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It is now understood that identical gene fusions may be shared by different entities. We report a distinctive neoplasm of the skin and subcutis, harboring the Ewing sarcoma-associated EWSR1::FLI1 fusion but differing otherwise from Ewing sarcoma. Slides and blocks for 5 cutaneous neoplasms coded as other than Ewing sarcoma and harboring EWSR1::FLI1 were retrieved. Immunohistochemical and molecular genetic results were abstracted from reports. Methylation profiling was performed. Clinical information was obtained. The tumors occurred in 4 men and 1 woman (median: 25 years of age; range: 19-69 years) and involved the skin/subcutis of the back (2), thigh, buttock, and chest wall (median: 2.4 cm; range: 1-11 cm). Two tumors were present "years" before coming to clinical attention. The lesions were multinodular and circumscribed and consisted of nests of bland, round cells admixed with hyalinized collagenous bands containing spindled cells. Hemorrhage and cystic change were often present; necrosis was absent. All were diffusely S100 protein/SOX10-positive; 4 of 5 were CD99-negative. One tested case was strongly positive for NKX2.2. A variety of other tested markers were either focally positive (glial fibrillary acidic protein, p63) or negative. Molecular genetic results were as follows: EWSR1 exon 7::FLI1 exon 8, EWSR1 exon 11::FLI1 exon 5, EWSR1 exon 11::FLI1 exon 6, EWSR1 exon 7::FLI1 exon 6, and EWSR1 exon 10::FLI1 exon 6. Methylation profiling (3 cases) showed these to form a unique cluster, distinct from Ewing sarcoma. All patients underwent excision with negative margins; one received 1 cycle of chemotherapy. Clinical follow-up showed all patients to be alive without disease (median: 17 months; range: 11-62 months). Despite similar gene fusions, the morphologic, immunohistochemical, epigenetic, and clinical features of these unique EWSR1::FLI1-fused neoplasms of the skin and subcutis differ substantially from Ewing sarcoma. Interestingly, EWSR1 rearrangements involved exons 10 or 11, only rarely seen in Ewing sarcoma, in a majority of cases. Superficial neurocristic EWSR1::FLI1 fusion tumors should be rigorously distinguished from true cutaneous Ewing sarcomas.
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Biomarcadores Tumorais , Proteína Homeobox Nkx-2.2 , Proteínas de Fusão Oncogênica , Proteínas S100 , Fatores de Transcrição SOXE , Neoplasias Cutâneas , Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , Idoso , Adulto Jovem , Biomarcadores Tumorais/genética , Fatores de Transcrição SOXE/genética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Proteínas S100/genética , Proteínas S100/metabolismo , Sarcoma de Ewing/genética , Sarcoma de Ewing/patologia , Proteína EWS de Ligação a RNA/genética , Fatores de Transcrição/genética , Imuno-Histoquímica , Proteína Proto-Oncogênica c-fli-1/genética , Metilação de DNA , Proteínas de Ligação a RNA/genética , Proteínas Nucleares , Proteínas de Homeodomínio , Proteínas de Peixe-ZebraRESUMO
We recently described novel dermal tumors with melanocytic differentiation and morphologic and biological similarities to cutaneous clear cell sarcoma, including CRTC1::TRIM11 cutaneous tumor, and clear cell tumors with melanocytic differentiation and either ACTIN::MITF or MITF::CREM. Here, we describe a series of 3 patients presenting with tumors reminiscent of CRTC1::TRIM11 cutaneous tumor, found to demonstrate a novel MED15::ATF1 fusion. All 3 patients were children (5-16 years old). Primary excision of case 1 showed a circumscribed wedge-shaped silhouette with peripheral intercalation into collagen fibers and scattered lymphoid aggregates. All 3 tumors abutted the epidermis; one showed a junctional component. Tumors were highly cellular and comprised of monomorphic, oval-to-round epithelioid cells arranged in vague nests and short fascicles in variably fibrotic stroma. Mitotic rate was high (hotspot 6-12/mm2), without atypical mitoses. Necrosis was focally present in case 3. All cases showed strong, diffuse nuclear staining for SOX10 and MITF (2/2) but showed variable expression for S100 protein (1/3) and other melanocytic markers-Melan-A (focal in 2/3), HMB45 (focal in 1/3), and Pan-Melanoma (patchy in 1/1). Whole-exome RNA sequencing demonstrated a MED15::ATF1 fusion without any other notable alterations. Cases 1 and 2 were completely excised without recurrence (12 months). Case 3 developed a grossly apparent regional lymph node spread shortly after primary biopsy. The patient was treated with wide excision, radiation, cervical lymph node dissection (4/46 with >75% lymph node replacement), and neoadjuvant and adjuvant nivolumab (alive without disease at cycle 11). This series is presented to aid in future diagnosis of this novel dermal tumor with melanocytic differentiation and emphasize the potential for aggressive biologic behavior, which should be considered in patient management planning.
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Melanoma , Sarcoma de Células Claras , Neoplasias Cutâneas , Adolescente , Criança , Pré-Escolar , Humanos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Complexo Mediador , Melanoma/diagnóstico , Sarcoma de Células Claras/diagnóstico , Sarcoma de Células Claras/genética , Sarcoma de Células Claras/patologia , Neoplasias Cutâneas/patologia , Fatores de Transcrição/genética , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/genéticaRESUMO
Acral fibrochondromyxoid tumor (AFCMT) is a recently described likely benign mesenchymal neoplasm arising in the distal extremities with distinctive histologic features and a recurrent THBS1::ADGRF5 fusion. We studied an additional 37 cases of AFCMT and expanded on the so-far reported clinicopathologic and molecular findings. Tumors occurred in 21 females and 16 males, ranging in age from 17-78 years (median age: 47), and solely involved the hands (24/37, 65%) or feet (13/37, 35%). Histologic examination revealed well-delineated uni- or multinodular tumors with prominent vasculature-rich septa and bland, chondrocyte-like tumor cells set within abundant chondromyxoid stroma. Immunohistochemical studies showed tumor cells were positive for CD34 (25/27; 93%) and ERG (27/27; 100%), while negative for S100 protein (0/31). Molecular analysis revealed evidence of a THBS1::ADGRF5 fusion in 17 of 19 (89%) successfully tested tumors. Clinical follow-up was available in 8 cases (median: 97 months), with multiple local recurrences in 1 case at 276, 312, and 360 months. We conclude that AFCMT is a distinct entity with reproducible morphologic, immunohistochemical, and molecular genetic features that should be differentiated from other similar appearing acral mesenchymal neoplasms.
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AIMS: The majority of dermatofibrosarcoma protuberans (DFSP) harbour PDGFB or PDGFD rearrangements. We encountered ALK expression/rearrangement in a PDGFB/D-negative CD34-positive spindle cell neoplasm with features similar to DFSP, prompting evaluation of ALK-rearrangements in DFSP and plaque-like CD34-positive dermal fibroma (P-LDF). METHODS AND RESULTS: We searched the archives of academic institutions for cases previously coded as DFSP and P-LDF. NGS-naïve or PDGFB-negative DFSP were screened for ALK (clone D5F3) expression by immunohistochemistry. NGS or ALK FISH was performed on ALK-positive cases. Methylome profiling studies were performed and compared with conventional DFSP. One case of "DFSP" and two "P-LDF" with ALK expression were identified from the archives, while four cases were detected prospectively. These seven cases (6F:1M; 8 months to 76 years) arose in the dermis of the arm (two), scalp, eyelid, thigh, abdomen, and shoulder and ranged from 0.4 to 4.2 cm. Tumours were composed of spindled cells and displayed a storiform growth pattern. Cytologic atypia was absent, and mitotic figures were scarce (0-2/10 HPFs, high power fields). The lesional cells were diffusely positive for CD34 and ALK and negative for S100 protein. By NGS (n = 5), ALK fusion partners included DCTN1 (2), PLEKHH2, and CLIP2 in DFSP-like cases and FLNA in P-LDF-like lesions. ALK FISH was positive in one (of two) cases previously labelled P-LDF. Methylome profiling of two (of three) ALK-rearranged DFSP-like tumours showed clustering with conventional DFSP in the UMAP dimension reduction plot. To date, no tumour has recurred (n = 2; 26, 27 months). CONCLUSION: We describe a cohort of novel ALK-rearranged tumours with morphologic features similar to DFSP.
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Crystal-storing histiocytosis (CSH) is a rare condition in which crystals accumulate in the cytoplasm of histiocytes and is usually associated with a lymphoplasmacytic neoplasm. Cutaneous CSH is extraordinarily rare and limited to case reports in the literature. We report two cases of this disease with cutaneous involvement. Case 1 was a 65-year-old male with a 4-month history of a pruritic eruption that started as a solitary pink to skin-colored indurated plaque on the anterior neck before progressing to involve the whole neck, chest wall, and face. Case 2 was a 54-year-old woman with a history of unspecified "lymphoma" who presented with a soft nodule on the forearm. Biopsies from both cases had similar findings and showed a proliferation of epithelioid cells with pink cytoplasm and intracellular crystalline structures infiltrating the dermis and subcutaneous fat. In the first case, the cells were positive for CD43, CD45, CD68, and IgG kappa, and in the second case, the crystals were positive for IgG lambda. Based on these findings, the patients were diagnosed with cutaneous CSH. We highlight this rare diagnosis and the importance of investigating an underlying lymphoplasmacytic neoplasm.
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Histiocitose , Humanos , Idoso , Masculino , Feminino , Histiocitose/patologia , Histiocitose/metabolismo , Pessoa de Meia-Idade , Histiócitos/patologia , Histiócitos/metabolismo , Cristalização , Dermatopatias/patologia , Dermatopatias/metabolismoRESUMO
AIMS: Angiofibroma of soft tissue is a benign soft tissue tumour characterised by bland spindle cells and a distinct branching vascular network. The majority of soft tissue angiofibromas harbour AHRR::NCOA2 gene fusions. Here we present three cases of EWSR1::GFI1B-fused soft tissue tumours that are morphologically most reminiscent of soft tissue angiofibroma. METHODS AND RESULTS: All three cases presented in male patients with an age range of 35-78 years (median = 54 years). Two cases presented as subcutaneous nodules on the trunk (posterior neck and chest wall); one was an intramuscular foot mass. The tumours were unencapsulated nodules with infiltrative margins ranging from 2.2 to 3.4 cm in greatest dimension. Histologically, the tumours contained uniformly bland fibroblastic spindle cells with ovoid to fusiform nuclei and delicate cytoplasmic processes embedded in a myxoid to myxocollagenous stroma. All three cases were characterised by a thin-walled, branching vascular network evenly distributed throughout the tumour. Overt cytological atypia or conspicuous mitotic activity was absent. The spindle cells had an essentially null immunophenotype. By targeted RNA sequencing, an in-frame gene fusion between EWSR1 exons 1-7 and GFI1B exons 6-11 or 7-11 was detected in all three cases. The tumours were marginally excised. For all three cases, there were no documented local recurrence or distant metastases during a limited follow-up period of 6-10 months. CONCLUSIONS: We propose that EWSR1::GFI1B may represent a novel fusion variant of soft tissue angiofibroma.
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Angiofibroma , Neoplasias de Cabeça e Pescoço , Neoplasias de Tecidos Moles , Humanos , Masculino , Adulto , Pessoa de Meia-Idade , Idoso , Angiofibroma/genética , Angiofibroma/patologia , Fusão Gênica , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia , Neoplasias de Cabeça e Pescoço/genética , Éxons , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Proteína EWS de Ligação a RNA/genéticaRESUMO
Pseudoxanthoma elasticum (PXE) is an autosomal recessive genetic disorder characterized by aberrant fragmentation and calcification of elastic fibers, leading to characteristic cutaneous, ophthalmic, and cardiovascular manifestations. PXE demonstrates significant phenotypic variability; involvement of the oral mucosa may be the only clue to the diagnosis. Reports on mucous membrane involvement in PXE are scarce. Here, we present a case of PXE-like changes in the oral cavity. A 70-year-old male patient presented with a painless leukoplakic lesion on the soft palate. Biopsy revealed numerous degenerated fibers in the lamina propria. Verhoeff-van Gieson and von Kossa staining confirmed their identity as calcified elastic fibers. A histopathological diagnosis of PXE-like changes was made; the patient was referred to ophthalmology where angioid streaks were visualized fundoscopically. PXE-like changes in the absence of the characteristic genetic mutation have also been reported with or without systemic manifestations. Furthermore, PXE-like changes have been reported in up to 10% of oral biopsy specimens undertaken without clinical suspicion for PXE. Therefore, the significance of such changes in isolation is unclear. Clinicians and pathologists should be aware of the potential oral manifestations of PXE to facilitate prompt diagnosis and subspecialist referral.
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Pseudoxantoma Elástico , Masculino , Humanos , Idoso , Pseudoxantoma Elástico/diagnóstico , Pseudoxantoma Elástico/patologia , Pele/patologia , Tecido Elástico/patologia , Palato Mole/patologia , MutaçãoRESUMO
AIM: Post-radiation angiosarcoma is an iatrogenic event seen in the setting of breast cancer treatment. Histopathologically, there are morphologic variants of angiosarcoma that mimic benign entities, including the capillary lobule variant of post-radiation angiosarcoma. We present the largest case series to date of this histopathologic variant of post-radiation angiosarcoma. METHODS AND RESULTS: Cases of the capillary lobule variant of post-radiation angiosarcoma from institutional/consultation archives from 2008 to June 2022 were reviewed. For inclusion, tumors had to occur in irradiated skin and exhibit a multi-lobular proliferation of tightly packed capillary-like vessels, as previously described in this variant. Prior ancillary studies were also reviewed. Eight cases met the criteria. All occurred in women treated with radiation for breast cancer (median age 75 years). All cases had similar findings, including a multi-lobular proliferation of tightly packed vessels, infiltrative cords, and atypical single endothelial cells. A conventional angiosarcoma pattern was also seen in five cases. All cases tested were positive for vascular markers (CD31, CD34, and/or ERG) and MYC. MYC amplification was shown by FISH in all cases tested. Smooth muscle actin (SMA) was positive in pericytes in the capillary lobules in all five cases tested and areas of conventional angiosarcoma in two of three cases. CONCLUSIONS: The capillary lobule variant of angiosarcoma is a rare and therefore potentially under-recognized variant of post-radiation angiosarcoma. The lobular architecture and SMA positivity may mimic benign vascular proliferations. Careful attention to histopathologic features and ancillary tests may facilitate accurate diagnosis.
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Neoplasias da Mama , Hemangiossarcoma , Neoplasias Cutâneas , Doenças Vasculares , Feminino , Humanos , Hemangiossarcoma/etiologia , Hemangiossarcoma/patologia , Células Endoteliais/patologia , Neoplasias da Mama/radioterapia , Neoplasias da Mama/patologia , Pele/patologia , Doenças Vasculares/patologia , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/patologiaRESUMO
BACKGROUND: Low-grade fibromyxoid sarcoma (LGFMS) typically involves deep soft tissue (beneath the fascia) of the proximal extremities and trunk. Long-term follow-up has shown a high rate of local recurrence, metastasis, and death. To the best of our knowledge, there is only one previous large series focusing on superficial LGFMS suggesting superficial tumors are disproportionately more common in children and may have a better prognosis. Our study's primary goals are to confirm these findings and increase general awareness that LGFMS may arise in superficial soft tissue. METHODS: We retrieved our cases of superficial LGFMS diagnosed between 2008 and 2020. Available slides were reviewed, and clinical data and follow-up information were obtained. RESULTS: The patients included nine males and 14 females with a median age of 29 years; eight (35%) were children (<18 years) and five (22%) were young adults (18-30 years). The majority involved the lower extremities (65%). The tumors were primarily centered in the subcutis (91%) and dermis (9%). Microscopically, they had typical features of LGFMS with alternating fibrous and myxoid zones composed of bland, slightly hyperchromatic spindled cells. All were positive for MUC4 by immunohistochemistry and/or FUS rearrangement by FISH. Follow-up on 14 cases ranged from 11 to 148 months (median 61 months) with no evidence of recurrences or distant metastases. CONCLUSIONS: Compared to conventional deep-seated counterparts, superficial LGFMS is more likely to occur in the extremities of children and young adults and may have a better clinical outcome. Further studies with longer follow-up will likely help support these findings.
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Fibrossarcoma , Neoplasias de Tecidos Moles , Masculino , Feminino , Humanos , Neoplasias de Tecidos Moles/patologia , Fibrossarcoma/patologia , Imuno-HistoquímicaRESUMO
BACKGROUND: Spitzoid melanocytic neoplasms are diagnostically challenging; criteria for malignancy continue to evolve. The ability to predict chromosomal abnormalities with immunohistochemistry (IHC) could help select cases requiring chromosomal evaluation. METHODS: Fluorescence in situ hybridization (FISH)-tested spitzoid neoplasms at our institution (2013-2021) were reviewed. p16, BRAF V600E, and preferentially expressed antigen in melanoma (PRAME) IHC results were correlated with FISH. RESULTS: A total of 174 cases (1.9F:1M, median age 28 years; range, 5 months-74 years) were included; final diagnoses: Spitz nevus (11%), atypical Spitz tumor (47%), spitzoid dysplastic nevus (9%), and spitzoid melanoma (32%). Sixty (34%) were FISH positive, most commonly with absolute 6p25 gain (RREB1 > 2). Dermal mitotic count was the only clinicopathologic predictor of FISH. Among IHC-stained cases, p16 was lost in 55 of 134 cases (41%); loss correlated with FISH positive (p < 0.001, Fisher exact test). BRAF V600E (14/88, 16%) and PRAME (15/56, 27%) expression did not correlate with FISH alone (p = 0.242 and p = 0.359, respectively, Fisher exact test). When examined together, however, p16-retained/BRAF V600E-negative lesions had low FISH-positive rates (5/37, 14%; 4/37, 11% not counting isolated MYB loss); all other marker combinations had high rates (56%-75% of cases; p < 0.001). CONCLUSIONS: p16/BRAF V600E IHC predicts FISH results. "Low-risk" lesions (p16+ /BRAF V600E- ) uncommonly have meaningful FISH abnormalities (11%). PRAME may have limited utility in this setting.
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Melanoma , Nevo de Células Epitelioides e Fusiformes , Neoplasias Cutâneas , Humanos , Proteínas Proto-Oncogênicas B-raf/genética , Hibridização in Situ Fluorescente , Melanoma/diagnóstico , Melanoma/genética , Melanoma/metabolismo , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Aberrações Cromossômicas , Nevo de Células Epitelioides e Fusiformes/diagnóstico , Nevo de Células Epitelioides e Fusiformes/genética , Diagnóstico Diferencial , Antígenos de NeoplasiasRESUMO
BACKGROUND: Giant cell tumor of soft tissue (GCT-ST) is a rare soft tissue neoplasm that is morphologically similar to but genetically distinct from giant cell tumor of bone. A novel keratin-positive GCT-ST (KPGCT-ST) harboring HMGA2::NCOR2 fusions was recently discovered. Fewer than 30 cases have been described; herein is reported an additional seven. METHODS: Cases diagnosed as GCT-ST were retrieved from institutional archives and consultation files. The histopathologic characteristics were assessed, and the electronic medical record was reviewed. RESULTS: Seven tumors were identified in six women and one man with a median age of 23 years. All patients underwent excision; no recurrences or metastases were noted during a median follow-up period of 7 months. Histopathologically, the tumors were characterized by a multinodular proliferation of keratin-positive mononuclear cells with evenly admixed osteoclast-like giant cells and absent neoplastic bone. A fibrous capsule with lymphoid cuffing was frequently seen. Foamy macrophages, inflammation, hemorrhage, and hemosiderin were variably present. The HMGA2::NCOR2 fusion was detected in all cases. CONCLUSIONS: Our findings support previously reported hypotheses that KPGCT-ST is a spectrum of the same entity as the recently described xanthogranulomatous epithelial tumor. Although follow-up data are limited, to date, KPGCT-ST appears to follow an indolent course.
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Tumores de Células Gigantes , Neoplasias de Tecidos Moles , Masculino , Humanos , Feminino , Adulto Jovem , Adulto , Queratinas , Tumores de Células Gigantes/patologia , Neoplasias de Tecidos Moles/patologia , Diagnóstico Diferencial , Células Gigantes/patologia , Correpressor 2 de Receptor NuclearRESUMO
Acral melanocytic neoplasms often pose diagnostic difficulty. Preferentially expressed antigen in melanoma (PRAME) expression and loss of p16 expression have diagnostic utility in melanocytic tumors. We examined PRAME and p16 expression in 30 acral melanocytic neoplasms (n = 11 nevi; n = 2 dysplastic nevi; n = 7 Spitz nevi; n = 10 acral melanomas). PRAME was scored as % positive nuclei: negative = 0%; 1% to 25% = 1+; 25% to 50% = 2+; 50% to 75% = 3+, or positive: 75% to 100% = 4+. p16 expression was defined as retained (homogeneous or checkerboard) or lost (complete or partial/regionally). PRAME expression was negative in all benign, dysplastic, and Spitz nevi. Conversely, all acral melanomas were diffusely (4+) positive for PRAME expression. p16 expression was retained in all benign acral nevi (8/11 homogeneous, 3/11 checkerboard), completely lost in one dysplastic nevus, and retained in all acral Spitz nevi (3/7 homogeneous, 4/7 checkerboard). p16 was retained in five of 10 acral melanomas (3/10 homogeneous; 2/10 checkerboard), and negative in five of 10 acral melanomas (absent in 3/10, partially lost in 2/10). Our data suggest that 4+ PRAME expression is highly sensitive and specific in the setting of acral melanomas and is a more predictive diagnostic tool compared with p16 immunohistochemistry.
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Antígenos de Neoplasias/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Melanoma/metabolismo , Nevo/metabolismo , Neoplasias Cutâneas/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Nevo/patologia , Neoplasias Cutâneas/patologia , Adulto JovemRESUMO
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".
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Quinase do Linfoma Anaplásico/genética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Rearranjo Gênico , Humanos , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Fusão OncogênicaRESUMO
Dedifferentiation and transdifferentiation are rare and only poorly understood phenomena in cutaneous melanoma. To study this disease more comprehensively we have retrieved 11 primary cutaneous melanomas from our pathology archives showing biphasic features characterized by a conventional melanoma and additional areas of de-/trans-differentiation as defined by a lack of immunohistochemical expression of all conventional melanocytic markers (S-100 protein, SOX10, Melan-A, and HMB-45). The clinical, histologic, and immunohistochemical findings were recorded and follow-up was obtained. The patients were mostly elderly (median: 81 years; range: 42-86 years) without significant gender predilection, and the sun-exposed skin of the head and neck area was most commonly affected. The tumors were deeply invasive with a mean depth of 7 mm (range: 4-80 mm). The dedifferentiated component showed atypical fibroxanthoma-like features in the majority of cases (7), while additional rhabdomyosarcomatous and epithelial transdifferentiation was noted histologically and/or immunohistochemically in two tumors each. The background conventional melanoma component was of desmoplastic (4), superficial spreading (3), nodular (2), lentigo maligna (1), or spindle cell (1) types. For the seven patients with available follow-up data (median follow-up period of 25 months; range: 8-36 months), two died from their disease, and three developed metastases. Next-generation sequencing of the cohort revealed somatic mutations of established melanoma drivers including mainly NF1 mutations (5) in the conventional component, which was also detected in the corresponding de-/trans-differentiated component. In summary, the diagnosis of primary cutaneous de-/trans-differentiated melanoma is challenging and depends on the morphologic identification of conventional melanoma. Molecular analysis is diagnostically helpful as the mutated gene profile is shared between the conventional and de-/trans-differentiated components. Importantly, de-/trans-differentiation does not appear to confer a more aggressive behavior.
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Genômica , Melanoma/patologia , Neurofibromina 1/genética , Neoplasias Cutâneas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Diferenciação Celular , DNA de Neoplasias/genética , Diagnóstico Diferencial , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Melanoma/genética , Melanoma/metabolismo , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismoRESUMO
YAP1-TFE3-fused hemangioendothelioma is an extremely rare malignant vascular tumor. We present the largest multi-institutional clinicopathologic study of YAP1-TFE3-fused hemangioendothelioma to date. The 24 cases of YAP1-TFE3-fused hemangioendothelioma showed a female predominance (17 female, 7 male) across a wide age range (20-78 years old, median 44). Tumors were most commonly located in soft tissue (50%), followed by bone (29%), lung (13%), and liver (8%), ranging from 3 to 115 mm in size (median 40 mm). About two-thirds presented with multifocal disease, including 7 cases with distant organ metastasis. Histopathologically, we describe three dominant architectural patterns: solid sheets of coalescing nests, pseudoalveolar and (pseudo)vasoformative pattern, and discohesive strands and clusters of cells set in a myxoid to myxohyaline stroma. These patterns were present in variable proportions across different tumors and often coexisted within the same tumor. The dominant cytomorphology (88%) was large epithelioid cells with abundant, glassy eosinophilic to vacuolated cytoplasm, prominent nucleoli and well-demarcated cell borders. Multinucleated or binucleated cells, prominent admixed erythrocytic and lymphocytic infiltrates, and intratumoral fat were frequently present. Immunohistochemically, ERG, CD31, and TFE3 were consistently expressed, while expression of CD34 (83%) and cytokeratin AE1/AE3 (20%) was variable. CAMTA1 was negative in all but one case. All cases were confirmed by molecular testing to harbor YAP1-TFE3 gene fusions: majority with YAP1 exon 1 fused to TFE3 exon 4 (88%), or less commonly, TFE3 exon 6 (12%). Most patients (88%) were treated with primary surgical resection. Over a follow-up period of 4-360 months (median 36 months) in 17 cases, 35% of patients remained alive without disease, and 47% survived many years with stable, albeit multifocal and/or metastatic disease. Five-year progression-free survival probability was 88%. We propose categorizing YAP1-TFE3-fused hemangioendothelioma as a distinct disease entity given its unique clinical and histopathologic characteristics in comparison to conventional epithelioid hemangioendothelioma.
Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Biomarcadores Tumorais/genética , Fusão Gênica , Hemangioendotelioma Epitelioide/genética , Hemangioendotelioma/genética , Proteínas de Sinalização YAP/genética , Adulto , Idoso , Ásia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/análise , Biomarcadores Tumorais/análise , Europa (Continente) , Éxons , Feminino , Predisposição Genética para Doença , Hemangioendotelioma/química , Hemangioendotelioma/patologia , Hemangioendotelioma/cirurgia , Hemangioendotelioma Epitelioide/química , Hemangioendotelioma Epitelioide/patologia , Hemangioendotelioma Epitelioide/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , América do Norte , Fenótipo , Intervalo Livre de Progressão , Fatores de Tempo , Adulto JovemRESUMO
The knowledge of clinical features and, particularly, histopathological spectrum of EWSR1-PATZ1-rearranged spindle and round cell sarcomas (EPS) remains limited. For this reason, we report the largest clinicopathological study of EPS to date. Nine cases were collected, consisting of four males and five females ranging in age from 10 to 81 years (average: 49 years). Five tumors occurred in abdominal wall soft tissues, three in the thorax, and one in the back of the neck. Tumor sizes ranged from 2.5 to 18 cm (average 6.6 cm). Five patients had follow-up with an average of 38 months (range: 18-60 months). Two patients had no recurrence or metastasis 19 months after diagnosis. Four patients developed multifocal pleural or pulmonary metastasis and were treated variably by surgery, radiotherapy, and chemotherapy. The latter seemed to have little to no clinical benefit. One of the four patients was free of disease 60 months after diagnosis, two patients were alive with disease at 18 and 60 months, respectively. Morphologically, low, intermediate, and high-grade sarcomas composed of a variable mixture of spindled, ovoid, epithelioid, and round cells were seen. The architectural and stromal features also varied, resulting in a broad morphologic spectrum. Immunohistochemically, the following markers were most consistently expressed: S100-protein (7/9 cases), GFAP (7/8), MyoD1 (8/9), Pax-7 (4/5), desmin (7/9), and AE1/3 (4/9). By next-generation sequencing, all cases revealed EWSR1-PATZ1 gene fusion. In addition, 3/6 cases tested harbored CDKN2A deletion, while CDKN2B deletion and TP53 mutation were detected in one case each. Our findings confirm that EPS is a clinicopathologic entity, albeit with a broad morphologic spectrum. The uneventful outcome in some of our cases indicates that a subset of EPS might follow a more indolent clinical course than previously appreciated. Additional studies are needed to validate whether any morphological and/or molecular attributes have a prognostic impact.
Assuntos
Biomarcadores Tumorais/genética , Fatores de Transcrição Kruppel-Like/genética , Proteína EWS de Ligação a RNA/genética , Proteínas Repressoras/genética , Sarcoma/genética , Neoplasias de Tecidos Moles/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Criança , Europa (Continente) , Feminino , Fusão Gênica , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Sarcoma/química , Sarcoma/patologia , Sarcoma/cirurgia , Neoplasias de Tecidos Moles/química , Neoplasias de Tecidos Moles/patologia , Neoplasias de Tecidos Moles/cirurgia , Resultado do Tratamento , Estados UnidosRESUMO
Synovial sarcoma accounts for 5% to 10% of soft tissue sarcoma and it typically presents as a deep soft tissue mass. Primary cutaneous presentation is exceptionally rare, with only isolated case reports. We report a case of primary cutaneous synovial sarcoma in a 58-year-old woman that presented as a nodule involving the left occipital scalp. A complete radiologic evaluation of the patient failed to reveal any other mass lesion. Histologic sections showed a densely cellular, diffuse spindle cell proliferation within the subcutis. The lesion was composed of uniform, plump spindled cells with nuclei and vesicular chromatin, arranged in haphazard fascicles. There was admixed hemorrhage and a hemangiopericytoma-like vasculature. Immunohistochemically, the spindled cells showed focal strong positivity for cytokeratin (CK) OSCAR, CK5/6, CK34BE12, and pan-CK. Fluorescence in situ hybridization was positive for a rearrangement of SYT (SS18), confirming the diagnosis of monophasic synovial sarcoma. Synovial sarcoma should be considered in the differential diagnosis of monomorphous spindle cell tumors, especially if the tumors have a hemangiopericytoma-like vasculature or express keratins. In such cases, confirmatory molecular testing should be performed to confirm the diagnosis.
Assuntos
Biomarcadores Tumorais , Rearranjo Gênico , Neoplasias de Cabeça e Pescoço , Proteínas Proto-Oncogênicas , Proteínas Repressoras , Sarcoma Sinovial , Neoplasias Cutâneas , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Feminino , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Sarcoma Sinovial/diagnóstico , Sarcoma Sinovial/genética , Sarcoma Sinovial/metabolismo , Sarcoma Sinovial/patologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologiaRESUMO
Syringocystadenocarcinoma papilliferum (SCACP) is a rare cutaneous adnexal tumor thought to originate from its benign counterpart, syringocystadenoma papilliferum. These tumors are predominantly located on the head and neck with their location on the breast extraordinarily reported; mammary localization poses a great diagnostic dilemma to the practicing pathologist. Herein, we report an unusual case of an 85-year-old woman with an outside diagnosis on a core needle biopsy of metaplastic mammary carcinoma. Upon consultative review of the partial mastectomy specimen, SCACP was identified. Herein, we review SCACP and the diagnostic challenge it poses, especially when localized to the breast. Furthermore, we perform a retrospective review of institutional pathology reports and identified four additional cases of SCACP diagnosed at our institution within the last decade. Finally, we briefly review the literature of SCACP. The entity of SCACP should be well known to pathologists to avoid misdiagnosis.
Assuntos
Neoplasias da Mama/patologia , Neoplasias das Glândulas Sudoríparas/patologia , Adenomas Tubulares de Glândulas Sudoríparas/patologia , Idoso de 80 Anos ou mais , Feminino , Humanos , Estudos RetrospectivosRESUMO
Symplastic hemangiomas (SH) are benign vascular lesions that show atypia in vascular smooth muscle and interstitial cells with sparing of endothelial cells. We present four cases of this rare tumor. The patients (two males; two females) ranged in age from 57 to 83 years (median 74); lesions were located on the leg (n = 3) and back (n = 1), and ranged from 6 to 8 mm. SH were well-circumscribed and dermal-based, often with an epidermal collarette (3/4). They were characterized by the presence of variably atypical, hyperchromatic/pleomorphic epithelioid to spindled cells within vascular walls (3/4) and/or perivascular stroma (4/4). Atypical multinucleated cells were present in three of four cases. The overall mitotic rate was low (0-2 mitotic figures per 10 HPFs; mean 0.75 per 10 HPFs), but atypical mitotic figures were seen in two of four cases. Atypical cells were negative for SMA (0/2), desmin (0/2), AE1/3 (0/2), and CAM5.2 (0/1). ERG, CD31, and CD34 stains were positive in endothelial cells but negative in atypical cells (4/4). Lesional cells and vessels were negative for podoplanin (3/3). Symplastic hemangioma is a benign tumor with bizarre atypia that may be mistaken for malignancy. We present four cases of this rare entity to increase awareness of this tumor and discuss the differential diagnosis.
Assuntos
Hemangioma/patologia , Neoplasias Cutâneas/patologia , Idoso , Idoso de 80 Anos ou mais , Diagnóstico Diferencial , Feminino , Hemangioma/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Cutâneas/diagnósticoRESUMO
BACKGROUND: Perineuriomatous nevi are rare and diagnostically problematic. We report a series of eight perineuriomatous nevi to highlight the diagnostic features. METHODS: Cases were retrospectively reviewed and characterized. RESULTS: Median age was 42.5 years (range 25-64), with equal sex distribution. Lesions occurred on the arm (n = 4), trunk (n = 2), and head/neck (n = 2). Median size was 7.5 mm (range 5-12 mm). Clinical differential diagnoses included atypical nevus (3), blue nevus (1), neurofibroma (1), and dermatofibroma (1). Lesions were circumscribed, dome-shaped (5/8), and biphasic (8/8) with nested epithelioid cells and wavy spindled cells arranged in whorled fascicles in a myxocollagenous stroma. When present, junctional growth was lentiginous (4/8). No cases displayed pleomorphism or mitotic figures. The perineuriomatous component stained positively for epithelial membrane antigen (8/8 focal to diffuse) and CD34 (4/5 focal to diffuse). SOX10 and S100 protein stained all nevoid cells and in some cases a subset of intermingled spindled cells in perineuriomatous areas, where other melanocytic markers were negative. p16 protein expression was uniformly retained (3/3), and p53 negative (0/2). Nevoid cells in most lesions were positive for BRAFV600E (5/7). Ki67 was mildly elevated (~5%) in 3/3 cases. CONCLUSIONS: Recognizing the histopathologic and immunophenotypic features in these unusual nevi helps avoid overdiagnosis.