Cher-Wei Liang

The utility of discovered on gastrointestinal stromal tumor 1 (DOG1) antibody in surgical pathology-the GIST of it.

DOG1 (discovered on GIST 1), known also as TMEM16A and ANO1, has emerged in recent years as a promising biomarker for gastrointestinal stromal tumors (GIST). It was originally discovered through microarray expression profiling analysis as gene that is highly expressed in GIST, and subsequent immunohistochemical studies have shown its use in its diagnosis. The results from several series have shown a high overall sensitivity and specificity for DOG1 in the detection of GISTs and about 6% of GISTs overall exhibiting a DOG1+/KIT-immunoprofile. DOG1 antibodies are more sensitive than KIT antibodies in detecting tumors of gastric origin, tumors with epithelioid morphology, and tumors harboring PDGFRA mutation. Furthermore, DOG1 immunoreactivity is rarely observed in other mesenchymal and nonmesenchymal tumor types. These results support the use of DOG1 as a diagnostic biomarker for GIST. When used in combination with KIT, this panel of diagnostic biomarkers can help pathologists and clinicians to identify more patients who may benefit from targeted therapies.

Sorafenib Inhibits Many Kinase Mutations Associated with Drug-Resistant Gastrointestinal Stromal Tumors

Sorafenib has substantial clinical activity as third- or fourth-line treatment of imatinib- and sunitinib-resistant gastrointestinal stromal tumors (GIST). Because sorafenib targets both angiogenesis-related kinases (VEGFR) and the pathogenetic kinases found in GIST (KIT or PDGFRA), the molecular basis for sorafenib efficacy in this setting remains unknown. We sought to determine the spectrum of activity of sorafenib against different mutant kinases associated with drug-sensitive and drug-resistant GIST. We compared the activity of imatinib and sorafenib against transiently expressed mutant forms of KIT and PDGFRA, including various secondary mutations that have been identified in imatinib-resistant or sunitinib-resistant GISTs. We also examined these drugs against four GIST cell lines, three of which are imatinib resistant. In our in vitro studies, we determined that sorafenib inhibited imatinib-resistant mutations in exons encoding the ATP/drug-binding pocket and in exons encoding the activation loop, with the exception of substitutions at KIT codon D816 and PDGFRA codon 842. Notably our data indicate that sorafenib is more effective than imatinib or sunitinib for inhibiting the kinase activity of drug-resistant KIT mutants (as assessed by biochemical IC50). We hypothesize that a major determinant of the efficacy of sorafenib for treatment of advanced GIST is the activity of this agent against KIT or PDGFRA-mutant kinases. These results have implications for the further development of treatments for drug-resistant GIST. Mol Cancer Ther; 11(8); 1770–80. ©2012 AACR.

Identification of a novel FN1–FGFR1 genetic fusion as a frequent event in phosphaturic mesenchymal tumour

Phosphaturic mesenchymal tumours (PMTs) are uncommon soft tissue and bone tumours that typically cause hypophosphataemia and tumour‐induced osteomalacia (TIO) through secretion of phosphatonins including fibroblast growth factor 23 (FGF23). PMT has recently been accepted by the World Health Organization as a formal tumour entity. The genetic basis and oncogenic pathways underlying its tumourigenesis remain obscure. In this study, we identified a novel FN1–FGFR1 fusion gene in three out of four PMTs by next‐generation RNA sequencing. The fusion transcripts and proteins were subsequently confirmed with RT‐PCR and western blotting. Fluorescence in situ hybridization analysis showed six cases with FN1–FGFR1 fusion out of an additional 11 PMTs. Overall, nine out of 15 PMTs (60%) harboured this fusion. The FN1 gene possibly provides its constitutively active promoter and the encoded proteins oligomerization domains to overexpress and facilitate the activation of the FGFR1 kinase domain. Interestingly, unlike the prototypical leukaemia‐inducing FGFR1 fusion genes, which are ligand‐independent, the FN1–FGFR1 chimeric protein was predicted to preserve its ligand‐binding domains, suggesting an advantage of the presence of its ligands (such as FGF23 secreted at high levels by the tumour) in the activation of the chimeric receptor tyrosine kinase, thus effecting an autocrine or a paracrine mechanism of tumourigenesis. Copyright

TERT promoter mutation is uncommon in acral lentiginous melanoma.

Melanoma is a heterogeneous group of diseases with distinct sets of genetic changes. Recurrent and mutually exclusive C>T or CC>TT transition mutations were identified in the promoter region of the reverse transcriptase catalytic subunit of the telomerase gene (TERT) in melanoma recently, and it was suggested that they enhanced the expression of TERT gene and played important roles in the melanoma pathogenesis. These mono or di‐nucleotide transitions were ultraviolet (UV)‐signature mutations.

NUT Midline Carcinoma Case Report and Review of the Literature

NUT midline carcinoma (NMC) is a recently described, undifferentiated carcinoma with specific NUT gene rearrangement, which often involves midline organs such as the nasal cavity, paranasal sinuses, mediastinum, or intrathoracic organs. It was previously considered a disease of children or young adults, but middle-aged or elderly patients have subsequently been seen. Here, the authors report the case of a 54-year-old woman who presented with a left-nasal-cavity mass and diplopia. The tumor enlarged rapidly and extended to the left orbital cavity and brain base despite chemotherapy and radiotherapy. Pathological examination of the resected tumor showed an undifferentiated carcinoma with occasional abrupt keratinizing squamous differentiation. Immunohistochemical analysis with an antibody to NUT revealed that most of the tumor cells were positive. BRD4-NUT gene fusion was demonstrated by fluorescence in situ hybridization, confirming the diagnosis of NMC. This case emphasizes the importance of considering NMC in the differential diagnosis in older adults.

Alternative lengthening of telomeres phenotype in malignant vascular tumors is highly associated with loss of ATRX expression and is frequently observed in hepatic angiosarcomas

Alternative lengthening of telomeres (ALT) is a mechanism using homologous recombination to maintain telomere length and sustain limitless replicability of cancer cells. Recently, ALT has been found to be associated with inactivation of either α-thalassemia/mental retardation syndrome X-linked (ATRX) or death domain-associated (DAXX) protein. In this study, 119 tumors (88 angiosarcomas, 11 epithelioid hemangioendotheliomas, and 20 Kaposi sarcomas) were analyzed to determine the ALT status, its relationship to loss of ATRX/DAXX expression, and the clinicopathological features. In addition, the mutation status in the telomerase reverse transcriptase gene (TERT) promoter was also studied. Loss of ATRX expression was observed in 21% (16/77) of the primary angiosarcomas and 9% (1/11) of epithelioid hemangioendotheliomas. DAXX expression was intact in all but 2 ATRX-deficient angiosarcomas. Telomere-specific fluorescence in situ hybridization assay showed 28% (17/61) of the primary angiosarcomas were ALT positive. Remarkably, ALT was highly associated with loss of ATRX expression: all but 2 ALT-positive angiosarcomas were ATRX deficient. Notably, hepatic angiosarcomas were frequently ATRX deficient (8/13) and/or ALT positive (8/12). None of the secondary angiosarcomas were ATRX/DAXX deficient or ALT positive. The only ATRX-deficient epithelioid hemangioendothelioma was positive for ALT. Forty-seven angiosarcomas were tested for TERT promoter mutation. Despite the fact that angiosarcoma occurs most commonly in sun-damaged skin, mutation was detected in only 1 radiation-associated angiosarcoma (2%). We conclude that ALT is an important telomere maintenance mechanism in primary angiosarcomas. This feature is highly associated with loss of ATRX expression and is frequently observed in hepatic angiosarcomas.

Intrathyroidal thymic carcinoma: a case report.

Carcinoma showing thymus-like differentiation (CASTLE) is a rare malignancy that occurs in the soft tissues of the neck or in the thyroid gland. When it occurs in the thyroid, it is difficult to differentiate from thyroid tumor. Here, we report such a case. A 34-year-old man presented with a mass in the left lower neck in August 1999. Thyroid ultrasonography showed a hypoechoic mass, which replaced most of the left thyroid gland. Fine-needle aspiration cytology showed poorly differentiated carcinoma. He received left lobectomy in February 2001. Grossly, the mass measuring 3.7 x 3.5 x 3.5 cm was located in the lower part of the left lobe of the thyroid gland. The cut surface was yellowish gray. Microscopically, the tumor was separated into lobules by fibrous tissues infiltrated with small lymphocytes. It was composed of poorly differentiated squamoid cells and focal keratin pearls. Thymus-like tissue with Hassalls corpuscles was seen adjacent to the tumor cells. Immunohistochemically, the tumor cells were positive for cytokeratin and CD5, but negative for thyroglobulin. Keratinizing squamous cell carcinoma arising from intrathyroid thymic tissue was diagnosed. Because of a dubious section margin, adjuvant radiotherapy with a total dose of 5000 cGy was given. There was no evidence of recurrence twenty months after surgery. Although intrathyroidal thymic carcinoma is rare, it should be differentiated from anaplastic thyroid carcinoma because these conditions have different prognosis.

Dedifferentiated liposarcoma with homologous lipoblastic differentiation: expanding the spectrum to include low‐grade tumours

Dedifferentiated liposarcoma (DDLPS) is traditionally defined as a non‐lipogenic high‐grade sarcoma arising from a well‐differentiated liposarcoma that confers metastatic potential. Recently, DDLPSs with lipoblastic differentiation, i.e. morphologically lipogenic DDLPSs, were reported. Because of the lipoblastic differentiation, these tumours caused confusion, and were reported under different names. However, cytogenetic and molecular studies have revealed their DDLPS nature. So far, the cases reported have been high‐grade pleomorphic liposarcoma‐like tumours. In this study we have collected another series that contains low‐grade tumours, and expand the histological spectrum.

Downregulation of Brg-1 Repressed Expression of Cd44s in Cervical Neuroendocrine Carcinoma and Adenocarcinoma

Neuroendocrine carcinomas of the uterine cervix are rare tumors with early metastases, highly aggressive clinical behavior, and poor clinical outcome. Several adhesion molecules like cadherins have been tested in an attempt to explain their unique characteristics. Cluster differentiation 44 (CD44) is a widely expressed cell surface glycoprotein that serves as an adhesion molecule in cell-to-substrate and cell-to-cell interaction. We have examined the expression of the standard CD44 (CD44s) by immunohistochemical stains in the paraffin-embedded cervical neoplasm tissue of 17 cases of primary cervical neuroendocrine carcinoma, 28 cases of cervical adenocarcinoma, and 50 cases of cervical squamous cell carcinoma. Loss of CD44s expression was found in 16 of 17 neuroendocrine carcinomas, 14 of 28 adenocarcinomas, and three of 50 squamous cell carcinomas. The differences were statistically significant. We also examined immunohistochemically the expression of the BRG-1 subunit of the SWI-SNF complex, which has been reported to regulate the expression of CD44 in all cases. Loss of BRG-1 expression was observed in 12/16, 6/14, and 1/3 CD44s-negative neuroendocrine carcinomas, adenocarcinomas, and squamous cell carcinomas, respectively. This study suggests that loss of the CD44s molecule may imply special biological behaviors of cervical neuroendocrine carcinomas, and loss of expression of BRG-1 may contribute to this.

Trisomy 18 is a consistent cytogenetic feature in pilomatricoma.

Pilomatricoma, also known as ‘calcifying epithelioma of Malherbe’, is a common skin adnexal tumor that mimics hair growth. Its proliferating cells seem distinctly programmed to undergo terminal differentiation and death. We report the first cytogenetic investigations of pilomatricoma. Trisomy 18 was shown, in an index case, by G-banded karyotyping. This aberration was corroborated by interphase fluorescence in situ hybridization, using a chromosome 18 pericentromeric probe, in the basaloid epithelial component of 7 of 11 pilomatricomas, including the index case. Trisomy 18 was present in a small subset of cells, suggesting a role in pilomatricoma progression, rather than in tumor initiation. We conclude that trisomy 18 is a consistent feature in pilomatricoma, suggesting that genes carried on this chromosome, such as that for the antiapoptotic oncoprotein BCL2, may have a role in the growth and differentiation of this benign self-limited tumor.