Cutaneous soft tissue tumors: diagnostically disorienting epithelioid tumors that are not epithelial, and other perplexing mesenchymal lesions.

Cutaneous soft tissue tumors with epithelioid features present a diagnostic challenge given that many entities in this category are rare, and they show morphologic overlap with significantly more common cutaneous epithelial and melanocytic neoplasms. The challenge is compounded by overlapping expression of epithelial or melanocytic markers in some of these entities. A broad spectrum of primary cutaneous epithelioid soft tissue tumors exists, including benign and malignant counterparts of tumors with various differentiation including melanocytic, peripheral nerve sheath, angiomatous, fibrohistiocytic, and myoid or myoepithelial, in addition to translocation-associated tumors lacking a derivative tissue type. Given this spectrum, an initial targeted immunohistochemical panel for epithelioid dermal and subcutaneous neoplasms is recommended, covering a broad spectrum of differentiation. In diagnostically challenging cases, select molecular studies can be employed to make critical distinctions between entities sharing morphologic and immunohistochemical properties. Due to sometimes marked differences in prognosis and treatment, knowledge and familiarity with epithelioid soft tissue tumors is key for any surgical pathologist who evaluates skin and subcutaneous biopsies and excision specimens. This concise review provides brief descriptions, key diagnostic features, and important modern ancillary studies for the diagnosis of non-epithelial, non-melanocytic cutaneous tumors that can exhibit a prominent degree of epithelioid morphology.

Update on Peripheral Nerve Sheath Tumors.

Recent work has revealed SMARCB1/INI1 loss by immunohistochemistry in a subset of epithelioid schwannomas and explored the significance of cytologic atypia and increased mitotic activity in these tumors. Additional studies have evaluated the utility and limitations of histone H3K27 trimethylation in diagnosis of high-grade and low-grade malignant peripheral nerve sheath tumors. New terminology regarding nerve sheath tumors in neurofibromatosis type 1 patients was proposed during a 2016 conference to better define guidelines for classification of this group of tumors. This review highlights novel findings and practical applications relating to these topics in peripheral nerve sheath tumors.

Recent advances in the diagnosis of soft tissue tumours.

Soft tissue tumours are relatively rare, but are diagnostically challenging as they comprise a large spectrum of diagnostic entities. Substantial advances have been made in recent years in identifying the underlying recurrent chromosomal and genomic alterations in a significant subset of soft tissue tumours, and this continues to enrich our understanding of the biological mechanisms of tumour development and progression. Ongoing validation and integration of these findings into existing pathological-diagnostic algorithms has led to re- or subclassification of diagnostic categories and will continue to shape a more nuanced (and hopefully clinically relevant) tumour classification system in the future. This review provides a selective overview of recent diagnostic or conceptual advances in the categories of peripheral nerve sheath tumours, vascular and adipocytic tumours, round cell and myogenic sarcomas, and gastrointestinal stromal tumours, as well as their underlying molecular mechanisms, some of which have been translated successfully into useful immunohistochemical stains. A thorough and critical validation of newly identified diagnostic markers-acknowledging the fact that some genetic alterations may not necessarily be tumour-specific-and ongoing correlation with clinical and prognostic implications will be necessary in this regard.

[Soft tissue tumors : Epidemiology, classification and staging]. / Weichteiltumoren : Epidemiologie, Klassifikation und Stadieneinteilung.

Benign, intermediate and malignant soft tissue tumors can be differentiated histologically. Furthermore, the tumors can be subdivided according to their linear differentiation. In the new World Health Organization (WHO) classification of soft tissue tumors from 2013 changes have been made relating to the allocation of known entities, e. g. undifferentiated sarcomas have been formed into a new subgroup and are no longer assigned to the fibrohistiocytic tumors. The term malignant fibrous histiocytoma has been replaced by the undifferentiated sarcoma. Furthermore, two new subgroups were incorporated, the nerve sheath tumors and gastrointestinal stromal tumors. These were previously included in the tumor classification of other organ systems. These changes in the new classification are related to the rapid increase in knowledge of the genetics and the cell biology of soft tissue tumors. Malignant soft tissue tumors only represent 1% of all malignant tumors in adults. The largest subgroup of soft tissue tumors in adults is the adipocytic tumors. The liposarcoma, which belongs to this subgroup is one of the most common malignant soft tissue tumors in adults. In childhood malignant soft tissue tumors represent 15% of malignant tumors and rhabdomyosarcoma is the most common malignant soft tissue tumor.

Methylation-based classification of benign and malignant peripheral nerve sheath tumors.

The vast majority of peripheral nerve sheath tumors derive from the Schwann cell lineage and comprise diverse histological entities ranging from benign schwannomas and neurofibromas to high-grade malignant peripheral nerve sheath tumors (MPNST), each with several variants. There is increasing evidence for methylation profiling being able to delineate biologically relevant tumor groups even within the same cellular lineage. Therefore, we used DNA methylation arrays for methylome- and chromosomal profile-based characterization of 171 peripheral nerve sheath tumors. We analyzed 28 conventional high-grade MPNST, three malignant Triton tumors, six low-grade MPNST, four epithelioid MPNST, 33 neurofibromas (15 dermal, 8 intraneural, 10 plexiform), six atypical neurofibromas, 43 schwannomas (including 5 NF2 and 5 schwannomatosis associated cases), 11 cellular schwannomas, 10 melanotic schwannomas, 7 neurofibroma/schwannoma hybrid tumors, 10 nerve sheath myxomas and 10 ganglioneuromas. Schwannomas formed different epigenomic subgroups including a vestibular schwannoma subgroup. Cellular schwannomas were not distinct from conventional schwannomas. Nerve sheath myxomas and neurofibroma/schwannoma hybrid tumors were most similar to schwannomas. Dermal, intraneural and plexiform neurofibromas as well as ganglioneuromas all showed distinct methylation profiles. Atypical neurofibromas and low-grade MPNST were indistinguishable with a common methylation profile and frequent losses of CDKN2A. Epigenomic analysis finds two groups of conventional high-grade MPNST sharing a frequent loss of neurofibromin. The larger of the two groups shows an additional loss of trimethylation of histone H3 at lysine 27 (H3K27me3). The smaller one retains H3K27me3 and is found in spinal locations. Sporadic MPNST with retained neurofibromin expression did not form an epigenetic group and most cases could be reclassified as cellular schwannomas or soft tissue sarcomas. Widespread immunohistochemical loss of H3K27me3 was exclusively seen in MPNST of the main methylation cluster, which defines it as an additional useful marker for the differentiation of cellular schwannoma and MPNST.

The Evolution of Pediatric Soft Tissue Sarcoma Classification in the Last 50 Years.

This review discusses the history of the classification of soft tissue sarcomas in children and adolescents, the current transition toward integration of morphology and molecular genetics as new entities emerge, and future perspectives.

[Nerve sheath tumours]. / Les tumeurs des gaines des nerfs périphériques.

Peripheral nerve sheath tumors are common neoplasms in daily practice. Diagnosis and classification of most conventional peripheral nerve sheath tumors are relatively straightforward for the experienced observer; but on occasion, they are diagnostically challenging (especially with locally aggressive and malignant tumors). This article aims to provide an update of the data (clinical, histological, immunohistochemistry and genomic) of benign, intermediate and malignant peripheral nerve sheath tumors, thanks to the latest WHO "Classification of Tumors of Soft Tissue and Bone", published in 2013, which includes a new chapter on "Nerve Sheath Tumors". Advances in molecular biology have provided new insights into the nature of the various peripheral nerve sheath tumors, and have begun to suggest novel targeted therapeutic approaches.

Benign cutaneous biphasic hybrid tumor of perineurioma and cellular neurothekeoma: A case report expanding the clinical and histopathologic features of a recently described entity.

Benign cutaneous plexiform hybrid tumor of perineurioma and cellular neurothekeoma (BCPHTPCN) is a recently described entity that presents as a solitary papule in the perioral area. As implied by its name, BCPHTPCN displays microscopic features of both perineurioma and cellular neurothekeoma arranged in a plexiform pattern. We report a case of nonplexiform benign cutaneous biphasic hybrid tumor of perineurioma and cellular neurothekeoma in a 36-year-old woman, who presented with a 4-year history of a firm, flesh-colored left ankle nodule. Histologically, there was a biphasic, well-circumscribed unencapsulated dermal mesenchymal proliferation with no connection to the epidermis, which exhibited mild acanthosis with slightly pigmented basal keratinocytes and overlying parakeratosis. The proliferation consisted of uniform bland spindle cells with bipolar cytoplasmic processes arranged in whorls with interspersed islands of epithelioid cells. Immunohistochemically, the spindle cell component was positive for CD34, EMA, and GLUT-1, consistent with perineurial differentiation, whereas the epithelioid nests were positive for NKI/C3 and MiTF, as expected in neurothekeoma. Stains for S100 protein, SOX10, desmin, claudin, pan-melanoma markers, and NSE were negative. We believe this case expands the histopathologic spectrum of BCPHTPCN showing that it can be grown in a nonplexiform pattern, and we suggest the term benign cutaneous biphasic hybrid tumor of perineurioma and cellular neurothekeoma as a more precise name. It is also, to the best of our knowledge, the first case reported outside the head and neck area.

[The new WHO classification and recent results in soft tissue tumor pathology]. / Die neue WHO-Klassifikation und aktuelle Ergebnisse in der Weichteiltumorpathologie.

The new World Health Organization (WHO) classification presents a comprehensive description of soft tissue tumors which was published in book format at the beginning of 2013. Changes have been made relating to the allocation of known entities, e.g. undifferentiated sarcomas are formed into a new group and are not longer assigned to the so-called fibrohistiocytic tumors and new subgroups were incorporated, such as nerve sheath tumors and gastrointestinal stroma tumors which were previously included in the tumor classification of other organ systems. This development is important from the practical point of view as most of relevant soft tissue tumors are now summarized and can be found in a single book. This is also related to the rapid increase in knowledge of the genetics and cell biology of soft tissue tumors. At present there is considerable progress in tumor pathology illustrated by the fact that important new findings have been published after completion of the classification, such as those related to the identification of the recurrent NAB2-STAT6 gene fusion in solitary fibrous tumors and the detection of frequent mutations in the promoter of the hTERT gene in malignant melanoma. In this report some new findings and clinically relevant aspects of soft tissue tumor pathology will be presented.

Use of electron microscopy to classify canine perivascular wall tumors.

The histologic classification of canine perivascular wall tumors (PWTs) is controversial. Many PWTs are still classified as hemangiopericytomas (HEPs), and the distinction from peripheral nerve sheath tumors (PNSTs) is still under debate. A recent histologic classification of canine soft tissue sarcomas included most histologic types of PWT but omitted those that were termed undifferentiated. Twelve cases of undifferentiated canine PWTs were evaluated by transmission electron microscopy. The ultrastructural findings supported a perivascular wall origin for all cases with 4 categories of differentiation: myopericytic (n = 4), myofibroblastic (n = 1), fibroblastic (n = 2), and undifferentiated (n = 5). A PNST was considered unlikely in each case based on immunohistochemical expression of desmin and/or the lack of typical ultrastructural features, such as basal lamina. Electron microscopy was pivotal for the subclassification of canine PWTs, and the results support the hypothesis that canine PWTs represent a continuum paralleling the phenotypic plasticity of vascular mural cells. The hypothesis that a subgroup of PWTs could arise from a pluripotent mesenchymal perivascular wall cell was also considered and may explain the diverse differentiation of canine PWTs.

Hybrid schwannoma/perineurioma: report of 10 Chinese cases supporting a distinctive entity.

Hybrid schwannoma/perineurioma is a recently described benign nerve sheath tumor that typically manifests as a dermal tumor on the extremities and trunk. Occurrence outside the skin is uncommon. This article describes 10 cases of hybrid schwannoma/perineurioma arising in diverse anatomic locations. They all occurred in adult patients (age range 27-81 years, median 35 years) with a marked female predominance (2 males and 8 females). Of the 10 tumors, 7 were situated in the subcutis of trunk (n = 3), extremities (n = 2), neck (n = 1), and labium majus (n = 1) and 3 in the submucosa of nasal cavity, sigmoid colon, and rectum, respectively. Histologically, they were composed of intimately admixed plump spindle cells and elongated slender spindle cells forming storiform, lamellar or fascicular architecture. By immunohistochemistry, the tumor showed dual differentiation of schwannian cells (plump-spindled) and perineurial cells (slender-spindled), characterized by strong S100 protein expression in the former component and variable immunoreactivity of epithelial membrane antigen, claudin-1, and CD34 in the latter. Awareness of its morphological characteristics and potential occurrence in diverse sites may aid in the recognition of this rare tumor type.

Malignant peripheral nerve sheath tumours of the spine: clinical manifestations, classification, treatment, and prognostic factors.

BACKGROUND AND OBJECTIVES: To summarise our experience treating patients with spinal malignant peripheral nerve sheath tumours (MPNSTs). METHODS: We retrospectively reviewed the records of patients diagnosed with spinal MPNSTs who received surgical treatment from January 1998 to December 2009. RESULTS: Postoperative follow-up data were available for 14/16 patients with spinal MPNSTs (7 men, 7 women; median age = 44 years [range: 23-68 years]). Eight of 14 (57.1%) patients had primary and 6/14 (42.9%) recurrent MPNSTs. A total of 12/14 (85.7%) patients underwent total tumour resection, whereas 2/14 (14.3%) patients underwent subtotal tumour resection. Malignancies were graded low in 4 (28.6%) and high in 10 (71.1%) cases. A total of 12/14 (85.7%) patients experienced tumour recurrence and 10/14 (71.4%) patients died during the course of follow-up. The 0.5- 1-, 3-, and 5-year survival rates were 64.3, 48.2, 32.1, and 21.4%, respectively. Overall survival was significantly associated with tumour malignant degree (P = 0.012). CONCLUSION: Diagnosis of spinal MPNSTs should be made with reference to clinical, radiological, and pathological findings. Surgical resection is the best available option for treating spinal MPNST; however, postoperative prognosis is poor.

Molecular and immunohistochemical distinction of equine sarcoid from schwannoma.

Ten equine skin tumors that had been classified as schwannomas on routine histological examination were analyzed by polymerase chain reaction for bovine papillomavirus DNA. All 10 were positive for bovine papillomavirus 1 or 2, and all 10 were immunohistochemically negative for S-100 protein and strongly positive for vimentin. Nine tumors were moderately positive for laminin and 8, for smooth muscle actin. Five tumors were variably and weakly positive for type IV collagen. The lack of S-100 protein expression made Schwann cells an unlikely cell of origin, as opposed to peripheral nerve sheath tumors, which typically express S-100 protein, at least in some neoplastic cells. The immunohistochemical reactivity is consistent with myofibroblastic origin of the neoplastic cells, although smooth muscle cell or pericyte origin cannot be ruled out. These tumors represent an atypical form of equine sarcoid. Polymerase chain reaction for bovine papillomavirus and S-100 immunohistochemistry are strongly recommended for all equine skin tumors with histological characteristics typical of schwannoma or peripheral nerve sheath tumor.

Immunohistochemistry for 2',3'-cyclic nucleotide-3'-phosphohydrolase in 63 bovine peripheral nerve sheath tumors.

To establish a simple and uniform classification of bovine peripheral nerve sheath tumors (PNSTs), 63 tumors from 44 cattle were examined histologically and immunohistochemically with antibodies against S100 protein and 2',3'-cyclic nucleotide-3'-phosphohydrolase (CNPase). Immunohistochemically, all the tumors were positive for S100 protein, CNPase, or both. Four types of PNST were recognized: 35 schwannomas, 9 neurofibromas, 14 hybrid (neurofibroma-schwannoma) tumors, and 5 malignant PNSTs. Axons were identified by immunohistochemistry for neurofilament in a proportion of tumors of each type of PNST. In conclusion, bovine PNSTs commonly have both schwannomatous and neurofibromatous areas. Moreover, the Schwann cell markers S100 protein and CNPase, in combination with antibodies against neurofilament, are valuable diagnostic tools to classify bovine PNSTs.

Benign serrated colorectal fibroblastic polyps/intramucosal perineuriomas are true mixed epithelial-stromal polyps (hybrid hyperplastic polyp/mucosal perineurioma) with frequent BRAF mutations.

Colorectal fibroblastic polyp and intramucosal perineurioma are 2 synonyms for a recently described benign mucosal lesion with a predilection for the rectosigmoid colon. These lesions are characterized by aggregates of bland spindled cells separating and distorting mucosal crypts. The latter frequently showed a serrated architecture. The pathogenesis of fibroblastic polyp/intramucosal perineurioma and the nature of serrated crypts observed in them are poorly understood. We analyzed the clinicopathological features of 29 fibroblastic polyps and investigated them for the first time for mutations known to be involved in serrated colorectal epithelial polyps (BRAF, KRAS, and PIK3CA). Patients were 23 women and 6 men with a mean age of 64 years (range: 47 to 84 y). All lesions represented asymptomatic solitary polyps (mean size 3.5 mm) localized predominantly in the rectosigmoid colon (81%). Hyperplastic polyps, classical adenoma, and sessile serrated adenoma/lesion coexisted in 12 (44%), 12 (44%), and 5 (17%) patients, respectively. All lesions showed irregular aggregates of bland spindled cells separating and distorting mucosal crypts. Serrated (hyperplastic) crypts were observed on the top or contiguous with the lesion in all cases. Immunohistochemistry revealed expression of at least one perineurial cell marker (epithelial membrane antigen, claudin-1, and glucose transporter-1) in 26 out of 27 lesions (96%), but expression of CD34 was less common (8 of 27; 30%). Immunostaining for hMLH1 showed a normal nuclear expression. Molecular analysis in 22 cases showed V600E BRAF mutation in 14 cases (63%) and KRAS mutation in 1 (4%). The remainder were wild-type for all 3 genes. Our results indicate that serrated fibroblastic polyps/intramucosal perineuriomas represent a unique type of mixed epithelial-stromal polyps (hybrid hyperplastic polyp/mucosal perineurioma). The perineurial stromal component might be derived from modified pericryptic fibroblasts as a consequence of a yet poorly understood epithelial-stromal interaction.

[Neurogenic tumors of the mediastinum in adults]. / Tumeurs nerveuses du médiastin de l'adulte.

In adults, mediastinal neurogenic tumours constitute the third group of mediastinal tumours, after thymomas and lymphomas. If the group of neurogenic tumour is frequent, each type of tumour is relatively unusual in everyday's clinic. Among them, nerve sheath tumours are the more frequent, followed by tumour of the autonomic system. Askin tumour remains uncommon. Treatment of this tumour requires complete preoperative work-up, including standard radiography, CT-scan, MRI, and sometimes nuclear imaging. In most cases, the treatment is based on surgical resection, and may be associated with radiotherapy or chemotherapy in case of malignant tumour or incomplete resection. Better understanding of these tumours, including their molecular abnormalities, may lead to new changes in their classifications, and to their management.

Malignant peripheral nerve sheath tumors.

Malignant peripheral nerve sheath tumors (MPNSTs) are a rare variety of soft tissue sarcoma of ectomesenchymal origin. MPNSTs arise from major or minor peripheral nerve branches or sheaths of peripheral nerve fibers and are derived from Schwann cells or pluripotent cells of neural crest origin. Arthur Purdy Stout played a pivotal role in the development of our current understanding of the pathogenesis of peripheral nerve sheath tumors by identifying the Schwann cell as the major contributor to the formation of benign and malignant neoplasms of the nerve sheath. Although this fact remains essentially true, the cell of origin of the MPNST remains elusive and has not yet conclusively been identified. Some have suggested these tumors may have multiple cell line origins. In the present review, MPNSTs and their epidemiology, diagnosis, management, and treatment are discussed.