Qin Shen

PSF/SFPQ is a very common gene fusion partner in TFE3 rearrangement-associated perivascular epithelioid cell tumors (PEComas) and melanotic Xp11 translocation renal cancers: clinicopathologic, immunohistochemical, and molecular characteristics suggesting classification as a distinct entity.

An increasing number of TFE3 rearrangement–associated tumors, such as TFE3 rearrangement–associated perivascular epithelioid cell tumors (PEComas), melanotic Xp11 translocation renal cancers, and melanotic Xp11 neoplasms, have recently been reported. We examined 12 such cases, including 5 TFE3 rearrangement–associated PEComas located in the pancreas, cervix, or pelvis and 7 melanotic Xp11 translocation renal cancers, using clinicopathologic, immunohistochemical, and molecular analyses. All the tumors shared a similar morphology, including a purely nested or sheet-like architecture separated by a delicate vascular network, purely epithelioid cells displaying a clear or granular eosinophilic cytoplasm, a lack of papillary structures and spindle cell or fat components, uniform round or oval nuclei containing small visible nucleoli, and, in most cases (11/12), melanin pigmentation. The levels of mitotic activity and necrosis varied. All 12 cases displayed moderately (2+) or strongly (3+) positive immunoreactivity for TFE3 and cathepsin K. One case labeled focally for HMB45 and Melan-A, whereas the others typically labeled moderately (2+) or strongly (3+) for 1 of these markers. None of the cases were immunoreactive for smooth muscle actin, desmin, CKpan, S100, or PAX8. PSF-TFE3 fusion genes were confirmed by reverse transcription polymerase chain reaction in cases (7/7) in which a novel PSF-TFE3 fusion point was identified. All of the cases displayed TFE3 rearrangement associated with Xp11 translocation. Furthermore, we developed a PSF-TFE3 fusion fluorescence in situ hybridization assay for the detection of the PSF-TFE3 fusion gene and detected it in all 12 cases. Clinical follow-up data were available for 7 patients. Three patients died, and 2 patients (cases 1 and 3) remained alive with no evidence of disease after initial resection. Case 2 experienced recurrence and remained alive with disease. Case 5, a recent case, remained alive with extensive abdominal cavity metastases. Our data suggest that these tumors belong to a single clinicopathologic spectrum and expand the known characteristics of TFE3 rearrangement–associated tumors.

Frequent co-inactivation of the SWI/SNF subunits SMARCB1, SMARCA2 and PBRM1 in malignant rhabdoid tumours

Malignant rhabdoid tumours (MRTs) are highly aggressive malignancies of early infancy characterized by inactivation of SMARCB1, a core member of the SWI/SNF chromatin‐remodelling complex. The aim of this study was to explore the status of multiple key subunits of the SWI/SNF complex in MRTs.

Xp11 neoplasm with melanocytic differentiation of the prostate harbouring the novel NONO-TFE3 gene fusion: report of a unique case expanding the gene fusion spectrum.

Recently, an increasing number of TFE3 rearrangement‐associated tumours have been reported, such as TFE3 rearrangement‐associated perivascular epithelioid cell tumours (PEComas), melanotic Xp11 translocation renal cancers and melanotic Xp11 neoplasms. We have suggested that these tumours belong to a single clinicopathological spectrum. ‘Xp11 neoplasm with melanocytic differentiation’ or ‘melanotic Xp11 neoplasm’ have been proposed to designate this unique neoplasm. Herein, we describe the first case of an Xp11 neoplasm with melanocytic differentiation to be described in the prostate, bearing the novel NONO–TFE3 gene fusion. This study both adds to the spectrum regarding melanotic Xp11 neoplasms and expands its gene fusion spectrum. Moreover, we discuss the relationship of these rare tumours to neoplasms such as conventional PEComas, alveolar soft part sarcomas, malignant melanomas, clear cell sarcomas and Xp11 translocation renal cancers.

Detection of ALK protein expression in lung squamous cell carcinomas by immunohistochemistry

BackgroundThe echinoderm microtubule-associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene rearrangements occur in approximately 5% of lung adenocarcimomas (ACA), leading to ALK overexpression and predicting response to targeted therapy. To the present, few studies have been focused on the expression of ALK protein in lung squamous cell carcinomas (SqCC). Only several cases of lung SqCC were reported expression of ALK protein. No clinical study has been published to explicit the relationship between ALK expression and the response to targeted therapy in SqCC.MethodsIn this study, we analyzed ALK protein expression with a specific rabbit monoclonal Ig antibody (D5F3 clone) in 207 cases of lung SqCC. The positive cases were confirmed with ALK fluorescence in situ hybridization (FISH) and RT-PCR.ResultsWe found that 3 out of 207 (1.4%) cases of lung SqCC were ALK positive detected by IHC staining, which were confirmed by ALK FISH and RT-PCR.ConclusionsOur results indicate that ALK protein expression is not a rare molecular event in SqCC. Although the frequency of EML4-ALK rearrangements is lower in lung SqCC than that in lung adenocarcinomas, their presence may provide additional treatment options in lung SqCC. The response of SqCC patients with ALK expression to target therapy of crizotinib should be explored.

EphB4 promotes the proliferation, invasion, and angiogenesis of human colorectal cancer

OBJECTIVE Eph/Ephrin signalling plays an important role in tumorigenesis, neovascularization, and vasculogenesis. However, studies concerning the role of EphB4 in colorectal cancer (CRC) show inconsistent results, and the function of EphB4 in the formation of CRC-related blood vessels is not fully understood. The aim of this study is to investigate the EphB4 expression in CRC and the role of EphB4 in tumour angiogenesis. MATERIALS AND METHODS EphB4 and EphrinB2 expressions were detected in 200 CRC samples and 50 paired colorectal mucosae by immunohistochemistry. Xenograft animal models were established by stable knockdown and stable overexpression of EphB4, and control cell lines were used to investigate the role of EphB4 in CRC. Microvessels were stained with anti-CD34, and microvessel density (MVD) was assessed. RESULTS EphB4 protein was more highly expressed in CRC tissues compared with adjacent normal mucosae (P<0.05), while EphrinB2 levels were unchanged. Modulation of EphB4 levels in colon cancer cell line SW480 resulted in significant effects on tumour growth and invasion in vivo, with stable overexpression of EphB4 associated with faster growth and invasion. Furthermore, microvessel density values in xenograft tumours were significantly correlated with EphB4 (P<0.05). CONCLUSION EphB4 acts as a tumour promoter associated with proliferation, invasion, and angiogenesis, and may be used as a potential CRC therapeutic target.

Loss of BRM expression is a frequently observed event in poorly differentiated clear cell renal cell carcinoma

The aim of this study was to examine the status of Brahma (BRM), a key SWI/SNF complex subunit, in clear cell renal cell carcinomas (RCCs), and to analyse the histopathology, immunophenotype, molecular features and prognosis of the BRM‐negative cases.

The Value of Prognostic Factors for Survival in Synchronous Multifocal Lung Cancer: A Retrospective Analysis of 164 Patients

BACKGROUND We reviewed patients treated for synchronous multifocal lung cancers (SMLCs) to analyze outcomes and evaluate valuable prognostic factors. METHODS From January 2010 to June 2016, 3,031 patients underwent lung cancer resection at Jinling Hospital and Suzhou Hospital affiliated to Nanjing Medical University, and 164 (5.4%) had SMLC. The Kaplan-Meier method was used for survival analysis, and a multivariable Cox proportional hazards regression model was used for identification of independent survival predictors. RESULTS The overall survival and progression-free survival rates with SMLC were 72.6% and 61.0%, respectively. A statistically significant difference existed for overall survival and progression-free survival between synchronous multiple primary lung cancer and intrapulmonary metastases according to Martini criteria. There was no statistical difference among the subgroups categorized by the TNM classification. Furthermore, small tumor size showed a benefit for overall survival and progression-free survival. Patients whose tumors were 0.8 cm or smaller had a 5-year survival rate of 100%. Tumor size, lymphatic metastases, and histologic differentiation were identified by univariate and multivariate regression analysis as independent survival predictors. CONCLUSIONS Survival of patients with SMLC is strongly correlated with the tumor size, differentiation, and lymphatic metastases but not with clinical TNM stage. The Martini criteria based on histologic subtyping has certain predictive value to survival. In comparison, tumor size is of greater value for prognosis. Both of the criteria above are much better than the TNM classification. The 5-year survival rate of 100% in patients with tumors sized 0.8 cm or smaller is extremely valuable for predicting survival after surgical resection.

Novel gene fusion of PRCC-MITF defines a new member of MiT family translocation renal cell carcinoma: clinicopathological analysis and detection of the gene fusion by RNA sequencing and FISH

MITF, TFE3, TFEB and TFEC belong to the same microphthalmia‐associated transcription factor family (MiT). Two transcription factors in this family have been identified in two unusual types of renal cell carcinoma (RCC): Xp11 translocation RCC harbouring TFE3 gene fusions and t(6;11) RCC harbouring a MALAT1–TFEB gene fusion. The 2016 World Health Organisation classification of renal neoplasia grouped these two neoplasms together under the category of MiT family translocation RCC. RCCs associated with the other two MiT family members, MITF and TFEC, have rarely been reported. Herein, we identify a case of MITF translocation RCC with the novel PRCC–MITF gene fusion by RNA sequencing.