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ABSTRACT: Clear-cell dermal duct tumor is a benign adnexal neoplasm composed of dermal multiple solid islands of clear cells, displaying ductal differentiation. Histopathologically, lesions can be subdivided into 2 distinct subgroups: (1) "pure" clear-cell dermal duct tumors, entirely composed of clear cells, and (2) "mixed" clear-cell dermal duct tumors, showing an associated conventional poroid component. Such a subclassification may be significant for the differential diagnosis: the less frequent "mixed" variant may be more easily recognized because of the presence of poroid and cuticular cells and the more frequent "pure" variant is to be distinguished from many other benign and malignant dermal clear-cell epithelial tumors.
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Poroma , Neoplasias das Glândulas Sudoríparas , Humanos , Poroma/patologia , Neoplasias das Glândulas Sudoríparas/patologiaRESUMO
ABSTRACT: Melanocytic nevi can show a great number of morphological, cytoarchitectural, and stromal variations. Some of these histopathological patterns, infrequent or unusual, can occasionally produce diagnostic doubts or problems. A 22-year-old female patient presented a poorly pigmented cutaneous polypoid lesion of the scalp. Histopathological examination showed an intradermal melanocytic nevus composed of aggregates, nests, and cords of benign melanocytes, with collagenous stroma and large lipomatous areas. In the lipidized portion of the lesion, nevus cells, arranged in clusters, nests, and cords, were intimately associated with mature-appearing adipocytes, CD34-positive spindle cells, Alcian Blue-positive fibromyxoid stroma, and eosinophilic collagen bundles, findings resembling those typically seen in spindle cell lipoma. Spindle cell lipomatous metaplasia, rarely observed in some benign nonmelanocytic skin lesions, can be considered an additional unusual, not previously described, stromal variation occurring in melanocytic nevi.
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Metaplasia , Nevo Pigmentado , Neoplasias Cutâneas , Humanos , Feminino , Metaplasia/patologia , Nevo Pigmentado/patologia , Neoplasias Cutâneas/patologia , Adulto Jovem , Lipoma/patologia , Couro Cabeludo/patologia , Imuno-HistoquímicaRESUMO
Studies on the genomic aberrations in melanocytic neoplasms have shown a complex genomic landscape. In nevi and melanomas, a MAP-kinase pathway activation was generally found, produced by different chromosomal aberrations, including BRAF, NRAS, HRAS, GNAQ, GNA11, BAP1, CTNNB1, MAP2K1, PRKAR1A, and NF1 mutations, and ALK, ROS1, NTRK1, RET, MET, BRAF, NTRK3, and PRKCA fusions. Melanomas also showed a variable number of additional mutations ablating tumor-suppression mechanisms and activating other oncogenic pathways, including CDKN2A loss, PTEN loss, as well as TP53 and TERT-promoter mutations. Moreover, borderline melanocytic tumors displayed the same chromosomal aberrations, but more mutations than nevi and fewer than melanomas. In this context, the notion that melanocytic neoplasms can be classified as benign/malignant is hardly supportable, because all neoplasms harbor a certain number of mutations and the progression risk, that is, the malignant potential, is related and proportional to the burden of pathogenic mutations. Moreover, from the genomic analysis, in parallel to the current diagnostic categories of "nevi," "melanomas," and "melanocytomas," some aggregations or classes of tumors based on the characteristic types of driver mutations/fusions emerge as possible and more rationale, including Spitzoid neoplasms, blue neoplasms, BAP1-inactivated melanocytic neoplasms, deep penetrating melanocytic neoplasms, pigment-synthesizing melanocytic neoplasms, and "common" melanocytic neoplasms. Each of these classes, showing the same driver mutations/fusions, demonstrates to have the same pathogenesis and may be genetically considered as a single tumor, although with a variable amount of progression risk. Histologic features, being an expression of the mutational state, could be used to obtain an approximate risk assessment in each single tumor.
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Aberrações Cromossômicas , Subunidades alfa de Proteínas de Ligação ao GTP/genética , Melanoma/genética , Nevo de Células Epitelioides e Fusiformes/genética , Neoplasias Cutâneas/genética , beta Catenina/genética , Biópsia por Agulha , Educação Médica Continuada , Feminino , Predisposição Genética para Doença/epidemiologia , Estudo de Associação Genômica Ampla , Genômica , Humanos , Imuno-Histoquímica , Masculino , Melanoma/patologia , Mutação , Nevo de Células Epitelioides e Fusiformes/patologia , Sensibilidade e Especificidade , Neoplasias Cutâneas/patologiaRESUMO
Testing for NRAS is now integral part in the assessment of metastatic melanoma patients because there is evidence that NRAS-mutated patients may be sensitive to MEK inhibitors, and RAS mutation is a common mechanism of acquired resistance during treatment with BRAF inhibitors. This study evaluated the sensitivity and specificity of immunohistochemical analysis using an N-Ras (Q61R) antibody to detect the presence of the NRASQ61R mutation in melanoma patients. A total of 98 primary cutaneous melanomas that have undergone examination of NRAS mutation were retrieved from a multicentric database. Formalin-fixed and paraffin-embedded melanoma tissues were analyzed for BRAF and NRAS mutations by independent, blinded observers using both conventional DNA molecular techniques and immunohistochemistry with the novel anti-human N-Ras (Q61R) monoclonal antibody (clone SP174). The antibody showed a sensitivity of 100% (14/14) and a specificity of 100% (83/83) for detecting the presence of an NRASQ61R mutation. Of the NRAS-mutated cases, none of the non-Q61R cases stained positive with the antibody (0/7). There were three cases with discordant NRAS mutational results. Additional molecular analysis confirmed the immunohistochemically obtained NRAS result in all cases, suggesting that a multiple analytical approach can be required to reach the correct sample classification. The reported immunohistochemical method is an accurate, rapid, and cost-effective method for detecting NRASQ61R mutation in melanoma patients, and represents a valuable supplement to traditional mutation testing. If validated in further studies, genetic testing would only be required for immunohistochemistry-negative patients to detect non-Q61R mutations.
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GTP Fosfo-Hidrolases/metabolismo , Imuno-Histoquímica , Melanoma/metabolismo , Proteínas de Membrana/metabolismo , Mutação , Neoplasias Cutâneas/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , GTP Fosfo-Hidrolases/genética , Humanos , Masculino , Melanoma/genética , Melanoma/patologia , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Adulto JovemRESUMO
We report the case of an old woman with an eccrine porocarcinoma unusually localized in the perianal area treated by electrochemotherapy, a new technique, emerging as a very effective local treatment of different skin metastases and selected primary tumors. Electrochemotherapy was performed taking into account patient wishes and refusal of demolitive surgery. The electrochemotherapy treatment was well tolerated by the patient, it gave an excellent clinical response and a complete clinical regression with no sphincter dysfunction and signs of relapse observed during follow-up. The case is of particular interest for the exceptional localization of porocarcinoma for the first time treated by electrochemotherapy in this area. Electrochemotherapy could be considered as an alternative option for selected cases of cutaneous tumors.
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Neoplasias do Ânus/diagnóstico , Porocarcinoma Écrino/diagnóstico , Neoplasias Cutâneas/diagnóstico , Idoso de 80 Anos ou mais , Neoplasias do Ânus/tratamento farmacológico , Porocarcinoma Écrino/tratamento farmacológico , Eletroquimioterapia , Feminino , Humanos , Neoplasias Cutâneas/tratamento farmacológico , Resultado do TratamentoRESUMO
Merkel cell polyomavirus (MCPyV) is associated with Merkel cell carcinoma (MCC). In tumor cells the MCPyV large T antigen (LT-Ag) is frequently found truncated and this is considered a major tumor-specific signature. The role of MCPyV in other, non-MCC tumours, is little known. Viral DNA and/or tumour-specific mutations have been sometimes detected in different tumours, but such data are not unequivocal and the involvement of the virus in the tumorigenesis is not clear. In a previous study, we demonstrated a significantly higher prevalence of MCPyV DNA in formalin fixed paraffin embedded (FFPE) porocarcinoma tissues compared to the normal skin. In the present study, we investigated the presence of truncating mutations in MCPyV LT-Ag coding region in porocarcinoma specimens. Using several overlapped PCR primer pairs, the complete LT-Ag sequence from two biopsies were obtained. No truncating mutations were detected. The lack of truncating mutations in LT-Ag sequence does not seem to support the role of MCPyV in porocarcinoma oncogenesis. However, an oncogenetic mechanism, different from that proposed for MCC and not associated with the LT-Ag mutations/deletions, cannot be excluded. Further studies of more sequences coding for LT-Ag would be needed to verify this hypothesis.
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After 25 years, "Ackerman's conundrum", namely, the distinction of benign from malignant Spitz neoplasms, remains challenging. Genomic studies have shown that most Spitz tumors harbor tyrosine and serine/threonine kinase fusions, including ALK, ROS1, NTRK1, NTRK2, NTRK3, BRAF and MAP3K8, or some mutations, such as HRAS and MAP3K8. These chromosomal abnormalities act as drivers, initiating the oncogenetic process and conferring basic bio-morphological features. Most Spitz tumors show no additional genomic alterations or few ones; others harbor a variable number of mutations, capable of conferring characteristics related to clinical behavior, including CDKN2A deletion and TERT-p mutation. Since the accumulation of mutations is gradual and progressive, tumors appear to form a bio-morphologic spectrum, in which they show a progressive increase of clinical risk and histological atypia. In this context, a binary classification Spitz nevus-melanoma appears as no longer adequate, not corresponding to the real genomic substrate of lesions. A ternary classification Spitz nevus-Spitz melanocytoma-Spitz melanoma is more adherent to the real neoplastic pathway, but some cases with intermediate ambiguous features remain difficult to diagnose. A prognostic stratification of Spitz tumors, based on the morphologic and genomic characteristics, as a complement to the diagnosis, may contribute to better treatment plans for patients.
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Folliculosebaceous cystic hamartoma is a cutaneous malformation composed of a cystic folliculosebaceous structure associated with mesenchymal elements, generally consisting of fibrous stroma, adipocytes and small vascular channels. We report the case of a 55-year-old female patient with a cutaneous nodule of the right nasal wing. Microscopically, the lesion showed a dilated hair follicle with multiple sebaceous glands, surrounded by a mesenchymal component composed of fibromyxoid stroma, spindle cells, mature-appearing adipocytes and collagen bundles, resembling spindle cell lipoma, associated with an additional neural component, consisting of small nerve bundles. In folliculosebaceous cystic hamartoma, the association of spindle cell lipomatous and neural components has not previously reported.
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Porocarcinoma Écrino/diagnóstico , Porocarcinoma Écrino/cirurgia , Neoplasias das Glândulas Sudoríparas/diagnóstico , Idoso , Amputação Cirúrgica , Biópsia , Diagnóstico Diferencial , Porocarcinoma Écrino/patologia , Humanos , Masculino , Neoplasias das Glândulas Sudoríparas/patologia , Dedos do PéAssuntos
Transformação Celular Neoplásica/patologia , Melanoma/patologia , Nevo Azul/patologia , Nevo de Células Epitelioides e Fusiformes/patologia , Neoplasias Cutâneas/patologia , Biópsia por Agulha , Estudos de Coortes , Diagnóstico Diferencial , Feminino , Humanos , Imuno-Histoquímica , Masculino , Melanoma/fisiopatologia , Nevo Azul/fisiopatologia , Nevo de Células Epitelioides e Fusiformes/fisiopatologia , Medição de Risco , Neoplasias Cutâneas/fisiopatologiaRESUMO
Over the past several decades, the study of Spitz neoplasms has flourished, with expanded conceptualization and refined terminology, providing a framework for the assessment and classification of Spitz nevi, atypical Spitz Tumors, and Spitz melanoma. Cancer genomics have generated concepts such as driver and passenger genes and clonal evolution, which can be applied to Spitz tumors. Herein, we provide a historical perspective, followed by a summary of current knowledge and clinical approaches for these challenging tumors.
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Eruptive melanocytic nevi (EMN) describes the sudden onset of cutaneous nevi over weeks or months. Such a clinical event is generally seen in young adult patients and may be related to several possible causes. We report here a case of EMN in an old male patient followed up for a thick amelanotic cutaneous melanoma. A few months after the eruption, multiple hepatic masses, diagnosed as melanoma metastasis, were detected. The presented case may suggest that EMN may be a paraneoplastic phenomenon of alert in patients being followed for melanoma or other malignancies.
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Melanoma Amelanótico/complicações , Nevo Pigmentado/etiologia , Idoso de 80 Anos ou mais , Humanos , Masculino , Nevo Pigmentado/fisiopatologia , Síndromes ParaneoplásicasRESUMO
Deep penetrating nevi (DPNs) are rare melanocytic neoplasms consisting of pigmented spindled or epithelioid melanocytes with a distinctive wedge-shaped configuration showing activation of the WNT pathway, with unusual cyto-architectural features. It is unclear whether they show a distinct genomic profile associated with a diverse metastatic potential. We describe herein a cohort of 21 atypical DPNs analyzed by next-generation sequencing using the Ion AmpliSeq™ Comprehensive Cancer Panel. We found that ß-catenin exon 3 was mutated in 95% and MAP kinase pathway genes in 71% of the cases. Less frequent mutations were observed in HRAS (19%) and MAP2K1 (24%). Isocitrate dehydrogenases 1 (IDH1) mutations, including R132C, V178I, and S278L, were identified in 38% of cases and co-existed with BRAF/HRAS mutations. The only case with progressive nodal disease carried alterations in the ß-catenin pathway and mutations in IDH1 and NRAS (codon 61). By a comprehensive mutation analysis, we found low genetic heterogeneity and a lack of significant associations between specific gene mutations and histopathological features, despite atypical features. Whether the acquisition of an NRAS or IDH1 mutation in an atypical DPN may represent a molecular evolution implying a pathway to melanoma progression should be confirmed in a larger series.
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We report a 20-year-old male patient with an atypical Spitz tumor, located in the dorsal aspect of his left hand, and a positive sentinel axillary lymph node. After lymphadenectomy, 1 of 23 non-sentinel lymph nodes excised was found to contain small multiple deposits of large spindle atypical melanocytes. Reviewing the pertinent literature, 5 of 29 patients with atypical Spitz tumors and positive sentinel nodes who had undergone lymphadenectomy have shown non-sentinel node involvement (17.2%), a proportion similar to that reported in melanoma patients. The exact nature of atypical Spitz tumors and the interpretation of cell deposits detected in sentinel nodes are still debated; data regarding the non-sentinel lymph node involvement in patients with atypical Spitz tumors may contribute to better understand the real biological potential of such tumors.
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Metástase Linfática/patologia , Nevo de Células Epitelioides e Fusiformes/patologia , Neoplasias Cutâneas/patologia , Adulto , Mãos/patologia , Humanos , Linfonodos/patologia , Masculino , Nevo de Células Epitelioides e Fusiformes/metabolismo , Nevo de Células Epitelioides e Fusiformes/cirurgia , Biópsia de Linfonodo Sentinela , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/cirurgiaRESUMO
This study aimed to investigate the sentinel lymph node (SLN) tumour burden to predict the non-SLN positivity rate and the survival of melanoma patients to evaluate whether SLN microstaging could predict the prognosis, similar to what is currently performed by examining the lymph nodes excised by complete lymph node dissection. Of 1130 consecutive melanoma patients who underwent SLN biopsy, 226 were tumour-positive and 204 were included in this study. SLN metastases were classified on the basis of dimensional (Rotterdam) and topographic (Dewar) criteria either separately or combined. SLN metastases more than 1 mm in diameter had the highest non-SLN positivity rate (31%) compared with metastases 0.1-1 mm (10%) and less than 0.1 mm (4%). The non-SLN positivity rate was 45% for extensive metastases, 5% for subcapsular metastases and 23-29% for parenchymal, combined and multifocal classes, therefore suggesting a simplification of the parenchymal SLN metastases into only two classes: extensive and 'not extensive'. The dimension of the metastasis was correlated with a different non-SLN positivity rate only when the metastasis was in the parenchyma (20-36%) and not when it was in the subcapsular location (4-7%). Interestingly, the 5-year melanoma-specific survival (MSS) was 89% for patients with subcapsular less than 0.1 mm metastases and 45% for patients with nonsubcapsular more than 1 mm metastases (P=0.017). In the parenchyma, larger metastases (>1 mm) were related to a lower 5-year MSS (46%) than smaller (<1 mm) metastases (MSS 77%). SLN tumour burden characterization can be simplified and it can provide prognostic information on non-SLN positivity and survival, which is especially useful in patients who do not undergo complete lymph node dissection.
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Excisão de Linfonodo/métodos , Metástase Linfática/fisiopatologia , Melanoma/complicações , Linfonodo Sentinela/fisiopatologia , Neoplasias Cutâneas/complicações , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Prognóstico , Neoplasias Cutâneas/patologia , Carga Tumoral , Adulto JovemRESUMO
Most nodal nevi are intracapsular and present the morphology of conventional nevi; less frequently, they show the appearance of common and cellular blue nevi. We report a case of an nodal capsular, trabecular and intraparenchymal melanocytic nevus with balloon-cell change in a patient with a malignant melanoma which arose in a pre-existing cutaneous giant congenital nevus, showing balloon-cell degeneration.
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Linfonodos/patologia , Melanócitos/patologia , Melanoma/patologia , Nevo Pigmentado/patologia , Neoplasias Cutâneas/patologia , Adulto , Síndrome do Nevo Displásico/patologia , Evolução Fatal , Humanos , Metástase Linfática/patologia , Masculino , Nevo Pigmentado/congênito , Biópsia de Linfonodo SentinelaRESUMO
Malignant melanoma is among the most aggressive cancers and its incidence is increasing worldwide. Targeted therapies and immunotherapy have improved the survival of patients with metastatic melanoma in the last few years; however, available treatments are still unsatisfactory. While the role of the BRAF-MEK1/2-ERK1/2 pathway in melanoma is well established, the involvement of mitogen-activated protein kinases MEK5-ERK5 remains poorly explored. Here we investigated the function of ERK5 signaling in melanoma. We show that ERK5 is consistently expressed in human melanoma tissues and is active in melanoma cells. Genetic silencing and pharmacological inhibition of ERK5 pathway drastically reduce the growth of melanoma cells and xenografts harboring wild-type (wt) or mutated BRAF (V600E). We also found that oncogenic BRAF positively regulates expression, phosphorylation, and nuclear localization of ERK5. Importantly, ERK5 kinase and transcriptional transactivator activities are enhanced by BRAF. Nevertheless, combined pharmacological inhibition of BRAFV600E and MEK5 is required to decrease nuclear ERK5, that is critical for the regulation of cell proliferation. Accordingly, combination of MEK5 or ERK5 inhibitors with BRAFV600E inhibitor vemurafenib is more effective than single treatments in reducing colony formation and growth of BRAFV600E melanoma cells and xenografts. Overall, these data support a key role of the ERK5 pathway for melanoma growth in vitro and in vivo and suggest that targeting ERK5, alone or in combination with BRAF-MEK1/2 inhibitors, might represent a novel approach for melanoma treatment.