gal-3 and HBME-1 were present in 54.3% (25/46), 67.4% (31/46) and 58.7% (27/46) in FTC; 50.0% (17/34), 29.4% (10/34) and 32.4% (11/34) in FTA; 100% (29/29), 93.1% (27/29) and 89.7% (26/29) in FVPC, the differences were statistically significant as well (χ² = 21.20 and 8.22; P < 0.01). (3) According to the expressions of CK19, Gal-3, HBME-1 and GADD153, we divided the results into low expression group (0 or 1+) and high expression group (2+ or 3+), the sensitivity and the specificity were calculated. in FTA, the sensitivity were 26.5%, 8.8%, 2.9% and 11.8%; the specificity were 50.7%, 52.0%, 54.7% and 58.7%. in FTC, the sensitivity were 19.6%, 26.1%, 23.9% and 65.2%; the specificity were 41.3%, 57.1%, 62.0% and 92.1%. in FVPC, the sensitivity were 96.6%, 82.8%, 79.3% and 3.4%; the specificity were 77.5%, 81.3%, 85.0% and 57.5%. CONCLUSIONS: The sensitivity and the specificity of GADD153 expression are well for diagnosing FTC, and CK19, Gal-3, HBME-1 are well for FVPC. The four markers when used in combination, are better to identify the follicular tumors of the thyroid.

[Clinicopathologic study on 61 cases of uterine papillary serous carcinoma with or without adjuvant therapy].

OBJECTIVE: To study the clinicopathologic features of uterine papillary serous carcinoma (UPSC) and the roles of adjuvant therapy. METHODS: Sixty-one cases of UPSC with operation done and followed up for a period of 4 to 9 years were enrolled into the study. The histology of slides specimens were reviewed and immunohistochemical study was performed. The follow-up and survival data were analyzed. RESULTS: All of the 61 patients were post-menopausal, with a median age of 68 years. The clinical presentations included abnormal vaginal bleeding, abdominal symptoms and abnormal Pap smears. The median size of the tumors was 7.5 cm (range=1.2 to 14.8 cm). There were 27.9% cases in FIGO stage I (8.2% in stage IA, 14.8% in stage IB and 4.9% in stage IC), 9.8% in stage II, 32.8% in stage III and 29.5% in FIGO stage IV. The histologic features were similar to those of the ovarian counterpart, with tumor cells containing the high-grade nuclei and arranged in complex papillae. Psammoma bodies were identified in 24.6% of the cases. Immunohistochemical study showed that the tumor cells demonstrated diffuse and strong nuclear staining for p53 and Ki-67. They were negative for estrogen receptor and progesterone receptor. Fifteen of the 61 cases (24.6%) showed no evidence of myometrial invasion. However, ten of the 15 cases had extrauterine disease, with peritoneal (6/15) and nodal (9/15) involvement. Tumors with deep myometrial invasion, lymphovascular permeation and nodal metastasis were associated with worse prognosis by univariate analysis. Fifty-six patients received adjuvant therapy. The number of patients receiving adjuvant chemotherapy alone, adjuvant radiotherapy alone and combined adjuvant chemotherapy/radiotherapy were 42, 24 and 10, respectively. The median survivals of the chemotherapy group and non-chemotherapy group (with or without radiotherapy) were 66.4 months and 32.8 months, respectively. CONCLUSIONS: UPSC has distinctive clinical and pathologic features. The tumor stage, lymph node status, lymphovascular permeation and depth of myometrial invasion were important prognostic factors. Adjuvant chemotherapy for stage III/IV tumors or recurrent UPSC may have survival benefit.

Bilateral Posterior Uveitis and Retinal Detachment During Immunotherapy: A Case Report and Literature Review.

Immune checkpoint inhibitors (ICIs) cause fewer toxicities than conventional chemotherapy. Although most of the immune-related adverse events (irAEs) are mild, reversible, and manageable, potentially severe and rare irAEs remain relevant. We present a 24-year-old man with advanced hereditary renal cancer who developed bilateral posterior uveitis and retinal detachment after systematic treatment of ICI and an anti-angiogenic drug. Axitinib and pembrolizumab were administered with a partial response and following the severe ocular irAE and systemic corticosteroid treatment was initiated. Our case indicates that ocular irAEs may occur rapidly. To the best of our knowledge, this is the first case of posterior uveitis and retinal detachment in hereditary renal cancer patients treated with ICI and anti-angiogenic drugs.

Clinicopathologic and Molecular Analysis of the TFEB Fusion Variant Reveals New Members of TFEB Translocation Renal Cell Carcinomas (RCCs): Expanding the Genomic Spectrum.

Xp11 renal cell carcinoma (RCC) with different gene fusions may have different clinicopathologic features. We sought to identify variant fusions in TFEB translocation RCC. A total of 31 cases of TFEB RCCs were selected for the current study; MALAT1-TFEB fusion was identified in 25 cases (81%, 25/31) using fusion probes. The remaining 6 cases (19%, 6/31) were further analyzed by RNA sequencing and 5 of them were detected with TFEB-associated gene fusions, including 2 ACTB-TFEB, 1 EWSR1-TFEB, 1 CLTC-TFEB, and 1 potential PPP1R10-TFEB (a paracentric inversion of the TFEB gene, consistent with "negative" TFEB split FISH result, and advising a potential diagnostic pitfall in detecting TFEB gene rearrangement). Four of the 5 fusion transcripts were successfully validated by reverse transcription-polymerase chain reaction and Sanger sequencing. Morphologically, approximately one third (29%, 9/31) of TFEB RCCs showed typical biphasic morphology. The remaining two thirds of the cases (71%, 22/31) exhibited nonspecific morphology, with nested, sheet-like, or papillary architecture, resembling other types of renal neoplasms, such as clear cell RCC, Xp11 RCC, perivascular epithelioid cell tumor (PEComa), or papillary RCC. Although cases bearing a MALAT1-TFEB fusion demonstrated variable morphologies, all 9 cases featuring typical biphasic morphology were associated with MALAT1-TFEB genotype. Accordingly, typical biphasic morphology suggests MALAT1-TFEB fusion, whereas atypical morphology did not suggest the specific type of fusion. Isolated or clustered eosinophilic cells were a common feature in TFEB RCCs, which may be a useful morphology diagnostic clue for TFEB RCCs. Clinicopathologic variables assessment showed that necrosis was the only morphologic feature that correlated with the aggressive behavior of TFEB RCC (P=0.004). In summary, our study expands the genomic spectrum and the clinicopathologic features of TFEB RCCs, and highlights the challenges of diagnosis and the importance of subtyping of this tumor by combining morphology and multiple molecular techniques.

Multicentric hyaline-vascular Castleman's disease in the retroperitoneum.

BACKGROUND: Castleman's disease is a rare lymphoproliferative disease of unknown cause. Most multicentric cases described have been of the plasma-cell variety. This article presents a case of multicentric hyaline-vascular Castleman's disease in the retroperitoneum with the ultrasonographic and computed tomography (CT) imaging manifestations. METHODS: During routine physical examination, a mass was detected in the left abdomen of a 53-year-old man with no signs or symptoms. The patient underwent ultrasound-guided aspiration biopsy and operative excision after laboratory examination, ultrasonography, and CT. RESULTS: Ultrasonography demonstrated a dominant hypoechogenic mass with hypervascularity in the retroperitoneum. CT detected a relatively homogenous enhanced lesion and several satellite nodules. After the mass and several lymph nodes were resected, histopathologic examination demonstrated a lymphocyte-predominant infiltrate surrounding the germinal centres and extensive capillary proliferation, consistent with the hyaline-vascular type of Castleman's disease. The patient received postoperative chemotherapy and remained free of recurrence 3 months later. CONCLUSION: Ultrasonography and contrast-enhanced CT can provide a positive differential diagnosis of hyaline-vascular Castleman's disease which is a kind of giant lymph node hyperplasia with hypervascularity.

[Gastrointestinal stromal tumor of small intestine associated with lymph node metastasis: a report of 2 cases with review of literatures].

OBJECTIVE: To study the clinicopathologic features of gastrointestinal stromal tumor (GIST) of small intestine with lymph node metastasis and evaluate the respond to imatinib mesylate (Glivec) therapy. METHODS: Two cases of GIST of small intestine associated with lymph node metastasis were collected and investigated by light microscopy and immunohistochemistry. Mutation in exon 9, 11 and of c-kit gene were analyzed by polymerase chain reaction and DNA sequencing. RESULTS: The cases presented as small intestinal mass of irregular shape. Histologically, the tumors consisted of epithelioid and spindled cells, with areas of coagulative necrosis and hemorrhage. The mitotic count measured about 2 per 50 high-power fields. Immunohistochemical study showed that the tumor cells were diffusely distributed and strongly positive for CD117. Mutation analysis revealed that case 1 had an in-frame deletion of 11 amino-acid residues corresponding to 559-569 and carried two missense mutations involving codons 570, 571 in exon 11 of c-kit gene. Case 2 revealed an in-frame deletion involved condons 559-565 in exon 11 of c-kit gene. These two cases were all underwent primary chemotherapy with imatinib mesylate and without new tumor was found during follow-up periods (18, 26 months) after operation. CONCLUSIONS: GIST with nodal metastasis is very rare and needs to be distinguished from other soft tissue sarcomas occurring in this site. The responsiveness to imatinib mesylate therapy correlates with the mutation status of c-kit gene.

[Clinical significance and prognostic value of RON protein expression in gastric carcinoma].

OBJECTIVE: To investigate the protein expression of RON, a tyrosine kinase receptor, protein in gastric carcinoma and the relationship between its expression and prognosis of cancer. METHOD: s 98 samples of gastric carcinoma obtained from 98 patients, 70 males and 28 females, aged 58 (21 -76), 29 specimens of paraneoplastic tissue, and 10 specimens of normal gastric mucosa were examined using immunohistochemical Envision method; 19 samples of gastric carcinoma fresh tissue, paraneoplastic tissue, and paraneoplastic lymph nodes with metastasis obtained from patients during operation underwent Western blotting to detect the protein expression of RON. And 10 specimens of normal gastric mucosa and normal lymph nodes were examined as controls. All cases were followed up for 3 - 89 months. RESULTS: (1) The RON positive rate of the gastric carcinoma tissue was 56.1% (55/98), significantly higher than that of the paraneoplastic tissue (25.6%, 8/29, P < 0.01). No RON expression was observed in the normal gastric mucosa. (2) RON expression was positively correlated with the invasive depth of the tumor (P < 0.05), perigastric lymph nodes metastasis (P < 0.05), and TNM stage (P < 0.01), but was not correlated with the growing manner of the tumor (Borrmann staging), histopathological grade of the tumor, and distant metastasis (all P > 0.05). (3) RON expression was not related to the survival rate (P > 0.05). (4) The splicing variant of RON was strongly expressed in the fresh gastric carcinoma tissue, corresponding paraneoplastic tissue and perigastric lymph nodes with metastatic carcinoma cell. No expression of the splicing variant of RON was observed in the normal gastric mucosa and normal lymph nodes. CONCLUSION: RON and its splice variant may play an important role in the pathogenesis, progression, and metastasis of gastric carcinoma, and represent potential markers that can be used to evaluate the biological activity of gastric carcinoma.