Research IndicatorsGraph generated 01 September 2019 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex
Specific Cancers (4)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: CAMTA1 (cancer-related)
Anderson WJ, Hornick JLImmunohistochemical correlates of recurrent genetic alterations in sarcomas.
Genes Chromosomes Cancer. 2019; 58(2):111-123 [PubMed
] Related Publications
Accurate diagnosis of sarcomas relies on the integration of clinical, histopathological and molecular features. Our understanding of the latter has increased dramatically in recent years with the application of high-throughput sequencing. Concomitantly, the role of immunohistochemistry has expanded as genomic alterations have been exploited by the development of diagnostic markers that serve as surrogates for their detection. Herein, we review selected immunohistochemical markers that can infer the presence of diverse molecular events. These include gene fusions in vascular neoplasms (FOSB, CAMTA1 and TFE3), round cell sarcomas (BCOR, DUX4 and WT1), and fibroblastic/myofibroblastic tumors (STAT6, ALK and Pan-TRK); amplifications in well-differentiated and dedifferentiated liposarcomas (MDM2 and CDK4); and deletions in several aggressive neoplasms (SMARCB1 and SMARCA4). Protein correlates of single nucleotide variants (beta-catenin in desmoid fibromatosis) and epigenetic alterations (histone H3K27me3 in malignant peripheral nerve sheath tumor) and markers discovered through gene expression profiling (NKX2.2 and MUC4) are also discussed.
Thway K, Mentzel T, Perrett CM, Calonje EMulticentric visceral epithelioid hemangioendothelioma, with extremity dermal deposits, unusual late recurrence on the nasal bridge, and TFE3 gene rearrangement.
Hum Pathol. 2018; 72:153-159 [PubMed
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Epithelioid hemangioendothelioma (EHE) is a malignant neoplasm with vascular differentiation that most frequently occurs within soft tissues, bone, lung, and liver. It is histologically typified by epithelioid or spindle cells present singly or in cords or clusters, many with cytoplasmic vacuoles that can contain intraluminal erythrocytes (in keeping with primitive vascular differentiation), within myxohyaline or sclerotic matrix. Up to 50% present with synchronous lesions as multifocal disease. The WWTR1-CAMTA1 fusion has been demonstrated in EHEs at a variety of sites and is considered to represent its genetic hallmark. We describe a case of EHE in a patient who initially presented with multiple liver and pulmonary deposits, was found to have a soft tissue lesion in the foot, and then presented with further lesions on the nasal bridge and the arm approximately 6 years after initial presentation. Interestingly, the case showed diffuse CAMTA1 expression but negative TFE3 immunohistochemically, but in contrast showed TFE3 gene rearrangement with fluorescence in situ hybridization but no evidence of WWTR1-CAMTA1 translocation. The clinical behavior of EHE is unpredictable, and this case highlights unusual anatomic, immunohistochemical, and molecular cytogenetic findings. Characterization of the genetics of EHE is important because targeted therapies toward products of the specific WWTR1-CAMTA1 gene fusion may have an impact in the near future.
Kuo FY, Huang HY, Chen CL, et al.TFE3-rearranged hepatic epithelioid hemangioendothelioma-a case report with immunohistochemical and molecular study.
APMIS. 2017; 125(9):849-853 [PubMed
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A recurrent YAP1-TFE3 gene fusion has been identified in WWTR1-CAMTA1-negative epithelioid hemangioendotheliomas arising in soft tissue, bone, and lung, but not in liver. We present the first case of TFE3-rearranged hepatic epithelioid hemangioendothelioma in a 39-year-old Taiwanese woman. Computed tomography scan revealed multifocal, ill-defined nodules involving both hepatic lobes. She then underwent deceased donor liver transplantation. Histologically, the tumors in the liver explant showed a biphasic growth pattern. One component was composed of dilated and well-formed blood vessels lined by epithelioid cells with abundant eosinophilic cytoplasm, mimicking an alveolar pattern, whereas the other component was composed of cords and single cells, featuring intracytoplasmic vacuoles, separated by a myxoid stroma. The tumor cells showed vesicular nuclei and small indistinct nucleoli with mild to moderate cytologic atypia. Most tumor cells showed factor VIII, CD34, CD31, and TFE3 positivity in immunohistochemical study. Fluorescence in situ hybridization analysis for the tumor cells exhibited TFE3 gene rearrangement. The patient is currently alive, and no post-operative tumor recurrence developed during a 13-year follow-up. Awareness of this rare vasoformative variant and identification of the gene rearrangement would be helpful on differential diagnosis with other high-grade carcinoma and angiosarcoma of liver.
Hung YP, Fletcher CD, Hornick JLFOSB is a Useful Diagnostic Marker for Pseudomyogenic Hemangioendothelioma.
Am J Surg Pathol. 2017; 41(5):596-606 [PubMed
] Related Publications
Pseudomyogenic (epithelioid sarcoma-like) hemangioendothelioma is a distinctive vascular neoplasm of intermediate biological potential with a predilection for young adults and frequent multifocal presentation. Pseudomyogenic hemangioendothelioma is characterized by loose fascicles of plump spindled and epithelioid cells with abundant eosinophilic cytoplasm and coexpression of keratins and endothelial markers. Recently, a SERPINE1-FOSB fusion has been identified as a consistent genetic alteration in pseudomyogenic hemangioendothelioma. FOSB gene fusions have also been reported in a subset of epithelioid hemangiomas. The purpose of this study was to assess the potential diagnostic utility of FOSB immunohistochemistry for pseudomyogenic hemangioendothelioma compared with other endothelial neoplasms and histologic mimics. We evaluated whole-tissue sections from 274 cases including 50 pseudomyogenic hemangioendotheliomas, 84 other vascular tumors (24 epithelioid hemangiomas [including 6 cases with angiolymphoid hyperplasia with eosinophilia histology], 20 epithelioid angiosarcomas, 20 epithelioid hemangioendotheliomas [17 CAMTA1 positive, 2 TFE3 positive], 10 spindle-cell angiosarcomas, and 10 epithelioid angiomatous nodules), and 140 other histologic mimics (20 each epithelioid sarcoma, proliferative fasciitis, nodular fasciitis, cellular benign fibrous histiocytoma, spindle-cell squamous cell carcinoma, spindle-cell rhabdomyosarcoma, and leiomyosarcoma). Immunohistochemistry for FOSB was performed following pressure cooker antigen retrieval using a rabbit monoclonal antibody. Diffuse nuclear immunoreactivity for FOSB (>50% of cells) was observed in 48 of 50 (96%) pseudomyogenic hemangioendotheliomas and 13 of 24 (54%) epithelioid hemangiomas (including all angiolymphoid hyperplasia with eosinophilia type). Both FOSB-negative pseudomyogenic hemangioendothelioma cases were decalcified bone tumors. Only 7 other tumors showed diffuse FOSB expression: 2 proliferative fasciitis, 2 nodular fasciitis, 1 epithelioid angiosarcoma, 1 spindle-cell angiosarcoma, and 1 epithelioid hemangioendothelioma. Of note, the FOSB-positive epithelioid hemangioendothelioma was negative for CAMTA1 and TFE3. Focal weak FOSB staining was observed in a subset of histologic mimics and is therefore not diagnostically meaningful. In conclusion, FOSB is a highly sensitive and diagnostically useful marker for pseudomyogenic hemangioendothelioma. Immunohistochemistry for FOSB may be helpful to distinguish pseudomyogenic hemangioendothelioma from histologic mimics including epithelioid sarcoma and other vascular neoplasms. As expected, a subset of epithelioid hemangiomas expresses FOSB, including angiolymphoid hyperplasia with eosinophilia. Although occasional cases of nodular and proliferative fasciitis are positive for FOSB, distinction between these tumor types and pseudomyogenic hemangioendothelioma is usually straightforward based on morphology and other immunophenotypic findings.
Hepatocellular carcinoma (HCC) is the most common subtype of liver malignancy, and it is characterized by poor prognosis because of cancer stem cell (CSC)-mediated high postsurgical recurrence rates. Thus, targeting CSCs, or HCC cells with CSC-like properties, is an effective strategy for HCC therapy. Here, using long noncoding RNA (lncRNA) microarray analysis, we identified a novel lncRNA termed lncCAMTA1 that is increased in both liver CSCs and HCC. High lncCAMTA1 expression in HCC indicates poor clinical outcome. In vitro and in vivo functional experiments showed that overexpression of lncCAMTA1 promotes HCC cell proliferation, CSC-like properties, and tumorigenesis. Conversely, depletion of lncCAMTA1 inhibits HCC cell proliferation, CSC-like properties, and tumorigenesis. Mechanistically, we demonstrated that lncCAMTA1 physically associates with the calmodulin binding transcription activator 1 (CAMTA1) promoter, induces a repressive chromatin structure, and inhibits CAMTA1 transcription. Furthermore, CAMTA1 is required for the effects of lncCAMTA1 on HCC cell proliferation and CSC-like properties, and the expression of lncCAMTA1 and CAMTA1 is significantly negatively correlated in HCC tissues. Collectively, our study revealed the important roles and underlying molecular mechanisms of lncCAMTA1 on HCC, and suggested that lncCAMTA1 could be an effective prognostic factor and a potential therapeutic target for HCC.
Shah AA, Ohori NP, Yip L, et al.Epithelioid Hemangioendothelioma: a Rare Primary Thyroid Tumor with Confirmation of WWTR1 and CAMTA1 Rearrangements.
Endocr Pathol. 2016; 27(2):147-52 [PubMed
] Related Publications
We report a rare case of epithelioid hemangioendothelioma as a primary thyroid tumor. To our knowledge, there are only two prior unequivocal cases of primary thyroid epithelioid hemangioendothelioma reported in the English literature. This is the first case in the thyroid with molecular confirmation.
Epithelioid hemangioendotheliomas (EHEs) are vascular tumors of intermediate malignancy that can undergo high-grade malignant transformations. EHEs have been characterized by tumor-specific WW domain-containing transcription regulator 1(WWTR1)-calmodulin-binding transcription activator 1 (CAMTA1) translocations, and recently, a novel Yes-associated protein 1 (YAP1)-transcription factor E3 (TFE3) gene fusion was identified in EHEs. In this study, we examined the expression levels of TFE3 and CAMTA1 via immunohistochemical staining and identified chromosomal alterations using fluorescence in situ hybridization (FISH) assays and RT-PCR tests. Although all of the EHEs were CAMTA1-positive in immunohistochemical staining, only five out of 18 EHEs (27.78%) positively expressed nuclear TFE3. The five TFE3-positive EHEs exhibited TFE3 gene break-apart in FISH assays. YAP1-TFE3 gene fusions were confirmed by RT-PCR. Interestingly, we observed CAMTA1 gene break-apart in all of the five TFE3-positive EHEs via FISH assays, and four out of the five TFE3-positive EHEs exhibited WWTR1-CAMTA1 gene fusions via RT-PCR. These results indicate that these two chromosomal alterations are not mutually exclusive but compossible in EHEs. Finally, primary tumor sites in TFE3-positive EHEs consistently contained single masses (P = 0.0359) with larger sizes (P = 0.0550) compared to TFE3-negative EHEs. Similar to previous reports, we observed well-formed vessels more frequently in TFE3-positive EHEs than in TFE3-negative EHEs (P = 0.0441). In addition, TFE3-positive EHEs tended to more frequently demonstrate high-grade nuclear atypia (P = 0.0654) and hypercellularity (P=0.0987) than TFE3-negative EHEs. Thus, we have now established two clinically distinct subgroups of EHEs: TFE3-positive and TFE3-negative EHEs.
Galateau-Salle F, Churg A, Roggli V, et al.The 2015 World Health Organization Classification of Tumors of the Pleura: Advances since the 2004 Classification.
J Thorac Oncol. 2016; 11(2):142-54 [PubMed
] Related Publications
A new World Health Organization (WHO) Classification of Tumors of the Pleura has recently been published. While the histologic classification of pleural malignant mesothelioma remains the same in the 2015 WHO classification as it was in the 2004 classification, multiple new observations have been recorded. First, more detailed study has been performed of histologic subtyping of epithelioid mesothelioma. In particular, it has been recognized that the pleomorphic subtype is associated with a poor prognosis, similar to that of sarcomatoid malignant mesothelioma. Second, there is improved understanding of the role of immunohistochemistry in distinguishing mesothelioma from carcinomas of various sites. Third, the criteria for distinguishing malignant mesothelioma from reactive mesothelial proliferations has been further refined. Fourth, additional studies of sarcomatoid mesothelioma have defined the frequency and spectrum of various histologic and immunohistochemical features, including heterologous elements. Finally, pleural well-differentiated papillary mesotheliomas are better defined and cases with invasive foci are recognized. In addition, several promising observations in mesothelioma pathology and genetics have been made in the past decade. These are now the subject of further investigation to determine if they can be validated in ways that will significantly impact clinical practice. These include a preliminary study of grading, suggesting that nuclear atypia and mitotic count are independent prognostic markers. The discovery of inactivating mutations in the BRCA1-associated protein 1 gene in sporadic and hereditary mesothelioma has opened up a variety of novel molecular, clinical, and diagnostic investigations. One possible diagnostic application includes the setting of separating mesothelioma from reactive mesothelial proliferations, where it may play a role in conjunction with p16 FISH. Another useful discovery was that the NAB2-STAT6 fusion is characteristic of solitary fibrous tumors. This led to development of a STAT6 antibody that is a reliable immunohistochemical marker for solitary fibrous tumors. Genetic studies also led to the finding that WWTR1-CAMTA1 fusions are useful diagnostic markers for epithelioid hemangioendotheliomas, which can present as pleural-based masses. Finally, desmoid type fibromatosis, a locally aggressive tumor that can present in the pleura, has been shown to frequently have CTNNB1 gene mutations and express β-catenin by immunohistochemistry.
Costigan DC, Doyle LAAdvances in the clinicopathological and molecular classification of cutaneous mesenchymal neoplasms.
Histopathology. 2016; 68(6):776-95 [PubMed
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In recent years, there have been several important refinements in the classification of cutaneous mesenchymal neoplasms, including the description of new tumour types, along with the identification of novel and recurrent molecular genetic findings. In addition to providing new insights into tumour biology, many of these advances have had significant clinical consequences with regard to diagnostics, management, and prognostication. Newly described entities include pseudomyogenic haemangioendothelioma, haemosiderotic fibrolipomatous tumour, and fibroblastic connective tissue naevus, which are reviewed in the context of the principal differential diagnoses and significant clinical implications. Genetic characterization of several soft tissue tumour types that occur in the skin has resulted in the identification of diagnostically useful markers: ALK gene rearrangement with corresponding ALK protein expression by immunohistochemistry in epithelioid fibrous histiocytoma; the WWTR1-CAMTA1 fusion gene with CAMTA1 protein expression in epithelioid haemangioendothelioma; MYC amplification and overexpression in radiation-associated angiosarcoma; and EWSR1 gene rearrangement in cutaneous myoepithelial tumours. Finally, the classification of intradermal smooth muscle tumours and unclassified/pleomorphic dermal sarcoma has been refined, resulting in both improved classification and improved prognostication. Many of the tumour types listed above are encountered not only by specialist dermatopathologists, but also by practising general surgical pathologists, and this review should therefore provide a widely applicable update on the histological and molecular classification of cutaneous mesenchymal neoplasms, along with the appropriate use of ancillary diagnostic tests, in particular immunohistochemistry, in the evaluation of such lesions and their histological mimics.
Doyle LA, Fletcher CD, Hornick JLNuclear Expression of CAMTA1 Distinguishes Epithelioid Hemangioendothelioma From Histologic Mimics.
Am J Surg Pathol. 2016; 40(1):94-102 [PubMed
] Related Publications
Epithelioid hemangioendothelioma (EHE) is a malignant endothelial neoplasm characterized by recurrent translocations involving chromosomal regions 1p36.3 and 3q25, resulting in the formation of a WWTR1-CAMTA1 fusion gene in approximately 90% of cases; a small subset (<5%) have a YAP1-TFE3 fusion gene. The WWTR1-CAMTA1 fusion gene leads to overexpression of both genes. WWTR1 protein is expressed in many different cell types, whereas CAMTA1 expression is normally limited to the brain. A prior study using a polyclonal antibody directed against regions within the C-terminus of CAMTA1 reported widespread expression in both normal tissues and diverse tumor types. In contrast, a recent study using a different polyclonal antibody directed against the C-terminus of CAMTA1 suggested that this other antibody is a potentially useful diagnostic marker for EHE. Our study aimed to validate this finding in a large series of EHE cases and to determine whether CAMTA1 is expressed in other epithelioid mesenchymal tumors that may mimic EHE. Protein expression of CAMTA1 was evaluated in whole-tissue sections of 204 tumors using a polyclonal anti-CAMTA1 antibody: 59 EHE (48 conventional, 11 "malignant"; 4 with known TFE3 gene rearrangement); 70 other epithelioid vascular tumors; and 75 nonendothelial epithelioid mesenchymal neoplasms. In total, 51/59 cases (86%) of EHE showed diffuse nuclear staining for CAMTA1, including 44/48 cases (92%) with conventional histology and 7/11 cases (64%) with "malignant" histology. Of the 8 CAMTA1-negative tumors, 6 were positive for TFE3. With the exception of 1 case previously diagnosed as epithelioid angiosarcoma on core biopsy, all other tumor types examined were negative for CAMTA1. In conclusion, in keeping with the reported frequency of WWTR1-CAMTA1 in EHE, nuclear CAMTA1 expression is identified in the majority of EHE cases, whereas other epithelioid mesenchymal neoplasms are negative for CAMTA1. These findings support the diagnostic utility of immunohistochemistry for CAMTA1 in distinguishing EHE from histologic mimics, in particular benign epithelioid vascular tumors, epithelioid angiosarcoma, and epithelioid sarcoma, an important distinction given the differences in biological potential and clinical course.
Mohamed AD, Tremblay AM, Murray GI, Wackerhage HThe Hippo signal transduction pathway in soft tissue sarcomas.
Biochim Biophys Acta. 2015; 1856(1):121-9 [PubMed
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Sarcomas are rare cancers (≈1% of all solid tumours) usually of mesenchymal origin. Here, we review evidence implicating the Hippo pathway in soft tissue sarcomas. Several transgenic mouse models of Hippo pathway members (Nf2, Mob1, LATS1 and YAP1 mutants) develop various types of sarcoma. Despite that, Hippo member genes are rarely point mutated in human sarcomas. Instead, WWTR1-CAMTA1 and YAP1-TFE3 fusion genes are found in almost all cases of epithelioid haemangioendothelioma. Also copy number gains of YAP1 and other Hippo members occur at low frequencies but the most likely cause of perturbed Hippo signalling in sarcoma is the cross-talk with commonly mutated cancer genes such as KRAS, PIK3CA, CTNNB1 or FBXW7. Current Hippo pathway-targeting drugs include compounds that target the interaction between YAP and TEAD G protein-coupled receptors (GPCR) and the mevalonate pathway (e.g. statins). Given that many Hippo pathway-modulating drugs are already used in patients, this could lead to early clinical trials testing their efficacy in different types of sarcoma.
Juhlin CC, Stenman A, Haglund F, et al.Whole-exome sequencing defines the mutational landscape of pheochromocytoma and identifies KMT2D as a recurrently mutated gene.
Genes Chromosomes Cancer. 2015; 54(9):542-54 [PubMed
] Free Access to Full Article Related Publications
As subsets of pheochromocytomas (PCCs) lack a defined molecular etiology, we sought to characterize the mutational landscape of PCCs to identify novel gene candidates involved in disease development. A discovery cohort of 15 PCCs wild type for mutations in PCC susceptibility genes underwent whole-exome sequencing, and an additional 83 PCCs served as a verification cohort for targeted sequencing of candidate mutations. A low rate of nonsilent single nucleotide variants (SNVs) was detected (6.1/sample). Somatic HRAS and EPAS1 mutations were observed in one case each, whereas the remaining 13 cases did not exhibit variants in established PCC genes. SNVs aggregated in apoptosis-related pathways, and mutations in COSMIC genes not previously reported in PCCs included ZAN, MITF, WDTC1, and CAMTA1. Two somatic mutations and one constitutional variant in the well-established cancer gene lysine (K)-specific methyltransferase 2D (KMT2D, MLL2) were discovered in one sample each, prompting KMT2D screening using focused exome-sequencing in the verification cohort. An additional 11 PCCs displayed KMT2D variants, of which two were recurrent. In total, missense KMT2D variants were found in 14 (11 somatic, two constitutional, one undetermined) of 99 PCCs (14%). Five cases displayed somatic mutations in the functional FYR/SET domains of KMT2D, constituting 36% of all KMT2D-mutated PCCs. KMT2D expression was upregulated in PCCs compared to normal adrenals, and KMT2D overexpression positively affected cell migration in a PCC cell line. We conclude that KMT2D represents a recurrently mutated gene with potential implication for PCC development.
The WWTR1 (protein is known as TAZ)-CAMTA1 (WC) fusion gene defines epithelioid hemangioendothelioma, a malignant vascular cancer. TAZ (transcriptional coactivator with PDZ binding motif) is a transcriptional coactivator and end effector of the Hippo tumor suppressor pathway. It is inhibited by phosphorylation by the Hippo kinases LATS1 and LATS2. Such phosphorylation causes cytoplasmic localization, 14-3-3 protein binding and the phorphorylation of a terminal phosphodegron promotes ubiquitin-dependent degradation (the phosphorylation of the different motifs has several effects). CAMTA1 is a putative tumor suppressive transcription factor. Here we demonstrate that TAZ-CAMTA1 (TC) fusion results in its nuclear localization and constitutive activation. Consequently, cells expressing TC display a TAZ-like transcriptional program that causes resistance to anoikis and oncogenic transformation. Our findings elucidate the mechanistic basis of TC oncogenic properties, highlight that TC is an important model to understand how the Hippo pathway can be inhibited in cancer, and provide approaches for targeting this chimeric protein.
Shibuya R, Matsuyama A, Shiba E, et al.CAMTA1 is a useful immunohistochemical marker for diagnosing epithelioid haemangioendothelioma.
Histopathology. 2015; 67(6):827-35 [PubMed
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AIMS: The diagnosis of epithelioid haemangioendothelioma (EHE) is usually straightforward, based on characteristic histological features. However, it is sometimes difficult to differentiate EHE from a variety of other tumours with epithelioid morphology. The WW domain-containing transcription regulator 1-calmodulin-binding transcription activator 1 (WWTR1-CAMTA1) fusion gene, resulting in the overexpression of CAMTA1, is demonstrated in approximately 90% of EHEs, and the yes-associated protein 1-transcription factor E3 (YAP1-TFE3) fusion gene, associated with the strong and diffuse nuclear expression of TFE3, is present in another small subset of EHEs. The aim of our study was to examine CAMTA1 expression in EHEs and a variety of other tumours to evaluate its diagnostic utility, and to analyse TFE3 expression status in EHEs.
METHODS AND RESULTS: Immunohistochemistry was performed on 16 EHEs, including five cases with CAMTA1 rearrangement and 276 non-EHE tumours. Fourteen of 16 EHEs and only one case of ductal carcinoma of the breast were positive for CAMTA1 and its expression was focal and weak in the latter (sensitivity 87.5%, specificity 99.6%). TFE3 expression was expressed focally and weakly in three (19%) EHEs (two with the CAMTA1 rearrangement).
CONCLUSIONS: Nuclear CAMTA1 expression is sensitive and highly specific for EHE and can be applied to diagnostic immunohistochemistry in epithelioid tumours.
Puls F, Niblett A, Clarke J, et al.YAP1-TFE3 epithelioid hemangioendothelioma: a case without vasoformation and a new transcript variant.
Virchows Arch. 2015; 466(4):473-8 [PubMed
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Epithelioid hemangioendothelioma is a rare vascular tumor of borderline malignancy characterized by recurrent WWTR1-CAMTA1 gene fusions in approximately 90 % of cases. In addition, a recurrent YAP1-TFE3 gene fusion has been identified in WWTR1-CAMTA1 negative epithelioid hemangioendotheliomas. This subset has been reported as having a distinct morphology with more obvious vasoformation, voluminous eosinophilic cytoplasm, and TFE3 positivity on immunohistochemistry. We report a case of a YAP1-TFE3 translocated epithelioid hemangioendothelioma arising in a groin lymph node in a 29-year-old male. Plump spindle cell morphology and absence of vasoformation made correct diagnosis particularly difficult. Immunohistochemistry showed nuclear positivity for both ERG and TFE3, fluorescence in situ hybridization showed break apart for TFE3 and RT-PCR identified a YAP1 exon1 to TFE3 exon 6 transcript, a previously unreported fusion variant. Awareness of this solid morphology and variant fusion will aid in identification of future cases of this rare vascular tumor.
Anderson T, Zhang L, Hameed M, et al.Thoracic epithelioid malignant vascular tumors: a clinicopathologic study of 52 cases with emphasis on pathologic grading and molecular studies of WWTR1-CAMTA1 fusions.
Am J Surg Pathol. 2015; 39(1):132-9 [PubMed
] Free Access to Full Article Related Publications
Malignant thoracic epithelioid vascular tumors are an uncommon and heterogenous group of tumors that include low-grade to intermediate-grade epithelioid hemangioendothelioma (EHE) and high-grade epithelioid angiosarcoma (EAS). We examine the morphologic and immunohistochemical features of 52 malignant epithelioid vascular tumors (10 low-grade EHE, 29 intermediate-grade EHE, and 13 EAS) involving the thorax (lung, pleura, mediastinum, heart, great vessels) including cases with exclusively thoracic disease (35) and with multiorgan disease including the thorax (17). Intermediate-grade EHE differs from low-grade EHE by the presence of necrosis, increased mitotic activity, and increased atypia. Morphologic features such as intranuclear inclusions, intracytoplasmic vacuoles, and stromal changes (chondroid, myxoid, or hyalinized stroma) are seen more frequently in EHE, whereas blood lakes, proliferation of slit-like vessels, and prominent nucleoli favor EAS. Fluorescence in situ hybridization analysis showed CAMTA1-WWTR1 fusions in 4/7 low-grade and 23/23 intermediate-grade EHE (P<0.001). In EAS, CAMTA1 rearrangement was negative in all cases, whereas a WWTR1 complex abnormality was found in 1/5 cases (P<0.001). This offers an objective means of differentiating intermediate-grade EHE from EAS, especially on limited biopsies. All cases show expression of at least 1 vascular marker, which allows differentiation from primary thoracic epithelial malignancies, although keratin expression is a potential pitfall with 29% of EHE and 25% of EAS showing keratin expression. Survival analysis shows that higher tumor grade for all tumors (P=0.026) as well as lung and pleural tumors only (P=0.010) and the presence of pleural involvement in lung and/or pleural tumors (P=0.042) correlate with poor prognosis.
Yusıflı Z, Kösemehmetoğlu KCAMTA1 immunostaining is not useful in differentiating epithelioid hemangioendothelioma from its potential mimickers.
Turk Patoloji Derg. 2014; 30(3):159-65 [PubMed
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OBJECTIVE: Epithelioid hemangioendothelioma is a rare member of vascular tumors of intermediate malignancy. Recently, presence of t(1;3) translocation and WWTR1/CAMTA1 gene fusion, which enhances CAMTA1 expression, are found to be specific to this tumor. We investigated the CAMTA1 immune expression profile of epithelioid hemangioendothelioma and its potential mimickers using a commercially available CAMTA1 antibody.
MATERIAL AND METHOD: Standard whole sections from the formalin fixed, paraffin embedded blocks of 12 epithelioid hemangioendotheliomas, 10 angiosarcomas, 9 epithelioid sarcomas, 8 malignant melanomas, 8 signet ring carcinomas, 7 lobular carcinomas of breast, 2 epithelioid mesotheliomas, 2 rhabdoid tumors and 12 miscellaneous hemangiomas were immunostained for anti-CAMTA1 (ab64119, 1:200; Abcam) after pretreatment with citrate pH 6.0 for 20 minutes using Leica Bond detection kit with DAB chromogen. Strong nuclear CAMTA1 expression was scored for its extent as 'negative' ( < 5% positive), '+1' (5-25% positive), '2+' (25-50% positive) and '3+' ( > 50% positive).
RESULTS: In 60 out of 70 cases (86%) either 2+ or 3+ strong nuclear staining was seen. Eighty-three % of epithelioid hemangioendotheliomas, 100% of angiosarcomas, 89% of epithelioid sarcomas, 89% of malignant melanomas, 63% of signet ring carcinomas, 71% of lobular carcinomas of breast, 100% of epithelioid mesotheliomas, 50% of rhabdoid tumors and 100% of hemangiomas were stained. Besides neurons, CAMTA1 expression was also observed in squamous epithelium, skin adnexa, breast lobules, prostate glands, bile ducts, colonic mucosa and gastric pits.
CONCLUSION: Epithelioid hemangioendothelioma, its potential morphological mimickers and other benign or malignant vascular tumors showed strong and diffuse CAMTA1 expression, nullifying the potential use of CAMTA1 immunohistochemistry as an adjunct in the differential diagnosis.
BACKGROUND: Epithelioid hemangioendothelioma is a malignant, often indolent vascular tumor which occurs at various anatomic sites. Based on a reciprocal translocation t (1;3)(p36;q25), a consistent WWTR1-CAMTA1 fusion gene has been found. An alternate YAP1-TFE3 fusion has been detected in a small and distinct subset of cases.
METHODS: Thirty-nine tumors, from 24 females and 15 males with an age range 9-85 years, were located in soft tissue (head and neck , trunk , upper extremities , lower extremities , mediastinal , and paratesticular ), lymph node (1), breast (1), skin (2), bone (6), lung (7), and liver (2). The cases were investigated using a panel of immunohistochemical markers. The aforementioned fusion-genes were examined using RT-PCR and/or FISH in order to validate their diagnostic value.
RESULTS: Follow-up available for 17 patients ranged from 3 months to 7 years (median interval 1.5 years). Eleven patients were alive without disease, 2 patients were alive with disease after 1.5 and 2 years, respectively. Four patients died of disease after 4 months (n = 1), 5 months (n = 2), and 1.5 years (n = 1).The size, known for 30 lesions, was >3 cm in 9 of them. Histologically, all lesions had classical features, at least focally. Four tumors counted >3 mitoses/50 HPF. Immunohistochemically, all cases tested stained positive for ERG (21), FLI1 (5) and CD31 (39). CD34 and D2-40 positivity was seen in 81% and 71% of the examined cases, respectively. 11/35 cases expressed pan-keratin and 6/20 cases CK8.18. TFE3 showed a nuclear reaction in 21/24 cases, irrespective of TFE3 rearrangement.Molecular genetically, 35/35 cases revealed one of the fusion genes by FISH and/or RT-PCR with WWTR1-CAMTA1 in 33 cases and YAP1-TFE3 in 2 cases.
CONCLUSIONS: These results demonstrate the high diagnostic value of FISH and RT-PCR in detecting the fusion genes of EHE. The immunohistochemical utility of TFE3 appears questionable in this study.
VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/4010279141259481.
Ha SY, Choi IH, Han J, et al.Pleural epithelioid hemangioendothelioma harboring CAMTA1 rearrangement.
Lung Cancer. 2014; 83(3):411-5 [PubMed
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Pleural epithelioid hemangioendothelioma (EHE) is a very rare disease with adverse clinical outcomes. Recently, CAMTA1 rearrangement has been introduced as a consistent genetic abnormality in EHEs of different anatomical locations. We report a 71-year-old man with pleural EHE harboring CAMTA1 rearrangement confirmed by fluorescence in situ hybridization on paraffin embedded tissue.
Although benign hemangiomas are among the most common diagnoses amid connective tissue tumors, sarcomas showing endothelial differentiation (ie, angiosarcoma and epithelioid hemangioendothelioma) represent under 1% of all sarcoma diagnoses, and thus it is likely that fewer than 500 people in the United States are affected each year. Differential diagnosis of malignant vascular tumors can be often quite challenging, either at the low end of the spectrum, distinguishing an epithelioid hemangioendothelioma from an epithelioid hemangioma, or at the high-grade end of the spectrum, between an angiosarcoma and a malignant epithelioid hemangioendothelioma. Within this differential diagnosis both clinico-radiological features (ie, size and multifocality) and immunohistochemical markers (ie, expression of endothelial markers) are often similar and cannot distinguish between benign and malignant vascular lesions. Molecular ancillary tests have long been needed for a more objective diagnosis and classification of malignant vascular tumors, particularly within the epithelioid phenotype. As significant advances have been recently made in understanding the genetic signatures of vascular tumors, this review will take the opportunity to provide a detailed update on these findings. Specifically, this article will focus on the following aspects: (1) pathological and molecular features of epithelioid hemangioendothelioma, including the more common WWTR1-CAMTA1 fusion, as well as the recently described YAP1-TFE3 fusion, identified in a morphological variant of epithelioid hemangioendothelioma; (2) discuss the heterogeneity of angiosarcoma clinical, morphological and genetic spectrum, with particular emphasis of MYC and FLT4 gene amplification in radiation-induced angiosarcoma; and (3) provide a practical guide in the differential diagnosis of epithelioid vascular tumors using molecular testing.
Lee SE, Park HY, Kim S, et al.Epithelioid hemangioendothelioma with extensive cystic change and CAMTA1 rearrangement.
Pathol Int. 2013; 63(10):502-5 [PubMed
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Epithelioid hemangioendothelioma (EHE) is a rare vascular neoplasm that has the ability to recur locally and metastasize. Thus, it is important to distinguish this tumor from other epithelioid vascular neoplasms. A 47-year-old man presented to our hospital with a pelvic mass with severe ischialgia and weight loss. Surgical resection was performed, and the mass was found to have dark red multiloculated cysts with hemorrhage and calcification. The histopathologic examination showed a central sclerotic, hypocellular zone and a peripheral cellular zone. Only the peripheral portion of the wall revealed nested tumor cells in light blue myxoid stroma. These tumors are typically composed of short strands or cords of bland epithelioid cells with occasional intracytoplasmic lumens embedded in a myxohyalinized stroma. The tumor cells were positive for CD31 and CD34 and negative for factor VIII-related antigen, CK (AE1/AE3) and S-100. The tumor nuclei showed distinct break-apart signals with individual green and/or red signals, indicating the presence of CAMTA1 rearrangement. In this study, we report a case of EHE that was difficult to diagnose based on histology alone. Therefore, we also performed fluorescence in situ hybridization, and found that the tumor harbored a CAMTA1 gene rearrangement, which confirmed the diagnosis.
Bochenek G, Häsler R, El Mokhtari NE, et al.The large non-coding RNA ANRIL, which is associated with atherosclerosis, periodontitis and several forms of cancer, regulates ADIPOR1, VAMP3 and C11ORF10.
Hum Mol Genet. 2013; 22(22):4516-27 [PubMed
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The long non-coding RNA ANRIL is the best replicated genetic risk locus of coronary artery disease (CAD) and periodontitis (PD), and is independently associated with a variety of other immune-mediated and metabolic disorders and several forms of cancer. Recent studies showed a correlation of decreased concentrations of proximal ANRIL transcripts with homozygous carriership of the CAD and PD main risk alleles. To elucidate the relation of these transcripts to disease manifestation, we constructed a short hairpin RNA in a stable inducible knock-down system of T-Rex 293 HEK cell lines, specifically targeting the proximal transcripts EU741058 and DQ485454. By genome-wide expression profiling using Affymetrix HG1.0 ST Arrays, we identified the transcription of ADIPOR1, VAMP3 and C11ORF10 to be correlated with decreased ANRIL expression in a time-dependent manner. We validated these findings on a transcriptional and translational level in different cell types. Exploration of the identified genes for the presence of disease associated variants, using Affymetrix 500K genotyping and Illumina custom genotyping arrays, highlighted a region upstream of VAMP3 within CAMTA1 to be associated with increased risk of CAD [rs10864294 P = 0.015, odds ratio (OR) = 1.30, 95% confidence interval (CI) = 1.1-1.6, 1471 cases, 2737 controls] and aggressive PD (AgP; P = 0.008, OR = 1.31, 95% CI = 1.1-1.6, 864 cases, 3664 controls). In silico replication in a meta-analysis of 14 genome-wide association studies of CAD of the CARDIoGRAM Consortium identified rs2301462, located on the same haplotype block, as associated with P = 0.001 upon adjustment for sex and age. Our results give evidence that specific isoforms of ANRIL regulate key genes of glucose and fatty acid metabolism.
Conventional epithelioid hemangioendotheliomas (EHE) have a distinctive morphologic appearance and are characterized by a recurrent t(1;3) translocation, resulting in a WWTR1-CAMTA1 fusion gene. We have recently encountered a fusion-negative subset characterized by a somewhat different morphology, including focally well-formed vasoformative features, which was further investigated for recurrent genetic abnormalities. Based on a case showing strong transcription factor E3 (TFE3) immunoreactivity, fluorescence in situ hybridization (FISH) analysis for TFE3 gene rearrangement was applied to the index case as well as to nine additional cases, selected through negative WWTR1-CAMTA1 screening. A control group, including 18 epithelioid hemangiomas, nine pseudomyogenic HE, and three epithelioid angiosarcomas, was also tested. TFE3 gene rearrangement was identified in 10 patients, with equal gender distribution and a mean age of 30 years old. The lesions were located in somatic soft tissue in six cases, lung in three and one in bone. One case with available frozen tissue was tested by RNA sequencing and FusionSeq data analysis to detect novel fusions. A YAP1-TFE3 fusion was thus detected, which was further validated by FISH and reverse transcription polymerase chain reaction (RT-PCR). YAP1 gene rearrangements were then confirmed in seven of the remaining nine TFE3-rearranged EHEs by FISH. No TFE3 structural abnormalities were detected in any of the controls. The TFE3-rearranged EHEs showed similar morphologic features with at least focally, well-formed vascular channels, in addition to a variably solid architecture. All tumors expressed endothelial markers, as well as strong nuclear TFE3. In summary, we are reporting a novel subset of EHE occurring in young adults, showing a distinct phenotype and YAP1-TFE3 fusions.
Glioblastoma multiforme (GBM), the most common and malignant type of glioma, is characterized by a poor prognosis and the lack of an effective treatment, which are due to a small sub-population of cells with stem-like properties, termed glioma stem cells (GSCs). The term "multiforme" describes the histological features of this tumor, that is, the cellular and morphological heterogeneity. At the molecular level multiple layers of alterations may reflect this heterogeneity providing together the driving force for tumor initiation and development. In order to decipher the common "signature" of the ancestral GSC population, we examined six already characterized GSC lines evaluating their cytogenomic and epigenomic profiles through a multilevel approach (conventional cytogenetic, FISH, aCGH, MeDIP-Chip and functional bioinformatic analysis). We found several canonical cytogenetic alterations associated with GBM and a common minimal deleted region (MDR) at 1p36.31, including CAMTA1 gene, a putative tumor suppressor gene, specific for the GSC population. Therefore, on one hand our data confirm a role of driver mutations for copy number alterations (CNAs) included in the GBM genomic-signature (gain of chromosome 7- EGFR gene, loss of chromosome 13- RB1 gene, loss of chromosome 10-PTEN gene); on the other, it is not obvious that the new identified CNAs are passenger mutations, as they may be necessary for tumor progression specific for the individual patient. Through our approach, we were able to demonstrate that not only individual genes into a pathway can be perturbed through multiple mechanisms and at different levels, but also that different combinations of perturbed genes can incapacitate functional modules within a cellular networks. Therefore, beyond the differences that can create apparent heterogeneity of alterations among GSC lines, there's a sort of selective force acting on them in order to converge towards the impairment of cell development and differentiation processes. This new overview could have a huge importance in therapy.
Henrich KO, Schwab M, Westermann F1p36 tumor suppression--a matter of dosage?
Cancer Res. 2012; 72(23):6079-88 [PubMed
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A broad range of human malignancies is associated with nonrandom 1p36 deletions, suggesting the existence of tumor suppressors encoded in this region. Evidence for tumor-specific inactivation of 1p36 genes in the classic "two-hit" manner is scarce; however, many tumor suppressors do not require complete inactivation but contribute to tumorigenesis by partial impairment. We discuss recent data derived from both human tumors and functional cancer models indicating that the 1p36 genes CHD5, CAMTA1, KIF1B, CASZ1, and miR-34a contribute to cancer development when reduced in dosage by genomic copy number loss or other mechanisms. We explore potential interactions among these candidates and propose a model where heterozygous 1p36 deletion impairs oncosuppressive pathways via simultaneous downregulation of several dosage-dependent tumor suppressor genes.
PURPOSE: Children diagnosed at age ≥ 18 months with metastatic MYCN-nonamplified neuroblastoma (NBL-NA) are at high risk for disease relapse, whereas those diagnosed at age < 18 months are nearly always cured. In this study, we investigated the hypothesis that expression of genes related to tumor-associated inflammatory cells correlates with the observed differences in survival by age at diagnosis and contributes to a prognostic signature.
METHODS: Tumor-associated macrophages (TAMs) in localized and metastatic neuroblastomas (n = 71) were assessed by immunohistochemistry. Expression of 44 genes representing tumor and inflammatory cells was quantified in 133 metastatic NBL-NAs to assess age-dependent expression and to develop a logistic regression model to provide low- and high-risk scores for predicting progression-free survival (PFS). Tumors from high-risk patients enrolled onto two additional studies (n = 91) served as independent validation cohorts.
RESULTS: Metastatic neuroblastomas had higher infiltration of TAMs than locoregional tumors, and metastatic tumors diagnosed in patients at age ≥ 18 months had higher expression of inflammation-related genes than those in patients diagnosed at age < 18 months. Expression of genes representing TAMs (CD33/CD16/IL6R/IL10/FCGR3) contributed to 25% of the accuracy of a novel 14-gene tumor classification score. PFS at 5 years for children diagnosed at age ≥ 18 months with NBL-NA with a low- versus high-risk score was 47% versus 12%, 57% versus 8%, and 50% versus 20% in three independent clinical trials, respectively.
CONCLUSION: These data suggest that interactions between tumor and inflammatory cells may contribute to the clinical metastatic neuroblastoma phenotype, improve prognostication, and reveal novel therapeutic targets.
BACKGROUND: The controversy surrounding diagnosis of an epithelioid hemangioma (EH), particularly when arising in skeletal locations, stems not only from its overlapping features with other malignant vascular neoplasms, but also from its somewhat aggressive clinical characteristics, including multifocal presentation and occasional lymph node involvement. Specifically, the distinction from epithelioid hemangioendothelioma (EHE) has been controversial. The recurrent t(1;3)(p36;q25) chromosomal translocation, resulting in WWTR1-CAMTA1 fusion, recently identified in EHE of various anatomic sites, but not in EH or other epithelioid vascular neoplasms, suggests distinct pathogeneses.
QUESTION/PURPOSES: We investigated the clinicopathologic and radiologic characteristics of bone and soft tissue EHs in patients treated at our institution with available tissue for molecular testing.
PATIENTS AND METHODS: Seventeen patients were selected after confirming the pathologic diagnosis and fluorescence in situ hybridization analysis for the WWTR1 and/or CAMTA1 rearrangements. Four patients had multifocal presentation. Most patients with EH of bone were treated by intralesional curettage. None of the patients died of disease and only four patients had a local recurrence.
RESULTS: Our results, using molecular testing to support the pathologic diagnosis of EH, reinforce prior data that EH is a benign lesion characterized by an indolent clinical course with an occasional multifocal presentation and rare metastatic potential to locoregional lymph nodes.
CONCLUSION: These findings highlight the importance of distinguishing EH from other malignant epithelioid vascular tumors as a result of differences in their management and clinical outcome.
LEVEL OF EVIDENCE: Level IV, prognostic study. See Guidelines for Authors for a complete description of levels of evidence.
Tanas MR, Sboner A, Oliveira AM, et al.Identification of a disease-defining gene fusion in epithelioid hemangioendothelioma.
Sci Transl Med. 2011; 3(98):98ra82 [PubMed
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Integrating transcriptomic sequencing with conventional cytogenetics, we identified WWTR1 (WW domain-containing transcription regulator 1) (3q25) and CAMTA1 (calmodulin-binding transcription activator 1) (1p36) as the two genes involved in the t(1;3)(p36;q25) chromosomal translocation that is characteristic of epithelioid hemangioendothelioma (EHE), a vascular sarcoma. This WWTR1/CAMTA1 gene fusion is under the transcriptional control of the WWTR1 promoter and encodes a putative chimeric transcription factor that joins the amino terminus of WWTR1, a protein that is highly expressed in endothelial cells, in-frame to the carboxyl terminus of CAMTA1, a protein that is normally expressed only in brain. Thus, CAMTA1 expression is activated inappropriately through a promoter-switch mechanism. The gene fusion is present in virtually all EHEs tested but is absent from all other vascular neoplasms, demonstrating it to be a disease-defining genetic alteration. A sensitive and specific break-apart fluorescence in situ hybridization assay was also developed to detect the translocation and will assist in the evaluation of this diagnostically challenging neoplasm. The chimeric WWTR1/CAMTA1 transcription factor may represent a therapeutic target for EHE and offers the opportunity to shed light on the functions of two poorly characterized proteins.
Cancer stem cells or cancer initiating cells are believed to contribute to cancer recurrence after therapy. MicroRNAs (miRNAs) are short RNA molecules with fundamental roles in gene regulation. The role of miRNAs in cancer stem cells is only poorly understood. Here, we report miRNA expression profiles of glioblastoma stem cell-containing CD133(+) cell populations. We find that miR-9, miR-9(*) (referred to as miR-9/9(*)), miR-17 and miR-106b are highly abundant in CD133(+) cells. Furthermore, inhibition of miR-9/9(*) or miR-17 leads to reduced neurosphere formation and stimulates cell differentiation. Calmodulin-binding transcription activator 1 (CAMTA1) is a putative transcription factor, which induces the expression of the anti-proliferative cardiac hormone natriuretic peptide A (NPPA). We identify CAMTA1 as an miR-9/9(*) and miR-17 target. CAMTA1 expression leads to reduced neurosphere formation and tumour growth in nude mice, suggesting that CAMTA1 can function as tumour suppressor. Consistently, CAMTA1 and NPPA expression correlate with patient survival. Our findings could provide a basis for novel strategies of glioblastoma therapy.