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Christopher Dm Fletcher - One of the best experts on this subject based on the ideXlab platform.
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Epithelioid fibrous Histiocytoma: molecular characterization of ALK fusion partners in 23 cases
Modern Pathology, 2018Co-Authors: Brendan C Dickson, David Swanson, George S Charames, Christopher Dm Fletcher, Jason L HornickAbstract:Epithelioid 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.
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ALK rearrangement and overexpression in epithelioid fibrous Histiocytoma
Modern Pathology, 2015Co-Authors: Leona A Doyle, Christopher Dm Fletcher, Adrián Mariño-enriquez, Jason L HornickAbstract:Epithelioid benign fibrous Histiocytoma, also known as ‘epithelioid cell Histiocytoma,’ has traditionally been considered a morphologic variant of cutaneous fibrous Histiocytoma (dermatofibroma). In addition to its characteristic epithelioid cytomorphology, several phenotypic differences suggest that epithelioid fibrous Histiocytoma may differ biologically from other variants. Recently, ALK rearrangement was described in two cases of epithelioid fibrous Histiocytoma and separately in two cases reported as ‘atypical’ fibrous Histiocytoma (with epithelioid features), with corresponding ALK expression detectable by immunohistochemistry. The goals of this study were to determine the frequency of ALK expression by immunohistochemistry in epithelioid fibrous Histiocytoma, to determine its value for the diagnosis of epithelioid fibrous Histiocytoma among variants and other histologic mimics, and to evaluate ALK gene rearrangement in epithelioid fibrous Histiocytoma. ALK protein expression was evaluated in whole tissue sections from 33 epithelioid fibrous Histiocytomas, 41 other cases of fibrous Histiocytoma (11 conventional and 10 each cellular, atypical, and aneurysmal types), 10 cutaneous syncytial myoepitheliomas, and 5 atypical fibroxanthomas, using a mouse anti-ALK monoclonal antibody. Fluorescence in situ hybridization (FISH) was performed using break-apart probes. In total, 29/33 (88%) cases of epithelioid fibrous Histiocytoma showed diffuse cytoplasmic ALK expression. Staining was moderate to strong in intensity in all cases except one, which showed diffuse weak expression. All other tumor types were negative for ALK expression. FISH demonstrated ALK rearrangement in all ALK-immunoreactive cases evaluated ( n =13), and not in one ALK expression-negative epithelioid fibrous Histiocytoma successfully examined. In conclusion, the majority of epithelioid fibrous Histiocytomas demonstrate ALK expression and ALK gene rearrangement. ALK expression is not seen in other variants of fibrous Histiocytoma, providing a useful diagnostic tool to distinguish epithelioid fibrous Histiocytoma from most histologic mimics. The expression of ALK suggests that epithelioid fibrous Histiocytoma is a biologically distinct tumor type, unrelated to conventional fibrous Histiocytoma and histologic variants.
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atypical fibrous Histiocytoma of the skin clinicopathologic analysis of 59 cases with evidence of infrequent metastasis
The American Journal of Surgical Pathology, 2002Co-Authors: Steven Kaddu, Mairin E Mcmenamin, Christopher Dm FletcherAbstract:Atypical fibrous Histiocytoma is an uncommon, poorly documented variant of cutaneous fibrous Histiocytoma. We studied 59 cases of atypical fibrous Histiocytoma to better characterize the clinicopathologic spectrum. There were 33 males and 26 females (median age 38 years; range 5-79 years) with solitary lesions arising on lower (25 cases) and upper (17 cases) extremities, trunk (6 cases), head and neck (4 cases), and vulva (1 case); anatomic location was not stated in six cases. Lesions measured 0.4-8 cm in diameter (median 1.5 cm) and clinically were nodules (40 cases), polypoid tumors (18 cases), or a slightly elevated plaque (1 case). Histologically, the lesions were primarily dermal with superficial involvement of the subcutis in one third of the cases. Salient features included a proliferation of pleomorphic, plump, spindle, and/or polyhedral cells with mainly large, hyperchromatic, irregular, or bizarre nuclei, set in a background of classic features of fibrous Histiocytoma, including spindle cell areas showing a storiform pattern and entrapped thickened, hyaline collagen bundles, especially at the periphery. Multinucleated giant cells, often with bizarre nuclei and foamy, sometimes hemosiderin-rich, cytoplasm were also variably present. The degree of pleomorphism varied from only focal and minimal (14 cases) or moderate (24 cases) to marked (21 cases). Mitotic activity was observed in 55 lesions, and the number of mitotic figures ranged from 1 to 15 per 10 high power fields. Atypical mitoses were noted in 20 lesions. Furthermore, some cases of atypical fibrous Histiocytoma displayed other worrisome features less often observed in ordinary FH, including unusually large size (diameter >2 cm, 8 cases), involvement of the superficial subcutis (19 cases), and geographic necrosis (7 cases). Immunohistochemical studies performed in 42 cases showed only focal smooth muscle actin (10 cases) and CD34 (4 cases) positivity, whereas CD68, S-100 protein, desmin, pan-keratin, and epithelial membrane antigen were negative. Clinical follow-up data available in 21 patients (mean duration of follow-up 50.6 months, median 43 months) revealed local recurrences in three patients (one repeated); two patients developed distant metastases, one of whom died after 96 months. These two cases were not histologically distinct from the group as a whole. We conclude that atypical fibrous Histiocytoma has a broader clinicopathologic spectrum than previously realized. Lesions with floridly atypical features represent potential pitfalls for overinterpretation as pleomorphic sarcoma, which would appear to be inappropriate in most cases. Provided that atypical fibrous Histiocytoma is treated by complete excision, a benign outcome is to be expected in most cases. However, similar to the cellular and aneurysmal variants of fibrous Histiocytoma, atypical fibrous Histiocytoma shows a higher tendency to recur locally than ordinary fibrous Histiocytoma and may rarely metastasize.
Ahmed A. Hidayat - One of the best experts on this subject based on the ideXlab platform.
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nonepithelial tumors of the lacrimal sac
American Journal of Ophthalmology, 1994Co-Authors: Jacob Peer, Mary A Stefanyszyn, Ahmed A. HidayatAbstract:Lacrimal sac tumors are rare and mostly of epithelial origin. We conducted a clinicopathologic study of 35 cases of nonepithelial tumors of the lacrimal sac. These tumors included 13 fibrous Histiocytomas, one hemangiopericytoma, one lipoma, ten lymphoid lesions, eight malignant melanomas, one granulocytic sarcoma, and one neurofibroma. Except for one 9-year-old child with fibrous Histiocytoma, all neoplasms involved adults (age range, 27 to 90 years). The most common initial signs and symptoms were epiphora, chronic inflammation, or lacrimal mass. A bloody nasal discharge and bleeding from the punctum occurred in a patient with malignant melanoma. In none of the patients was the clinical diagnosis of a lacrimal sac tumor made preoperatively. Some of the nonepithelial neoplasms of the lacrimal sac can be life-threatening; therefore, early diagnosis and treatment are important.
Jason L Hornick - One of the best experts on this subject based on the ideXlab platform.
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Epithelioid fibrous Histiocytoma: molecular characterization of ALK fusion partners in 23 cases
Modern Pathology, 2018Co-Authors: Brendan C Dickson, David Swanson, George S Charames, Christopher Dm Fletcher, Jason L HornickAbstract:Epithelioid 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.
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ALK rearrangement and overexpression in epithelioid fibrous Histiocytoma
Modern Pathology, 2015Co-Authors: Leona A Doyle, Christopher Dm Fletcher, Adrián Mariño-enriquez, Jason L HornickAbstract:Epithelioid benign fibrous Histiocytoma, also known as ‘epithelioid cell Histiocytoma,’ has traditionally been considered a morphologic variant of cutaneous fibrous Histiocytoma (dermatofibroma). In addition to its characteristic epithelioid cytomorphology, several phenotypic differences suggest that epithelioid fibrous Histiocytoma may differ biologically from other variants. Recently, ALK rearrangement was described in two cases of epithelioid fibrous Histiocytoma and separately in two cases reported as ‘atypical’ fibrous Histiocytoma (with epithelioid features), with corresponding ALK expression detectable by immunohistochemistry. The goals of this study were to determine the frequency of ALK expression by immunohistochemistry in epithelioid fibrous Histiocytoma, to determine its value for the diagnosis of epithelioid fibrous Histiocytoma among variants and other histologic mimics, and to evaluate ALK gene rearrangement in epithelioid fibrous Histiocytoma. ALK protein expression was evaluated in whole tissue sections from 33 epithelioid fibrous Histiocytomas, 41 other cases of fibrous Histiocytoma (11 conventional and 10 each cellular, atypical, and aneurysmal types), 10 cutaneous syncytial myoepitheliomas, and 5 atypical fibroxanthomas, using a mouse anti-ALK monoclonal antibody. Fluorescence in situ hybridization (FISH) was performed using break-apart probes. In total, 29/33 (88%) cases of epithelioid fibrous Histiocytoma showed diffuse cytoplasmic ALK expression. Staining was moderate to strong in intensity in all cases except one, which showed diffuse weak expression. All other tumor types were negative for ALK expression. FISH demonstrated ALK rearrangement in all ALK-immunoreactive cases evaluated ( n =13), and not in one ALK expression-negative epithelioid fibrous Histiocytoma successfully examined. In conclusion, the majority of epithelioid fibrous Histiocytomas demonstrate ALK expression and ALK gene rearrangement. ALK expression is not seen in other variants of fibrous Histiocytoma, providing a useful diagnostic tool to distinguish epithelioid fibrous Histiocytoma from most histologic mimics. The expression of ALK suggests that epithelioid fibrous Histiocytoma is a biologically distinct tumor type, unrelated to conventional fibrous Histiocytoma and histologic variants.
Sharon W Weiss - One of the best experts on this subject based on the ideXlab platform.
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angiomatoid malignant fibrous Histiocytoma a follow up study of 108 cases with evaluation of possible histologic predictors of outcome
The American Journal of Surgical Pathology, 1990Co-Authors: Michael J Costa, Sharon W WeissAbstract:Described by Enzinger in 1979, angiomatoid malignant fibrous Histiocytoma is a distinctive tumor of adolescence and early adult life characterized by sheets of relatively bland rounded or spindled cells separated by areas of cystic hemorrhage and surrounded by a prominent inflammatory infiltrate and often a fibrous pseudocapsule. On the basis of the original 41 cases, the tumor has been considered a low-grade malignancy. We are reporting the clinicopathologic findings and follow-up information of 108 new cases of angiomatoid malignant fibrous Histiocytoma to determine the long-term behavior of this tumor and whether various histologic features (atypia, mitoses, infiltrative borders, and inflammatory infiltrate) are useful in predicting outcome. Follow-up information was obtained in 94 (87%) cases. Local recurrences developed in 11 patients (12%), all of whom were cured by re-excision. The initial excision in all patients developing local recurrence appeared to be incomplete. Local recurrence was statistically associated with irregular tumor border and head and neck location. Five patients developed metastases. Four had only local metastases, which responded to surgery, whereas the fifth patient developed presumed pulmonary and cerebral metastases and died. The development of both local and distant metastases was correlated with invasion into the deep fascia or muscle but not to various histologic parameters such as mitotic rate and pleomorphism. We conclude that angiomatoid malignant fibrous Histiocytoma is intrinsically a low-grade tumor, and assessment of various histologic parameters or grading provides little or no additional prognostic information. Because death from disease occurred in only one patient (1%) in our series, it seems reasonable to reclassify angiomatoid malignant fibrous Histiocytoma with fibrohistiocytic tumors of intermediate malignancy rather than with the conventional malignant fibrous histocytoma, the majority of which are high-grade sarcomas.
Jeanmichel Coindre - One of the best experts on this subject based on the ideXlab platform.
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most malignant fibrous Histiocytomas developed in the retroperitoneum are dedifferentiated liposarcomas a review of 25 cases initially diagnosed as malignant fibrous Histiocytoma
Modern Pathology, 2003Co-Authors: Jeanmichel Coindre, Odette Mariani, Frederic Chibon, Aline Mairal, Nicolas De Saint Aubain Somerhausen, Elizabeth Favreguillevin, Eberhard Stoeckle, Isabelle Hostein, Alain AuriasAbstract:Forty-four samples from 25 cases of retroperitoneal sarcoma initially diagnosed as malignant fibrous Histiocytoma were histologically reviewed. Immunohistochemistry for mdm2 and cdk4 was performed on 20 cases. Comparative genomic hybridization was performed on 18 samples from 13 patients. Seventeen cases were reclassified as dedifferentiated liposarcoma. Twenty-one of 32 samples from these patients showed areas of well-differentiated liposarcoma, allowing the diagnosis of dedifferentiated liposarcoma. Immunohistochemistry performed in 15 of these cases showed positivity for mdm2 and cdk4. Comparative genomic hybridization analysis performed on 15 samples from 11 of these patients showed an amplification of the 12q13–15 region. Eight cases were reclassified as poorly differentiated sarcoma. Twelve samples from these patients showed no area of well-differentiated liposarcoma. Immunohistochemistry showed positivity for mdm2 and cdk4 in one of six of these patients and showed positivity for CD34 in another one. Comparative genomic hybridization analysis performed on three samples from two of these patients showed no amplification of the 12q13–15 region but showed complex profiles. This study shows that most so-called malignant fibrous Histiocytomas developed in the retroperitoneum are dedifferentiated liposarcoma and that a poorly differentiated sarcoma in this area should prompt extensive sampling to demonstrate a well-differentiated liposarcoma component, immunohistochemistry for mdm2 and cdk4, and if possible, a cytogenetic or a molecular biology analysis.
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metastasizing fibrous Histiocytoma of the skin a clinicopathologic and immunohistochemical analysis of three cases
Modern Pathology, 2000Co-Authors: Louis Guillou, Sandra Gebhard, Manuel Salmeron, Jeanmichel CoindreAbstract:The clinicopathologic and immunohistochemical features of three metastasizing fibrous Histiocytomas of the skin are presented. The first patient had a 1.3-cm nodule in the right thigh, with right inguinal lymph node metastases 19 years later. The second patient, who had a 3-cm nodule excised from his left thigh and inguinal lymph node metastasis after 4 months, had a favorable outcome 14 years after local radiotherapy and chemotherapy. The third had a 2-cm nodule in his neck, which recurred 16 months later. Four months later, cervical lymph node metastases were found. The patient was alive and well 26 months after initial surgery. All three primary skin tumors involved the dermis and subcutis, appeared well-delineated but nonencapsulated, were associated with some degree of epidermal hyperplasia, and showed features of aneurysmal/atypical or cellular fibrous Histiocytoma. The number of mitoses ranged from 6 to 11 per 10 high-power fields. Recurrences and metastases showed morphologic features similar to primary lesions. Tumor cells were positive, at least focally, for CD 68, Ki-M1p, and Factor XIIIa, and occasionally for smooth muscle actin. Desmin, CD 34, S-100 protein, and cytokeratin stainings were negative. Primary neoplasms, recurrences, and metastases showed a Mib-1 labeling index of 10% or less. Cellular, aneurysmal, and atypical (pseudosarcomatous) fibrous Histiocytomas of the skin can metastasize, yet they often show a protracted clinical course. Risk factors for metastatic dissemination include large size, high cellularity, aneurysmal changes, marked cellular pleomorphism, high mitotic activity, tumor necrosis, and repeated local recurrences.