GNA11 joins GNAQ and GNA14 as a recurrently mutated gene in anastomosing hemangioma

Abstract

Anastomosing hemangioma (AH) is a distinct benign vascular tumor that may be histologically confused with an angiosarcoma. Recently, recurrent GNAQ and GNA14 mutations were identified in AH. GNA11, another paralogue of GNAQ and the one that shows the highest degree of homology to GNAQ, has not yet been found to be mutated in AH. In this study, we investigated the clinicopathological and molecular features of 26 AHs. By Sanger sequencing and MassARRAY analysis, mutually exclusive mutations in exon 5 of GNAQ, GNA11, and GNA14 were identified in 10, 5, and 5 tumors, respectively, of the 22 investigated tumors, with an overall mutation rate of 91%. No notable differences in the clinicopathological features were observed between GNAQ-, GNA11-, or GNA14-mutated tumors. Our results implicated GNA11 mutations, as well as previously known mutations of its paralogues GNAQ and GNA14, as essential drivers in the pathogenesis of AH.

What’s new in nerve sheath tumors

Abstract

Peripheral nerve sheath tumors are commonly encountered and frequently pose challenges to the pathologist and the clinician. This review discusses the wide range of entities with an emphasis on new discoveries in the past decade. Clinical, histologic, immunohistochemical, and pathogenetic findings are discussed with an emphasis on clinical implications and differential diagnosis.

Secondary INI1-deficient rhabdoid tumors of the central nervous system: analysis of four cases and literature review

Abstract

Atypical teratoid/rhabdoid tumors (AT/RT) are rare, highly malignant neoplasms of the central nervous system that predominantly occur in infants, and are characterized by the presence of rhabdoid cells and inactivation of INI1 or (extremely rarely) BRG1. The vast majority of AT/RT are recognized as primary tumors; however, rare AT/RT or INI1-deficient RT arising from other primary tumors have been reported. To better characterize secondary RT, we performed a histological and molecular analysis of four RT arising from pleomorphic xanthoastrocytoma (PXA), anaplastic PXA, low-grade astrocytoma, or ependymoma. Histologically, although conventional AT/RT are usually not largely composed of rhabdoid cells, three secondary RT were composed mainly of rhabdoid cells, two of which arising from (anaplastic) PXA exhibited marked nuclear pleomorphism reminiscent of that in the precursor lesions. Regarding INI1 alterations, although mutations including small indels are frequent in conventional AT/RT, only in one secondary RT had a mutation. Moreover, together with previously reported cases, biallelic INI1 inactivation in secondary RT was mostly due to biallelic focal and/or broad deletions. Although conventional AT/RT have stable chromosomal profiles, i.e., the frequency of copy number changes involving chromosomes other than chromosome 22 is remarkably low, our array comparative genomic hybridization analysis revealed numerous copy number changes in the secondary RT. In conclusion, secondary RT of the central nervous system are clinicopathologically and molecularly different from conventional pediatric AT/RT, and a nosological issue is whether these secondary RT should be called secondary “AT/RT” as most of the reported cases were.

What is new in pericytomatous, myoid, and myofibroblastic tumors?

Abstract

Recent advances in molecular techniques in soft tissue pathology, including the widespread application of next-generation sequencing, have led to significant progress in our understanding of mesenchymal tumors. Recognition of the genetic signatures of these neoplasms not only clarifies the relationship of these entities but also provides a mechanism for more accurate diagnosis. More importantly, insight into the genetic underpinnings of these lesions may offer therapeutic targets for cases not amenable to surgical treatment. This review highlights the clinicopathologic features and novel molecular findings in pericytic, myoid, and myofibroblastic tumors.

Update on selected advances in the immunohistochemical and molecular genetic analysis of soft tissue tumors

Abstract

Although traditional morphological evaluation remains the cornerstone for the diagnosis of soft tissue tumor, ancillary diagnostic modalities such as immunohistochemistry and molecular genetic analysis are of ever-increasing importance in this field. New insights into the molecular pathogenesis of soft tissue tumors, often obtained from high-throughput sequencing technologies, has enabled significant progress in the characterization and biologic stratification of mesenchymal neoplasms, expanding the spectrum of immunohistochemical tests (often aimed towards recently discovered genetic events) and molecular genetic assays (most often fluorescence in situ hybridization and reverse transcription-polymerase chain reaction). This review discusses selected novel molecular and immunohistochemical assays with diagnostic applicability in mesenchymal neoplasms, with emphasis on diagnosis, refinement of tumor classification, and treatment stratification.

What is new about the molecular genetics in matrix-producing soft tissue tumors? -The contributions to pathogenetic understanding and diagnostic classification

Abstract

Soft tissue tumors encompass a wide variety of mesenchymal neoplasms exhibiting diverse clinical, pathologic, and molecular features. Among these, osteoid and/or chondroid matrix deposition in some soft tissue tumors represents a noticeable characteristic. Unlike matrices present in bone tumors where they likely reveal the respective cells of origin (i.e., osteoblastic or chondroblastic precursors), those existing in soft tissue tumors more often denote a metaplastic phenomenon and reflect the diversity of differentiation these tumors can display. While many soft tissue tumor types can occasionally harbor metaplastic bone or cartilage as an incidental component or heterologous differentiation, in some other tumor types, the production of these matrices is a frequent and distinctive, if not diagnostic, feature. This review focuses on the latter tumor types where emerging immunohistochemical and molecular evidence has significantly improved our understanding of their respective pathogenesis and histopathological spectra. These tumor types include ossifying fibromyxoid tumor, phosphaturic mesenchymal tumor, synovial chondromatosis, soft tissue chondroma, calcifying aponeurotic fibroma, giant cell tumor of soft tissue, myositis ossificans and related diseases, mesenchymal chondrosarcoma, and extraskeletal osteosarcoma.

Correction to: Abstracts

In E-Poster Sessions of the published abstract, the authors' affiliations as well as the abstract text were incorrectly presented. The correct abstract and the author's affiliations are shown in full in this article.

Small-bowel carcinomas associated with celiac disease: transcriptomic profiling shows predominance of microsatellite instability-immune and mesenchymal subtypes

Abstract

Celiac disease (CD) is a risk factor for developing small-bowel carcinoma with a 14-fold higher risk compared with general population. As small-bowel carcinomas associated with CD (CD-SBCs) are extremely rare, very few molecular data are available about their pathogenesis, and information about their transcriptomic profiling is lacking. We generated RNA-seq data on 13 CD-SBCs, taken from the largest well-characterized series published so far, collected by the Small Bowel Cancer Italian Consortium, and compared the tumor transcriptional signatures with the four Consensus Molecular Subtypes (CMS) of colorectal carcinoma by applying the “CMS classifier.” CpG Island Methylator Phenotype (CIMP) was evaluated using methylation-sensitive multiple ligation-dependent probe amplification. Up to 12 of 13 cancers fell within the two main subtypes exhibiting high immune and inflammatory signatures, i.e., subtypes 1 and 4. The first and predominant subset was commonly microsatellite unstable, and exhibited CIMP and high CD3+ and CD8+ T cell infiltration. Moreover, it showed increased expression of genes associated with T helper 1 and natural killer cell infiltration, as well as upregulation of apoptosis, cell cycle progression, and proteasome pathways. By contrast, cancers falling in subtype 4 showed prominent transforming growth factor-β activation and were characterized by complement-associated inflammation, matrix remodeling, cancer-associated stroma production, and angiogenesis. Parallel histologic and histochemical analysis confirmed such tumor subtyping. In conclusion, two molecular subtypes have been consistently identified in our series of CD-SBCs, a microsatellite instability-immune and a mesenchymal subtype, the former likely associated with an indolent and the latter with a worse tumor behavior.

The current landscape of rhabdomyosarcomas: an update

Abstract

Rhabdomyosarcomas are malignancies associated with a rhabdomyoblastic phenotype which can be demonstrated morphologically or by immunohistochemistry for MYOD1 and myogenin. Rhabdomyosarcomas are currently subdivided into 4 types in the 2013 WHO classification of tumors of soft tissue and bone, including embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma, spindle cell/sclerosing rhabdomyosarcoma, and pleomorphic rhabdomyosarcoma. Recent studies have significantly impacted this classification with the emergence of three distinct new subtypes of rhabdomyosarcomas, namely rhabdomyosarcoma with MYOD1 mutations, rhabdomyosarcoma with TFCP2 fusions, and rhabdomyosarcoma with VGLL2/NCOA2 fusions. Although all these tumors share the terminology “rhabdomyosarcoma,” their morphology, clinical behavior, and underlying molecular alterations are dramatically different. Finally, the presence of a rhabdomyoblastic phenotype within a tumor is by no means a diagnostic of a rhabdomyosarcoma, as this may be seen in many other mesenchymal malignancies, such as mesenchymal chondrosarcomas, malignant peripheral nerve sheaths tumors, and biphenotypic sinonasal sarcomas. In this review, we present the main clinical, morphological, and molecular features of these tumors and discuss the evolution of the current classification.