Gastrointestinal stromal tumors (GISTs), KIT or platelet derived growth factor receptor alpha (PDGFRA) signaling driven mesenchymal tumors of the gastrointestinal (GI)-tract and abdomen, require a precise diagnosis so that the patients may benefit from the newly introduced tyrosine kinase inhibitor drugs. The limitations of the current main tools, KIT immunohistochemistry and KIT/PDGFRA mutation analysis, include lack of KIT expression and mutations in some GISTs. In this study we examined 1168 GISTs of different sites and histologic subtypes, and 672 other tumors and normal tissues for discovered on GIST-1 (DOG1) clone K9, a newly introduced immunohistochemical marker, a chloride channel protein. All GISTs and selected non-GISTs were independently evaluated for KIT. In the GI tract, Cajal cells and gastric surface epithelia were DOG1-positive. The overall sensitivity of DOG1 and KIT in GISTs was nearly identical: 94.4% and 94.7%, and results in GISTs were generally concordant. Gastric spindle cell GISTs was nearly uniformly positive for both markers, whereas DOG1 performed slightly better in gastric epithelioid GISTs that included PDGFRA mutant GISTs. In the intestinal GISTs, KIT was slightly more sensitive than DOG1. Negativity for both DOG1 and KIT was observed in 2.6% of GISTs of GI tract. KIT or PDGFRA mutations were detected in 11/24 DOG1-negative GISTs supporting the diagnosis of GIST. DOG1 expression was also generally present in extragastrointestinal and metastatic GISTs. DOG1 was highly specific for GIST, but exceptional DOG1-positive other mesenchymal tumors included uterine type retroperitoneal leiomyomas, peritoneal leiomyomatosis, and synovial sarcomas (positive in 5/42, 4/17, and 6/37 cases). Leiomyomas colonized by DOG1-positive Cajal cells should not be confused with GISTs. DOG1 positivity was relatively common in esophageal squamous cell and gastric carcinomas, whereas it was rare in colorectal carcinomas. DOG1 should be added into the diagnostic panel evaluating GI and other abdominal tumors, but limitations in its sensitivity and specificity should be recognized.

ERG, an ETS family transcription factor, is known to be expressed in endothelial cells, and oncogenic ERG gene fusions occur in subsets of prostatic carcinoma, acute myeloid leukemia, and Ewing sarcoma. In this study, we immunohistochemically investigated nuclear ERG expression using a new monoclonal antibody, CPDR ERG-MAb, that is highly specific for detecting ERG protein and ERG-expressing prostate carcinomas. A broad range of vascular endothelial (n = 250), other mesenchymal (n = 973), and epithelial tumors (n = 657) was examined to determine the use of ERG immunohistochemistry in surgical pathology. Only immunostains with ERG-positive normal endothelia (internal control) were considered valid, and only nuclear staining was considered to be positive. In adult tissues, ERG was restricted to endothelial cells and to a subset of bone marrow precursors, but early fetal mesenchyme and subpopulations of fetal cartilage were also positive. In vascular tumors, ERG was expressed in endothelia of all hemangiomas and lymphangiomas, and typically extensively expressed in 96 of 100 angiosarcomas, 42 of 43 epithelioid hemangioendotheliomas, and all 26 Kaposi sarcomas. Among nonvascular mesenchymal tumors, only blastic extramedullary myeloid tumors (7 of 10) and rare Ewing sarcomas (2 of 29) were positive. Among epithelial tumors, 30 of 66 prostatic adenocarcinomas showed focal-to-extensive ERG positivity, with no immunoreactivity in the normal prostate. Other carcinomas and epithelial tumors (n = 643) were ERG negative, with the exception of 1 of 42 large cell undifferentiated pulmonary carcinomas and 1 of 27 mesotheliomas, each of which showed focal nuclear ERG positivity. On the basis of the above observations, ERG is a highly specific new marker for benign and malignant vascular tumors. Among epithelial tumors, ERG shows a great promise as a marker to identify prostatic carcinoma in both primary and metastatic settings.

Most gastrointestinal stromal tumors (GISTs) are driven by KIT or PDGFRA activating mutations, but a small subset is associated with loss function of the succinate dehydrogenase (SDH) complex of mitochondrial inner membrane proteins. This occurs via germline mutations of the SDH subunit genes and hitherto unknown mechanisms. SDH-deficient GISTs especially include pediatric GISTs and those associated with Carney triad (CT) or Carney-Stratakis syndromes (CSS); the latter two also include paraganglioma as a component. SDH-deficient GISTs were identified in this study based on immunohistochemical loss of SDHB, which signals functional loss of the SDH complex. We found 66 SDH-deficient GISTs among 756 gastric GISTs, with an estimated frequency of 7.5% of unselected cases. Nearly all gastric GISTs in patients <20 years and a substantial percentage of those in patients <40 years belonged to this group, but only rare GISTs in older adults were SDH-deficient. There was an over 2:1 female predominance. Two patients each had either pulmonary chondroma or paraganglioma (CT), but none of the examined cases had SDH germline mutations (CSS) or somatic KIT/PDGFRA or BRAF mutations. SDH-deficient GISTs were often multiple and typically showed plexiform muscularis propria involvement and epithelioid hypercellular morphology. They were consistently KIT- and DOG1/Ano 1-positive and almost always SMA-negative. Tumor size and mitotic activity varied, and the tumors were somewhat unpredictable with some with low mitotic rates developing metastases. Gastric recurrences occurred in 11 patients and peritoneal and liver metastases 8 and 10 patients. Lymph node metastases were detected in 5 patients, but lymphovascular invasion was present in >50% of cases studied; these two were not related to adverse outcome. Seven patients died of disease, but many had long survivals, even with peritoneal or liver metastases. All 378 non-gastric GISTs and 34 gastric non-GIST mesenchymal tumors were SDHB-positive. SDH-deficient GISTs constitute a small subgroup of gastric GISTs, usually occur in children and young adults, and often have a chronic course similar to that of pediatric and Carney triad GISTs and potential association with paraganglioma, necessitating long-term follow-up.

The inflammatory fibroid polyp is a rare benign lesion occurring throughout the digestive tract. It usually forms a solitary mass, characterized by a proliferation of fibrovascular tissue infiltrated by a variable number of inflammatory cells. The etiology of this lesion is unknown and conflicting histogenetic theories have been proposed. Recently, mutations in platelet-derived growth factor receptor (PDGFRA) and PDGFRA expression were reported in gastric inflammatory fibroid polyps. In this study, PDGFRA exons 12, 14, and 18 were screened for activating mutations in 60 small intestinal inflammatory fibroid polyps. In addition, the PDGFRA expression was evaluated immunohistochemically. Mutations in PDGFRA were identified in 33 of 60 (55%) cases, whereas 95% expressed PDGFRA. There were 26 deletions, three deletion-insertions, duplication, and single nucleotide substitution in exon 12, and a single nucleotide substitution and deletion in exon 18. The majority (n ¼ 23) of exon 12 deletions were 1837_1851del leading to S566_E571delinsR. However, 1835_1852delinsCGC leading to the same S566_E571delinsR, were found in two tumors. Three inflammatory fibroid polyps had 1836_1850del leading to S566_E571delinsK. A complex deletion-insertion affecting a similar region (1837_1856delinsGATT-GATGATC) and leading to S566_I573delinsRIDDL was identified once. In addition, duplication and single nucleotide substitution were found 5 0 to the common inflammatory fibroid polyp mutational 'hot spot'. These mutations consist of 1808_1828dup leading to I557_E563dup, and 1821T4A resulting in 561V4D substitution. A 2664A4T and 2663_2674del leading to 842D4V and D842_H845del, respectively, were identified in exon 18. Similar gain-of-function PDGFRA mutations reported in gastrointestinal stromal tumors have been considered to be a driving pathogenetic force. This study showed consistent expression and common mutational activation of PDGFRA in small intestinal inflammatory fibroid polyps as in their gastric counterparts, and these lesions should be considered PDGFRA-driven benign neoplasms. We also suggest that these polyps may develop from earlier described PDGFRA-positive mesenchymal cells distributed along the villus membrane after oncogenic PDGFRA activation.

Glomangiopericytoma (sinonasal-type hemangiopericytoma) is a rare mesenchymal neoplasm with myoid phenotype (smooth muscle actin-positive), which distinguishes this tumor from soft tissue hemangiopericytoma/solitary fibrous tumor. Molecular genetic changes underlying the pathogenesis of glomangiopericytoma are not known. In this study, 13 well-characterized glomangiopericytomas were immunohistochemically evaluated for b-catenin expression. All analyzed tumors showed strong expression and nuclear accumulation of b-catenin. Following this observation, b-catenin glycogen serine kinase-3 beta phosphorylation region, encoded by exon 3, was PCR amplified in all cases and evaluated for mutations using Sanger sequencing. Heterozygous mutations were identified in 12 of 13 tumors. All mutations consisted of single-nucleotide substitutions: three in codon 32 (c.94G4C (n ¼ 2) and c.95A4T), four in codon 33 (two each c.98C4G and c.98C4T), two in codon 37 (c.109T4G), one in codon 41 (c.121A4G), and two in codon 45 (c.133T4C). At the protein level, these substitutions would lead to p.D32H, p.D32V, p.S33C, p.S33F, p.S37A, p.T41A, and p.S45L mutations, respectively. Previously, similar mutations have been reported in different types of cancers and shown to trigger activation of b-catenin signaling. All analyzed glomangiopericytomas showed prominent nuclear expression of cyclin D1, as previously shown for tumors with nuclear expression of b-catenin as a sign of oncogenic activation. These results demonstrate that mutational activation of b-catenin and associated cyclin D1 overexpression may be central events in the pathogenesis of glomangiopericytoma. In additon, nuclear accumulation of b-catenin is a diagnostic marker for glomangiopericytoma. Modern Pathology (2015) 28, 715-720; doi:10.1038/modpathol.2014.161; published online 28 November 2014Glomangiopericytoma (sinonasal-type hemangiopericytoma) is a rare mesenchymal neoplasm of the nasal cavity and sinuses of low biologic potential. [1][2][3][4] It shows a myoid phenotype with consistent expression of smooth muscle actin. 3 b-Catenin, a cadherin-associated membrane protein, participates in the regulation of cell-to-cell adhesion and in some circumstances, also gene transcription as a nuclear protein, a terminal component of the canonical Wnt-signaling pathway. Aberrant expression of b-catenin encoded by CTNNB1 gene is a well-known event in tumorigenesis and tumor progression. 5,6 Among soft tissue tumors, somatic mutations in CTNNB1 are well known in the pathogenesis of sporadic desmoid-type fibromatosis. 7,8 These mutations cluster in CTNNB1 glycogen serine kinase-3 beta (GSK3b) phosphorylation region and constitutionally activate b-catenin signal by upholding cellular b-catenin levels. This happens via interference of ubiquitin-mediated proteolytic degradation by elimination of the phosphorylation sites necessary for ubiquitin action. 7,8 Accumulation of b-catenin in turn results in nuclear translocation, which is a telltale sign of a mutation, typically seen in sporadic de...