RESUMO
AIMS: Poroma is a benign adnexal neoplasm with differentiation towards the upper portion of the sweat gland apparatus. In 2019, Sekine et al. demonstrated recurrent YAP1::MAML2 and YAP1::NUTM1 fusion in poroma and porocarcinoma. Follicular, sebaceous and/or apocrine differentiation has been reported in rare cases of poroma and whether these tumours constitute a variant of poroma or represent a distinctive tumour is a matter to debate. Herein we describe the clinical, immunophenotypic, and molecular features of 13 cases of poroma with folliculo-sebaceous differentiation. METHODS AND RESULTS: Most of the tumours were located on the head and neck region (n = 7), and on the thigh (n = 3). All presented were adults with a slight male predilection. The median tumour size was 10 mm (range: 4-25). Microscopically, lesions displayed features of poroma with nodules of monotonous basophilic cells associated with a second population of larger eosinophilic cells. In all cases, ducts and scattered sebocytes were identified. Infundibular cysts were present in 10 cases. In two cases high mitotic activity was noted, and in three cases cytologic atypia and areas of necrosis were identified. Whole transcriptome RNA sequencing demonstrated in-frame fusion transcripts involving RNF13::PAK2 (n = 4), EPHB3::PAK2 (n = 2), DLG1::PAK2 (n = 2), LRIG1::PAK2 (n = 1), ATP1B3::PAK2 (n = 1), TM9SF4::PAK2 (n = 1), and CTNNA1::PAK2 (n = 1). Moreover, fluorescence in situ hybridisation (FISH) analysis revealed PAK2 rearrangement in an additional case. No YAP1::MAML2 or YAP1::NUTM1 fusion was detected. CONCLUSION: Recurrent fusions involving the PAK2 gene in all analysed poroma with folliculo-sebaceous differentiation in this study confirms that this neoplasm represents a separate tumour entity distinct from YAP1::MAML2 or YAP1::NUTM1 rearranged poromas.
Assuntos
Poroma , Neoplasias das Glândulas Sudoríparas , Masculino , Humanos , Poroma/genética , Poroma/patologia , Fatores de Transcrição , Neoplasias das Glândulas Sudoríparas/genética , Neoplasias das Glândulas Sudoríparas/patologia , Diferenciação Celular , Quinases Ativadas por p21 , ATPase Trocadora de Sódio-Potássio , Proteínas de MembranaRESUMO
AIMS: Recently, YAP1 fusion genes have been demonstrated in eccrine poroma and porocarcinoma, and the diagnostic use of YAP1 immunohistochemistry has been highlighted in this setting. In other organs, loss of YAP1 expression can reflect YAP1 rearrangement or transcriptional repression, notably through RB1 inactivation. In this context, our objective was to re-evaluate the performance of YAP1 immunohistochemistry for the diagnosis of poroma and porocarcinoma. METHODS AND RESULTS: The expression of the C-terminal part of the YAP1 protein was evaluated by immunohistochemistry in 543 cutaneous epithelial tumours, including 27 poromas, 14 porocarcinomas and 502 other cutaneous tumours. Tumours that showed a lack of expression of YAP1 were further investigated for Rb by immunohistochemistry and for fusion transcripts by real-time PCR (YAP1::MAML2 and YAP1::NUTM1). The absence of YAP1 expression was observed in 24 cases of poroma (89%), 10 porocarcinoma (72%), 162 Merkel cell carcinoma (98%), 14 squamous cell carcinoma (SCC) (15%), one trichoblastoma and one sebaceoma. Fusions of YAP1 were detected in only 16 cases of poroma (n = 66%), 10 porocarcinoma (71%) all lacking YAP1 expression, and in one sebaceoma. The loss of Rb expression was detected in all cases except one of YAP1-deficient SCC (n = 14), such tumours showing significant morphological overlap with porocarcinoma. In-vitro experiments in HaCat cells showed that RB1 knockdown resulted in repression of YAP1 protein expression. CONCLUSION: In addition to gene fusion, we report that transcriptional repression of YAP1 can be observed in skin tumours with RB1 inactivation, including MCC and a subset of SCC.
Assuntos
Carcinoma , Porocarcinoma Écrino , Poroma , Neoplasias Cutâneas , Neoplasias das Glândulas Sudoríparas , Humanos , Poroma/genética , Poroma/metabolismo , Poroma/patologia , Neoplasias das Glândulas Sudoríparas/diagnóstico , Porocarcinoma Écrino/genética , Porocarcinoma Écrino/patologia , Neoplasias Cutâneas/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Proteínas de Ligação a Retinoblastoma/metabolismoRESUMO
Tumors of the perivascular epithelioid cells (PEComa) of the uterus are rare mesenchymal tumors that are characterized by the expression of both melanocyte and smooth muscle markers. It is often difficult to distinguish PEComas from other uterine tumors: endometrial stromal sarcoma, smooth muscle tumors including epithelioid tumors, melanoma and clear cell sarcoma. We report two cases of malignant PEComas of the uterus, treated in two different hospitals, found in women over 60, presenting a clinical picture of metrorrhagia in a context of myomatous uterus. In the first case, the histological examination of the hysterectomy specimen found a diffuse proliferation of epithelioid cells expressing HMB45. In the second case, the question of the differential diagnosis of the PEComa with a uterine epithelioid leiomyosarcoma arose, in front of the weak or even absent expression of the melanocytic immunohistochemical markers (melanA negative and focal HMB 45). The opinion requested from a network of experts (RRePS) had made it possible to validate the diagnosis of PEComa, notably by carrying out a complement of immunohistochemistry (expression of cathepsin K) by the tumor cells. In spite of its rarity, the diagnosis of PEComa should be considered before this type of epithelioid or clear cell uterine tumor because of the possibility of treatment by targeted therapies such as the mTOR (mammalian target of rapamycin) inhibitors.
Assuntos
Neoplasias de Células Epitelioides Perivasculares , Tumor de Músculo Liso , Biomarcadores Tumorais , Células Epitelioides , Feminino , Humanos , Imuno-Histoquímica , Neoplasias de Células Epitelioides Perivasculares/diagnóstico , Tumor de Músculo Liso/diagnóstico , ÚteroRESUMO
We report the case of a 13-year-old young lady with a one year reccuring bullous dermatitis history for which the diagnostic hypothesis of dermatitis arterfacta was made. This hypothesis was made by the pathologist, without it being suggested by the dermatologist, after observing singular histological lesions coresponding to a cutaneous blister associated with epidermic necrosis with multinucleated keratinocytes. When dermatitis artefacta is suspected, a biopsy is usually conducted to rule out differential diagnosis such as auto-immmune dermatitis when there is a blister. Confession from patients is rarely obtained. Therefore, having positive histogical clues for dermatitis artefacta would be of a great use to help making the diagnosis in difficult cases.
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Dermatopatias Vesiculobolhosas/diagnóstico , Adolescente , Biópsia , Dermatite/diagnóstico , Dermatite/patologia , Diagnóstico Diferencial , Feminino , Humanos , Queratinócitos/patologia , Dermatopatias Vesiculobolhosas/patologiaRESUMO
In 2008, Feng et al. identified Merkel cell polyomavirus integration as the primary oncogenic event in ~80% of Merkel cell carcinoma cases. The remaining virus-negative Merkel cell carcinoma cases associated with a high mutational load are most likely caused by UV radiation. The current study aimed to compare the morphological and immunohistochemical features of 80 virus-positive and 21 virus-negative Merkel cell carcinoma cases. Microscopic evaluation revealed that elongated nuclei-similar to the spindle-shape variant of small cell lung cancer-were less frequent in Merkel cell polyomavirus-positive Merkel cell carcinoma compared to the virus-negative subset (p = 0.005). Moreover, virus-negative cases more frequently displayed a "large-cell neuroendocrine carcinoma" phenotype with larger cell size (p = 0.0026), abundant cytoplasm (p = 4×10-7) and prominent nucleoli (p = 0.002). Analysis of immunohistochemical data revealed frequent positivity for thyroid transcription factor 1 and cytokeratin 7, either absence or overexpression of p53, as well as frequent lack of neurofilament expression in virus-negative cases. By contrast, cytokeratin 8, 18 and 20 and a CD99 with a dot pattern as well as high EMA expression were identified as characteristic features of virus-positive Merkel cell carcinoma. In particular, the CD99 dot-like expression pattern was strongly associated with presence of the Merkel cell polyomavirus in Merkel cell carcinoma (sensitivity = 81%, specificity = 90%, positive likelihood ratio = 8.08). To conclude, virus-positive and -negative Merkel cell carcinoma are characterized by distinct morphological and immunohistochemical features, which implies a significant difference in tumor biology and behavior. Importantly, we identified the CD99 staining pattern as a marker indicating the virus status of this skin cancer.
Assuntos
Antígeno 12E7/biossíntese , Biomarcadores Tumorais/análise , Carcinoma de Célula de Merkel/patologia , Infecções por Polyomavirus/patologia , Neoplasias Cutâneas/patologia , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Célula de Merkel/virologia , Feminino , Humanos , Imunofenotipagem , Masculino , Poliomavírus das Células de Merkel , Infecções por Polyomavirus/complicações , Infecções por Polyomavirus/virologia , Neoplasias Cutâneas/virologia , Infecções Tumorais por Vírus/patologia , Infecções Tumorais por Vírus/virologiaRESUMO
Microcystic variant of serous cystadenoma of the pancreas is a rare neoplasm; essentially located in the body or tail of the pancreas and associated with the von Hippel-Lindau. Often, patients are asymptomatic and the neoplasm is incidentally discovered. Usually radiographic manifestations are characteristic. Histopathological examination revealed uniform clear cuboidal cells; they can be confused with other clear cell neoplasms like renal cell carcinomas, well-differentiated neuroendocrine tumors and solid pseudopapillary tumors of the pancreas. Immunohistochemistry can be help to establish the diagnosis and to remove differential diagnosis. Serous cystadenoma is a benign neoplasm whose prognosis is excellent. We herein report two cases of microcystic serous cystadenomas of the pancreas diagnosed in two asymptomatic women and review analysis in the literature to remind the main features of this lesion and the main differential diagnosis.
Assuntos
Cistadenoma Seroso/patologia , Neoplasias Pancreáticas/patologia , Idoso , Idoso de 80 Anos ou mais , Feminino , HumanosRESUMO
Merkel cell carcinoma is a rare neuroendocrine carcinoma of the skin mostly induced by Merkel cell polyomavirus integration. Cytokeratin 20 (CK20) positivity is currently used to distinguish Merkel cell carcinomas from other neuroendocrine carcinomas. However, this distinction may be challenging in CK20-negative cases and in cases without a primary skin tumor. The objectives of this study were first to evaluate the diagnostic accuracy of previously described markers for the diagnosis of Merkel cell carcinoma and second to validate these markers in the setting of difficult-to-diagnose Merkel cell carcinoma variants. In a preliminary set (n = 30), we assessed optimal immunohistochemical patterns (CK20, thyroid transcription factor 1 [TTF-1], atonal homolog 1 [ATOH1], neurofilament [NF], special AT-rich sequence-binding protein 2 [SATB2], paired box protein 5, terminal desoxynucleotidyl transferase, CD99, mucin 1, and Merkel cell polyomavirus-large T antigen) and Merkel cell polyomavirus load thresholds (real-time PCR). The diagnostic accuracy of each marker was then assessed in a validation set of 103 Merkel cell carcinomas (9 CK20-negative cases and 15 cases without a primary skin tumor) and 70 extracutaneous neuroendocrine carcinoma cases. The most discriminant markers for a diagnosis of Merkel cell carcinoma were SATB2, NF expression, and Merkel cell polyomavirus DNA detection (positive likelihood ratios: 36.6, 44.4, and 28.2, respectively). Regarding Merkel cell carcinoma variants, cases without a primary skin tumor retained a similar immunohistochemical profile and CK20-negative tumors displayed a different profile (decrease frequency of NF and SATB2 expression), but Merkel cell polyomavirus DNA remained detected (78% of cases by qPCR). Moreover, 8/9 (89%) CK20-negative Merkel cell carcinoma cases but only 3/61 (5%) CK20-negative extracutaneous neuroendocrine cases were positive for at least one of these markers. In conclusion, detection of SATB2 and NF expression and Merkel cell polyomavirus DNA helps distinguish between Merkel cell carcinoma classical and variant cases and extracutaneous neuroendocrine carcinomas.
Assuntos
Biomarcadores Tumorais/análise , Carcinoma de Célula de Merkel/diagnóstico , Carcinoma Neuroendócrino/diagnóstico , Neoplasias Cutâneas/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Diagnóstico Diferencial , Feminino , Humanos , Imuno-Histoquímica/métodos , Masculino , Pessoa de Meia-IdadeAssuntos
Síndrome de Hiperostose Adquirida/tratamento farmacológico , Dermatite/tratamento farmacológico , Fármacos Dermatológicos/uso terapêutico , Granuloma/tratamento farmacológico , Imunossupressores/efeitos adversos , Isoxazóis/efeitos adversos , Ustekinumab/uso terapêutico , Adulto , Dermatite/etiologia , Toxidermias/tratamento farmacológico , Toxidermias/etiologia , Feminino , Granuloma/induzido quimicamente , Humanos , LeflunomidaRESUMO
Rhabdomyomas are the most common benign cardiac tumors. They may often be associated with tuberous sclerosis. In many cases, cardiac rhabdomyomas undergo spontaneous regression. Here, we report the unusual case of an infant with a large nonobstructive right ventricular rhabdomyoma at birth and at four months of age, which subsequently caused severe right ventricle outflow tract obstruction at six months of age, prompting surgery to remove the tumor. Close monitoring should be done in infants with large nonobstructive cardiac rhabdomyomas.
Assuntos
Neoplasias Cardíacas/diagnóstico por imagem , Rabdomioma/diagnóstico por imagem , Obstrução do Fluxo Ventricular Externo/diagnóstico por imagem , Progressão da Doença , Neoplasias Cardíacas/complicações , Neoplasias Cardíacas/cirurgia , Ventrículos do Coração/patologia , Humanos , Lactente , Masculino , Rabdomioma/complicações , Rabdomioma/cirurgia , Resultado do Tratamento , Ultrassonografia Pré-Natal , Obstrução do Fluxo Ventricular Externo/etiologia , Obstrução do Fluxo Ventricular Externo/cirurgiaRESUMO
To evaluate the diagnostic value of MDM2 status in craniofacial fibro-osseous lesions, we investigated MDM2 expression by immunohistochemistry and analyzed MDM2 amplification by qPCR in 30 cases of ossifying fibroma (including 13 cases of the juvenile variant) and 17 cases of fibrous dysplasia. Two cases of uncommon extragnathic psammomatoid fibrous dysplasia and a mixed control group of 15 cases of low-grade osteosarcoma and 15 cases of well-differentiated/dedifferentiated liposarcoma were included. MDM2 amplification was found in 33% of ossifying fibromas (peak of 69% for the juvenile variant) and in 12% of fibrous dysplasia, in none of which was MDM2 overexpressed. All control cases exhibited MDM2 amplification and overexpression. To investigate possible polysomy of chromosome 12, we studied RASAL1 amplification, a gene telomeric to MDM2 on the long arm of chromosome 12. RASAL1 amplification was reported in all benign fibro-osseous lesions exhibiting MDM2 amplification but not in controls. Simultaneous amplification of these two genes was significantly higher in juvenile ossifying fibromas compared with fibrous dysplasia (P=0.004), non-juvenile ossifying fibromas (P=0.001), and all other benign craniofacial fibro-osseous lesions combined (P=0.0001). Of the nine cases of juvenile ossifying fibroma exhibiting amplification, three were locally invasive and four were recurrent, suggesting aggressive disease. The two cases of extragnathic psammomatoid fibrous dysplasia also showed MDM2 and RASAL1 amplification with no MDM2 overexpression. This large chromosome 12 rearrangement, spanning MDM2 and RASAL1, is the first recurrent molecular abnormality to be reported in juvenile ossifying fibroma. It may represent both a molecular diagnostic marker and a characteristic of more aggressive forms with a higher risk of recurrence. Finally, the presence of this rearrangement in extragnathic psammomatoid fibro-osseous lesions mimicking ossifying fibromas might reflect a common molecular pathway in their pathogenesis and calls into question the classification of such lesions within fibrous dysplasia.
Assuntos
Neoplasias Ósseas/genética , Cromossomos Humanos Par 12/genética , Fibroma Ossificante/genética , Displasia Fibrosa Óssea/genética , Proteínas Ativadoras de GTPase/genética , Proteínas Proto-Oncogênicas c-mdm2/genética , Adolescente , Adulto , Idoso , Neoplasias Ósseas/diagnóstico , Criança , Pré-Escolar , Ossos Faciais , Feminino , Fibroma Ossificante/diagnóstico , Displasia Fibrosa Óssea/diagnóstico , Rearranjo Gênico , Humanos , Imuno-Histoquímica , Lactente , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Estudos Retrospectivos , Crânio , Neoplasias Cranianas/diagnóstico , Neoplasias Cranianas/genética , Adulto JovemRESUMO
Angiosarcomas are rare aggressive neoplasms that can occur secondary to chronic lymphedema (Stewart-Treves syndrome). Although secondary angiosarcomas are commonly described after-mastectomy and/or after-radiotherapy, few cases have been reported in association with chronic lymphedema of congenital origin. We report the clinical, pathological, and cytogenetic findings in a case of cutaneous epithelioid clear cells angiosarcoma that occurred in a 21-year-old woman with hemibody congenital lymphedema. Surgical biopsies of the tumor mass revealed diffuse epithelioid proliferation of clear atypical cells, for which immunophenotyping highlighted the vascular differentiation. Despite en bloc resection of the tumor, the patient died of metastatic disease three months after diagnosis. This case illustrates the clinical and pathology characteristics of angiosarcoma that is a rare entity secondary to chronic lymphedema. It is the first reported case for which the c-MYC amplification status was assessed. The diagnostic value of this amplification should be further evaluated in this specific context.
RESUMO
GNAS (guanine nucleotide-binding protein/α-subunit) mutations that induce the activation of G-protein α-subunit participate in the pathogenesis of fibrous dysplasia. The aim of this study was to evaluate the sensitivity and specificity of GNAS mutations in fibrous dysplasia and other fibro-osseous lesions, to assess the value of investigating this mutation in the diagnosis of fibro-osseous lesions. We studied 91 cases of fibrous dysplasia. The quality and/or quantity of genomic DNA were suitable for molecular analysis for 51 cases of fibrous dysplasia. GNAS mutations were investigated by three techniques: high-resolution melting (exon 8), allele-specific PCR (exons 8 and 9) and/or direct DNA sequencing (exons 8 and 9). Fibrous dysplasia samples were classified blind to the GNAS mutation status into six histological subtypes as conventional, fibro-involutive, osteosclerosing, cementifying, osteocartilaginous and with prominent aneurysmal cystic changes. We also studied 14 cases of low-grade osteosarcoma, 21 cases of ossifying fibroma, 3 cases of osteofibrous dysplasia, 1 case of osseous dysplasia of the jawbone and 1 post-traumatic lesion of the ribs. Twenty-three cases of fibrous dysplasia (45%) showed mutations of codon 201 (exon 8, p.R201H or p.R201C). No mutation was found on codon 227 (exon 9). GNAS mutations in conventional fibrous dysplasia were detected in the same proportion (47%) as in the other histological subtypes (47%, P=0.96), regardless of sex (P=0.44), age (P=0.90) and location (P=1). GNAS mutations were not detected in any other fibro-osseous lesions. The GNAS mutation was thus specific to fibrous dysplasia in the context of fibro-osseous lesions. The particular mosaicism of mutant and non-mutant cells within the lesion or the existence of other mutations not already described could explain the lack of GNAS mutation in cases of fibrous dysplasia. Investigating this mutation may constitute a valuable complementary diagnostic tool, despite its low sensitivity, particularly in unconventional morphologically different subtypes of fibrous dysplasia.