RESUMEN
Cutaneous mixed tumors exhibit a wide morphologic diversity and are currently classified into apocrine and eccrine types based on their morphologic differentiation. Some cases of apocrine-type cutaneous mixed tumors (ACMT), namely, hyaline cell-rich apocrine cutaneous mixed tumors (HCR-ACMT) show a prominent or exclusive plasmacytoid myoepithelial component. Although recurrent fusions of PLAG1 have been observed in ACMT, the oncogenic driver of eccrine-type cutaneous mixed tumors (ECMT) is still unknown. The aim of the study was to provide a comprehensive morphologic, immunohistochemical, and molecular characterization of these tumors. Forty-one cases were included in this study: 28 cases of ACMT/HCR-ACMT and 13 cases of ECMT. After morphologic and immunohistochemical characterization, all specimens were analyzed by RNA sequencing. By immunohistochemistry, all cases showed expression of SOX10, but only ACMT/HCR-ACMT showed expression of PLAG1 and HMGA2. RNA sequencing confirmed the presence of recurrent fusion of PLAG1 or HMGA2 in all cases of ACMT/HCR-ACMT, with a perfect correlation with PLAG1/HMGA2 immunohistochemical status, and revealed internal tandem duplications of SOX10 (SOX10-ITD) in all cases of ECMT. Although TRPS1::PLAG1 was the most frequent fusion, HMGA2::WIF1 and HMGA2::NFIB were detected in ACMT cases. Clustering analysis based on gene expression profiling of 110 tumors, including numerous histotypes, showed that ECMT formed a distinct group compared with all other tumors. ACMT, HCR-ACMT, and salivary gland pleomorphic adenoma clustered together, whereas myoepithelioma with fusions of EWSR1, FUS, PBX1, PBX3, POU5F1, and KLF17 formed another cluster. Follow-up showed no evidence of disease in 23 cases across all 3 tumor types. In conclusion, our study demonstrated for the first time SOX10-ITD in ECMT and HMGA2 fusions in ACMT and further refined the prevalence of PLAG1 fusions in ACMT. Clustering analyses revealed the transcriptomic distance between these different tumors, especially in the heterogenous group of myoepitheliomas.
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Adenoma Pleomórfico , Mioepitelioma , Neoplasias de las Glándulas Salivales , Neoplasias Cutáneas , Neoplasias de las Glándulas Sudoríparas , Humanos , Adenoma Pleomórfico/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Mioepitelioma/genética , Mioepitelioma/patología , Proteínas Represoras , Neoplasias de las Glándulas Salivales/genética , Neoplasias Cutáneas/genética , Factores de Transcripción SOXE , Neoplasias de las Glándulas Sudoríparas/genética , Factores de TranscripciónRESUMEN
Among skin epithelial tumors, recurrent mutations in the APC/CTNNB1 genes resulting in activation of the Wnt/ß-catenin pathway have been reported predominantly in neoplasms with matrical differentiation. In the present study, we describe the morphologic, immunohistochemical, and genetic features of 16 primary cutaneous carcinomas harboring mutations activating the Wnt/ß-catenin pathway without evidence of matrical differentiation, as well as four combined tumors in which a similar Wnt/ß-catenin activated carcinoma component was associated with Merkel cell carcinoma or pilomatrical carcinoma. Among the pure tumor cases, 6/16 patients were female with a median age of 80 years (range: 58-98). Tumors were located on the head and neck (n=7, 44%), upper limb (n=4, 25%), trunk (n=3, 18%), and leg (n=2, 13%). Metastatic spread was observed in 4 cases resulting in death from disease in one patient. Microscopically, all cases were poorly differentiated neoplasms infiltrating the dermis and/or subcutaneous tissue. In 13 cases, solid "squamoid" areas were associated with a basophilic component characterized by rosette/pseudoglandular formation resulting in a biphasic appearance. Three specimens consisted only of poorly differentiated carcinoma lacking rosette formation. Immunohistochemical studies showed frequent expression of EMA (100%), BerEP4 (100%), cytokeratin 7 (94%), chromogranin A (44%), synaptophysin (82%) and cytokeratin 20 (69%). Complete loss of Rb expression was observed in all but one case. Nuclear ß-catenin and CDX2 expressions were detected in all cases. Recurrent pathogenic somatic mutations were observed in APC (60%), CTNNB1 (40%) and RB1 (n=47%). Global methylation analysis confirmed that cases with rosette formation constituted a homogenous tumor group distinct from established skin tumor entities (pilomatrical carcinoma, Merkel cell carcinoma and squamous cell carcinoma) while the 3 other cases lacking such morphologic features did not. In addition, we identified four combined neoplasms in which there was a component showing a similar poorly differentiated rosette forming carcinoma demonstrating Rb loss and beta-catenin activation associated with either Merkel cell carcinoma (n=3) or pilomatrical carcinoma (n=1). In conclusion, we describe a distinctive neoplasm, for which we propose the term "Wnt/ß-catenin activated rosette-forming carcinoma", morphologically characterized by the association of rosette formation, squamous and/or neuroendocrine differentiation, diffuse CDX2 expression, Rb loss, and mutations in CTNNB1/APC genes.
RESUMEN
Poroma is a benign sweat gland tumour showing morphological features recapitulating the superficial portion of the eccrine sweat coil. A subset of poromas may transform into porocarcinoma, its malignant counterpart. Poroma and porocarcinoma are characterised by recurrent gene fusions involving YAP1, a transcriptional co-activator, which is controlled by the Hippo signalling pathway. The fusion genes frequently involve MAML2 and NUTM1, which are also rearranged in other cutaneous and extracutaneous neoplasms. We aimed to review the clinical, morphological and molecular features of this category of adnexal neoplasms with a special focus upon emerging differential diagnoses, and discuss how their systematic molecular characterisation may contribute to a standardisation of diagnosis, more accurate classification and, ultimately, refinement of their prognosis and therapeutic modalities.
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Porocarcinoma Ecrino , Poroma , Neoplasias Cutáneas , Neoplasias de las Glándulas Sudoríparas , Humanos , Poroma/genética , Poroma/metabolismo , Poroma/patología , Porocarcinoma Ecrino/genética , Porocarcinoma Ecrino/patología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Neoplasias de las Glándulas Sudoríparas/diagnóstico , Piel/patología , Factores de Transcripción/genéticaRESUMEN
The accurate diagnosis of skin adnexal neoplasms is sometimes challenging but is necessary because medical management and follow-up may differ between tumors. GATA6 transcription factor has been identified as a new marker of the upper folliculosebaceous compartment (lower infundibulum, junctional zone and isthmus, and upper sebaceous gland) in the human skin. We aimed to determine the diagnostic accuracy of GATA6 immunostaining to diagnose sebaceous tumors compared with that to diagnose other adnexal and nonadnexal cutaneous neoplasms. We conducted a retrospective, evaluator-nonblinded study comparing the reference standard (diagnosis by an expert dermatopathologist) with GATA6 immunostaining to identify sebaceous tumors in a cohort containing 234 different tumors. The GATA6 expression score was significatively higher in sebaceous than that in nonsebaceous tumors. In addition, tumors originating from the upper hair follicle showed positive results for GATA6 staining; however, they showed lower GATA6 expression scores. Detection of sebaceous tumors using GATA6 positivity had a sensitivity of 95.7% (95% CI, 85.8-99.2), specificity of 80.8% (95% CI, 74.5-85.8), positive predictive value of 55.6% (95% CI, 44.7-65.9), and negative predictive value of 98.7% (95% CI, 95.4-99.8). GATA6 showed similar sensitivity to adipophilin, the reference marker; however, the specificity of GATA6 was higher, as observed in a cohort of 106 tumors enriched in squamous cell carcinomas with clear-cell histology. In addition, GATA6 positivity was assessed in 39 sebaceous carcinomas and compared with epithelial membrane antigen (EMA), CK7, and androgen receptor (AR) staining results. Although CK7 staining displayed lower diagnostic performances, GATA6 staining showed comparable results as EMA and AR. Finally, we found GATA6 expression in skin metastases of gastrointestinal origin, whereas GATA6 was absent in metastases originating from breast or lung cancers. Overall, our work identified GATA6 immunostaining as a new diagnostic tool for sebaceous tumors.
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Neoplasias de las Glándulas Sebáceas , Neoplasias Cutáneas , Humanos , Estudios Retrospectivos , Neoplasias de las Glándulas Sebáceas/diagnóstico , Piel/patología , Neoplasias Cutáneas/patología , Glándulas Sebáceas/metabolismo , Glándulas Sebáceas/patología , Factor de Transcripción GATA6RESUMEN
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.
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Poroma , Neoplasias de las Glándulas Sudoríparas , Masculino , Humanos , Poroma/genética , Poroma/patología , Factores de Transcripción , Neoplasias de las Glándulas Sudoríparas/genética , Neoplasias de las Glándulas Sudoríparas/patología , Diferenciación Celular , Quinasas p21 Activadas , ATPasa Intercambiadora de Sodio-Potasio , Proteínas de la MembranaRESUMEN
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.
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Carcinoma , Porocarcinoma Ecrino , Poroma , Neoplasias Cutáneas , Neoplasias de las Glándulas Sudoríparas , Humanos , Poroma/genética , Poroma/metabolismo , Poroma/patología , Neoplasias de las Glándulas Sudoríparas/diagnóstico , Porocarcinoma Ecrino/genética , Porocarcinoma Ecrino/patología , Neoplasias Cutáneas/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Proteínas de Unión a Retinoblastoma/metabolismoRESUMEN
BACKGROUND: Sebaceous neoplasms (SNs) always raise the possibility of an association with Muir-Torre syndrome (MTS) and permit to screen internal malignancies, colorectal and endometrial carcinomas, before they become symptomatic. Immunohistochemistry (IHC), molecular biology, and clinical examination are different approaches for detection of MTS. We conducted a retrospective analysis of non-selected SNs in order to determine the optimal tools to implement for MTS screening. METHODS: Deficient MMR phenotype (dMMR) was determined by either IHC using antibodies directed to four mismatch repair (MMR) antigens on tissue microarray or molecular biology using pentaplex PCR. The Mayo Clinic risk score of MTS was calculated from medical records. Sensibility and specificity of each test for the detection of MTS were determined. RESULTS: We included 107 patients, 8 with multiple SNs, for a total of 123 SNs (43 sebaceous adenomas, 19 sebaceomas, and 61 sebaceous carcinomas (SC)). Loss of at least one MMR protein was observed in 70.7% of tumors, while 48% had a microsatellite instable phenotype. Concordance between both techniques was 92.9%, with a 0.85 Cohen's kappa coefficient. Nineteen patients (20.2%) had a ≥2 points Mayo Clinic risk score, one having a pMMR SC. Among the 13 patients with confirmed MTS, 2 had a low Mayo Clinic risk score (1 point). IHC had the highest sensitivity for MTS screening (100%) with a specificity of 34.1%, while a >2-point Mayo Clinic risk score had a lower sensitivity (92%) but a higher specificity (89%). CONCLUSION: To detect MTS in SN patients, the first-line Mayo Clinic risk score followed by IHC appears to be the most accurate strategy with lower cost for society. This strategy should be adapted to the medico-economic resources of each country.
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Carcinoma Basocelular , Síndrome de Muir-Torre , Neoplasias de las Glándulas Sebáceas , Humanos , Síndrome de Muir-Torre/diagnóstico , Síndrome de Muir-Torre/genética , Síndrome de Muir-Torre/patología , Inmunohistoquímica , Estudios Retrospectivos , Neoplasias de las Glándulas Sebáceas/diagnóstico , Neoplasias de las Glándulas Sebáceas/genética , Neoplasias de las Glándulas Sebáceas/patología , Biología MolecularRESUMEN
BACKGROUND & AIMS: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver cancer (PLC) associated with a poor prognosis. Given the challenges in its identification and its clinical implications, biomarkers are critically needed. We aimed to investigate the diagnostic and prognostic value of the immunohistochemical expression of Nestin, a progenitor cell marker, in a large multicentric series of PLCs. METHODS: We collected 461 cHCC-CCA samples from 32 different clinical centers. Control cases included 368 hepatocellular carcinomas (HCCs) and 221 intrahepatic cholangiocarcinomas (iCCAs). Nestin immunohistochemistry was performed on whole tumor sections. Diagnostic and prognostic performances of Nestin expression were determined using receiver-operating characteristic curves and Cox regression modeling. RESULTS: Nestin was able to distinguish cHCC-CCA from HCC with AUCs of 0.85 and 0.86 on surgical and biopsy samples, respectively. Performance was lower for the distinction of cHCC-CCA from iCCA (AUCs of 0.59 and 0.60). Nestin, however, showed a high prognostic value, allowing identification of the subset of cHCC-CCA ("Nestin High", >30% neoplastic cells with positive staining) associated with the worst clinical outcome (shorter disease-free and overall survival) after surgical resection and liver transplantation, as well as when assessment was performed on biopsies. CONCLUSION: We show in different clinical settings that Nestin has diagnostic value and that it is a useful biomarker to identify the subset of cHCC-CCA associated with the worst clinical outcome. Nestin immunohistochemistry may be used to refine risk stratification and improve treatment allocation for patients with this highly aggressive malignancy. LAY SUMMARY: There are different types of primary liver cancers (i.e. cancers that originate in the liver). Accurately identifying a specific subtype of primary liver cancer (and determining its associated prognosis) is important as it can have a major impact on treatment allocation. Herein, we show that a protein called Nestin could be used to refine risk stratification and improve treatment allocation for patients with combined hepatocellular carcinoma, a rare but highly aggressive subtype of primary liver cancer.
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Neoplasias de los Conductos Biliares , Carcinoma Hepatocelular , Colangiocarcinoma , Neoplasias Hepáticas , Humanos , Nestina , Carcinoma Hepatocelular/diagnóstico , Pronóstico , Neoplasias Hepáticas/diagnóstico , Colangiocarcinoma/diagnóstico , Neoplasias de los Conductos Biliares/diagnóstico , Conductos Biliares IntrahepáticosRESUMEN
AIMS: Basal cell carcinoma (BCC) is a common cancer, with a high risk of local recurrence. A quantifiable measurement of the histological margins of BCC in excisions is a recurrent demand of clinicians; however, there are currently no international guidelines indicating its value. METHODS AND RESULTS: A questionnaire validated by four experts in dermatopathology and formatted under a 'Google Forms'-type interface was sent by e-mail to physicians specializing in surgical pathology or dermatopathology and practising in France from 20 March 2018 to 20 May 2018. The results were compared between subgroups according to age and subspecialisation, especially dermatopathology. The questionnaire was completed by 225 practitioners. Microscopic margins were systematically measured in 77.3% of cases, sometimes in 19.6% and never in 3.1%. The main reason was to report factually insufficient margins (66.5%), followed by laboratory routine (45%) or clinician requests (43.1%). For 72% of respondents, the clinical or histopathological criteria did not influence their practice. The most used tool was a graduated ruler placed under a microscope (44.3% of cases). Compared to other groups, dermatopathologists measured BCC margins less systematically [only in certain situations (33.3 versus 14.9%) or never (10.5 versus 0.6%) (P < 0.001)] and used an eyepiece reticle more extensively (53.1 versus 29.8%; P = 0.0029). CONCLUSION: The measurement of histological margins in BCC is common practice in France, although there are no recommendations. Our survey suggests that it represents a way for pathologists to specify an insufficient margin and therefore the need for scar revision.
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Carcinoma Basocelular/patología , Carcinoma Basocelular/cirugía , Márgenes de Escisión , Pautas de la Práctica en Medicina , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/cirugía , Adulto , Factores de Edad , Dermatología , Femenino , Francia , Encuestas de Atención de la Salud , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/prevención & control , Patología QuirúrgicaRESUMEN
Deficient mismatch repair system (dMMR)/microsatellite instability (MSI) is found in about 5% of metastatic colorectal cancers (mCRCs) with a major therapeutic impact for immune checkpoint inhibitor (ICI) use. We conducted a multicentre study including all consecutive patients with a dMMR/MSI mCRC. MSI status was determined using the Pentaplex panel and expression of the four MMR proteins was evaluated by immunohistochemistry (IHC). The primary endpoint was the rate of discordance of dMMR/MSI status between primary tumours and paired metastases. We included 99 patients with a dMMR/MSI primary CRC and 117 paired metastases. Only four discrepancies (3.4%) with a dMMR/MSI primary CRC and a pMMR/MSS metastasis were initially identified and reviewed by expert pathologists and molecular biologists. Two cases were false discrepancies due to human or technical errors. One discordant case could not be confirmed due to the low level of tumour cells. The last case had a confirmed discrepancy with a dMMR/MSI primary CRC and a pMMR/MSS peritoneal metastasis. Our study demonstrated a high concordance rate of dMMR/MSI status between primary CRCs and their metastases. The analysis of one sample, either from the primary tumour or metastasis, with consistent dMMR and MSI status seems to be sufficient prior to treatment with ICI.
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Neoplasias Colorrectales , Inestabilidad de Microsatélites , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/terapia , Reparación de la Incompatibilidad de ADN/genética , Humanos , Inmunohistoquímica , InmunoterapiaRESUMEN
Conjunctival melanoma (CM) iss a rare and aggressive tumour that is increasing in frequency. The prognostic value of PD-L1 expression, alone or in combination with CD8 and PD-1 expression and the BRAF and NRAS status, has not been determined in CM to date. We evaluated the expression of PD-L1, CD8, PD-1 in CM and investigated whether there was an association between the expression of these markers and the BRAF and NRAS molecular profile as well as some clinico-pathological criteria. A total of sixty-five CM were assessed for PD-L1, PD-1, and CD8 expression by immunohistochemistry (IHC) and for BRAF and NRAS genomic alterations using molecular biology techniques and anti-BRAF and anti-NRAS antibodies. PD-L1 expression in tumour cells (TC) was very low or absent but detected in tumour-infiltrating immune cells (IC). A correlation was observed between the expression of PD-L1, CD8, and PD-1 in IC. No correlation between PD-L1 expression (in tumour and/or immune cells) and BRAF or NRAS mutations was observed. PD-L1 expression in IC correlated with a higher pTNM stage and PD-L1 expression in TC with worse disease-specific survival. PD-L1 expression is a potential prognostic biomarker that correlates with poor prognosis in CM patients.
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Antígeno B7-H1/genética , Biomarcadores de Tumor , Neoplasias de la Conjuntiva/genética , Neoplasias de la Conjuntiva/mortalidad , Expresión Génica , Melanoma/genética , Melanoma/mortalidad , Antígeno B7-H1/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/patología , Neoplasias de la Conjuntiva/patología , Femenino , Humanos , Inmunohistoquímica , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Linfocitos Infiltrantes de Tumor/patología , Masculino , Melanoma/patología , Mutación , PronósticoRESUMEN
The diagnosis of a uterine smooth muscle lesion is, in the majority of cases, straightforward. However, in a small number of cases, the morphological criteria used in such lesions cannot differentiate with certainty a benign from a malignant lesion and a diagnosis of smooth muscle tumor with uncertain malignant potential (STUMP) is made. Uterine leiomyosarcomas are often easy to diagnose but it is difficult or even impossible to identify a prognostic factor at the moment of the diagnosis with the exception of the stage. We hypothesize, for uterine smooth muscle lesions, that there is a gradient of genomic complexity that correlates to outcome. We first tested this hypothesis on STUMP lesions in a previous study and demonstrated that this 'gray category' could be split according to genomic index into two groups. A benign group, with a low to moderate alteration rate without recurrence and a malignant group, with a highly rearranged profile akin to uterine leiomyosarcomas. Here, we analyzed a large series of 77 uterine smooth muscle lesions (from 76 patients) morphologically classified as 19 leiomyomas, 14 STUMP and 44 leiomyosarcomas with clinicopathological and genomic correlations. We confirmed that genomic index with a cut-off=10 is a predictor of recurrence (P<0.0001) and with a cut-off=35 is a marker for poor overall survival (P=0.035). For the tumors confined to the uterus, stage as a prognostic factor was not useful in survival prediction. At stage I, among the tumors reclassified as molecular leiomyosarcomas (ie, genomic index ≥10), the poor prognostic markers were: 5p gain (overall survival P=0.0008), genomic index at cut-off=35 (overall survival P=0.0193), 13p loss including RB1 (overall survival P=0.0096) and 17p gain including MYOCD gain (overall survival P=0.0425). Based on these findings (and the feasibility of genomic profiling by array-comparative genomic hybridization), genomic index, 5p and 17p gains prognostic value could be evaluated in future prospective chemotherapy trials.
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Perfilación de la Expresión Génica , Análisis de Secuencia por Matrices de Oligonucleótidos , Tumor de Músculo Liso/diagnóstico , Tumor de Músculo Liso/genética , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/genética , Adulto , Anciano , Anciano de 80 o más Años , Cromosomas Humanos Par 13/genética , Cromosomas Humanos Par 17/genética , Cromosomas Humanos Par 5/genética , Femenino , Humanos , Leiomioma/diagnóstico , Leiomioma/genética , Leiomioma/patología , Leiomiosarcoma/diagnóstico , Leiomiosarcoma/genética , Leiomiosarcoma/patología , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Pronóstico , Tumor de Músculo Liso/patología , Análisis de Supervivencia , Neoplasias Uterinas/patologíaRESUMEN
OBJECTIVES: Inflammasomes are multiprotein complexes that sense pathogens and trigger biological mechanisms to control infection. Nucleotide-binding oligomerisation domain-like receptor (NLR) containing a PYRIN domain 1 (NLRP1), NLRP3 and NLRC4 plays a key role in this innate immune system by directly assembling in inflammasomes and regulating inflammation. Mutations in NLRP3 and NLRC4 are linked to hereditary autoinflammatory diseases, whereas polymorphisms in NLRP1 are associated with autoimmune disorders such as vitiligo and rheumatoid arthritis. Whether human NLRP1 mutation is associated with autoinflammation remains to be determined. METHODS: To search for novel genes involved in systemic juvenile idiopathic arthritis, we performed homozygosity mapping and exome sequencing to identify causative genes. Immunoassays were performed with blood samples from patients. RESULTS: We identified a novel disease in three patients from two unrelated families presenting diffuse skin dyskeratosis, autoinflammation, autoimmunity, arthritis and high transitional B-cell level. Molecular screening revealed a non-synonymous homozygous mutation in NLRP1 (c.2176C>T; p.Arg726Trp) in two cousins born of related parents originating from Algeria and a de novo heterozygous mutation (c.3641C>G, p.Pro1214Arg) in a girl of Dutch origin. The three patients showed elevated systemic levels of caspase-1 and interleukin 18, which suggested involvement of NLRP1 inflammasome. CONCLUSIONS: We demonstrate the responsibility of human NLRP1 in a novel autoinflammatory disorder that we propose to call NAIAD for NLRP1-associated autoinflammation with arthritis and dyskeratosis. This disease could be a novel autoimmuno-inflammatory disease combining autoinflammatory and autoimmune features. Our data, combined with that in the literature, highlight the pleomorphic role of NLRP1 in inflammation and immunity. TRIAL REGISTRATION NUMBER: NCT02067962; Results.
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Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Reguladoras de la Apoptosis/genética , Artritis Juvenil/genética , Enfermedades Autoinmunes/genética , Enfermedades Autoinflamatorias Hereditarias/genética , Enfermedades de la Piel/genética , Adolescente , Argelia , Artritis Juvenil/complicaciones , Artritis Juvenil/inmunología , Enfermedades Autoinmunes/complicaciones , Enfermedades Autoinmunes/inmunología , Linfocitos B/inmunología , Población Negra , Caspasa 1/inmunología , Niño , Consanguinidad , Femenino , Enfermedades Autoinflamatorias Hereditarias/complicaciones , Enfermedades Autoinflamatorias Hereditarias/inmunología , Homocigoto , Humanos , Interleucina-18/inmunología , Masculino , Mutación , Proteínas NLR , Países Bajos , Células Precursoras de Linfocitos B/inmunología , Enfermedades de la Piel/complicaciones , Enfermedades de la Piel/inmunología , Síndrome , Población BlancaRESUMEN
AIMS: Distinction between primary cutaneous follicular lymphoma (PCFL) and primary cutaneous marginal zone lymphoma (PCMZL) is challenging, as clear-cut immunophenotypical and cytogenetic criteria to segregate both entities are lacking. METHODS AND RESULTS: To characterize PCFL and PCMZL more clearly and to define criteria helpful for the differential diagnosis, we compared expression of immunohistochemical markers [LIM-only transcription factor 2 (LMO2), human germinal centre-associated lymphoma (HGAL), stathmin 1 (STMN1), activation-induced cytidine deaminase (AID), myeloid cell nuclear differentiation antigen (MNDA)] and the presence of cytogenetic abnormalities described previously in nodal follicular lymphoma [B cell lymphoma 2 (BCL2) and BCL6 breaks, 1p36 chromosomal region deletion (del 1p36)] in a series of 48 cutaneous follicular and marginal zone lymphomas [cutaneous follicular lymphoma (CFL) and cutaneous marginal zone lymphoma (CMZL)]. Immunostaining for STMN1, LMO2, HGAL and AID allowed the distinction between CFL and CMZL, and STMN1 was the most sensitive marker (100% CFL, 0% CMZL). LMO2, HGAL and AID were positive in 93.2%, 82.1% and 86.2% CFL (all CMZL-negative). MNDA was expressed in both entities without significant difference (10.3% CFL, 30.8% CMZL, P = 0.18). BCL2, BCL6 breaks and the del 1p36 were present in 16.7%, 10.7% and 18.5% CFL and no CMZL. Finally, three and 29 CFL were reclassified as secondary cutaneous follicular lymphomas (SCFL) and PCFL without significant differences concerning phenotypical and cytogenetic features. BCL2, BCL6 breaks and the del 1p36 were present in 11.1%, 8% and 16.7% PCFL and did not impact the prognosis. CONCLUSION: LMO2, HGAL, STMN1 and AID, but not MNDA, are discriminant for the recognition between CFL and CMZL. BCL2, BCL6 rearrangements and the del 1p36 have a role in the pathogenesis of PCFL, the latest being the most common alteration.
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Biomarcadores de Tumor/genética , Cromosomas Humanos Par 1/genética , Linfoma de Células B de la Zona Marginal/genética , Linfoma de Células B/genética , Linfoma Folicular/genética , Neoplasias Cutáneas/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Adulto , Anciano , Anciano de 80 o más Años , Deleción Cromosómica , Citidina Desaminasa/genética , Femenino , Humanos , Péptidos y Proteínas de Señalización Intracelular , Proteínas con Dominio LIM/genética , Linfoma de Células B/patología , Linfoma de Células B de la Zona Marginal/patología , Linfoma Folicular/patología , Masculino , Proteínas de Microfilamentos , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Pronóstico , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-6/genética , Neoplasias Cutáneas/patología , Estatmina/genéticaRESUMEN
The pathogenesis of inflammatory skin diseases such as psoriasis involves the release of numerous proinflammatory cytokines, including members of the IL-1 family. Here we report overexpression of IL-1α, IL-1ß, and IL-1 receptor antagonist mRNA, associated to expression of IL-23p19, IL-17A, and IL-22 in skin cells, upon topical application of the TLR7 agonist imiquimod (IMQ) in C57BL/6J mice. IMQ-induced skin inflammation was partially reduced in mice deficient for both IL-1α/IL-1ß or for IL-1 receptor type 1 (IL-1R1), but not in IL-1α- or IL-1ß-deficient mice, demonstrating the redundant activity of IL-1α and IL-1ß for skin inflammation. NLRP3 or apoptosis-associated Speck-like protein containing a Caspase recruitment domain-deficient mice had no significant reduction of skin inflammation in response to IMQ treatment, mainly due to the redundancy of IL-1α. However, IMQ-induced skin inflammation was abolished in the absence of MyD88, the adaptor protein shared by IL-1R and TLR signaling pathways. These results are consistent with the TLR7 dependence of IMQ-induced skin inflammation. Thus, IL-1R1 contributes to the IMQ-induced skin inflammation, and disruption of MyD88 signaling completely abrogates this response.
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Adyuvantes Inmunológicos/efectos adversos , Aminoquinolinas/efectos adversos , Proteínas Portadoras/inmunología , Erupciones por Medicamentos/inmunología , Inflamasomas/inmunología , Factor 88 de Diferenciación Mieloide/inmunología , Receptores Tipo I de Interleucina-1/inmunología , Transducción de Señal/inmunología , Adyuvantes Inmunológicos/farmacología , Aminoquinolinas/farmacología , Animales , Proteínas Portadoras/genética , Citocinas/genética , Citocinas/inmunología , Erupciones por Medicamentos/genética , Erupciones por Medicamentos/patología , Imiquimod , Inflamasomas/genética , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/inmunología , Ratones , Ratones Noqueados , Factor 88 de Diferenciación Mieloide/genética , Proteína con Dominio Pirina 3 de la Familia NLR , Receptores Tipo I de Interleucina-1/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Piel/inmunología , Piel/patología , Receptor Toll-Like 7/genética , Receptor Toll-Like 7/inmunologíaRESUMEN
Eccrine nevi are rare hamartomas characterized by an increase in the number or size of eccrine glands. A polypoid form located in the coccygeal area has been described in a few cases and termed coccygeal polypoid eccrine nevus (CPEN). No association with internal malformations was reported in any of these cases. We describe herein a case of CPEN associated with imperforate anus and unilateral multicystic kidney dysplasia. We review the clinical and pathological characteristics of CPENs and discuss the differential diagnoses.
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Anomalías Múltiples/patología , Ano Imperforado/complicaciones , Glándulas Ecrinas/patología , Hamartoma/patología , Riñón Displástico Multiquístico/complicaciones , Femenino , Hamartoma/complicaciones , Humanos , Lactante , Región SacrococcígeaRESUMEN
Cutaneous clear cell hidradenoma is an uncommon benign adnexal tumor which is not supposed to metastasize, contrary to its rare malignant counterpart, hidradenocarcinoma. We report the case of a 49-year-old man, who had had a stable inguinal lymph node enlargement for 6 years. An excision was performed and revealed an intra-nodal tumor, made of large clear cells with abundant cytoplasm and round nuclei without atypia or mitosis. The immunohistochemical staining showed diffuse positivity for keratin AE1/AE3, keratin 5/6 and p63, and focal staining with keratin 7, epithelial membrane antigen (EMA) and carcinous epithelial antigen (CEA), which underlined some ductular structures. Tumor cells were negative for renal markers PAX8 and CD10. Ki67 stained less than 1% of tumor cells. A translocation involving MAML2 gene was evidenced by fluorescence in situ hybridization (FISH) analysis. No primary cutaneous tumor was found after extensive examination. Altogether, these results are in favor of an isolated nodal hidradenoma, for which we discuss two hypothesis: a primary nodal lesion, or a 'benign metastasis' of a cutaneous tumor. Cases of morphologically benign hidradenoma with lymph node involvement are exceptional. Our case, similar to every other reported case, was associated with an excellent prognosis, supporting the idea that these patients should not be overtreated.
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Acrospiroma/patología , Ganglios Linfáticos/patología , Neoplasias de las Glándulas Sudoríparas/patología , Acrospiroma/genética , Biomarcadores de Tumor/análisis , Proteínas de Unión al ADN/genética , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Proteínas Nucleares/genética , Neoplasias de las Glándulas Sudoríparas/genética , Transactivadores , Factores de Transcripción/genética , Translocación GenéticaRESUMEN
BACKGROUND: Many cases of familial renal cell carcinoma (RCC) remain unexplained by mutations in the known predisposing genes or shared environmental factors. There are therefore additional, still unidentified genes involved in familial RCC. PBRM1 is a tumour suppressor gene and somatic mutations are found in 30-45% of sporadic clear cell (cc) RCC. METHODS: We selected 35 unrelated patients with unexplained personal history of ccRCC and at least one affected first-degree relative, and sequenced the PBRM1 gene. RESULTS: A germline frameshift mutation (c.3998_4005del [p.Asp1333Glyfs]) was found in one patient. The patient's mother, his sister and one niece also had ccRCC. The mutation co-segregated with the disease as the three affected relatives were carriers, while an unaffected sister was not, according with autosomal-dominant transmission. Somatic studies supported these findings, as we observed both loss of heterozygosity for the mutation and loss of protein expression in renal tumours. CONCLUSIONS: We show for the first time that an inherited mutation in PBRM1 predisposes to RCC. International studies are necessary to estimate the contribution of PBRM1 to RCC susceptibility, estimate penetrance and then integrate the gene into routine clinical practice.
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Carcinoma de Células Renales/genética , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Neoplasias Renales/genética , Proteínas Nucleares/genética , Factores de Transcripción/genética , Carcinoma de Células Renales/diagnóstico , Análisis Mutacional de ADN , Proteínas de Unión al ADN , Exones , Femenino , Heterocigoto , Humanos , Inmunohistoquímica , Neoplasias Renales/diagnóstico , Masculino , Proteínas Nucleares/metabolismo , Linaje , Factores de Transcripción/metabolismoRESUMEN
PURPOSE: Mastocytosis is characterized by clonal mast cell proliferation with accumulation within various organs and uncontrolled activation with excessive mast cell mediator release. Ocular manifestations have rarely been published. We describe a 63-year-old man with bilateral exophthalmos that led to the diagnosis of systemic mastocytosis. CASE REPORT: A patient presented with bilateral eyelid edema with exophthalmos associated with binocular diplopia. Ophthalmologic examination showed bilateral axial, symmetrical, and painless exophthalmos with eyelid edema, and limitation in elevation of the right eye. Visual acuity was normal. Orbital magnetic resonance imaging showed increased volume of both the superior and medial recti muscles and right inferior oblique muscle, and histopathological examination of orbital fat and muscle biopsies revealed an infiltration by mast cells. Serum tryptase was elevated. The patient also complained of a long history of pruritis and diffuse skin erythema that could be elicited with just mild pressure (Darier's sign). A bone marrow biopsy confirmed the infiltration of abnormal mast cells with a D816V mutation in the KIT gene. Treatment with cladribine was initiated and resulted in resolution of both ocular and systemic signs and symptoms that persisted without relapse 18 months after discontinuation. Ocular mastocytosis is a rare condition, which was previously reported to involve the conjunctiva, cornea, uvea, eyelid, orbit, and choroid. Cases of ocular mastocytosis can be classified into two main groups: mast cells tumors (mastocytomas) and ocular manifestations associated with systemic mastocytosis. Histological examination of ocular samples is rarely performed, and there are no standard criteria for the diagnosis of ocular mastocytosis. Our case emphasizes cladribine could represent an alternative treatment. CONCLUSIONS: Our case is the first published case of exophthalmos and eyelid edema associated with systemic mastocytosis confirmed by pathologic examination of periocular biopsies that was treated effectively with cladribine.