Clinicopathological and mutational characteristics of primary double mutant gastrointestinal stromal tumor: a single center study with review of the literature.

AIMS: Primary double KIT/PDGFRA mutations are very rare in gastrointestinal stromal tumours (GISTs) but have not been comprehensively studied to date. In the present study, we investigated the clinicopathologic and genetic features of eight cases of primary double-mutant GISTs, and we reviewed the literature. METHODS AND RESULTS: The tumours occurred in six males and two females (age range 57-83 years) and involved the small intestine (n = 4), stomach (n = 2), rectum (n = 1) and retroperitoneum (n = 1). Clinical manifestations were variable, ranging from indolent (no symptoms) to aggressive disease (tumour rupture and haemorrhage). All patients underwent surgical excision, and six of them were treated with imatinib. No one experienced recurrence or other complications during the follow-up time (10 to 61 months). Histologically, all the tumours exhibited mixed cell types, accompanied by variable interstitial changes. KIT mutations were detected in all cases, and the majority of them were present in different exons (n = 5). No PDGFRA exon 12, 14 or 18 mutations were found. All the mutations were validated by next-generation sequencing, and two additional variants with comparatively low allelic fractions were identified in one case. Two of the cases had available allele distribution data, one with an in cis compound mutation and the other with an in trans compound mutation. CONCLUSION: Primary double-mutant GISTs have distinctive clinicopathologic and mutational features. Studies of more cases are necessary for a better understanding of these tumours.

Oculopharyngodistal myopathy with CGG repeat expansions in GIPC1: the first report from southwestern China.

Oculopharyngodistal myopathy (OPDM) is a rare adult-onset hereditary muscular disease characterized by slowly progressive ptosis, external ophthalmoplegia and weakness of the facial, pharyngeal and distal limb muscles. Recently, CGG repeat expansion mutations in three genes, LRP12, GIPC1 and NOTCH2NLC, have been identified as causative factors for OPDM. Here, we report clinicopathologically typical familial OPDM patients from southwestern China. CGG repeat expansions in GIPC1 were detected in two OPDM-affected individuals. Our study was the first GIPC1-OPDM report from southwestern China, further confirming expanded GGC repeats in GIPC1 as the cause of OPDM.

High expression of microRNA20b is associated with malignant clinicopathological features and poor prognosis in breast phyllodes tumor.

BACKGROUND: microRNAs, which expound the transcriptional regulation of gene expression, have been validated as prognostic markers in many tumors. The deregulated expression of microRNAs has been shown to aid classification of tumors and predict outcome in many tumors including breast PTs. The aim of our study is to investigate the clinical significance and prognostic value of microRNAs in PTs to identify a biomarker which has the potential for predicting prognosis and target therapy. METHODS: Quantitative real-time PCR (qRT-PCR) was used to detect the expression level of microRNA20b in 123 breast PTs patients. The correlations between the expression of microRNA20b and clinicopathological parameters were investigated. The prognostic significance of microRNA20b was investigated by the Kaplan-Meier survival and Cox proportional hazards regression model. RESULTS: The expression level of microRNA20b increased with the increase in the tumor grade (p < 0.05). High expression of microRNA20b correlated with stromal overgrowth, marked stromal cellularity, high atypia of stromal cells, infiltrative tumor margin, high mitotic activity, tumor grade, local recurrence and metastasis (p < 0.05). High expression of microRNA20b correlated with the shorter disease-free survival (DFS) (log-rank test, p < 0.001). Multivariate Cox regression analysis showed that microRNA20b was an independent prognostic indicator for breast PTs patients. CONCLUSION: The study demonstrated the promising potential of applying microRNA20b as a prognostic biomarker in PT patients.

Whole exome and target sequencing identifies MAP2K5 as novel susceptibility gene for familial non-medullary thyroid carcinoma.

Although the genotype-phenotype for familial medullary thyroid carcinoma (FMTC) is well studied, only few low susceptibility risk loci were identified for familial non-medullary thyroid carcinoma (FNMTC). The aim of this study is to screen and identify high-penetrate genes for FNMTC. A total of 34 families with more than two first-degree relatives diagnosed as papillary thyroid cancer without other familial syndrome were recruited. Whole exome and target gene sequencing were performed for candidate variants. These variants were screened and analyzed with ESP6500, ExAC, 1000 genomes project, and the Cancer Genome Atlas (TCGA) with SIFT score and Polyphen2 prediction. Finally, we identified recurrent genetic mutation of MAP2K5 variants c.G961A and c.T1100C (p. A321T and p.M367 T) as susceptibility loci for FNMTC. The frequencies of MAP2K5 c.G961A and c.T1100C were found, 0.0385 and 0.0259 in FNMTC and 0 and 0.00022523 in healthy Chinese controls (n = 2200, P < 0.001), respectively. Both variants were located in the protein kinase domain. The functional study showed that MAP2K5 A321T or M367 T could consistently phosphorylate downstream protein ERK5 on site Ser731 + Thr733 or Ser496, promoting nuclear translocation and subsequently altering target gene expressions. Our data revealed that MAP2K5 variants A321T or M367 T can activate MAP2K5-ERK5 pathway, alter downstream gene expression, and subsequently induce thyroid epithelial cell malignant transformation. While classic MAP2K1/2(MEK1/2)-ERK1/2 signaling is well known for driving sporadic NMTC, our research indicated that MAP2K5 (MEK5) is a susceptibility gene for FNMTC. These findings highlight the potential application of MAP2K5 for molecular diagnosis as well as early prevention.

Amplification of FRS2 in atypical lipomatous tumour/well-differentiated liposarcoma and de-differentiated liposarcoma: a clinicopathological and genetic study of 146 cases.

AIMS: The aim of this study was to evaluate the frequency of FRS2 amplification and its relationship with the clinicopathological features of atypical lipomatous tumour (ALT)/well-differentiated liposarcoma (WDL)/de-differentiated liposarcoma (DDL). METHODS AND RESULTS: FRS2 and MDM2 fluorescence in-situ hybridisation (FISH) was performed on 146 tumours (70 ALT/WDLs and 76 DDLs). One hundred and eight control samples were included for FRS2 analysis. FRS2 amplification was detected in 136 of 146 (93.2%) ALT/WDL/DDLs, including 63 ALT/WDLs and 73 DDLs. A higher FRS2/CEP12 ratio was observed in DDLs than in ALT/WDLs (P = 0.0005). The FRS2/CEP12 ratio of peripheral tumours was lower than that of central tumours (P = 0.00004). All the ALT/WDL/DDLs showed MDM2 amplification (100%). The MDM2+ /FRS2- series included seven ALT/WDLs and three DDLs. Four of seven (57.1%) MDM2+ /FRS2- ALT/WDLs occurred in peripheral sites, slightly higher than the percentage of MDM2+ /FRS2+ ALT/WDLs (28 of 63, 44.4%). All the three MDM2+ /FRS2- DDLs (100%) were peripheral tumours, a much higher proportion than that of MDM2+ /FRS2+ DDLs (10 of 73, 13.7%). A high percentage of homologous pleomorphic liposarcoma-like DDLs (two of three) were observed in the MDM2+ /FRS2- group. In the control group all the parosteal osteosarcomas (five of five, 100%) were FRS2 amplified, whereas the remaining 103 samples were FRS2 non-amplified. CONCLUSIONS: These findings suggest that FRS2 is amplified consistently in ALT/WDL/DDLs and offer another avenue for the investigation of the biology of this tumour group. MDM2+ /FRS2- cases seem to be associated with certain clinicopathological features, and further investigation is needed.

Secreted protein acidic and rich in cysteine-like 1 suppresses metastasis in gastric stromal tumors.

BACKGROUND: Malignant growth and metastasis of gastrointestinal stromal tumors (GIST) occur in some patients even during the course of treatment, but their mechanisms remains poorly understand at the molecular level so far. METHODS: Profiles of protein expression in gastric GIST tissues were explored using protein microarray analysis, down-regulation of SPARCL1 (secreted protein acidic and rich in cysteine-like protein 1) was validated by RT-qPCR, western blot and immunohistochemistry. The effect of specific shRNA-induced SPARCL1 downregulation on the biological traits of GIST 882 cell was investigated. We then employed a mouse xenograft model to investigate whether the low-expression of SPARCL1 impact the metastasis ability of GIST cells in vivo. RESULTS: SPARCL1 was significantly downregulated in the gastric GIST with high-grade malignance as compared with low-grade malignance, its expression was closely correlated with tumor size, mitotic index, distant metastasis at the time of initial diagnosis and tumor progression of GIST (P < 0.05). Moreover, results of the Cox analysis showed that expression of SPARCL1 is an independent prognostic predictors for gastric GIST (P = 0.008; HR 0.157, 95% CI 0.040~ 0.612). Downregulation of SPARCL1 promoted cell migration and invasion, but did not affect proliferation, cell cycle and apoptosis of GIST 882 cells. In mouse xenograft model, GIST cells with the decreased expression of SPARCL1 presented an enhanced ability of liver metastasis (P < 0.05). CONCLUSIONS: Taken together, our present study demonstrated that SPARCL1 have a certain degree of malignancy-suppressing potential through inhibiting the metastasis of gastric GIST.

Surgical treatment and prognosis of gastric neuroendocrine neoplasms: a single-center experience.

BACKGROUND: Gastric neuroendocrine neoplasms (G-NENs) are uncommon, and data on their management is limited. We here investigated the clinicopathological characteristics, surgical and survival outcomes in G-NENs among Chinese. Moreover, we will discuss their prognostic value. METHODS: From existing databases of the West China Hospital, we retrospectively identified 135 consecutive patients who were surgically treated and pathologically diagnosed as G-NENs from January 2009 to August 2015. RESULTS: This entire cohort comprised 98 males and 37 females, with a median age of 60 years. Twenty-five patients underwent endoscopic resection, while 110 patients underwent open/laparoscopic surgery. Thirty-nine patients had neuroendocrine tumor G1 (NET G1), seven patients had neuroendocrine tumor G2 (NET G2), 69 patients had neuroendocrine carcinoma G3 (NEC G3) and 20 patients had mixed adenoneuroendocrine carcinoma (MANEC). The median survival was not achieved for both NET G1 and NET G2 versus 19 months (range 3-48) for NEC G3 and 10.5 months (range 3-45) for MANEC. The 3-year survival rates for stage I, II, III, and IV were 91.1 %, 78.6 %, 51.1 % and 11.8 %, respectively (P < 0.001). As for the prognostic analysis, both surgical margin and the newly updated World Health Organization (WHO) classification were independent predictors of overall survival (OS). CONCLUSIONS: G-NENs are a kind of rare tumors, and patients with NET G3 and MANEC have unfavorable prognosis even surgically treated. Moreover, surgical margin and the new 2010 WHO criteria are closely associated with OS for G-NENs.

[Characteristics of Clinicopathology and Genotype in 179 Cases with Gastrointestinal Stromal Tumor].

OBJECTIVE: To analyze the characteristics of the clinicopathology and genotypes in patients with gastrointestinal stromal tumor (GIST). METHODS: The clinicopathological and genotypic data of 179 patients with GIST, who underwent treatment and genetic testing in the Hostital of West China from September 2009 to February 2009 were collected retrospectively. RESULTS: The tumor sites of the cases were located in stomach (88 cases, 49.2%), small intestine (70 cases, 39.1%), colorectum (7 cases, 3.9%) and the other sites (14 cases, 7.8%) respectively. 94.4%, 74.9% and 93.3% of GIST patients were positive for CD117, CD34 and DOG-1 immunophenotypes respectively. C-kit and PDGFRα mutations were found in 151 cases (84.4%) and 8 cases (4.5%) except for the wild types of the rest 20 cases (11.2%). Among all the c-kit mutation, 92.2% mutation types in exon 11 were deletion mutation, point mutation and hybrid mutations, and in exon 9 the mutation types were just involving A502_Y503dup (n = 6) and Y403_F504ins (n = 14), while the mutation type were K642Q in exon 13 (n = 1) and N822K in 17 (n = 2). There were 6 patients with the mutation types of PDGFRα in exon 18, and 3 of them were type of D842V. In the GIST genotyping, DOG-1 positive rate in PDGFRα mutation patients were significantly lower than that in c-kit mutation and wild type patients (P = 0.007). In the various type of c-kit mutations, the positive rate of CD34 in point mutation patients were significantly lower than that in other mutation types (P < 0.001). The rate of high-risk patients in point mutation and insertion mutation patients were lower than that in deletion mutation and deletion + insertion mutation patients (P = 0.006). CONCLUSION: The most common localizaions of GISTs are the stomach and small intestine. The most frequent mutation type of GIST is c-kit exon 11. The individualized treatment is required for GIST patients because its high mutation rate and types.

Pulmonary blastoma is successfully treated with immunotherapy and targeted therapy.

Pulmonary blastomas (PB) are an extremely rare type of lung cancer. Currently, no standard treatment exists for PB. Immunotherapy with checkpoint inhibitors and anti-angiogenesis treatments has been an effective method for lung cancer; however, studies on PB treatment are lacking. Herein, we present a case report of successful conversion therapy with immunotherapy and targeted therapy for PB. After receiving treatment with a PD-1 inhibitor (penpulimab) and a multi-target tyrosine kinase inhibitor (anlotinib) treatment, the patient showed an impressive response and underwent a successful operation. We also summarized and reviewed literature reports on PubMed from January 1, 2000, to December 31, 2022, using the keyword "pulmonary blastoma", discussing the efficacy and specifics of chemotherapy and radiotherapy. Immunotherapy, in combination with targeted therapy, should be considered a potential therapeutic strategy for PB.

Prenatal sonographic diagnosis of mature renal teratoma: a case report.

Renal teratoma is an extremely rare condition found in adolescents and young adults. Here, we report a case in which renal teratoma was diagnosed by fetal ultrasound examination. To our knowledge, this is the first report to describe the imaging manifestation of renal teratoma in prenatal diagnosis.

NTRK-rearranged spindle cell neoplasms: a clinicopathological and molecular study of 13 cases with peculiar characteristics at one of the largest institutions in China.

NTRK-rearranged spindle cell neoplasms (NTRK-RSCNs) represent an emerging group of rare tumours defined using molecular means. To the best of our knowledge, there have been no large series of reports about this tumour in the Chinese population in English full-text articles. Herein, we present 13 NTRK-RSCNs with peculiar characteristics. Ten of the 13 (77%) patients were children without sex differences. The tumour locations included six trunks, four extremities, two recta, and one small bowel. The histological morphology included four lipofibromatosis-like neural tumour (LPF-NT)-like, eight malignant peripheral nerve sheath tumours (MPNST)/fibrosarcoma-like, and one extremely rare myxofibrosarcoma-like pattern. Immunohistochemically, all cases were CD34, pan-TRK and TRK-A positive, SOX-10 negative, and H3K27me3 intact. S-100 protein expression was identified in 11 of 13 (85%) cases. Genetically, NTRK1 rearrangements were considered positive (7/13, 54%) or suspicious for positivity (6/13, 46%) by fluorescence in situ hybridisation. Next-generation sequencing and Sanger sequencing confirmed NTRK1 fusions with a variety of partner genes, including five LMNA, three TPM3, one SQSTM1, three novel CPSF6, IGR (downstream PMVK), and GAS2L1 genes. Interestingly, the last tumour concurrently harboured a second EWSR1-PBX1 fusion, which has never been reported. Four patients developed local recurrence and two of them suffered metastasis. In our study, NTRK-RSCNs had peculiar fusions that displayed unusual or complicated clinicopathological features. Histological clues and IHC helped streamline a small subset of potential candidates. Although FISH is a powerful technology for identifying NTRK rearrangements, RNA-/DNA-based NGS is recommended for highly suspected cases in which FISH signal patterns are not discernible as classic positive patterns, particularly if targeted therapy is considered.

[Prognosis of patients with adrenocortical carcinoma].

OBJECTIVE: To investigate the prognosis and influencing factors of patients with adrenocortical carcinoma. METHODS: Thirty-five patients (20 males and 15 females) with biopsy-diagnosed adrenocortical carcinoma were followed retrospectively. Cox proportional hazards regression analysis was performed to identify factors that influenced the prognosis of the patients. RESULTS: Three patients were classified as stage I, 15 as stage II, 12 as stage III, and 5 as stage IV. Fourteen patients were still alive and 21 died at the end of the follow-up. The patients had a median survival time of 33 months, with a survival rate of 77.1%, 62.5%, and 38.3% for the first year, second year, and fifth year respectively. The univariate analysis found no significant differences in survival rates with gender, tumor location (left or right adrenal), diameter (> or = 10 cm or <10 cm) of tumor, functionality of tumor, smoking, hypertension and hypokalemia (P > 0.05). The multivariate analysis revealed that being male, younger than 50 years, non-smoking and early-stage of tumor were significant protective factors for the survival of patients with adrenocarcinoma. Patients at stage III and stage II had 52 and 3 times higher mortality than those at stage I, respectively. CONCLUSION: Clinical stage and age are the main factors that influence the survival of patients with adrenocortical carcinoma. Patients younger than 50 years and those with an earlier stage of tumor would have a better prognosis.

Case Report: Early Distant Metastatic Inflammatory Myofibroblastic Tumor Harboring EML4-ALK Fusion Gene: Study of Two Typical Cases and Review of Literature.

Inflammatory myofibroblastic tumor (IMT) is a distinctive neoplasm that frequently arises in the lung and accounts for ~1% of lung tumors. Distant metastatic IMT is extremely rare and has been poorly investigated. This analysis was specifically performed to explore the clinicopathological and genetic features of early distant metastatic IMT. Two typical patients with distant metastatic IMTs were selected, which accounted for 1.13% of all diagnosed IMTs in the last 5 years. One patient was a 55 year-old male, and the other patient was a 56 year-old female. Both primary tumors arose from the lung, and the initial clinical symptoms of the two patients involved coughing. Both of the imaging examinations showed low-density nodular shadows in the lungs with enhancement around the mass. Microscopically, dense arranged tumor cells, prominent cellular atypia, and high mitotic activity with atypical form were more prominent in the metastatic lesions than in the primary lesions. All of the primary and metastatic tumors in both cases showed positive anaplastic lymphoma kinase (ALK) immunostaining and ALK rearrangement via fluorescence in situ hybridization. The EML4 (exon 6)-ALK (exon 20) fusion variant (v3a/b) was identified by using next-generation sequencing (NGS) and was verified by using reverse transcription polymerase chain reaction (RT-PCR). Furthermore, intronic variants of NOTCH1 and synonymous variants of ARAF were also detected via NGS in one IMT for the first time and were verified in all of the primary and metastatic lesions via PCR. Distant metastasis occurred during a short period of time (1 and 2 months) after the first surgery. One patient presented with multiple metastases to the subcutaneous tissue and bone that responded to ALK inhibitor alectinib therapy, and the tumor was observed to regress 10 months after the initial ALK inhibitor therapy. In contrast, the other patient presented with subcutaneous neck metastasis without ALK inhibitor treatment and succumbed to the disease within 3 months after the surgery. This study demonstrated the possible role of EML4-ALKv3a/b in the malignant progression of IMT and proposed certain therapeutic effects of ALK inhibitors on multiple metastatic IMTs.

Abnormal decrement on high-frequency repetitive nerve stimulation in congenital myasthenic syndrome with GFPT1 mutations and review of literature.

Objectives: Congenital myasthenic syndrome (CMS) is a clinically and genetically heterogeneous group of inherited disorders characterized by neuromuscular junction defects. Mutations in GFPT1 have been shown to underlie CMS. An increasing number of patients with CMS due to mutations in GFPT1 have been reported. However, a comprehensive review of clinical and genetic analyses of GFPT-related CMS worldwide is lacking, especially, given that the common or hotspot mutations in GFPT1 have not been reported. Here, we described the clinical and genetic findings of three patients with GFPT1 mutations from southwestern China and reviewed the clinical and genetic features of patients with GFPT1-related CMS worldwide. Methods: Clinical, laboratory, electrophysiological, myopathological, and genetic analyses of three patients with GFPT1-related CMS from southwestern China were conducted, and a review of previously published or reported cases about congenital myasthenic syndrome with GFPT1 mutations in the PubMed database was made. Results: The clinical, laboratory, electrophysiological, and myopathological features by muscle biopsy of three patients with GFPT1-related CMS were consistent with those of previously reported patients with GFPT1 mutations. Additionally, an abnormal decrement in high-frequency RNS was found. Two different homozygous missense mutations (c.331C>T, p.R111C; c.44C>T, p.T15M) were detected by whole-exome sequencing (WES) or targeted neuromuscular disorder gene panels. Conclusion: A distinct decremental response to high-frequency RNS was found in three patients with GFPT1-related CMS from southwestern China, which has never been reported thus far. In addition, the location and degree of tubular aggregates (TAs) seemed to be associated with the severity of clinical symptoms and serum creatine kinase levels, further expanding the phenotypic spectrum of GFPT1-related CMS. Lastly, some potential hotspot mutations in GFPT1 have been found in GFPT1-CMS worldwide.

Unusual split green-orange signals in USP6 fluorescence in situ hybridization in a malignant peripheral nerve sheath tumor with a novel NF1-SCIMP fusion: a potential diagnostic pitfall.

Deletion of the neurofibromatosis 1 (NF1) gene is common, but NF1 rearrangement or fusion has rarely been reported in peripheral nerve sheath tumors. Here, we present a case of malignant peripheral nerve sheath tumor (MPNST) in a 36-year-old Chinese female. Histologically, the lesion was composed of spindle cells with moderate atypia, immature bone, and atypical cartilage elements. Fluorescence in situ hybridization (FISH) for USP6 revealed green-orange split signals, strongly suggesting the presence of USP6 rearrangement. Subsequent next-generation sequencing-based technology analyses revealed t(17,17) (p13.2, q11.2) intrachromosomal translocation resulting in a novel NF1-SCIMP fusion gene along with NF1 deletion. However, USP6 fusion was not identified. To the best of our knowledge, this is the first case with a confirmed NF1 gene fusion partner in a peripheral nerve sheath tumor. Notably, rearrangement of the SCIMP may cause a pitfall in the interpretation of USP6 FISH results.

Primary intrathoracic liposarcomas: A clinicopathologic and molecular study of 43 cases in one of the largest medical centers of China.

Introduction: Primary intrathoracic liposarcoma is extremely rare, and most published series lack genetic analyses. The aim of our study is to better understand the clinicopathologic and genetic features of these rare lesions. Materials and methods: Forty-three primary intrathoracic liposarcomas were identified and most cases were analyzed by systematic genetic studies, including fluorescence in situ hybridization (FISH), whole-exome sequencing (WES), and Sanger sequencing. Results: This series included 27 males and 16 females (ratios, 1.68:1) aged 24-73 years (median, 53 years). Tumors mainly occurred in the mediastinum (n=23, 53.5%), followed by pleural cavity (n=16, 37.2%) and lung (n=4, 9.3%). The study included 21 well-differentiated liposarcomas (WDLs), 19 dedifferentiated liposarcomas (DDLs), 2 myxoid pleomorphic liposarcomas (MPLs) and 1 pleomorphic liposarcoma (PL), without identification of myxoid liposarcoma. FISH analysis identified MDM2 amplification in 17 of 18 WDLs (94.4%) and all DDLs (16/16, 100.0%). The MDM2-nonamplified WDL was CDK4-nonamplified but FRS2-amplified. WES and Sanger sequencing found somatic TP53 mutation in the 2 MPLs. Follow-up information was available for 33 of 38 cases (86.8%). Thirteen patients (39.4%) showed no evidence of disease, 10 patients (30.3%) were alive with disease, and 8 patients (24.2%) died of disease. Fourteen cases developed recurrence and 1 with metastasis. Conclusions: WDL/DDL was the overwhelming subtype in this location, followed by MPL and PL. Analysis of the FRS2 gene, in combination with MDM2 and other genes of 12q13-15, may more precisely characterize WDL/DDLs. MPL is the most fatal subtype of this site. Further studies are needed to explore the role of TP53 in the pathogenesis of MPL.

Gastric adenocarcinoma: can perfusion CT help to noninvasively evaluate tumor angiogenesis?

BACKGROUND: Perfusion CT is an attractive technique to assess tumor vascularity, and no studies have addressed the relationship between CT perfusion imaging and gastric tumor angiogenesis with volume-based technique. This study aims to assess the correlation between perfusion CT parameters using a volume-based technique and immunohistochemical markers of angiogenesis in gastric adenocarcinoma. METHODS: 37 patients with gastric adenocarcinoma who completed whole tumor CT perfusion examination with volume-based technique were studied. Post surgical specimens were stained using a polyclonal antibody to VEGF and CD34. Perfusion measurements were correlated with microvessel density (MVD) and VEGF by using Pearson or Spearman rank correlation analysis, in which a P value < 0.05 was considered statistically significant. RESULTS: The mean MVD of all 37 tumors was 108.9 ± 38.2 vessels/0.723 mm². 70.3% (26 of 37) of tumors expressed VEGF positively. MVD of gastric adenocarcinoma was significantly correlated with blood volume (the Pearson correlation coefficient being 0.420, P = 0.001). No correlations were found between VEGF expression and perfusion CT parameters. There were no significant differences in the parameters between the high and low MVD groups, and between the positive and negative VEGF groups. CONCLUSIONS: Blood volume was significantly correlated with MVD. It could reflect the angiogenesis in gastric adenocarcinoma.

Extremity Gangrene Caused by HBV-Related Cryoglobulinemia Vasculitis in a Patient with Diabetes - A Case Report.

We presented a case of hepatitis B virus (HBV)-related type III cryoglobulinemia vasculitis (CryoVas) characterized by extremity gangrene in a patient with diabetes. The 60-year-old female had a 10-year history of poorly controlled type 2 diabetes mellitus. She complained of sudden onset pain and swelling of toes which quickly progressed to gangrene, with fingers becoming pain and dark violet. The patient was initially misdiagnosed as diabetic foot (DF). Although DF is one of the common chronic complications of diabetes, it rarely involves the hand. What is more, the ischemic manifestations of the extremity were not consistent with the results of the vascular examination and immune system changes. The patient had Raynaud's phenomenon, arthralgia, and extremity gangrene. Test results showed cryoglobulinemia multiple positive, polyclonal immunoglobulin with rheumatoid factor negative, lower complement 3, leukocytoclastic vasculitis, and HBV infection. HBV-related type III CryoVas was finally diagnosed, and a conservative therapy strategy was given. Six months after treatment with cyclophosphamide, corticosteroid, nucleoside/nucleotide analog therapy, local debridement, and dressing change, she recovered and kept no recurrence by following up for 30 months. To our knowledge, this is the first report of extremity gangrene caused by HBV-related CryoVas in a diabetic patient.

Atypical nodular fasciitis with a novel PAFAH1B1-USP6 fusion in a 22-month-old boy.

Nodular fasciitis (NF) rarely occurs in infants aged < 2 years although cranial fasciitis develops predominantly in this age group. Histologically, NF may present high cellularity and brisk mitoses, but atypical forms are generally absent. Here, we report a NF in a 22-month-old Chinese boy. Microscopically, the lesion was manifested as cellular variant of NF. Notably, atypical mitotic figures including multipolar form were identified. Immunohistochemically, the neoplastic cells showed strong positivity for smooth muscle actin. Fluorescence in situ hybridization analysis revealed an unbalanced rearrangement of USP6, along with the USP6 increased copies. Subsequent next-generation sequencing-based technology revealed a novel PAFAH1B1-USP6 fusion gene as well as unusual fusion point on USP6 (exon 9). To the best of our knowledge, this is the only reported case with overt atypical mitosis. This case is also the first published example of genetically confirmed infant NF. Additionally, PAFAH1B1-USP6 fusion has never been described in NF.

Expression of FRS2 in atypical lipomatous tumor/well-differentiated liposarcoma and dedifferentiated liposarcoma: an immunohistochemical analysis of 182 cases with genetic data.

BACKGROUND: The fibroblast growth factor receptor substrate 2 (FRS2) gene is located close to MDM2 and CDK4 within the 12q13-15 chromosomal region. FRS2 gene was recently found to be consistently amplified in atypical lipomatous tumor (ALT)/well-differentiated liposarcoma (WDL) and dedifferentiated liposarcoma (DDL), suggesting the detection of FRS2 amplification could be a diagnostic tool for ALT/WDL/DDLs. However, the expression of FRS2 protein and diagnostic value of FRS2 immunohistochemistry (IHC) has not been evaluated in a large cohort of ALT/WDL/DDLs. METHODS: A SNOMED search of hospital surgical pathology files from January 2007 to July 2020 identified 182 ALT/WDL/DDLs with available materials. FRS2 fluorescence in situ hybridization (FISH) and IHC were performed on 182 ALT/WDL/DDLs and 64 control samples. The expression of FRS2 was also compared with that of classic immunomarkers (MDM2 and CDK4) of this tumor entity. RESULTS: This study included 91 ALT/WDLs and 91 DDLs. The FISH results showed 172 of 182 (94.5%) cases were FRS2-amplified, and 10 cases were FRS2-nonamplified. Immunostaining results showed 171 (94.0%) ALT/WDL/DDLs were positive for FRS2 and 11 cases (6.0%) were FRS2-immunonegative. In 172 FRS2-amplified cases, 166 (96.5%) were FRS2-immunopositive, and 6 (3.5%) were negative. Among 10 FRS2-nonamplified ALT/WDL/DDL cases, 5 cases were FRS2-immunonegative, and 5 tumors displayed 1+ staining for this marker. In 64 control cases, none of them exhibited FRS2 amplification. Forty-seven (73.5%) control cases were negative for FRS2 immunostaining, while 17 cases (26.5%) were FRS2-immunopositive. Fifteen of these false positive samples (15/17, 88.2%) showed 1+ positivity and only 2 cases (2/17, 11.8%) displayed 2+ positivity. In ALT/WDL/DDLs, the sensitivity of FRS2 immunostaining was slightly lower than MDM2 (FRS2 vs. MDM2: 94.0% vs 100.0%) and CDK4 (FRS2 vs. CDK4: 94.0% vs 97.0%). However, the specificity of FRS2 (73.5%) was slightly higher than that of MDM2 (67.8%) and CDK4 (64.4%). CONCLUSION: This study indicated that FRS2 IHC had relatively good consistency with FRS2 FISH, suggesting that FRS2 immunostaining could be utilized as an additional screening tool for the diagnosis of ALT/WDL/DDL. It must be emphasized that MDM2/CDK4/FRS2 especially MDM2 FISH remains the gold standard and the most recommended method to diagnose this entity.