Shih-Chiang Huang

NAB2–STAT6 fusion types account for clinicopathological variations in solitary fibrous tumors

Solitary fibrous tumor (SFT) is characterized by the inv12(q13q13)-derived NAB2–STAT6 fusion, which exhibits variable breakpoints and drives STAT6 nuclear expression. The implications of NAB2–STAT6 fusion variants in pathological features and clinical behavior remain to be characterized in a large cohort of SFTs. We investigated the clinicopathological correlates of this genetic hallmark and analyzed STAT6 immunoexpression in 28 intrathoracic, 37 extrathoracic, and 23 meningeal SFTs. These 88 tumors were designated as histologically nonmalignant in 75 cases and malignant in 13, including 1 dedifferentiated SFT. Eighty cases had formalin-fixed and/or fresh samples to extract assessable RNAs for RT-PCR assay, which revealed NAB2–STAT6 fusion variants comprising 12 types of junction breakpoints in 73 fusion-positive cases, with 65 (89%) falling into 3 major types. The predominant NAB2ex4–STAT6ex2 (n=33) showed constant breakpoints at the ends of involved exons, whereas the NAB2ex6–STAT6ex16 (n=16) and NAB2ex6–STAT6ex17 (n=16) might exhibit variable breakpoints and incorporate NAB2 or STAT6 intronic sequence. Including 73 fusion-positive and 7 CD34-negative SFTs, STAT6 distinctively labeled 87 (99%) SFTs in nuclei, exhibited diffuse reactivity in 73, but did not decorate 98 mimics tested. In seven fusion-negative cases, 6 were STAT6-positive, suggesting rare fusion variants not covered by RT-PCR assay. Regardless of histological subtypes, intrathoracic SFTs affected older patients (P=0.035) and tended to be larger in size (P=0.073). Compared with other variants, NAB2ex4–STAT6ex2/4 fusions were significantly predominant in the SFTs characterised by intrathoracic location (P<0.001), older age (P=0.005), decreased mitoses (P=0.0028), and multifocal or diffuse STAT6 staining (P=0.013), but not found to correlate with disease-free survival. Conclusively, STAT6 nuclear expression was distinctive in the vast majority of SFTs, including all fusion-positive tumors, and exploitable as a robust diagnostics of CD34-negative cases. Despite the associations of NAB2–STAT6 fusion variants with several clincopathological factors, their prognostic relevance should be further validated in large-scale prospective studies of SFTs.

The clinicopathological significance of NAB2‐STAT6 gene fusions in 52 cases of intrathoracic solitary fibrous tumors

NAB2‐STAT6 gene fusion drives STAT6 nuclear expression and is the pathognomonic hallmark of solitary fibrous tumors (SFTs). However, no study has systematically analyzed the clinicopathological features, STAT6 immunoexpression status, or the fusion variants of NAB2‐STAT6 in intrathoracic SFTs. Fifty‐two intrathoracic SFTs were retrieved to appraise histopathology, assess STAT6 immunoexpression, and determine NAB2‐STAT6 fusion variants by RT‐PCR. Location‐relevant histologic mimics served as controls. Thirty‐one pleura‐based, 12 mediastinal/pericardial, and nine intrapulmonary lesions were histologically categorized into eight malignant, eight atypical, and 36 conventional or cellular SFTs, including two fat‐forming and two giant cell angiofibroma‐like SFTs. STAT6 distinctively decorated the tumoral nuclei in 51 (98%) SFTs. However, no nuclear staining was observed in the histological mimics. NAB2‐STAT6 fusion was detected in 34 SFTs. Twenty‐nine (85.3%) exhibited the major NAB2ex4‐STAT6ex2/3 variant and 5 (14.7%) the minor NAB2ex6‐STAT6ex16/17. NAB2ex4‐STAT6ex2 was significantly associated with older age (P = 0.01) and pleuropulmonary tumors (P = 0.025). After a median follow‐up of 33.9 (range, 0.3–174.6) months, adverse outcomes occurred in one atypical and five malignant SFTs, including two local relapses, one intrapulmonary metastasis, and three extrathoracic metastases. Inferior disease‐free survival was univariately associated with atypical/malignant histology (P = 0.001) and a mitosis >4/10 HPFs (P = 0.0012) but was unrelated to fusion variants. In conclusion, the majority of intrathoracic SFTs exhibited STAT6 nuclear staining, and NAB2ex4‐STAT6ex2/3 was the predominant fusion type. However, clinical aggressiveness is associated with atypical/malignant histology primarily contributed by increased mitosis but was unrelated to the NAB2‐STAT6 fusion variants.

Hepatoid microcarcinoma of the pancreas: a case report and review of the literature.

Hepatoid differentiation in pancreatic carcinoma is a rare phenomenon. It occurs either as a pure form or as a component with other subtypes. Herein, we report a 52-year-old man with an ampullary large cell neuroendocrine carcinoma presenting with obstructive jaundice for 2 months. A 0.5-cm nodule was found in the pancreatic head. Morphologically, the nodule was composed of exclusively hepatocytic tumor cells and sinusoids with dysplastic cytology and capsular invasion. The patient did not have a hepatic mass or ectopic normal liver tissue. This is the first reported case of ampullary large cell neuroendocrine carcinoma coinciding with a pancreatic hepatoid microcarcinoma. The clinicopathological features of pancreatic hepatoid carcinomas and their histogenesis are discussed.

Clinicopathological and genetic heterogeneity of the head and neck solitary fibrous tumours: a comparative histological, immunohistochemical and molecular study of 36 cases

Solitary fibrous tumour (SFT) harbours recurrent inv12(q13q13)‐derived NAB2–STAT6 fusions, resulting in STAT6 nuclear expression. SFTs affecting the head and neck are rare, for which we reported their clinicopathological, immunohistochemical, and genetic features.

Alterations of the mTOR pathway in hepatic angiomyolipoma with emphasis on the epithelioid variant and loss of heterogeneity of TSC1/TSC2

To determine the significance of the epithelioid type and the corresponding molecular alterations in hepatic angiomyolipoma (AML).

NAB2-STAT6 gene fusion and STAT6 immunoexpression in extrathoracic solitary fibrous tumors: the association between fusion variants and locations

Solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm harboring NAB2‐STAT6 fusion, which drives STAT6 nuclear relocation. For extrathoracic SFTs, the clinical relevance of this molecular hallmark remains obscure. We assessed STAT6 immunoexpression for 61 extrathoracic SFTs exclusive of the meninges and head and neck, and 25 had analyzable RNAs to distinguish fusion variants by RT–PCR. The immunohistochemical and molecular findings were correlated with clincopathological features and disease‐free survival (DFS). Twenty‐eight males and 33 females had SFTs in the body cavities (n = 31), extremities (n = 17), and trunk (n = 13), categorized into 53 non‐malignant and 8 malignant tumors. The vast majority (n = 57, 93%) exhibited distinctive STAT6 nuclear expression, including malignant ones. The common fusion variants were NAB2ex6‐STAT6ex16/17 in 13 SFTs and NAB2ex4‐STAT6ex2 in 8, while miscellaneous variants were detected only in 4 SFTs in the limbs and trunk but not in any body cavity‐based cases (P = 0.026). The worse DFS was univariately associated with malignant histology (P = 0.04) but unrelated to tumor size, location, or fusion variant. Conclusively, extrathoracic SFTs mostly harbor NAB2ex6‐STAT6ex16/17, followed by NAB2ex4‐STAT6ex2. Miscellaneous variants are significantly rare in SFTs within the body cavities. The clinical aggressiveness of extrathoraic SFTs is associated with malignant histology but unrelated to the NAB2‐STAT6 fusion variants.

Prognostic factors in Epstein-Barr virus-associated stage I-III gastric carcinoma: Implications for a unique type of carcinogenesis

Epstein-Barr virus-associated gastric carcinoma (EBVaGC) has distinct clinicopathological features. However, the prognostic factors remain unclear, particularly in UICC/AJCC stage I-III cancer. We retrospectively enrolled 1,020 patients with stage I-III gastric cancer that received radical gastrectomy with lymphadenectomy. Formalin-fixed, paraffin‑embedded surgical specimens were retrieved to construct tissue microarrays. EBV positivity was identified by in situ hybridization with EBV-encoded small RNA, and the histological classification was reviewed. Fifty-two cases of EBVaGC were identified, exhibiting a male predominance (p=0.003), a higher prevalence in stump cancer (p<0.001), and poorly differentiated carcinoma (p=0.010) compared with the controls. The survival analysis revealed no difference in survival between the EBVaGC cases and the EBV-negative cases (p=0.977). The multivariate analysis showed that EBVaGC cases with a tumor size >5 cm, non-lymphoepithelioma-like carcinoma (LELC), or a lymph node ratio >0.15 had a worse overall survival (hazard ratio 2.884, 12.178 and 19.352; p=0.027, 0.005 and <0.0001, respectively). The depth of tumor invasion and the number of lymph node metastases did not reach statistical significance (p=0.834 and 0.833, respectively). These prognostic factors, tumor size, LELC classification and lymph node ratio, may reflect a unique type of carcinogenesis of EBVaGC and may be considered when selecting high-risk patients for adjuvant treatment.

Overexpression of MutL homolog 1 and MutS homolog 2 proteins have reversed prognostic implications for stage I–II colon cancer patients

Background The outcome of colon cancer patients without lymph node metastasis is heterogeneous. Searching for new prognostic markers is warranted. Methods One hundred twenty stage I–II colon cancer patients who received complete surgical excision during 1995–2004 were selected for this biomarker study. Immunohistochemical method was used to assess p53, epidermal growth factor receptor, MLH1, and MSH2 status. KRAS mutation was examined by direct sequencing. Results Thirty three patients (27.5%) developed metachronous metastasis during follow up. By multivariate analysis, only female gender (p = 0.03), high serum carcinoembryonic antigen (CEA) level (≧5 ng/ml) (p = 0.04), and MLH1 overexpression (p = 0.003) were associated with the metastasis group. The 5-year-survival rate were also significantly lower for female gender (71.7% versus 88.9%, p = 0.025), high CEA level (64.9% versus 92.4%, p < 0.001), and MLH1 overexpression (77.5% versus 94.4%, p = 0.039). In contrast, MSH2 overexpression was associated with better survival, 95.1% versus 75.5% (p = 0.024). Conclusions The reversed prognostic implications in the overexpression of MLH1 and MSH2 for stage I–II colon cancer patients is a novel finding and worthy of further confirmation.

Composite hepatocellular carcinoma and small cell carcinoma with early nodal metastasis: A case report

Rationale: Hepatocellular carcinoma (HCC) is known to grow in a mosaic pattern, and it can sometimes be combined with non-hepatocellular cells. Despites the variety of combination, HCC with a significant neuroendocrine carcinoma (NEC) component remains very rare. Most of the reported cases were treated as conventional HCC with a relatively poor prognosis. Early diagnosis may lead to a better treatment modality. Here, we report a case of composite HCC and small cell carcinoma (SCC) with nodal metastasis of the SCC component alone. Patient concerns: A 65-year-old man with chronic viral hepatitis C presented with abdominal discomfort for 2 months. Computed tomography and angiography of the liver showed a 4.3 cm hypervascular tumor in segment 4 and enlargement of the perihilar and paracaval lymph nodes. Interventions: Extended left lobectomy and regional lymph node dissection were performed. Diagnosis: The hepatic tumor was heterogeneous with two distinct gross components. The green part showed a grade III hepatocellular carcinoma with an immunoreaction to Hep Par 1, glypican 3 and &agr;-fetoprotein, whereas the white part exhibited a small cell carcinoma, as evidenced by expressions of chromogranin A and synaptophysin. The lymph node was metastasized by the SCC component. The SCC part was also positive for vimentin with perivascular accentuation. ß-catenin immunostain showed reduced membranous expression in the SCC component, as compared to HCC. Outcomes: The patient expired 39 days after the surgical intervention. Lessons: Clinicians should be highly alert to a composite hepatic tumor, especially in dealing with a small heterogeneous tumor (< 5 cm) with early lymph node metastasis.