Epithelioid Fibrous Histiocytoma Research Articles

A Rare Case of High grade Epithelioid Malignant Neoplasm with CAM 5.2 Expression and (EML4–ALK) Fusion in a Pediatric Patient

Abstract Introduction/Objective ALK (anaplastic lymphoma kinase) fusions have been identified in lymphomas and diverse cancer types including carcinomas, melanomas and mesenchymal neoplasms such as inflammatory myofibroblastic tumors (IMT), epithelioid fibrous histiocytoma (EFH). Herein we present a (non IMT, non EFH) ALK rearranged aggressive epithelioid neoplasm. Methods/Case Report We report a 17-year-old male with a 14.0 cm mediastinal mass and extensive metastatic disease involving brain, bones, pleura and lymph nodes. The tumor was made of epithelioid like cell with round nuclei, prominent nucleoli and a moderate amount of cytoplasm, arranged in a nested pattern. Ki-67 showed a high proliferative index, >70%. The tumor cells were positive for CAM 5.2; weakly positive for AE1/3, ALK, CD30; focally positive for p63, p53, S100. Additional stains including CD117, PLAP, OCT-4, Sall-4, glypican-3, synaptophysin, chromogranin, CK5/6, p40, pan-melanoma, myogenin, CD99, WT1, CD34, CD45, CD138, MUM1, CD2, CD4, CD5, CD3, CD7, CD15, CD23, CD31, CD20, CD79a, CD15, PAX8, PAX5, CD43, MPO, desmin, D2-40, Calretinin, ERG, SOX-10, PD-L1 and NUT-1 were all negative. Both BRG and INI1 were retained. The keratin positivity and the lack of “hallmark” cells made anaplastic large cell lymphoma (ALCL) less likely. The absence of desmin and CD30 excluded the rare epithelioid IMT sarcoma. Next-generation sequencing detected an (EML4–ALK) fusion. A diagnosis of high- grade epithelioid malignant neoplasm with (EML4–ALK) fusion was made. Most cases of this category were described as low grade-appearing spindled cells within a myxoid stroma arranged in fascicles (+S100, +CD34) and have unaggressive behavior. Only three cases, were characterized by epithelioid high- grade morphology and metastatic nature. They shared features like little collagenous stroma, conspicuous mitotic activity and tumor necrosis. Results (if a Case Study enter NA) NA Conclusion Identification of kinase fusions was essential for precise classification, better knowledge of this epithelioid high grade malignant neoplasm and for targeted therapy purposes. The significant clinicopathologic heterogeneity of this emerging group requires further investigation.

ALK-Rearranged Epithelioid Mesenchymal Neoplasm: Expanding the Spectrum of Tyrosine Kinase–Altered Mesenchymal Tumors

The anaplastic lymphoma kinase (ALK) gene encodes a receptor tyrosine kinase, and fusions involving this gene have been reported in a variety of mesenchymal neoplasms. ALK-altered tumors with epithelioid morphology have been described in epithelioid inflammatory myofibroblastic sarcoma and epithelioid fibrous histiocytoma. Herein, we describe the clinicopathologic features of 7 ALK-rearranged mesenchymal tumors with epithelioid morphology occurring predominately in the pediatric population. Tumors occurred in 4 females and 3 males with an age ranging from 1 month to 28 years. Five tumors were superficial and solitary, while 1 presented with multiple peritoneal/omental nodules, and 1 presented as a large mediastinal mass. Morphologically, all tumors comprised epithelioid cells arranged in sheets, anastomosing cords, or small clusters embedded in a myxohyaline stroma. The cells had slightly variably sized ovoid nuclei with moderately prominent nucleoli and abundant eosinophilic cytoplasm. Four cases had sparse mitotic figures without necrosis. The remaining 3 tumors (2 deep and 1 superficial) had more than 10 mitoses per 10 high-power fields as well as foci of necrosis. ALK fusions were identified in all cases. The fusion partners included HMBOX1 (n = 1), VCL (n = 1), PRRC2B (n = 1), MYH10 (n = 1), STRN (n = 1), and EML4 (n = 2). One tumor recurred locally 2 years after initial resection; 1 patient had widely metastatic disease (mediastinal tumor). At the time of last follow-up (n = 6), 4 patients were alive without evidence of disease, 1 died due to complications of therapy (peritoneal tumor), and 1 was alive with disease. Our findings expand the spectrum of ALK-rearranged mesenchymal tumors. Our cases predominately occurred in older children and mainly exhibited epithelioid to round cell morphology, as opposed to spindle cell morphology. We also show that tumors in a deep location with higher-grade features follow a more aggressive clinical course.

Gene fusions in superficial mesenchymal neoplasms: Emerging entities and useful diagnostic adjuncts.

Cutaneous mesenchymal neoplasms are diagnostically challenging because of their overlapping morphology, and, often, the limited tissue in skin biopsy specimens. Molecular and cytogenetic techniques have identified characteristic gene fusions in many of these tumor types, findings that have expanded our understanding of disease pathogenesis and motivated development of useful ancillary diagnostic tools. Here, we provide an update of new findings in tumor types that can occur in the skin and superficial subcutis, including dermatofibrosarcoma protuberans, benign fibrous histiocytoma, epithelioid fibrous histiocytoma, angiomatoid fibrous histiocytoma, glomus tumor, myopericytoma/myofibroma, non-neural granular cell tumor, CIC-rearranged sarcoma, hybrid schwannoma/perineurioma, and clear cell sarcoma. We also discuss recently described and emerging tumor types that can occur in superficial locations and that harbor gene fusions, including nested glomoid neoplasm with GLI1 alterations, clear cell tumor with melanocytic differentiation and ACTIN::MITF translocation, melanocytic tumor with CRTC1::TRIM11 fusion, EWSR1::SMAD3-rearranged fibroblastic tumor, PLAG1-rearranged fibroblastic tumor, and superficial ALK-rearranged myxoid spindle cell neoplasm. When possible, we discuss how fusion events mediate the pathogenesis of these tumor types, and we also discuss the related diagnostic and therapeutic implications of these events.

Epithelioid Fibrous Histiocytoma with CARS-ALK Fusion: First Case Report

Epithelioid fibrous histiocytoma (EFH) is a type of uncommon skin tumor mostly harboring Anaplastic Lymphoma Kinase (ALK) gene rearrangement, with different fusion partners reported. Whether this tumor is a separate entity or has a relationship with conventional fibrous histiocytomas is still a matter of debate. Benign course is the rule after complete surgical excision. A rare subtype of EFH with fusiform cells has been described, with specific fusion partners. Inflammatory myofibroblastic tumor (IMT) is a type of soft tissue tumor rarer than EFH, and it can display distant metastases. Some cases of primary cutaneous IMT included two with Cysteinyl-tRNA Synthetase 1 (CARS)-ALK rearrangement. IMT can have the same fusion partners as EFH, such as DCTN1, TMP3 or EML4 genes. We report the case of a 42-year-old woman presenting EFH with fusiform morphology harboring CARS-ALK fusion and discuss similarities and differences with IMT.

Epithelioid fibrous histiocytoma: three diagnostically challenging cases with novel ALK gene fusions, unusual storiform growth pattern, and a prominent spindled morphology.

Epithelioid fibrous histiocytoma (EFH) is a distinctive cutaneous neoplasm with a relatively variable morphological appearance. Recently, it has been shown that this tumor is molecularly characterized by ALK gene fusions. We report three EFHs with unusual histological presentation represented by a prominent/predominant spindle cell proliferation arranged in a variably storiform/whirling architectural pattern with or without stromal sclerosis. One of the cases closely resembled cellular fibrous histiocytoma. All three cases were immunohistochemically ALK-positive and were analyzed for ALK gene rearrangements using a next-generation sequencing-based assay (FusionPlex Sarcoma Kit, ArcherDx). Three novel fusions, namely AP3D1::ALK, COL1A::ALK, and LRRFIP2::ALK, were detected and further confirmed by FISH in all 3 cases and RT-PCR in 1 case. All patients were elderly (62-63years) and presented with a solitary polypoid lesion on the extremities. The awareness of these morphological variants is important since it entertains a wide and slightly different differential diagnosis than conventional EFH. We also presented evidence that a clear separation of EFH from BFH in all cases may not be as straightforward as previously thought. The consistent ALK immunoexpression and the continually expanding scale of ALK gene rearrangements provide a useful tool to distinguish EFH from its histologic mimics.

Molecular investigation of ALK-rearranged epithelioid fibrous histiocytomas identifies CLTC as a novel fusion partner and evidence of fusion-independent transcription activation.

Epithelioid fibrous histiocytoma (EFH) is a rare cutaneous neoplasm, which is characterized by the presence of rearrangements involving the ALK gene. Although EFH was long considered a variant of fibrous histiocytoma, the identification of its unique genetic signature confirmed that it represents a distinct entity. The aim of the present study was to examine a cohort of ALK-immunoreactive EFH cases to further characterize gene fusion partners. Next generation sequencing detected ALK fusions in 11 EFH cases identified in the pathology archives of two different institutions. The most common fusion partner was DCTN1 (N=4) followed by CLTC (N=2) and VCL (N=2), while the remaining cases harbored fusions involving SPECC1L, PPFIBP1, and PRKAR1A. In one case no fusion was detected by NGS and FISH despite suitable sample quality. Notably, IHC demonstrated positive ALK expression and the level of aligned ALK reads was comparable to the fusion-positive cases. To the best of our knowledge, this is the first report of CLTC as a fusion partner in EFH. The two CLTC rearranged cases in our cohort also represent the first two EFH cases in the literature that involve exon 19 of ALK, instead of exon 20. These findings underscore the remarkable plasticity of ALK as an oncogenic driver and further expand the list of its potential fusion partners in EFH. Lastly this is also the first report of ALK-immunoreactive EFH with no underlying fusion suggesting a fusion independent transcription mechanism as seen in other tumors.

Recent advances in the diagnosis, classification and molecular pathogenesis of cutaneous mesenchymal neoplasms.

The diagnosis of cutaneous mesenchymal neoplasms remains challenging, due to a combination of overlapping histological features, the rarity of some diagnoses and often inadequate sampling in superficial biopsies. Here, we describe recent advances in cutaneous mesenchymal neoplasms. We discuss improvements in our understanding of the molecular pathogenesis of non-neural granular cell tumour, epithelioid fibrous histiocytoma, composite and retiform haemangioendothelioma and dermatofibrosarcoma protuberans. We also discuss recently described tumour types, including some discovered via molecular testing: EWSR1::SMAD3-rearranged fibroblastic tumour, clear cell neoplasm with MITF::CREM rearrangement and melanocytoma with CRCT1::TRIM11 rearrangement, and some discovered via traditional histopathology: superficial CD34-positive fibroblastic tumour, plexiform myofibroblastoma and clear cell neoplasm with melanocytic differentiation and ACTIN::MITF translocation.

Analyzing the morphological spectrum of epithelioid fibrous histiocytoma and the immunohistochemical performance of the ALK D5F3 and ALK1 clones

Epithelioid fibrous histiocytoma (EFH) is a cutaneous neoplasm driven by translocations of the anaplastic lymphoma kinase (ALK) gene, which can be demonstrated by immunohistochemical (IHC) analysis. We analyzed the performance of two ALK clones, D5F3 and ALK1, in a cohort of EFHs and described the range of architectural variation of these lesions. TFE3 IHC was performed in ALK-negative EFHs. We identified 21 cases of EFH, 76.2% of which showed an exophytic appearance and 19% displayed flat architecture. A well-developed epidermal collarette was present in 48% of all cases with just more than a third of all the exophytic lesions presenting as dermal-based nodules. ALK D5F3 expression was identified in 76.2% (16/21) of all cases, but only 68.8% were concordantly positive with the ALK1 clone, indicative of a false-negative stain with ALK1 in 31.2% of the cases. For the subset of cases showing positivity for the ALK1 clone, a marked decrease in the percentage of immunolabelled cells was identified when compared with D5F3 (5-50% vs. 100%, respectively). Five cases (23.8%) did not demonstrate ALK expression for either clone, with 3 of those cases showing nuclear positivity for TFE3 IHCand the remaining 2 cases being double negative (ALK-/TFE3-). In summary, we identified that the prototypically described exophytic appearance with epidermal collarette is present in only less than half of the cases. We also demonstrated that the ALK1 antibody is suboptimal in EFH and should not be utilized in this setting. A subset of ALK-negative cases express TFE3, but double-negative cases occur.

Immunohistochemical analysis of epithelioid fibrous histiocytoma: a study of 16 cases

Immunohistochemical analysis of epithelioid fibrous histiocytoma: a study of 16 cases

Superficial ALK-rearranged myxoid spindle cell neoplasm: a cutaneous soft tissue tumor with distinctive morphology and immunophenotypic profile.

Gene rearrangements involving the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase gene have been identified in various neoplasms, including inflammatory myofibroblastic tumor and epithelioid fibrous histiocytoma. We present an ALK-rearranged cutaneous soft tissue tumor with unique morphologic and immunophenotypic features that are not shared by other entities with ALK rearrangements. The six cases involved two females and four males, aged 18-84 (mean 51) years old. Three tumors were on the back and three on the lower extremities (thigh, knee, shin); ranging from 0.5 to 5.6 (mean 2.1) cm. Four were confined to the dermis; two involved the subcutis. All six cases were characterized by the presence of spindled to ovoid cells arranged in concentric whorls and cords against a myxoid to myxohyaline stroma and relatively cellular aggregates of plump ovoid to epithelioid cells. Four cases showed distinct hyalinized blood vessels. Both cases that involved the subcutis showed peripheral lipofibromatosis-like areas. Tumor-infiltrating lymphocytes were absent to moderate. Severe cytologic atypia or conspicuous mitotic activity was not identified. Immunohistochemically, all tumors diffusely expressed ALK (D5F3) and CD34. All but one tumor was diffusely positive for S100 protein. All tumors were negative for EMA, AE1/AE3, SMA, and SOX10. Next-generation sequencing revealed ALK fusions with FLNA (3 cases), MYH10 (2 cases), and HMBOX1 (1 case) as the partner genes. In all six cases, the breakpoints involved exon 20 of ALK, which preserves the receptor tyrosine kinase domains of ALK in the fusion product. Of the four cases with limited follow-up information (2-18 months), none recurred. In conclusion, we report an ALK-rearranged cutaneous soft tissue tumor characterized by the presence of myxoid spindle cell whorls and cords, and co-expression of ALK, CD34, and frequently S100 protein, we term "superficial ALK-rearranged myxoid spindle cell neoplasm".

Spindle cell variant of epithelioid cell histiocytoma (spindle cell histiocytoma) with ALK gene fusions: Cases series and review of the literature.

Epithelioid fibrous histiocytoma (EFH) is an uncommon dermal neoplasm expressing anaplastic lymphoma kinase (ALK) protein. Rarely a histopathological variant of this entity exhibits exclusively spindle cells. We report three cases of EFH that do not completely fulfill phenotypic criteria featuring spindle cell morphology and expressing ALK protein. We also analyze the fusion partner genes rearranged with ALK in these cases. ALK expression and rearrangement status were evaluated by immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and next generation sequencing based gene fusion analysis. Three cases, all from females between 25 and 55 years old, have been biopsied from back, left arm, and thumb. All three cases showed tumor with exclusively spindle cell morphology without any epithelioid cells. The tumor cells exhibited strong ALK expression by IHC and FISH study confirmed ALK gene rearrangement in all three cases. DCTN1-ALK fusion was identified in two cases. EFH is not always purely epithelioid and its spindled cell variant, spindle cell histiocytoma, should be included in the differential diagnosis of superficial dermal spindled cell neoplasms. ALK immunostain is a useful diagnostic marker for this entity and further studies may be useful to investigate whether DCTN1-ALK fusion mutations are specific to EFH with spindled cell features.

Fibrous histiocytoma/dermatofibroma in children: the same as adults?

Fibrous histiocytoma (FH) or dermatofibroma is a common cutaneous lesionmostly seen in adults and rare in the first two years of life. Two hundred sixty-seven patients younger than 18 years with a diagnosis of FH or dermatomyofibroma, a lesion with morphologic overlap with FH, were identified from the files of a single institution, with only 13 (4.8%) occurring in patients younger than 5 years. Ten patients had either underlying neurologic, autoimmune, or metabolic disorders or a family history of autoimmune conditions. Histologic review of hematoxylin and eosin staining and immunostaining on 75 FHs and dermatomyofibroma in 70 patients showed the following results: 33 classic FHs, 8 classic FHs characterized by a peculiar retiform morphology with thin fascicles of elongated cells forming a network reminiscent of the eruptive variant of FH, 19 deep/cellular variants, 5 aneurysmal variants, 3 lipidized variants (including two lesions in a patient affected by mucopolysaccharidosis IV), 3 dermatomyofibromas, and 4 isolated cases of hemosiderotic, granular cell atypical, and epithelioid FH. Immunostaining for factor XIIIa highlighted a dense network of dendritic cells in FH, which was significantly reduced in the FH with retiform morphology. Smooth muscle actin staining was positive in a high percentage of FHs (85.3%). The current series demonstrates that FH in children may show unique clinical and morphologic features. The retiform pattern with decreased dendritic cells found in congenital lesions and in two older patients with lesions in two locations might have a different pathogenesis, probably related to an altered immune response in very young patients.

Epithelioid Fibrous Histiocytoma: A Concise Review.

Epithelioid fibrous histiocytoma (EFH) is a rare lesion believed to arise from dermal microvascular unit fibroblasts and dendritic histiocytes. EFH has long been considered a morphologic variant of benign fibrous histiocytoma (dermatofibroma), with prominent epithelioid cytomorphology that can mimic both vascular and melanocytic neoplasms. The molecular basis for the relationship between EFH and benign fibrous histiocytoma has remained largely unknown, with some authors suggesting that EFH represents an entity that is biologically distinct from benign fibrous histiocytoma. Recent molecular studies have identified the presence of recurrent anaplastic lymphoma kinase (ALK) gene rearrangements, a phenomenon that has not been described in benign fibrous histiocytoma. These new molecular findings highlight the uniqueness of this rare tumor and may prove useful as a diagnostic tool for differentiation from other histologic mimics.

Cutaneous soft tissue tumors: how do we make sense of fibrous and "fibrohistiocytic" tumors with confusing names and similar appearances?

In the 2018 World Health Organization Classification of Skin Tumors, a wide range of predominantly benign mesenchymal neoplasms are included in the fibroblastic, myofibroblastic, and "fibrohistiocytic" categories. By far the most common of these tumors is dermatofibroma (fibrous histiocytoma). There are many histologic variants of dermatofibroma, some of which (cellular, aneurysmal, and atypical) are associated with a higher risk of local recurrence; these variants may be mistaken for more aggressive tumor types, including sarcomas. Furthermore, distinguishing among the fibrous and "fibrohistiocytic" tumors can be a diagnostic challenge, given their sometimes-similar histologic appearances and confusing nomenclature. Immunohistochemistry and molecular genetic assays play a relatively limited role in the diagnosis of these tumor types, with notable exceptions (i.e., epithelioid fibrous histiocytoma and dermatofibrosarcoma protuberans). Proper recognition of dermatofibrosarcoma protuberans is critical, since this tumor type is associated with locally aggressive behavior; transformation to the fibrosarcomatous variant brings metastatic potential. In recent years, understanding of the molecular pathogenetic basis for cutaneous mesenchymal neoplasms has increased dramatically, with the discovery of gene rearrangements in some of these tumor types. In this review, the histologic features of the most common fibrous and "fibrohistiocytic" cutaneous mesenchymal neoplasms will be discussed, as well as recently identified molecular genetic alterations.

ALK Gene Fusions in Epithelioid Fibrous Histiocytoma: A Study of 14 Cases, With New Histopathological Findings.

Previous studies showed that ALK is often positive in epithelioid fibrous histiocytoma (EFH). Two cases of EFH with ALK gene fusions have been recorded. Our objective was to study a series of EFH to present histopathological variations of EFH, identify novel ALK gene fusions, and determine whether there is a correlation between histopathological features and particular gene. We investigated 14 cases of EFH, all ALK immunopositive. The cases were assessed histopathologically as well as for ALK and TFE-3 rearrangements using FISH and ALK gene fusions using next-generation sequencing. The analysis of the sequencing results was performed using the Archer Analysis software (v5; ArcherDX Inc). The study group consisted of 8 female and 6 male patients, ranging in age from 18 to 79 years (mean 42 years; median 37.5 years). All presented with a solitary lesion. Microscopically, most lesions were polypoid and composed of epithelioid cells with ample cytoplasm. In addition, a variable number of bi-, tri-, or multinucleated, spindled, multilobated, cells with eccentric nuclei, cells with nuclear pseudoinclusions, mucinous, and grooved cells were admixed. In 5 cases, the predominant epithelioid cell component consisted of rather small cells, whereas spindled cells dominated in 3 cases. Of these, 2 lesions were composed rather of pale eosinophilic to clear cells, occasioning a resemblance to PEComa or leiomyoma. Immunohistochemically, all cases expressed ALK and 11 were positive for TFE-3. The break apart test for ALK was positive in 11 cases, whereas specimens from the remaining 3 cases were not analyzable. ALK genes fusions were found in all but 3 cases and included SQSTM1-ALK (3), VCL-ALK (3), TMP3-ALK (2), PRKAR2A-ALK (1), MLPH-ALK (1), and EML4-ALK (1). No correlation between histological features and type of ALK fusion was found. TFE-3 break apart test was negative. It is concluded that ALK-immunopositive EFH shows ALK gene fusions that involve various protein-coding genes, implicated in a variety of biological processes. Rare variants of EFH rather consist of spindled "non-epithelioid" cells.

Microphthalmia-associated transcription factor (MiTF): Promiscuous staining patterns in fibrohistiocytic lesions is a potential pitfall

Microphthalmia-associated transcription factor (MiTF) is used as a marker of melanocytic differentiation. However, MiTF immunoexpression has also been observed in histiocytes, macrophages, smooth muscle cells and fibroblasts, which raise the concern of fibrohistiocytic (FH) lesions being misdiagnosed as melanoma based on MiTF immunoreactivity. MiTF has been known to be positive in FH tumors, but this is the first study evaluating ninety-three fibrohistiocytic neoplasms to understand and delineate the staining pattern of MiTF in these tumors. Ninety-three cases of FH, 30 cases of melanocytic lesions, and 20 miscellaneous cases were studied. The FH cases included benign fibrous histiocytoma (BFH, n = 29), angiofibroma (AF, n = 11), fibromatosis (FM, n = 14), keloid (KE, n = 10), atypical fibroxanthoma (AFX, n = 7), dermal scar (DS, n = 9), dermatofibrosarcoma protuberans (DFSP, n = 12), and pigmented DFSP (Bednar tumor, n = 1). Benign fibrous histiocytoma were sub-categorized into dermatofibroma (n = 15) and epithelioid fibrous histiocytoma (n = 14). The melanocytic lesions included desmoplastic melanoma (DM, n = 8), melanoma in-situ (MIS, n = 5), re-excision-free of melanoma (RFM, n = 10), blue nevus (BN, n = 5), and spitz nevus (SN, n = 3). The miscellaneous category included osteosarcoma (OS, n = 3), pigmented basal cell carcinoma (PBCC, n = 5), spindle cell squamous cell carcinoma (SCA, n = 2), and giant cell tumor of tendon sheath (GCTTS, n = 10). All BFH, AF, AFX, KE, and DS cases showed a positive MiTF staining of variable extent and intensity. MiTF positivity was observed in 86% (n = 12) cases of FM and 17% (n = 2) cases of DFSP. Amongst the miscellaneous category, all cases of PBCC and GCTTS and 50% (n = 1) cases of SCA were immunoreactive for MiTF. All melanocytic lesions were positive for MiTF. None of the OS and pigmented DFSP showed positive labeling. Because of the promiscuity of MiTF labeling, awareness of its pattern in FH proliferations may avoid potential pitfalls in the diagnosis of spindle cell lesions.

Epithelioid cell histiocytoma with SQSTM1-ALK fusion: a case report

BackgroundEpithelioid cell histiocytoma (ECH), which is also known as epithelioid benign fibrous histiocytoma, has been classified as a rare variant of fibrous histiocytoma (FH). However, the recent detection of ALK protein expression and/or ALK gene rearrangement in ECH suggests that it might be biologically different from conventional FH.Case presentationA 27-year-old male presented with nodule on his left foot, which had been present for 5 years. A macroscopic examination revealed an exophytic, hyperkeratotic nodule on the dorsum of the left foot. Tumorectomy was performed, and a microscopic examination showed a subepidermal lesion composed of sheets of tumor cells with oval to round nuclei and ill-defined eosinophilic cytoplasm. The tumor cells were diffusely positive for factor XIIIa and ALK, but were negative for AE1/AE3 keratin, alpha-smooth muscle actin, CD30, CD34, CD68, PU.1, melan A, MITF, and S-100 protein. ALK immunostaining showed a diffuse cytoplasmic staining pattern. ALK fluorescence in situ hybridization demonstrated break-apart signals, which was suggestive of ALK rearrangement. A 5′-rapid amplification of cDNA ends assay detected SQSTM1-ALK fusion, in which exon 5 of the SQSTM1 gene was fused to exon 20 of the ALK gene. The patient was free from recurrence and distant metastasis at the 1-year of follow-up.ConclusionWe were able to demonstrate the SQSTM1-ALK fusion gene in ECH. Practically, detecting immunopositivity for ALK and appropriate cell-lineage markers are the key to diagnosing ECH.

Epithelioid fibrous histiocytoma: molecular characterization of ALK fusion partners in 23 cases

AbstractEpithelioid fibrous histiocytoma is a rare and distinctive cutaneous neoplasm. Most cases harbor ALK rearrangement and show ALK overexpression, which distinguish this neoplasm from conventional cutaneous fibrous histiocytoma and variants. SQSTM1 and VCL have previously been shown to partner with ALK in one case each of epithelioid fibrous histiocytoma. The purpose of this study was to examine a large cohort of epithelioid fibrous histiocytomas by next-generation sequencing to characterize the nature and prevalence of ALK fusion partners. A retrospective archival review was performed to identify cases of epithelioid fibrous histiocytoma (2012–2016). Immunohistochemistry was performed to confirm ALK expression. Targeted next-generation sequencing was applied on RNA extracted from formalin-fixed paraffin-embedded tissue to identify the fusion partners. Twenty-three cases fulfilled inclusion criteria. The mean patient age was 39 years (range, 8–74), there was no sex predilection, and >75% of cases involved the lower extremities. The most common gene fusions were SQSTM1-ALK (N=12; 52%) and VCL-ALK (N=7; 30%); the other four cases harbored novel fusion partners (DCTN1, ETV6, PPFIBP1, and SPECC1L). The pattern of ALK immunoreactivity was usually granular cytoplasmic (N=12; 52%) or granular cytoplasmic and nuclear (N=10; 43%); the case containing an ETV6 fusion partner showed nuclear staining alone. There was no apparent relationship between tumor morphology and the ALK fusion partner. In summary, SQSTM1 and VCL are the most common ALK fusion partners in epithelioid fibrous histiocytoma; DCTN1, ETV6, PPFIBP1, and SPECC1L represent rare fusion partners. The proteins encoded by these genes play diverse roles in scaffolding, cell adhesion, signaling, and transcription (among others) without clear commonalities. These findings expand the oncogenic promiscuity of many of these ALK fusion genes, which drive neoplasia in tumors of diverse lineages with widely varied clinical behavior. This is the first documented account of ETV6-ALK and SPECC1L-ALK translocations in neoplasms.

Anaplastic Lymphoma Kinase in Cutaneous Malignancies.

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that has been implicated in the pathogenesis of a variety of neoplasms. As suggested by its name, ALK was first described as part of a translocation product in cases of anaplastic large-cell lymphoma, with other genetic and cytogenetic ALK mutations subsequently coming to attention in the development of many other hematologic and solid organ malignancies. ALK has now been shown to play a role in the pathogenesis of several cutaneous malignancies, including secondary cutaneous systemic anaplastic large-cell lymphoma (ALCL) and primary cutaneous ALCL, melanoma, spitzoid tumors, epithelioid fibrous histiocytoma, Merkel cell carcinoma, and basal cell carcinoma. The characterization of ALK-positivity in these cutaneous malignancies presents exciting opportunities for utilizing ALK-targeted inhibitors in the treatment of these diseases.

Advances in the clinicopathological and molecular classification of cutaneous mesenchymal neoplasms.

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.