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.

Predicting the prognosis of undifferentiated pleomorphic soft tissue sarcoma: a 20-year experience of 266 cases.

BACKGROUND: Undifferentiated pleomorphic sarcoma (UPS) is a rare malignant tumour of mesenchymal origin, which was conceived following re-classification of malignant fibrous histiocytoma (MFH). The objective of this study is to determine prognostic factors for the outcome of UPS, following multi-modal treatment. METHODS: Data of UPS tumours from 1996 to 2016 were collected, totalling 266 unique UPS patients. Median follow-up was 7.8 years. All tumours were retrospectively analysed for prognostic factors of the disease, including local recurrence (LR) and metastatic disease (MD) at diagnosis, tumour size, grade, location and depth, patient age, adjuvant therapy and surgical margin. Overall survival (OS), post-treatment LR and metastatic-free survival were assessed as outcomes. RESULTS: The 5- and 10-year OS rates for all ages were 60% and 48%, respectively, with a median survival time of 10.1 years. Multivariate analysis revealed that the adverse prognostic factors associated with decreased OS were older age (P < 0.001; hazard ratio 1.03) and MD at diagnosis (P = 0.001; 2.89), with upper extremity tumours being favourable (P = 0.043; 2.30). Poor prognosis for post-operative LR was associated with older age (P = 0.046; 1.03) and positive surgical margins (P = 0.028; 2.68). Increased post-treatment MD was seen in patients with large tumours (5-9 cm (P < 0.001; 4.42), ≥10 cm (P < 0.001; 6.80)) and MD at diagnosis (P < 0.001; 3.99), adjuvant therapy was favourable, shown to reduce MD (P < 0.001; 0.34). CONCLUSIONS: UPS is a high-grade soft tissue sarcoma, for which surgery striving for negative margins, with radiotherapy, is the treatment of choice. Older age, lower extremity location, MD at presentation, large size and positive surgical margins, were unfavourable.

Plexiform Xanthomatous Tumor, Variety of Xanthoma or Subtype of Fibrohistiocytic Tumors?

Plexiform xanthomatous tumor was proposed as an independent neoplasm within fibrohistiocytic tumor group a few years ago. The arguments were based on their different clinical features as well as their own morphological and immunohistochemical findings. Nevertheless, it has not been widely studied yet, and there are few reports about this entity. Regarding a case, we reviewed the diagnostic characteristics of this underdiagnosed tumor.

[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.

[Fibrohistiocytic tumors of the skin: a heterogeneous group of superficially located mesenchymal neoplasms]. / Fibrohistiozytäre Tumoren der Haut: Eine heterogene Gruppe oberflächlich lokalisierter mesenchymaler Neoplasien.

So-called fibrohistiocytic tumors of the skin comprise a heterogeneous spectrum of superficially located neoplasms that often show fibroblastic and/or myofibroblastic differentiation. In this review clinicopathologically important variants of dermatofibroma and dermatofibrosarcoma protuberans and their differential diagnoses are discussed in detail. In addition, the clinicopathological features of atypical fibroxanthoma, angiomatoid fibrous histiocytoma, plexiform fibrohistiocytic tumors and pleomorphic dermal sarcoma are presented. Entities that have to be considered in the differential diagnosis are also mentioned.

Global protein-expression profiling for reclassification of malignant fibrous histiocytoma.

According to the newest World Health Organization (WHO) classification for soft tissue tumors in 2013, malignant fibrous histiocytoma (MFH) has been gone. Most sarcomas called MFH were reclassified to be high-grade pleomorphic forms of leiomyosarcoma, liposarcoma, rhabdomyosarcoma, and other sarcomas by recent molecular technologies. However, about 10% to 15% of sarcomas called MFH before, still cannot be given a precise classification, and these are now called undifferentiated pleomorphic sarcoma or are still called MFH. Further molecular approaches including proteomic approaches are imperative to classify these unclassified sarcomas for improving clinical outcomes of the patients with soft tissue sarcomas. This article is part of a Special Issue entitled: Medical Proteomics.

Myxoid variant of so-called angiomatoid "malignant fibrous histiocytoma": clinicopathologic characterization in a series of 21 cases.

Angiomatoid "malignant fibrous histiocytoma" (AMFH) is a tumor of intermediate malignancy and undefined lineage, mostly arising in the extremities of young patients. Examples with a prominent myxoid matrix are very uncommon. Twenty-one cases of myxoid AMFH (among a total of 414) identified in consult files are described, including clinicopathologic features, fluorescence in situ hybridization analysis in a subset of cases, and follow-up. Thirteen patients were female and 8 male, ranging in age from 2 to 51 y (median 17 y). These circumscribed tumors arose in subcutaneous or deep somatic soft tissue, with a median size of 2.5 cm (range, 1 to 8 cm), being located in the extremities (14/21), trunk (4/21), and upper limb girdle (3/21). Characteristic features included a fibrous pseudocapsule (20/21), peritumoral lymphoplasmacytic infiltrates (20/21), blood-filled cystic spaces (17/21), and prominent myxoid morphology comprising 60% to 100% of the tumor surface area examined. Histiocytoid or spindled tumor cells exhibited vesicular nuclei, inconspicuous nucleoli, palely eosinophilic cytoplasm, and multinodular growth without necrosis. Mucin pools and scattered multinucleate giant cells were observed in a subset of cases. Mild to moderate atypia was observed in 4 cases; 1 tumor showed a pseudochondroid matrix. Immunohistochemically, 14/21 cases expressed desmin, 12/21 expressed EMA, and 4/7 exhibited EWSR1 rearrangement. Follow-up, available for 11 patients (median, 43 mo), revealed that 3 developed local recurrence after 2, 7, and 48 months, respectively. All patients were alive without metastases. AMFH may present with prominent myxoid features making diagnosis difficult and causing possible confusion with other myxoid tumors including low-grade fibromyxoid sarcoma, extraskeletal myxoid chondrosarcoma, and myxoid liposarcoma.

[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.

Pleomorphic spindle cell sarcoma (PSCS) formerly known as malignant fibrous histiocytoma (MFH): a complex malignant soft-tissue tumor.

A presentation defining the nature, characteristics, causation, treatment and outcome of patients with lesions formerly known as malignant fibrous histiocytoma and now as pleomorphic spindle cell sarcoma is clearly a very difficult subject. Many authors do not believe that the tumor exists and instead describe them as forms of fibrosarcomas, fibromyxoid lesions, dedifferentiated chondrosarcomas or even leiomyosarcomas. The reasons for this confusion are presumably related to the fact that the malignant pleomorphic spindle cell sarcoma does not seem to be a distinct type of lesion with specific histologic and genetic characteristics. Instead, the tumor has at least four separate histologic variations and no specific gene signature and in fact does not seem to be either familial or ethnic in presentation. In view of the fact that the tumor was traditionally the most frequently encountered malignant soft-tissue neoplasm, the world of orthopedic oncology is clearly distressed by the problems that these patients have and is joined by the radiation oncologists and chemotherapists in seeking new solutions.

[Pleomorphic high-grade soft tissue sarcomas: is the subclassification up to date?]. / Pleomorphe High-grade-Sarkome der Weichgewebe : Ist die Subklassifikation zeitgemäß?

The conceptual evolution in the classification of pleomorphic high-grade sarcomas is a paradigm of how the integrative morphological, immunohistochemical and molecular genetic analysis has contributed to a clinical, prognostic and therapy-oriented characterization of this complex group of tumors. The clinical and prognostic relevance of a refined subtyping of pleomorphic high-grade sarcomas, which until recently was considered a mere academic exercise, is now undisputed. It is imperative to unequivocally differentiate sarcomas from non-sarcomatous, clearly defined malignancies to start adequate therapy. Furthermore, pleomorphic sarcomas which are particularly aggressive and prone to poor prognosis, have to be separated from sarcomas which, in contrast to the pleomorphic phenotype, are characterized by a less aggressive behavior. Also, morphologically pleomorphic but benign mesenchymal tumors must be recognized. Finally, it is important to promote the promising, array-based identification of diagnostic, prognostic and clinically relevant gene signatures on larger collections of pathomorphologically and clinically precisely defined subtypes of pleomorphic high-grade sarcomas.

DNA copy number changes in human malignant fibrous histiocytomas by array comparative genomic hybridisation.

BACKGROUND: Malignant fibrous histiocytomas (MFHs), or undifferentiated pleomorphic sarcomas, are in general high-grade tumours with extensive chromosomal aberrations. In order to identify recurrent chromosomal regions of gain and loss, as well as novel gene targets of potential importance for MFH development and/or progression, we have analysed DNA copy number changes in 33 MFHs using microarray-based comparative genomic hybridisation (array CGH). PRINCIPAL FINDINGS: In general, the tumours showed numerous gains and losses of large chromosomal regions. The most frequent minimal recurrent regions of gain were 1p33-p32.3, 1p31.3-p31.2 and 1p21.3 (all gained in 58% of the samples), as well as 1q21.2-q21.3 and 20q13.2 (both 55%). The most frequent minimal recurrent regions of loss were 10q25.3-q26.11, 13q13.3-q14.2 and 13q14.3-q21.1 (all lost in 64% of the samples), as well as 2q36.3-q37.2 (61%), 1q41 (55%) and 16q12.1-q12.2 (52%). Statistical analyses revealed that gain of 1p33-p32.3 and 1p21.3 was significantly associated with better patient survival (P = 0.021 and 0.046, respectively). Comparison with similar array CGH data from 44 leiomyosarcomas identified seven chromosomal regions; 1p36.32-p35.2, 1p21.3-p21.1, 1q32.1-q42.13, 2q14.1-q22.2, 4q33-q34.3, 6p25.1-p21.32 and 7p22.3-p13, which were significantly different in copy number between the MFHs and leiomyosarcomas. CONCLUSIONS: A number of recurrent regions of gain and loss have been identified, some of which were associated with better patient survival. Several specific chromosomal regions with significant differences in copy number between MFHs and leiomyosarcomas were identified, and these aberrations may be used as additional tools for the differential diagnosis of MFHs and leiomyosarcomas.

MFH classification: differentiating undifferentiated pleomorphic sarcoma in the 21st Century.

The essence and origin of malignant fibrous histiocytoma (MFH) have been debated for now close to five decades. Originally characterized as a morphologically unique soft-tissue sarcoma subtype of unclear etiology in 1963, with a following 15 years of research only to conclude that "the issue of histogenesis [of MFH] is largely unresolvable"; it is "now regarded as synonymous with [high grade] undifferentiated pleomorphic sarcoma and essentially represents a diagnosis of exclusion". Yet despite this apparent lack of progress, the first decade of the 21st century has seen some significant progress in terms of defining the origins of MFH. Perhaps more importantly these origins might also pave the way for novel therapies. This manuscript will highlight MFH's troubled history, discuss recent advances, and comment as to what the coming years may promise and what further needs to be done to make sure that progress continues.

Malignant fibrous histiocytoma: between the past and the present.

The precise nature and diagnostic concept of malignant fibrous histiocytoma (MFH) has been debated for years. Currently, a histiocytic lineage of the tumor cells is no longer favored. The nomenclature and classification of MFH and its subtypes have also been changed. The MFH pattern, especially that of storiform-pleomorphic variant, is viewed as a morphologic pattern shared by a number of sarcomas as well as by other nonsarcomas. Therefore, a diagnosis of MFH based solely on morphology is no longer acceptable and identification of a line of differentiation should be sought. A diagnosis of MFH should be made only for pleomorphic sarcomas in which no specific line of differentiation is discerned. Precise categorization of MFH-like tumors may require thorough sampling of the tumor and judicious use of immunohistochemistry and/or electron microscopy. Familiarity with the current terminology and classification of MFH and its subtypes is of paramount significance in the modern practice of pathology.

Fibrohistiocitoma maligno: localización cefálica como presentación poco frecuente / Malignant Fibrohistiocitoma: cephalic location as presentation little frequents

Los sarcomas de tejidos blandos son tumores malignos derivados del mesodermo.El fibrohistiocitoma maligno(FHM) es el más común de los sarcomas de tejidos blandos en adultos(20-25%),aunque no es común como tumor primario localizado en piel. La edad de presentación es entre los 50 y 70 años; dos tercios de ellos ocurren en hombres, siendo las personas de raza blanca las más afectadas. Comprometen por lo general raíz de miembros y tronco. La extremidad cefálica fue la localización de los pacientes de nuestra serie, sitio infrecuente según la literatura. El objetivo de este trabajo es presentar tres pacientes varones, dos con lesiones en cuero cabelludo y otro en pabellón auricular. Planteamos el concepto de forodaño como posible factor predisponente.

Diagnosis and management of pleomorphic sarcomas (so-called "MFH") in adults.

The existence of "malignant fibrous histiocytoma" ("MFH") as a distinct entity is controversial. Previously accepted as the most common sarcoma affecting adults, it is now known to comprise a heterogeneous group of tumors without a specific known line of differentiation. Reclassification of many tumors in this group afforded better prognostication, but traditional treatments still apply. Pleomorphic soft tissue tumors for which a line of differentiation is debatable are presently categorized as undifferentiated pleomorphic sarcoma.

Expression profiles in malignant fibrous histiocytomas: clues for differentiating 'spindle cell' and 'pleomorphic' subtypes.

We analysed 21 samples of malignant fibrous histiocytoma (MFH) distinguished into the two principal morphological categories ('spindle cell' and the 'pleomorphic' subtypes). The aim of our study was to verify if a distinction between the two subclasses of MFH in terms of expression/activation of protein profiles could support and extend the morphological criteria. For this purpose, we carried out an immunohistochemical and immunoblotting analysis of proteins that could be relevant in sarcoma biology and potential diagnostic and therapeutical targets such as matrix metalloproteinases (MMPs) and molecules related to adhesive and proliferative properties. Our analysis revealed that MMP-1, MMP-9 expression and p27(kip1) cytoplasmic localisation can be considered valid parameters in the classification and potential explanation of the aggressive behaviour of this non-homogeneous group of MFH.

Gene expression analysis of soft tissue sarcomas: characterization and reclassification of malignant fibrous histiocytoma.

In soft tissue sarcomas, the diagnosis of malignant fibrous histiocytoma (MFH) has been a very controversial issue, and MFH is now considered to be reclassified into pleomorphic subtypes of other sarcomas. To characterize MFH genetically, we used an oligonucleotide microarray to analyze gene expression in 105 samples from 10 types of soft tissue tumors. Spindle cell and pleomorphic sarcomas, such as dedifferentiated liposarcoma, myxofibrosarcoma, leiomyosarcoma, malignant peripheral nerve sheath tumor (MPNST), fibrosarcoma and MFH, showed similar gene expression patterns compared to other tumors. Samples from those five sarcoma types could be classified into respective clusters based on gene expression by excluding MFH samples. We calculated distances between MFH samples and other five sarcoma types (dedifferentiated liposarcoma, myxofibrosarcoma, leiomyosarcoma, MPNST and fibrosarcoma) based on differentially expressed genes and evaluated similarities. Three of the 21 MFH samples showed marked similarities to one of the five sarcoma types, which were supported by histological findings. Although most of the remaining 18 MFH samples showed little or no histological resemblance to one of the five sarcoma types, 12 of them showed moderate similarities in terms of gene expression. These results explain the heterogeneity of MFH and show that the majority of MFHs could be reclassified into pleomorphic subtypes of other sarcomas. Taken together, gene expression profiling could be a useful tool to unveil the difference in the underlying molecular backgrounds, which leads to a rational taxonomy and diagnosis of a diverse group of soft tissue sarcomas.