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1.
Dermatol Surg ; 2021 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-33625139

RESUMO

BACKGROUND: Extramammary Paget disease (EMPD) poses treatment challenges. Invasive and noninvasive treatment modalities exist with variable success reported. Reflectance confocal microscopy (RCM) is emerging as an adjuvant diagnostic tool. OBJECTIVE: To evaluate the treatment of EMPD patients and the role of RCM. METHODS: Prospective study. Demographic and tumor characteristics were recorded. Handheld-RCM was performed and correlated with histology. Treatment, clearance, pathology, and follow-up were all recorded. RESULTS: Thirty-six EMPD lesions in 33 patients were included. Mean age was 71.7 years, and 23 were men. Mean number of surgical stages needed to clear margins was 1.9 (SD, 0.9; 1.0-3.0 stages), and mean margin needed to clear was 1.8 cm. Reflectance confocal microscopy correlated well with scouting punch biopsies (kappa, 0.93; p < .001). Disruption of the dermoepidermal junction was associated with invasive EMPD versus in situ (83.3% vs 25.9%) on histology (p = .01). LIMITATIONS: Relatively small sample size. CONCLUSION: Extramammary Paget disease is challenging, and lesion demarcation is of the utmost importance. Using a staged surgical excision approach, the mean margins needed were 1.8 cm, less than previously reported. Nonsurgical modalities, including radiation therapy, imiquimod, or photodynamic therapy can be considered if surgery is not pursued. Reflectance confocal microscopy is a valuable noninvasive imaging modality for the management of EMPD.

3.
Am J Surg Pathol ; 45(2): 277-285, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33428338

RESUMO

A subset of Spitz tumors is associated with a copy number increase of chromosome 11p and activating mutations of HRAS. These aberrations have been reported to occur in association with desmoplastic Spitz nevi. Little is known to what extent 11p gains can also be found in nondesmoplastic tumors. To learn more about the spectrum of microscopic and cytogenetic changes that can be seen in Spitz lesions in association with 11p gains, we reviewed the clinical and pathologic features of 40 cases. Patient ages ranged from 3 to 75 years. The most common anatomic site was the head and neck region, followed by the upper extremities. Prominent desmoplasia was present in 10 cases. Seven tumors lacked significant stromal fibrosis. Twenty tumors were mitotically active. Novel microscopic features encountered in a few cases include a tumor with a polypoid silhouette and papillomatous surface and rare atypical tumors with a deep bulbous growth pattern. Among 36 cases analyzed by single-nucleotide polymorphism array or comparative genomic hybridization, 28 tumors had gains of the entire or near-entire p-arm of chromosome 11 with no other coexisting unbalanced genomic aberration. Eight cases had additional changes; 6 of these with 1 additional aberration per case, and 2 cases had several chromosomal aberrations. We also examined a subset of tumors by fluorescence in situ hybridization for the HRAS gene locus (11p15.5). All tumors were fluorescence in situ hybridization-positive. In conclusion, we expand the spectrum of pathologic findings associated with Spitz tumors with 11p gains. This cytogenetic aberration is not restricted to desmoplastic Spitz nevi. It can also be seen in nondesmoplastic and papillomatous lesions and atypical melanocytic tumors with a deep bulbous growth. We also document that in some Spitz tumors additional cytogenetic aberrations may be found, the significance of which remains to be determined.


Assuntos
Cromossomos Humanos Par 11/genética , Nevo de Células Epitelioides e Fusiformes/genética , Neoplasias Cutâneas/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Aberrações Cromossômicas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nevo de Células Epitelioides e Fusiformes/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias Cutâneas/patologia , Adulto Jovem
4.
Dermatol Online J ; 26(6)2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32815687

RESUMO

To date, only twenty cases of cutaneous legionellosis have been reported. Cutaneous legionellosis has heterogeneous manifestations including abscesses, nodules, and cellulitis. The detection of most cutaneous Legionella species requires specific diagnostic cultures and assays. Herein, we report a case of cutaneous legionella in a hematopoietic cell transplantation recipient with culture-negative nodules unresponsive to empiric antibiotics. We also discuss the varied morphology of cutaneous legionellosis and important diagnostic considerations.


Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hospedeiro Imunocomprometido , Legionella , Legionelose/patologia , Dermatopatias Bacterianas/patologia , Adulto , Idoso , Antibacterianos/uso terapêutico , Criança , Diagnóstico Diferencial , Feminino , Humanos , Legionella/isolamento & purificação , Legionelose/diagnóstico , Legionelose/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Dermatopatias Bacterianas/diagnóstico , Dermatopatias Bacterianas/tratamento farmacológico
5.
Am J Surg Pathol ; 44(7): 893-900, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32317605

RESUMO

PRAME (PReferentially expressed Antigen in MElanoma) is a melanoma-associated antigen. Although diffuse immunoreactivity for PRAME is found in most primary cutaneous melanomas, melanocytic nevi express PRAME usually only in a subpopulation of tumor cells or not at all. Hence, testing for PRAME expression has the potential to provide useful information for the assessment for diagnostically ambiguous melanocytic neoplasms. Many of the latter tumors are currently studied by cytogenetic methods for ancillary evidence in support of or against a diagnosis of melanoma. In this study we analyzed 110 diagnostically problematic melanocytic tumors comparing results for PRAME immunohistochemistry (IHC) with those from fluorescence in situ hybridization and/or single nucleotide polymorphism-array, and each with the final diagnostic interpretation. In 90% of cases there was concordance between PRAME IHC and cytogenetic tests results, and in 92.7% concordance between PRAME IHC and the final diagnosis. The high concordance between PRAME IHC and cytogenetic test results as well as the final diagnosis supports the use of PRAME IHC as an ancillary test in the evaluation of ambiguous primary cutaneous melanocytic neoplasms, especially given its practical advantage of lower cost and faster turnaround over cytogenetic or gene expression studies. However, our results indicate that PRAME IHC and cytogenetic tests for melanocytic tumors are not entirely interchangeable and on occasion each type of test may yield false-negative or false-positive results.


Assuntos
Antígenos de Neoplasias , Biomarcadores Tumorais , Análise Citogenética , Imuno-Histoquímica , Melanoma/diagnóstico , Nevo Pigmentado/diagnóstico , Neoplasias Cutâneas/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Criança , Pré-Escolar , Diagnóstico Diferencial , Reações Falso-Negativas , Reações Falso-Positivas , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Melanoma/genética , Melanoma/metabolismo , Melanoma/patologia , Pessoa de Meia-Idade , Nevo Pigmentado/genética , Nevo Pigmentado/metabolismo , Nevo Pigmentado/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Adulto Jovem
6.
Oncologist ; 25(2): 140-149, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32043775

RESUMO

BACKGROUND: Checkpoint inhibitor therapy is widely known to cause a number of immune-related adverse events. One rare adverse effect that is emerging is eosinophilic fasciitis, a fibrosing disorder causing inflammatory infiltration of subcutaneous fascia. It is characterized clinically by edema and subsequent induration and tightening of the skin and subcutaneous tissues. The condition is rare, yet at our institutions we have seen four cases in the past 3 years. We describe our 4 cases and review 11 other cases reported in the literature. CASE PRESENTATION: We present four cases of eosinophilic fasciitis following treatment with programmed cell death protein 1 or programmed cell death-ligand 1 blockade. All patients had extremity involvement with characteristic skin changes ranging from peripheral edema to induration, tightening, and joint limitation. The patients had varying degrees of peripheral eosinophilia. In two of our patients, the diagnosis was made by full-thickness skin biopsy showing lymphocytic infiltration of the subcutaneous fascia, with CD4+ T cells predominating in one case and CD8+ T cells in the other. In the other two cases, the diagnosis was made on the basis of characteristic imaging findings in the context of clinical features consistent with the diagnosis. All four patients were treated with glucocorticoids with varying degrees of success; immunotherapy had to be discontinued in all four. Patients with advanced melanoma who experienced this adverse effect had either a partial response or a complete response to therapy. CONCLUSION: Eosinophilic fasciitis can occur as a result of checkpoint inhibitor therapy. Although a tissue diagnosis is the gold standard, imaging studies may facilitate the diagnosis in the presence of consistent clinical features, but a degree of suspicion is key to recognizing the condition early. Therapy requires a collaborative approach by oncology, rheumatology, and dermatology; physical therapy is an important adjunct in treatment. For advanced melanoma, it may be a good prognostic indicator. IMPLICATIONS FOR PRACTICE: It is important for clinicians to recognize that eosinophilic fasciitis is a potential immune-related adverse event (irAE) as a consequence of immune checkpoint inhibitor therapy. The presentation is quite stereotypical; the diagnosis can be made by imaging in the absence of a full-thickness skin biopsy. Early intervention is important to limit morbidity. This irAE may be a good prognostic sign among patients with melanoma.

7.
Int J Surg Pathol ; 28(5): 468-476, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31969038

RESUMO

Since the seminal study of Hart and Helwig in 1975, there are few detailed pathological studies of lichen sclerosus (LS). The aims of this study were to provide a detailed histopathological description of penile LS, as well as to explore its relationship with penile intraepithelial neoplasia (PeIN) or invasive carcinoma. We evaluated 200 patients and designed a topographical approach for the histological evaluation focusing in alterations of the following anatomical layers: squamous epithelium, lamina propria, dartos, and corpus spongiosum. We documented the quantity and topographical location of stromal lymphocytes. The prevalent lesions found were epithelial hyperplasia, atrophy, PeIN, basal cell vacuolization, lamina propria sclerosis, and variable patterns of lymphocytic infiltration. Various unique patterns of stromal sclerosis were described: perivascular, globular, linear, and solid fibrosis/hyalinization; any of them were found to be diagnostic for LS. The variation in the topography and density of lymphocytes was determinant for the identification of LS morphological variants: lichenoid, band-like, lymphocytic depleted, and mixed. A major finding was the identification of the variant designated as lymphocytic depleted LS, which we considered as the morphological prototype of LS associated with penile neoplasia. The detailed description of this complex lesion presented in this study may help pathologists in practice to identify and better define LS. The identification of the special variants suggests a role of the stromal lymphocytes in the process of carcinogenesis. Confirmation of the observations with more studies is necessary to determine the significance of these findings.

8.
Am J Surg Pathol ; 44(4): 503-508, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31633488

RESUMO

The distinction of metastatic melanoma from melanocytic nevi in lymph nodes can on occasion be difficult. As diffuse immunohistochemical (IHC) PRAME (PReferentially expressed Antigen in MElanoma) expression is detected in the majority of primary and metastatic melanomas, but rarely in nevi, we reasoned that PRAME could be a useful adjunct marker for the diagnosis of melanocytes in lymph nodes. In this study, we examined 45 nodal melanocytic deposits comprising 30 nodal nevi and 15 melanoma metastases. The latter were diagnostically not straightforward because they either coexisted with nodal nevi or were present in perinodal fibrous tissue. All nodal nevi (30/30) were negative for PRAME, whereas all melanoma metastases (15/15) were diffusely positive for PRAME IHC. We additionally report the novel use of a PRAME/Melan A dual-label immunostain. Our results show that PRAME IHC may be useful in the assessment of diagnostically challenging nodal melanocytic deposits, such as intraparenchymal nodal nevi, metastases confined to the capsular fibrous tissue, or in the setting of small metastases coexisting with a nodal nevus in the same lymph node.


Assuntos
Antígenos de Neoplasias/análise , Biomarcadores Tumorais/análise , Imuno-Histoquímica , Melanoma/química , Nevo/química , Linfonodo Sentinela/química , Neoplasias Cutâneas/química , Adulto , Idoso , Idoso de 80 Anos ou mais , Diagnóstico Diferencial , Feminino , Humanos , Metástase Linfática , Masculino , Melanoma/secundário , Pessoa de Meia-Idade , Nevo/patologia , Valor Preditivo dos Testes , Linfonodo Sentinela/patologia , Neoplasias Cutâneas/patologia
9.
J Am Acad Dermatol ; 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31812621

RESUMO

BACKGROUND: Lentigo maligna/lentigo maligna melanoma (LM/LMM) can present with subclinical extension that may be difficult to define preoperatively and lead to incomplete excision and potential recurrence. Preliminarily studies have used reflectance confocal microscopy (RCM) to assess LM/LMM margins. OBJECTIVE: To evaluate the correlation of LM/LMM subclinical extension defined by RCM compared to the gold standard histopathology. METHODS: Prospective study of LM/LMM patients referred for dermatologic surgery. RCM was performed at the clinically-defined initial surgical margin followed by margin-controlled staged excision with paraffin-embedded tissue and histopathology was correlated with RCM results. RESULTS: Seventy-two patients were included. Mean age was 66.8 years (SD 11.1; 38 - 89 years); 69.4% were males. 70/72 (97.2%) lesions were located on the head neck with mean largest clinical diameter of 1.3cm (0.3 - 5 cm). Diagnostic accuracy for detection of residual melanoma in the tumor debulk (after biopsy) had a sensitivity of 96.7% and a specificity of 66.7% when compared to the histopathology. RCM margin assessment revealed an overall agreement with final histopathology of 85.9% (kappa 0.71; p<0.001). LIMITATIONS: No RCM imaging beyond initial planned margins was performed. CONCLUSION: RCM showed moderate to excellent overall agreement between RCM imaging of LM/LMM and histopathology of staged excision margins.

10.
Oncologist ; 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31615951

RESUMO

BACKGROUND: Checkpoint inhibitor therapy is widely known to cause a number of immune-related adverse events. One rare adverse effect that is emerging is eosinophilic fasciitis, a fibrosing disorder causing inflammatory infiltration of subcutaneous fascia. It is characterized clinically by edema and subsequent induration and tightening of the skin and subcutaneous tissues. The condition is rare, yet at our institutions we have seen four cases in the past 3 years. We describe our 4 cases and review 11 other cases reported in the literature. CASE PRESENTATION: We present four cases of eosinophilic fasciitis following treatment with programmed cell death protein 1 or programmed cell death-ligand 1 blockade. All patients had extremity involvement with characteristic skin changes ranging from peripheral edema to induration, tightening, and joint limitation. The patients had varying degrees of peripheral eosinophilia. In two of our patients, the diagnosis was made by full-thickness skin biopsy showing lymphocytic infiltration of the subcutaneous fascia, with CD4+ T cells predominating in one case and CD8+ T cells in the other. In the other two cases, the diagnosis was made on the basis of characteristic imaging findings in the context of clinical features consistent with the diagnosis. All four patients were treated with glucocorticoids with varying degrees of success; immunotherapy had to be discontinued in all four. Patients with advanced melanoma who experienced this adverse effect had either a partial response or a complete response to therapy. CONCLUSION: Eosinophilic fasciitis can occur as a result of checkpoint inhibitor therapy. Although a tissue diagnosis is the gold standard, imaging studies may facilitate the diagnosis in the presence of consistent clinical features, but a degree of suspicion is key to recognizing the condition early. Therapy requires a collaborative approach by oncology, rheumatology, and dermatology; physical therapy is an important adjunct in treatment. For advanced melanoma, it may be a good prognostic indicator. IMPLICATIONS FOR PRACTICE: It is important for clinicians to recognize that eosinophilic fasciitis is a potential immune-related adverse event (irAE) as a consequence of immune checkpoint inhibitor therapy. The presentation is quite stereotypical; the diagnosis can be made by imaging in the absence of a full-thickness skin biopsy. Early intervention is important to limit morbidity. This irAE may be a good prognostic sign among patients with melanoma.

11.
Int J Surg Pathol ; 27(5): 477-482, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30614356

RESUMO

Lichen sclerosus (LSc) with penile cancer is found in about two thirds of specimens. It has been hypothesized that LSc represents a precancerous condition. To qualify as such, in addition to cytological atypia and similarity with the invasive tumor, a spatial correlation between LSc and neoplastic lesions needs to be demonstrated. The purpose of this study was to evaluate such a spatial relationship. Circumcision (28 cases) and penectomy (81 cases) specimens were evaluated. All cases had LSc, penile intraepithelial neoplasia (PeIN), and/or invasive squamous cell carcinomas. We examined LSc in relation to invasive carcinoma, PeIN, and normal epithelia. Invasive squamous cell carcinomas, classified according to the World Health Organization criteria as non-human papillomavirus (HPV)-related and HPV-related PeIN, were present in 100 cases. Non-HPV-related (differentiated) PeIN was the most common subtype associated with LSc (89%). There were 5 spatial patterns identified: (1) LSc adjacent to PeIN (23%), (2) LSc adjacent and comprising PeIN (42%), (3) LSc next to and within invasive carcinomas (8%), (4) LSc throughout the sequence PeIN-invasive carcinoma (24%), and (5) LSc was separate (with normal tissue between the lesions) from PeIN and/or invasive carcinomas in a minority of cases (3%). LSc within the cancer was not previously described. In this series, we found 35 cases with LSc within invasive carcinomas. The striking continuous spatial relationship among LSc, PeIN, and/or invasive carcinoma as shown in this study may be a necessary (but not sufficient) condition for the hypothesis postulating LSc as a penile precancerous lesion.


Assuntos
Carcinoma in Situ/patologia , Carcinoma de Células Escamosas/patologia , Líquen Escleroso e Atrófico/patologia , Neoplasias Penianas/patologia , Lesões Pré-Cancerosas/patologia , Carcinoma in Situ/cirurgia , Carcinoma de Células Escamosas/cirurgia , Circuncisão Masculina , Epitélio/patologia , Humanos , Líquen Escleroso e Atrófico/cirurgia , Masculino , Neoplasias Penianas/cirurgia , Pênis/patologia , Pênis/cirurgia , Lesões Pré-Cancerosas/cirurgia
12.
JAMA Dermatol ; 155(3): 347-352, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30624578

RESUMO

Importance: Melanoma incidence and the use of systemic treatments for it are rising. Current treatment monitoring uses clinical examination and radiologic examinations; however, cutaneous involvement and cutaneous metastasis may not be well visualized. Reflectance confocal microscopy (RCM) is a US Food and Drug Administration-approved, noninvasive technology that enables visualization of the skin with quasihistological resolution. Objective: To evaluate the feasibility of using RCM to monitor advanced melanomas treated with immunotherapy. Design, Setting, and Participants: This case report study took place from March 2017 to June 2018 and included 2 patients with locally advanced melanoma who were not candidates for surgery or were not willing to have surgery and who were started on an immunotherapy regimen at a tertiary care cancer hospital. Main Outcomes and Measures: Clinical and RCM findings correlated with histopathology. Results: In the patients, locally advanced melanoma with cutaneous involvement was treated with immunotherapy (pembrolizumab in 1 patient and an ipilimumab-nivolumab combination in the other) with resulting clearance of the lesions. Use of RCM showed the disappearance of clear melanoma features seen at baseline; these findings correlated with histopathology. The response was not seen with radiologic images, such as magnetic resonance imaging and computed tomography. Conclusions and Relevance: Although RCM will not replace larger field imaging (such as magnetic resonance imaging, positron emission tomography, and computed tomography) in the management and follow-up of melanoma or other tumors, for imaging of cutaneous involvement and disease monitoring, RCM holds promise as a novel noninvasive technique.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Melanoma/tratamento farmacológico , Melanoma/patologia , Couro Cabeludo , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Idoso , Biópsia por Agulha , Dermoscopia/métodos , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Imunoterapia/métodos , Masculino , Melanoma/diagnóstico por imagem , Microscopia Confocal/métodos , Pessoa de Meia-Idade , Imagem Multimodal/métodos , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Neoplasias Cutâneas/diagnóstico por imagem , Resultado do Tratamento
13.
Blood ; 132(26): 2763-2774, 2018 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-30381375

RESUMO

Nuclear factor erythroid-derived 2-like 2 (Nrf2) is a ubiquitously expressed transcription factor that is well known for its role in regulating the cellular redox pathway. Although there is mounting evidence suggesting a critical role for Nrf2 in hematopoietic stem cells and innate leukocytes, little is known about its involvement in T-cell biology. In this study, we identified a novel role for Nrf2 in regulating alloreactive T-cell function during allogeneic hematopoietic cell transplantation (allo-HCT). We observed increased expression and nuclear translocation of Nrf2 upon T-cell activation in vitro, especially in CD4+ donor T cells after allo-HCT. Allo-HCT recipients of Nrf2 -/- donor T cells had significantly less acute graft-versus-host disease (GVHD)-induced mortality, morbidity, and pathology. This reduction in GVHD was associated with the persistence of Helios+ donor regulatory T cells in the allograft, as well as defective upregulation of the gut-homing receptor LPAM-1 on alloreactive CD8+ T cells. Additionally, Nrf2 -/- donor CD8+ T cells demonstrated intact cytotoxicity against allogeneic target cells. Tumor-bearing allo-HCT recipients of Nrf2 -/- donor T cells had overall improved survival as a result of preserved graft-versus-tumor activity and reduced GVHD activity. Our findings characterized a previously unrecognized role for Nrf2 in T-cell function, as well as revealed a novel therapeutic target to improve the outcomes of allo-HCT.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas , Ativação Linfocitária , Fator 2 Relacionado a NF-E2/imunologia , Neoplasias Experimentais/imunologia , Doença Aguda , Aloenxertos , Animais , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/patologia , Camundongos , Camundongos Knockout , Fator 2 Relacionado a NF-E2/genética , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Neoplasias Experimentais/terapia
15.
Am J Surg Pathol ; 42(11): 1456-1465, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30045064

RESUMO

PRAME (PReferentially expressed Antigen in MElanoma) is a melanoma-associated antigen that was isolated by autologous T cells in a melanoma patient. While frequent PRAME mRNA expression is well documented in cutaneous and ocular melanomas, little is known about PRAME protein expression in melanocytic tumors. In this study we examined the immunohistochemical expression of PRAME in 400 melanocytic tumors, including 155 primary and 100 metastatic melanomas, and 145 melanocytic nevi. Diffuse nuclear immunoreactivity for PRAME was found in 87% of metastatic and 83.2% of primary melanomas. Among melanoma subtypes, PRAME was diffusely expressed in 94.4% of acral melanomas, 92.5% of superficial spreading melanomas, 90% of nodular melanomas, 88.6% of lentigo maligna melanomas, and 35% of desmoplastic melanomas. When in situ and nondesmoplastic invasive melanoma components were present, PRAME expression was seen in both. Of the 140 cutaneous melanocytic nevi, 86.4% were completely negative for PRAME. Immunoreactivity for PRAME was seen, albeit usually only in a minor subpopulation of lesional melanocytes, in 13.6% of cutaneous nevi, including dysplastic nevi, common acquired nevi, traumatized/recurrent nevi, and Spitz nevi. Rare isolated junctional melanocytes with immunoreactivity for PRAME were also seen in solar lentigines and benign nonlesional skin. Our results suggest that immunohistochemical analysis for PRAME expression may be useful for diagnostic purposes to support a suspected diagnosis of melanoma. It may also be valuable for margin assessment of a known PRAME-positive melanoma, but its expression in nevi, solar lentigines, and benign nonlesional skin can represent a pitfall and merits further investigations to better assess the potential clinical utility of this marker.


Assuntos
Antígenos de Neoplasias/análise , Biomarcadores Tumorais/análise , Sarda Melanótica de Hutchinson/imunologia , Melanócitos/imunologia , Melanoma/imunologia , Nevo Pigmentado/imunologia , Neoplasias Cutâneas/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Humanos , Sarda Melanótica de Hutchinson/patologia , Imuno-Histoquímica , Masculino , Melanócitos/patologia , Melanoma/secundário , Pessoa de Meia-Idade , Nevo Pigmentado/patologia , Reprodutibilidade dos Testes , Neoplasias Cutâneas/patologia , Adulto Jovem
17.
Am J Surg Pathol ; 42(8): 1052-1058, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29683819

RESUMO

A number of oncogenic driver mutations have been identified in melanocytic nevi and melanoma, but translocations also play a role in tumorigenesis and provide potential therapeutic targets for malignant lesions. Various translocations, such as those involving the anaplastic lymphoma kinase (ALK), neurotrophic tropomyosin receptor kinase 1 (NTRK1), and NTRK3 have been reported in spitzoid melanocytic neoplasms leading to kinase-fusion proteins that result in immunohistochemically detectable ALK or NTRK expression. We have previously reported that ALK expression can be found in nonspitzoid primary and metastatic cutaneous melanomas. In this study we report that nonspitzoid metastasizing melanomas of adults may also harbor NTRK fusions and that NTRK expression can be immunohistochemically detected in these tumors. Of 751 melanomas analyzed by next-generation sequencing, 4 metastatic melanomas were identified with NTRK fusions, 3 involving NTRK1, 1 involving NTRK2. They occurred in 3 women and 1 man. Two of the corresponding primary tumors were from the trunk, 1 from an extremity and 1 tumor arose in anal skin. One primary tumor displayed features of superficial spreading melanoma and 3 were nodular melanomas. All tumors were cytologically characterized by the presence of large epithelioid melanocytes. All tumors were immunoreactive with anti-Trk antibody. Next-generation sequencing documented that the NTRK1 fusion partners included TRIM63, DDR2, and GON4L. One tumor harbored an NTRK2-TRAF2 fusion. Thus, our findings document that NTRK kinase fusions can occur in nonspitzoid metastasizing melanomas of adults. The presence of an NTRK family fusion in these tumors may provide a therapeutic opportunity in a small subset of patients with metastatic melanoma.


Assuntos
Biomarcadores Tumorais/genética , Fusão Gênica , Melanoma/genética , Melanoma/secundário , Glicoproteínas de Membrana/genética , Receptor trkA/genética , Receptor trkB/genética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Adulto , Biomarcadores Tumorais/análise , Feminino , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Masculino , Melanoma/química , Glicoproteínas de Membrana/análise , Pessoa de Meia-Idade , Fenótipo , Receptor trkA/análise , Receptor trkB/análise , Neoplasias Cutâneas/química
18.
Oncologist ; 23(7): 814-821, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29445030

RESUMO

BACKGROUND: This study sought to determine the efficacy and safety profile of cabozantinib in patients with advanced Merkel cell carcinoma (MCC). EXPERIMENTAL DESIGN: This prospective, phase II, single-institution trial enrolled patients with platinum-failure, recurrent/metastatic MCC to receive cabozantinib 60 mg orally daily until disease progression, withdrawal from study, or severe toxicity. The primary endpoint was disease control rate. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and toxicity. Immunohistochemistry for VEGFR-2, MET, and HGF expression and next-generation sequencing of tumor tissue were performed and correlated with outcome. RESULTS: Eight patients were accrued from January 24, 2014, to June 8, 2016. The study was closed prematurely because of toxicity and lack of responses. The most frequent adverse events were grades 1 and 2 and included anorexia, fatigue, nausea, hypothyroidism, and dysgeusia. Two patients developed nonhealing, painful ulcers and tumor-skin fistula. One patient had stable disease for 8 months. One patient withdrew from the study after 2 weeks of therapy because of adverse events. Three patients required dose reduction because of toxicity. Median PFS and OS were 2.1 and 11.2 months, respectively. No expression of MET, HGF, or VEGFR-2 was identified in tumor cells by immunohistochemistry of patients' tissue samples. CONCLUSION: Cabozantinib was poorly tolerated and did not demonstrate activity in patients with recurrent/metastatic, platinum-failure MCC. It is unclear whether preselection of patients with the specific upregulation or genetic alteration in the targets for cabozantinib would have changed the results of this study. (Clinical trial identification number: NCT02036476) IMPLICATIONS FOR PRACTICE: This phase II study demonstrated poor tolerability and lack of activity of cabozantinib in an unselected group of patients with advanced Merkel cell carcinoma. Although it is unclear whether preselection of patients with the specific upregulation and genetic alterations in targets for cabozantinib would have changed the results of this study, this would have likely led to an extremely rare patient population that would take many years to accrue.


Assuntos
Anilidas/uso terapêutico , Carcinoma de Célula de Merkel/tratamento farmacológico , Piridinas/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Anilidas/efeitos adversos , Carcinoma de Célula de Merkel/patologia , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Estudos Prospectivos , Piridinas/efeitos adversos , Receptores Proteína Tirosina Quinases/efeitos adversos , Receptores Proteína Tirosina Quinases/uso terapêutico , Neoplasias Cutâneas/patologia
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