Asunto(s)
Porocarcinoma Ecrino , Perfilación de la Expresión Génica , Neoplasias de las Glándulas Sudoríparas , Humanos , Porocarcinoma Ecrino/genética , Porocarcinoma Ecrino/patología , Neoplasias de las Glándulas Sudoríparas/genética , Neoplasias de las Glándulas Sudoríparas/patología , Transcriptoma/genética , Lesiones Precancerosas/genética , Lesiones Precancerosas/patología , Femenino , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Masculino , Regulación Neoplásica de la Expresión Génica , Persona de Mediana EdadRESUMEN
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.
Asunto(s)
Porocarcinoma Ecrino , Perfilación de la Expresión Génica , Neoplasias de las Glándulas Sudoríparas , Humanos , Porocarcinoma Ecrino/genética , Porocarcinoma Ecrino/patología , Neoplasias de las Glándulas Sudoríparas/genética , Neoplasias de las Glándulas Sudoríparas/patología , Neoplasias de las Glándulas Sudoríparas/metabolismo , Lesiones Precancerosas/genética , Lesiones Precancerosas/patología , Femenino , Masculino , Transformación Celular Neoplásica/genética , Regulación Neoplásica de la Expresión Génica , Anciano , Persona de Mediana EdadRESUMEN
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.
Asunto(s)
Quinasa de Linfoma Anaplásico , Antígenos CD34 , Dermatofibrosarcoma , Reordenamiento Génico , Neoplasias Cutáneas , Humanos , Dermatofibrosarcoma/genética , Dermatofibrosarcoma/patología , Dermatofibrosarcoma/diagnóstico , Dermatofibrosarcoma/metabolismo , Quinasa de Linfoma Anaplásico/genética , Quinasa de Linfoma Anaplásico/metabolismo , Femenino , Masculino , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/diagnóstico , Antígenos CD34/metabolismo , Anciano , Adulto , Persona de Mediana Edad , Lactante , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/análisis , Adolescente , Adulto Joven , Niño , Preescolar , Diagnóstico Diferencial , Inmunohistoquímica , Hibridación Fluorescente in SituRESUMEN
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.
Asunto(s)
Carcinoma de Células de Merkel , Poliomavirus de Células de Merkel , Infecciones por Polyomavirus , Poroma , Neoplasias Cutáneas , Neoplasias de las Glándulas Sudoríparas , Humanos , Carcinoma de Células de Merkel/metabolismo , Poliomavirus de Células de Merkel/genética , Infecciones por Polyomavirus/complicaciones , Neoplasias Cutáneas/patología , GenómicaRESUMEN
The skin is exposed to viral pathogens, but whether they contribute to the oncogenesis of skin cancers has not been systematically explored. Here we investigated 19 skin tumor types by analyzing off-target reads from commonly available next-generation sequencing data for viral pathogens. We identified human papillomavirus 42 (HPV42) in 96% (n = 45/47) of digital papillary adenocarcinoma (DPA), an aggressive cancer occurring on the fingers and toes. We show that HPV42, so far considered a nononcogenic, "low-risk" HPV, recapitulates the molecular hallmarks of oncogenic, "high-risk" HPVs. Using machine learning, we find that HPV-driven transformation elicits a germ cell-like transcriptional program conserved throughout all HPV-driven cancers (DPA, cervical carcinoma, and head and neck cancer). We further show that this germ cell-like transcriptional program, even when reduced to the top two genes (CDKN2A and SYCP2), serves as a fingerprint of oncogenic HPVs with implications for early detection, diagnosis, and therapy of all HPV-driven cancers. SIGNIFICANCE: We identify HPV42 as a uniform driver of DPA and add a new member to the short list of tumorigenic viruses in humans. We discover that all oncogenic HPVs evoke a germ cell-like transcriptional program with important implications for detecting, diagnosing, and treating all HPV-driven cancers. See related commentary by Starrett et al., p. 17. This article is highlighted in the In This Issue feature, p. 1.
Asunto(s)
Adenocarcinoma de Células Claras , Adenocarcinoma Papilar , Neoplasias Óseas , Neoplasias de la Mama , Infecciones por Papillomavirus , Neoplasias Cutáneas , Neoplasias del Cuello Uterino , Femenino , Humanos , Virus del Papiloma Humano , Infecciones por Papillomavirus/complicaciones , Papillomaviridae/genética , Células Germinativas/patologíaRESUMEN
Malignant sweat gland tumours are rare, with the most common form being Eccrine porocarcinoma (EP). To investigate the mutational landscape of EP, we performed whole-exome sequencing (WES) on 14 formalin-fixed paraffin-embedded samples of matched primary EP and healthy surrounding tissue. Mutational profiling revealed a high overall median mutation rate. This was attributed to signatures of mutational processes related to ultraviolet (UV) exposure, APOBEC enzyme dysregulation, and defective homologous double-strand break repair. All of these processes cause genomic instability and are implicated in carcinogenesis. Recurrent driving somatic alterations were detected in the EP candidate drivers TP53, FAT2, CACNA1S, and KMT2D. The analyses also identified copy number alterations and recurrent gains and losses in several chromosomal regions including that containing BRCA2, as well as deleterious alterations in multiple HRR components. In accordance with this reduced or even a complete loss of BRCA2 protein expression was detected in 50% of the investigated EP tumours. Our results implicate crucial oncogenic driver pathways and suggest that defective homologous double-strand break repair and the p53 pathway are involved in EP aetiology. Targeting of the p53 axis and PARP inhibition, and/or immunotherapy may represent promising treatment strategies.
Asunto(s)
Porocarcinoma Ecrino , Neoplasias de las Glándulas Sudoríparas , Humanos , Mutación , Proteína p53 Supresora de Tumor/genética , Secuenciación del ExomaRESUMEN
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.
Asunto(s)
Cistadenocarcinoma/patología , Nevo/patología , Cuero Cabelludo/patología , Neoplasias de las Glándulas Sudoríparas/patología , Adenomas Tubulares de las Glándulas Sudoríparas/patología , Anciano , Transformación Celular Neoplásica/patología , Humanos , MasculinoRESUMEN
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.
Asunto(s)
Algoritmos , Eritema Nudoso/patología , Neutrófilos/patología , Paniculitis/etiología , Paniculitis/patología , Enfermedades Cutáneas Infecciosas/complicaciones , Enfermedades Autoinmunes/complicaciones , Síndrome de Behçet/patología , Cuerpos Extraños/complicaciones , Humanos , Enfermedades Pancreáticas/complicaciones , Paniculitis/diagnóstico , Inhibidores de Proteínas Quinasas/efectos adversos , Síndrome de Sweet/complicaciones , Deficiencia de alfa 1-Antitripsina/complicacionesRESUMEN
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.
Asunto(s)
Angiomatosis/patología , Enfermedades de la Piel/patología , Factores de Crecimiento Endotelial Vascular/metabolismo , Anciano , Anciano de 80 o más Años , Angiomatosis/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Enfermedades de la Piel/metabolismoRESUMEN
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.
Asunto(s)
Adenocarcinoma Sebáceo/patología , Biomarcadores de Tumor/metabolismo , Neovascularización Patológica/patología , Neoplasias de las Glándulas Sebáceas/patología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor C de Crecimiento Endotelial Vascular/metabolismo , Adenocarcinoma Sebáceo/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Biopsia con Aguja , Estudios de Cohortes , Ojo/patología , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Neoplasias de las Glándulas Sebáceas/fisiopatologíaRESUMEN
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.
Asunto(s)
Dermatosis Facial/patología , Hamartoma/patología , Neoplasias de Anexos y Apéndices de Piel/patología , Neoplasias Cutáneas/patología , Enfermedades de las Glándulas Sudoríparas/patología , Diagnóstico Diferencial , Dermatosis Facial/diagnóstico , Femenino , Hamartoma/diagnóstico , Humanos , Persona de Mediana Edad , Neoplasias de Anexos y Apéndices de Piel/diagnóstico , Neoplasias Cutáneas/diagnóstico , Enfermedades de las Glándulas Sudoríparas/diagnósticoRESUMEN
Spiradenoma and cylindroma are distinctive skin adnexal tumors with sweat gland differentiation and potential for malignant transformation and aggressive behaviour. We present the genomic analysis of 75 samples from 57 representative patients including 15 cylindromas, 17 spiradenomas, 2 cylindroma-spiradenoma hybrid tumors, and 24 low- and high-grade spiradenocarcinoma cases, together with morphologically benign precursor regions of these cancers. We reveal somatic or germline alterations of the CYLD gene in 15/15 cylindromas and 5/17 spiradenomas, yet only 2/24 spiradenocarcinomas. Notably, we find a recurrent missense mutation in the kinase domain of the ALPK1 gene in spiradenomas and spiradenocarcinomas, which is mutually exclusive from mutation of CYLD and can activate the NF-κB pathway in reporter assays. In addition, we show that high-grade spiradenocarcinomas carry loss-of-function TP53 mutations, while cylindromas may have disruptive mutations in DNMT3A. Thus, we reveal the genomic landscape of adnexal tumors and therapeutic targets.