Qun-Li Shi

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.

Concurrent loss of INI1, PBRM1, and BRM expression in epithelioid sarcoma: implications for the cocontributions of multiple SWI/SNF complex members to pathogenesis.

The loss of INI1 (SMARCB1) expression, caused by SMARCB1 (INI1, SNF5L4, BAF47) inactivation, frequently occurs in epithelioid sarcoma (ES) and could aid in confirming the diagnosis. Except for INI1, the expression of switch in mating type/sucrose nonfermentation complex members in ES has never been examined. In this study, the expression of key subunits of this complex-INI1, BRG1 (SMARCA4), BRM (SNF2L2, SMARCA2), PBRM1 (hPB1, BAF180), and BAF155 (SMARCC1)-was analyzed in 23 ES cases: 15 conventional and 8 proximal type. All of the cases were reviewed and reclassified by hematoxylin-eosin staining and immunostaining for cytokeratin AE1/3, epithelial membrane antigen, CD34, vimentin, and INI1 expression. Of the 23 ES cases, 19 (82.6%) showed a loss of PBRM1, and 18 (78.3%), a loss of INI1. In most cases (17, 73.9%), loss of INI1 and PBRM1 expression was observed. The pattern of PBRM1 expression was similar to that of INI1, that is, not correlated with changes in cellular morphology. The concurrent loss of BRM, PBRM1, and INI1expression was detected in 2 cases with pure rhabdoid tumor features. The frequent observation of concurrent loss of INI1 and PBRM1 suggests that certain switch in mating type/sucrose nonfermentation complex components might act synergistically in the pathogenesis of ES by unknown mechanisms and that these components could provide new targets for therapy. The usefulness of PBRM1 as a biomarker of ES and its mechanism in ES require further investigation. Loss of BRM in ES with pure rhabdoid features suggests that BRM might be involved in the underlying mechanisms of this type of ES.

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.

DCN deficiency promotes renal cell carcinoma growth and metastasis through downregulation of P21 and E-cadherin

Decorin (DCN), as an important component of the extracellular matrix (ECM), is a small leucine-rich proteoglycan and synthesized by fibroblasts. Although DCN is dysregulated in numerous cancer types, limited data are available on the expression level and important role of DCN proteins in renal cell carcinoma (RCC). In our study, we examined the expression patterns of DCN messenger RNA (mRNA) in RCCs through the Oncomine database and DCN protein in 94 RCC specimens by immunohistochemistry (IHC). The results revealed that DCN expression was decreased in cancerous tissues compared to adjacent noncancerous tissues and was highly correlated to tumor size. Then, via gain-of-function analyses, DCN overexpression could inhibit RCC cell proliferation and metastasis in vitro and vivo. At the mechanism level, we found that an ectopic expression of DCN significantly upregulated P21 and E-cadherin expression. Altogether, these results revealed that DCN is a tumor suppressor in RCC, and it could serve as a potential therapeutic target in patients with RCC.

Thymidine kinase 1 expression in ovarian serous adenocarcinoma is superior to Ki-67: A new prognostic biomarker:

Cancer is a disease with abnormally proliferating cells and therefore proliferation rate is an important index for assessing tumour growth. Ki-67 is a commonly used proliferation marker considered to be an unfavourable prognostic marker in some tumors, while Thymidine kinase 1 (TK1) is an interesting proliferation marker because its levels are highly dependent on the growth stage of cells. To define the immunohistochemistry (IHC) expression of the TK1 in patients with ovarian serous adenocarcinoma and establish its potential role as a new biomarker for progressive disease, we analyzed the expression patterns of TK1 and Ki-67 in 109 patients with ovarian serous adenocarcinoma. TK1 and Ki-67 expression both showed a statistically significant correlation to MD Anderson Cancer Center (MDACC) grade, but not to age, tumour size, lymph node metastasis or pathological TNM (pTNM) stages. TK1 expression, MDACC grades, pathological stages and lymph node metastasis correlate to relapse incident rate and overall survival, but Ki-67 does not. Although TK1 expression, MDACC grade, pTNM stage and lymph node metastasis significantly correlate to relapse in the Cox univariate analysis, in the multivariate Cox analysis only TK1 expression and lymph node metastasis were independent prognostic factors. The overall survival also correlated significantly to TK1 expression, MDACC grade, pTNM stage and lymph node metastasis in the Cox univariate analysis. However, only the pTNM stage was found to be an independent prognostic factor for survival in the Cox multivariate analysis. Therefore, though TK1 expression was an independent prognostic factor for relapse, but not for survival, TK1 is a more informative expression than Ki-67 for LI, relapse and overall survival rates. Thus, when TK1 is combined with MDACC grading, pTNM staging and lymph node metastasis, IHC determination of TK1 expression may improve the overall prediction of prognosis in patients with ovarian cancer.

Ovarian small-cell carcinoma hypercalcemic type successfully treated: a case report and literature review.

Ovarian small-cell carcinoma hypercalcemic type (OSCCHT) is a relatively rare and highly fatal gynecological malignancy. Prognosis is generally poor, and no treatment guidelines are offered. Here, we report a case of OSCCHT successfully treated by complete excision and a postoperative chemotherapy scheme of carboplatin and paclitaxel. A 29-year-old female with with pelvic mass and significantly increased serum calcium (4.90 mmol/L) was referred to our hospital on August 22, 2013. Abdominal ultrasonography and computed tomography revealed a pelvic nonhomogeneous echo of a 113×102 mm mass, possibly coming from the adnexa of the uterus. Preoperative examinations indicated high levels of serum calcium and relevant acute renal dysfunction; hence, continuous renal replacement therapy was performed until all tests reached minimum operation requirements. Interestingly, after excision, serum calcium levels decreased rapidly and therefore, extra calcium had to be taken in order to take the level back up to normal. The patient was diagnosed with OSCCHT based on the clinical data and pathological examinations. After six cycles of chemotherapy, the patient was in a good condition and on follow-up there were no signs of recurrence.