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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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AIMS: Merkel cell carcinoma (MCC) is frequently caused by the Merkel cell polyomavirus (MCPyV). Characteristic for these virus-positive (VP) MCC is MCPyV integration into the host genome and truncation of the viral oncogene Large T antigen (LT), with full-length LT expression considered as incompatible with MCC growth. Genetic analysis of a VP-MCC/trichoblastoma combined tumour demonstrated that virus-driven MCC can arise from an epithelial cell. Here we describe two further cases of VP-MCC combined with an adnexal tumour, i.e. one trichoblastoma and one poroma. METHODS AND RESULTS: Whole-genome sequencing of MCC/trichoblastoma again provided evidence of a trichoblastoma-derived MCC. Although an MCC-typical LT-truncating mutation was detected, we could not determine an integration site and we additionally detected a wildtype sequence encoding full-length LT. Similarly, Sanger sequencing of the combined MCC/poroma revealed coding sequences for both truncated and full-length LT. Moreover, in situ RNA hybridization demonstrated expression of a late region mRNA encoding the viral capsid protein VP1 in both combined as well as in a few cases of pure MCC. CONCLUSION: The data presented here suggest the presence of wildtype MCPyV genomes and VP1 transcription in a subset of MCC.
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Carcinoma de Célula de Merkel , Poliomavírus das Células de Merkel , Infecções por Polyomavirus , Poroma , Neoplasias Cutâneas , Neoplasias das Glândulas Sudoríparas , Humanos , Carcinoma de Célula de Merkel/metabolismo , Poliomavírus das Células de Merkel/genética , Infecções por Polyomavirus/complicações , Neoplasias Cutâneas/patologia , GenômicaRESUMO
BACKGROUND AND OBJECTIVES: Malignant sweat gland tumors are rare, with the most common being eccrine porocarcinoma (EP). Approximately 18% of benign eccrine poroma (EPO) transit to EP. Previous research has provided first insights into the mutational landscape of EP. However, only few studies have performed gene expression analyses. This leaves a gap in the understanding of EP biology and potential drivers of malignant transformation from EPO to EP. METHODS: Transcriptome profiling of 23 samples of primary EP and normal skin (NS). Findings from the EP samples were then tested in 17 samples of EPO. RESULTS: Transcriptome profiling revealed diversity in gene expression and indicated biologically heterogeneous sub-entities as well as widespread gene downregulation in EP. Downregulated genes included CD74, NDGR1, SRRM2, CDC42, ANXA2, KFL9 and NOP53. Expression levels of CD74, NDGR1, SRRM2, ANXA2, and NOP53 showed a stepwise-reduction in expression from NS via EPO to EP, thus supporting the hypothesis that EPO represents a transitional state in EP development. CONCLUSIONS: We demonstrated that EP is molecularly complex and that evolutionary trajectories correspond to tumor initiation and progression. Our results provide further evidence implicating the p53 axis and the EGFR pathway. Larger samples are warranted to confirm our findings.
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Porocarcinoma Écrino , Perfilação da Expressão Gênica , Neoplasias das Glândulas Sudoríparas , Humanos , Porocarcinoma Écrino/genética , Porocarcinoma Écrino/patologia , Neoplasias das Glândulas Sudoríparas/genética , Neoplasias das Glândulas Sudoríparas/patologia , Neoplasias das Glândulas Sudoríparas/metabolismo , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/patologia , Feminino , Masculino , Transformação Celular Neoplásica/genética , Regulação Neoplásica da Expressão Gênica , Idoso , Pessoa de Meia-IdadeRESUMO
Syringocystadenocarcinoma papilliferum (SCACP), the malignant counterpart of syringocystadenoma papilliferum (SCAP), is an extremely rare malignant adnexal neoplasm. It is described by the World Health Organization as a malignant transformation of SCAP occurring in middle-aged to elderly individuals with a predilection for the head and neck. SCACP seems to arise from a long-standing syringocystadenoma probably on a background of nevus sebaceous (NS) through a multistep progression. A 75-year-old man was referred to our department with a long-standing NS with a recent newly developing nodule on his scalp. The tumor was excised. On histology, the overall architecture of the tumor still resembled an unusual SCAP within NS but simultaneously showed transition to syringocystadenocarcinoma papilliferum in situ and invasive SCACP as recognizable by the presence of areas of nuclear atypia, increased proliferative activity, and infiltrative growth. In summary, we report an extremely rare case of an invasive SCACP of the scalp that demonstrates histological evidence for all transitive steps in the hypothetical multistep progression from NS to invasive SCACP in one single lesion. The implications of these findings are discussed in the light of the relevant literature.
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Cistadenocarcinoma/patologia , Nevo/patologia , Couro Cabeludo/patologia , Neoplasias das Glândulas Sudoríparas/patologia , Adenomas Tubulares de Glândulas Sudoríparas/patologia , Idoso , Transformação Celular Neoplásica/patologia , Humanos , MasculinoRESUMO
BACKGROUND: Cutaneous benign angioproliferations can be diagnostically challenging and may mimic vascular tumors. Keratinocytes express vascular endothelial growth factors (VEGFs). We studied the angiogenic factor expression pattern in cutaneous lesions with a distinctive pattern of remarkable dermal angiomatosis underlying prurigo-like epidermal changes. METHODS: Cases were selected retrospectively from 2012 to 2018, and their VEGF staining pattern was compared with normal skin and other reactive skin conditions. RESULTS: Thirty-eight patients, median age 76 years, mostly men (74%), presented with asymptomatic patches or plaques, most commonly located on the buttocks (n = 17) and/or intergluteal fold (n = 12), often eliciting concern for neoplasia (n = 19). Microscopically, all cases featured a prominent proliferation of dilated capillaries and postcapillary venules, underneath epidermal changes resembling prurigo or lichen simplex chronicus. In one-third, a subepidermal lymphocytic infiltrate was present. Immunostaining with VEGF was positive in the upper 4/5 of the epidermis overlying the angioproliferation, in contrast with nonlesional skin, where VEGF positivity was limited to the stratum granulosum. Receptor VEGFR-2 was expressed in the endothelia of neovessels. CONCLUSIONS: We propose the term prurigiform angiomatosis for the morphological picture of prurigo/lichen simplex chronicus-like epidermal hyperplasia with prominent dermal angioproliferation. Mechanical injury and inflammation are the likely triggers of this reactive angiogenesis pattern, driven by epidermal VEGF expression.
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Angiomatose/patologia , Dermatopatias/patologia , Fatores de Crescimento do Endotélio Vascular/metabolismo , Idoso , Idoso de 80 Anos ou mais , Angiomatose/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Dermatopatias/metabolismoRESUMO
Neutrophilic infiltrates in panniculitis can be seen in different clinical-pathological entities. There are a "mostly neutrophilic inflammatory infiltrate" in some entities classically defined as neutrophilic panniculitis and already included in algorithms, such as enzymatic panniculitis, infective and factitial ones, erythema induratum, or subcutaneous Sweet syndrome, but there are also other panniculitis where neutrophils are frequently observed such as panniculitis associated with inflammatory bowel disease or rheumatoid arthritis, or drug-induced panniculitis associated with BRAF inhibitors, and finally, some panniculitis are better classified in other panniculitides groups but may present with neutrophil-rich variants, such as the neutrophil-rich subcutaneous fat necrosis of the newborn. We review the main clinical and histopathological features of most of these panniculitides and construct a diagnostic algorithm including these diseases.
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Algoritmos , Eritema Nodoso/patologia , Neutrófilos/patologia , Paniculite/etiologia , Paniculite/patologia , Dermatopatias Infecciosas/complicações , Doenças Autoimunes/complicações , Síndrome de Behçet/patologia , Corpos Estranhos/complicações , Humanos , Pancreatopatias/complicações , Paniculite/diagnóstico , Inibidores de Proteínas Quinases/efeitos adversos , Síndrome de Sweet/complicações , Deficiência de alfa 1-Antitripsina/complicaçõesRESUMO
To shed more light on the pathogenesis of sebaceous carcinoma, we analysed the expression of proteins related to angiogenesis in 18 ocular and 22 extraocular sebaceous carcinomas using a broad panel of immunohistochemical markers. To quantify the expression of D2-40, vascular endothelial growth factor, vascular endothelial growth factor receptor-2 and -3, we calculated a quantification score by considering the percentage of positive tumour cells (0=0%, 1=up to 1%, 2=2-10%, 3=11-50%, and 4=>50%) in relation to the staining intensity (0=negative, 1=low, 2=medium, and 3=strong). Additionally, lymphatic microvessel density in the D2-40 stained sections was counted. Vascular endothelial growth factor receptor-3 (quantification score 9.42 ± 2.94) was significantly more strongly expressed than vascular endothelial growth factor receptor-2 (quantification score 2.15 ± 2.42, p < 0.001). Furthermore, epidermal vascular endothelial growth factor expression was negatively correlated with the intratumoural lymphatic vessel density, and the ratio of small lymphatics to large lymphatics was much higher in intratumoural tissue than in paratumoural tissue and in intraindividual control tissue, suggesting a lymphangiogenetic potential of sebaceous carcinoma.
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Adenocarcinoma Sebáceo/patologia , Biomarcadores Tumorais/metabolismo , Neovascularização Patológica/patologia , Neoplasias das Glândulas Sebáceas/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator C de Crescimento do Endotélio Vascular/metabolismo , Adenocarcinoma Sebáceo/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia por Agulha , Estudos de Coortes , Olho/patologia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Neoplasias das Glândulas Sebáceas/fisiopatologiaRESUMO
An otherwise healthy 50-year-old woman was evaluated for the presence of 2 erythematous, and slightly pruritic plaques, involving both cheeks for 30 years. Left-side skin biopsy showed a diffuse proliferation of ductal structures horizontally arranged and involving the reticular dermis that resembled tubular adenoma embedded in a sclerotic stroma and surrounded by a peculiar periductal desmoplasia. Nuclear atypia or mitosis was not found. Contralateral biopsy showed identical findings. Differential diagnosis included microcystic adnexal carcinoma (MAC) and plaque-like syringoma and a peculiarly horizontally arranged tubular adenoma. We ruled out MAC as the lesions were long-standing, without infundibular cysts, solid strands, or perineural infiltration. Our case closely resembled those previously described as sweat duct proliferation associated with aggregates of elastic tissue and atrophoderma vermiculatum, although striking differences were observed, as our case did not present aggregates of elastic tissue, did not involve the papillary and superficial reticular dermis, and presented evidences of decapitation secretion as a sign of apocrine differentiation. We consider our case as a MAC simulator and we propose the descriptive name of bilateral facial apocrine fibrosing hamartoma.
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Dermatoses Faciais/patologia , Hamartoma/patologia , Neoplasias de Anexos e de Apêndices Cutâneos/patologia , Neoplasias Cutâneas/patologia , Doenças das Glândulas Sudoríparas/patologia , Diagnóstico Diferencial , Dermatoses Faciais/diagnóstico , Feminino , Hamartoma/diagnóstico , Humanos , Pessoa de Meia-Idade , Neoplasias de Anexos e de Apêndices Cutâneos/diagnóstico , Neoplasias Cutâneas/diagnóstico , Doenças das Glândulas Sudoríparas/diagnósticoRESUMO
After a review of the physiology in the formation and degradation of cutaneous elastic tissue, we describe the clinicopathologic disorders characterized by increased and decreased cutaneous elastic tissue. Cutaneous disorders characterized by increased and/or abnormal elastic tissue in the dermis include elastoma, also named nevus elasticus, dermatosis lenticularis disseminata, pseudoxanthoma elasticum, late-onset focal dermal elastosis, linear focal elastosis, elastoderma, elastofibroma dorsi, and elastosis perforans serpiginosa. In some of these conditions, the specific histopathologic diagnosis may be rendered with hematoxylin-eosin stain, whereas in other ones special elastic tissue stains are necessary to demonstrate the anomalies. Cutaneous disorders characterized by decreased dermal elastic tissue include nevus anelasticus, papular elastorrhexis, perifollicular elastolysis, anetoderma cutis laxa, postinflammatory elastolysis and cutis laxa, white fibrous papulosis of the neck, pseudoxanthoma elasticum-like papillary dermal elastolysis, and mid dermal elastolysis. In most of these conditions, the histopathologic anomalies are only seen with elastic tissue stains, and cutaneous biopsies of these processes stained with hematoxylin-eosin show appearance of normal skin. The diagnosis of some of these disorders characterized by increased or decreased elastic dermal tissue should be followed by general exploration of the patient to rule out associated severe systemic anomalies, and in some cases, a genetic counseling should be offered to the family.
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Tecido Elástico/patologia , Dermatopatias/patologia , Doenças do Tecido Conjuntivo/patologia , HumanosRESUMO
Despite new horizons opened by recent advances in molecular pathology, histological evaluation still remains the diagnostic gold standard regarding cutaneous melanocytic neoplasms. Several histological variants of melanoma have been described, and their knowledge is crucial for accurate diagnosis and classification of cases with unusual clinico-pathological features. Uncommon histological variants of melanoma have been described based on a broad constellation of features, including architectural pattern, stromal alterations, cytological attributes, and other morphological properties. This review is aimed at providing an extensive discussion of unusual but distinctive histopathological variants of melanoma.
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Melanoma/patologia , Neoplasias Cutâneas/patologia , Humanos , Melanoma Maligno CutâneoRESUMO
Despite new horizons opened by recent advances in molecular pathology, histological evaluation still remains the diagnostic gold standard regarding cutaneous melanocytic neoplasms. Several histological variants of melanoma have been described, and their knowledge is crucial for accurate diagnosis and classification of cases with unusual clinicopathological features. Uncommon histological variants of melanoma have been described based on a broad constellation of features, including architectural pattern, stromal alterations, cytological attributes, and other morphological properties. This review is aimed at providing an extensive discussion of unusual but distinctive histopathological variants of melanoma.
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Melanoma/patologia , Neoplasias Cutâneas/patologia , Humanos , Melanoma Maligno CutâneoAssuntos
Porocarcinoma Écrino , Perfilação da Expressão Gênica , Neoplasias das Glândulas Sudoríparas , Humanos , Porocarcinoma Écrino/genética , Porocarcinoma Écrino/patologia , Neoplasias das Glândulas Sudoríparas/genética , Neoplasias das Glândulas Sudoríparas/patologia , Transcriptoma/genética , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/patologia , Feminino , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Masculino , Regulação Neoplásica da Expressão Gênica , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: Twelve cases of primary cutaneous secretory carcinoma (PCSC) have been published, 9 showing ETV6-NTRK3 translocation, a characteristic finding shared with secretory breast carcinoma and mammary analogue secretory carcinoma. CASE REPORT: A 34-year-old female presented a solitary nodule on the right groin. Biopsy revealed a secretory carcinoma staining positive with CK7, CAM5.2, mammaglobulin and S100 and negative with GATA3, CK20, podoplanin, calponin and CDX2. ETV6-NTRK3 was demonstrated by Fluorescence in situ hybridization (FISH). DISCUSSION: PCSC is a rare neoplasm, described in the skin in 2009, that affects more frequently females with a mean age of 42.3 years and it is most commonly located in axilla. Histopathologically, these tumor cells are characterized by bubbly eosinophilic secretions diastase-resistant and bland nuclei and they are arranged in various growth patterns, including microcystic, tubular, solid and papillary. S100, mammoglobin and CK7 are usually positive. We review the main histopathological features to rule out histopathologic mimics such as breast metastasis, salivary tumors, cribriform carcinoma and primary cutaneous adenoid cystic carcinoma. GATA3 negative staining, as in our case, can help to rule out breast metastasis. Moreover, long-term benign follow up (144 months) in this case as well as follow-up data on outcomes from literature review support that PCSC is a low-grade sweat gland carcinoma.
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Carcinoma Secretor Análogo ao Mamário/patologia , Neoplasias das Glândulas Sudoríparas/patologia , Biomarcadores Tumorais/análise , Feminino , Humanos , Carcinoma Secretor Análogo ao Mamário/genética , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , Neoplasias das Glândulas Sudoríparas/genéticaRESUMO
BACKGROUND: Primary cutaneous apocrine cribriform carcinoma (PCACC) is a rare tumor, clinically appearing as a solitary nodule, mostly involving extremities of females and this lesion usually raises a differential diagnosis with metastatic cribriform carcinomas, especially breast cancer. OBJECTIVE: To study GATA3 expression in a series of 14 primary cutaneous cribriform carcinomas and to test its usefulness to differentiate this tumor from metastatic breast cancer. METHODS: We retrieved 14 cases with PCACC (each from a different patient) from the files of the authors. Cases were dated from 1994 to 2014. We also evaluated 6 cases of cutaneous breast cancer metastasis RESULTS: No PCACCs expressed GATA3. Breast cancer metastases expressed GATA3 in 100% of our studied cases. CONCLUSION: Even though GATA3 expression has been reported in many benign and malignant adnexal tumors (mostly of sebaceous, follicular, and apocrine differentiation), as well as in many other neoplasms, GATA3 staining to differentiate PCACC from skin breast cancer metastasis has a high negative predictive value. A positive GATA3 staining in this context should permit one to rule out PCACC with a high level of confidence.
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Adenocarcinoma/diagnóstico , Neoplasias da Mama/diagnóstico , Fator de Transcrição GATA3/biossíntese , Neoplasias das Glândulas Sudoríparas/diagnóstico , Idoso , Biomarcadores Tumorais/análise , Neoplasias da Mama/secundário , Diagnóstico Diferencial , Feminino , Fator de Transcrição GATA3/análise , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos TestesRESUMO
Microcystic adnexal carcinoma (MAC) is a low-grade malignant tumor of the skin. Histologically, this tumor shows a biphasic pattern, with cords and nests of basaloid cells, as well as keratin horn cysts. This biphasic histological appearance has been interpreted by some authors as a sign of double eccrine and folliculosebaceous-apocrine differentiation, whereas some other authors defend a solely eccrine differentiation. In this context, sebaceous differentiation in MAC would support the first option. However, there are only 3 cases of MAC with sebaceous differentiation in the literature, and all of them were reported before adipophilin was available, which in the appropriate context (eg, testing clear cells for sebaceous vs eccrine differentiation) is very useful. In this study, we present 3 cases of MAC with focal sebaceous differentiation confirmed by immunoexpression of adipophilin in the sebaceous foci.
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Carcinoma de Apêndice Cutâneo/patologia , Glândulas Sebáceas/patologia , Neoplasias Cutâneas/patologia , Idoso , Biomarcadores Tumorais/análise , Diferenciação Celular , Feminino , Humanos , Perilipina-2/análise , Perilipina-2/biossínteseRESUMO
BACKGROUND: Solid carcinoma is a poorly characterized malignant apocrine neoplasm as only 16 cases have been published. OBJECTIVE: To characterize its clinical, histopathological, and immunohistochemical features. METHODS: We compiled 14 cases of solid carcinoma and clinical information were updated. Hematoxylin and eosin slides were reviewed and we stained all the cases for CEA, EMA, SMA, PHLDA-1, BerP4, nestin, p53, p63, p75, CK5/6, CK7 and some with remaining material for CK14, 15, CK10, CK19, S100, CD117, and CAM5. RESULTS: All the lesions were located on the scalp. Histopathologically, all the cases were characterized by solid aggregates of neoplastic epithelial cells without nuclear atypia or mitotic figures involving all the dermis. All the cases presented perineural infiltration and most of them had cornified cystic structures. CK5/6 and p63 were positive. CEA and EMA underlined the scarce ducts. Ki67 was lower than 1%. BerEP4 and PHLDA-1 were negative. CONCLUSION: Solid carcinoma is a solid variant of MAC affecting the scalp more frequently than classic MAC, mostly in old males and showing variable-sized nests involving the entire dermis and composed by poroid, clear-cells, or a mixture of both. It is positive for p63 and CK5/6 and negative for BerEP4 and PHLDA-1. Staining features with CK19 and PHLDA1 differ from classic MAC.
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Adenoma , Carcinoma , Neoplasias de Cabeça e Pescoço , Proteínas de Neoplasias/metabolismo , Neoplasias Cutâneas , Adenoma/metabolismo , Adenoma/patologia , Idoso , Idoso de 80 Anos ou mais , Carcinoma/metabolismo , Carcinoma/patologia , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Pessoa de Meia-Idade , Fatores Sexuais , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologiaRESUMO
Pilar sheath acanthoma is an uncommon, benign follicular neoplasm that frequently presents as a solitary lesion. This neoplasm usually appears on the skin around the upper lip of elderly patients. Histopathologically, the neoplasm usually shows a cystic configuration with epithelial lobules resembling to those of the outer root sheath of the hair follicle at the level of the isthmus emanating radially from the cyst wall. We present 3 peculiar cases of a pilar sheath acanthoma showing a plaque-like architecture because the lesions exhibited a horizontal configuration. To our knowledge, there are no previously reported examples of plaque-like pilar sheath acanthoma.
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Acantoma/patologia , Neoplasias Cutâneas/patologia , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-IdadeRESUMO
Sebaceous neoplasms with an organoid pattern (rippled, labyrinthine/sinusoidal, carcinoid-like, and petaloid) are rare. Previous studies suggested that the above patterns likely represent variations along a morphological continuum. The objectives of this study were to (1) validate this proposition by studying a large number of cases, (2) determine whether there are specific associations with clinical features, (3) establish their frequency, and (4) determine whether they have any association with Muir-Torre syndrome. Fifty-seven sebaceous neoplasms (54 sebaceomas and 3 sebaceous carcinomas) with organoid growth patterns were studied. These occurred in 36 men and 18 women (sex unknown in 3), with ages at diagnosis ranging from 22 to 89 years (mean, 63 years). All patients presented with a solitary nodule (mean size, 11 mm) on the head and neck area. Of the 57 tumors, 24 manifested a single growth pattern, 23 had a combination of 2 patterns, and 10 a combination of 3 patterns, indicating that these patterns are part of a morphological continuum of changes. The carcinoid-like pattern was the most frequent in the "monopatterned" neoplasms (13 cases), whereas the labyrinthine/sinusoidal pattern comprised most of the "polypatterned" lesions, in which various combinations occurred. Immunohistochemically, mismatch repair protein deficiency was detected in 3 of the 22 cases studied, whereas 5 of the 33 patients with available follow-up had an internal malignancy/premalignancy. In conclusion, sebaceous neoplasms with organoid growth patterns are predominantly sebaceomas having a predilection for the scalp, occurring as solitary lesions in elderly patients (male to female ratio of 2:1). Such patterns are expected to be found in a quarter of sebaceomas. In most cases, more than one of the organoid patterns is present. These lesions do not appear to be associated with internal malignancy or mismatch repair deficiency in most cases. However, confirmation of the absence of any significant association with Muir-Torre syndrome syndrome will require genetic studies.
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Neoplasias das Glândulas Sebáceas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Reparo de Erro de Pareamento de DNA/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome de Muir-Torre/complicações , Neoplasias das Glândulas Sebáceas/etiologia , Adulto JovemRESUMO
Dowling-Degos disease (DDD) is an autosomal-dominant genodermatosis characterized by progressive and disfiguring reticulate hyperpigmentation. We previously identified loss-of-function mutations in KRT5 but were only able to detect pathogenic mutations in fewer than half of our subjects. To identify additional causes of DDD, we performed exome sequencing in five unrelated affected individuals without mutations in KRT5. Data analysis identified three heterozygous mutations from these individuals, all within the same gene. These mutations, namely c.11G>A (p.Trp4*), c.652C>T (p.Arg218*), and c.798-2A>C, are within POGLUT1, which encodes protein O-glucosyltransferase 1. Further screening of unexplained cases for POGLUT1 identified six additional mutations, as well as two of the above described mutations. Immunohistochemistry of skin biopsies of affected individuals with POGLUT1 mutations showed significantly weaker POGLUT1 staining in comparison to healthy controls with strong localization of POGLUT1 in the upper parts of the epidermis. Immunoblot analysis revealed that translation of either wild-type (WT) POGLUT1 or of the protein carrying the p.Arg279Trp substitution led to the expected size of about 50 kDa, whereas the c.652C>T (p.Arg218*) mutation led to translation of a truncated protein of about 30 kDa. Immunofluorescence analysis identified a colocalization of the WT protein with the endoplasmic reticulum and a notable aggregating pattern for the truncated protein. Recently, mutations in POFUT1, which encodes protein O-fucosyltransferase 1, were also reported to be responsible for DDD. Interestingly, both POGLUT1 and POFUT1 are essential regulators of Notch activity. Our results furthermore emphasize the important role of the Notch pathway in pigmentation and keratinocyte morphology.
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Glucosiltransferases/genética , Hiperpigmentação/genética , Mutação , Dermatopatias Genéticas/genética , Dermatopatias Papuloescamosas/genética , Adolescente , Adulto , Exoma , Feminino , Estudo de Associação Genômica Ampla , Heterozigoto , Humanos , Queratinócitos/citologia , Queratinócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Linhagem , Conformação Proteica , Análise de Sequência de DNA , Pele/patologia , Adulto JovemRESUMO
Blue nevi are common melanocytic tumors arising in the dermal layer of the skin. Similar to uveal melanomas, blue nevi frequently harbor GNAQ and GNA11 mutations. Recently, recurrent CYSLTR2 and PLCB4 mutations were identified in uveal melanomas not harboring GNAQ or GNA11 mutations. All four genes (GNAQ, GNA11, CYSLTR2, and PLCB4) code for proteins involved in the same signaling pathway, which is activated by mutations in these genes. Given the related functional consequences of these mutations and the known genetic similarities between uveal melanoma and blue nevi, we analyzed a cohort of blue nevi to investigate whether CYSLTR2 and PLCB4 mutations occur in tumors lacking GNAQ or GNA11 mutations (as in uveal melanoma). A targeted next-generation sequencing assay covering known activating mutations in GNAQ, GNA11, CYSLTR2, PLCB4, KIT, NRAS, and BRAF was applied to 103 blue nevi. As previously reported, most blue nevi were found to harbor activating mutations in GNAQ (59%, n=61), followed by less frequent mutations in GNA11 (16%, n=17). Additionally, one BRAF (1%) and three NRAS (3%) mutations were detected. In three tumors (3%) harboring none of the aforementioned gene alterations, CYSLTR2 mutations were identified. All three CYSLTR2 mutations were the same c.386T>A, L129Q mutation previously identified in uveal melanoma that has been shown to lead to increased receptor activation and signaling. In summary, our study identifies CYSLTR2 L129Q alterations as a previously unrecognized activating mutation in blue nevi, occuring in a mutually exclusive fashion with known GNAQ and GNA11 mutations. Similar to GNAQ and GNA11 mutations, CYSLTR2 mutations, when present, are likely defining pathogenetic events in blue nevi.