RESUMO
Cutaneous metastases (CM) are neoplastic lesions involving the dermis or subcutaneous tissues, originating from another primary tumor. Breast cancer is commonest primary solid tumor, representing 24%-50% of CM patients. There is no "standard of care" on management. In particular, the role of surgery in the treatment of cutaneous metastases from breast carcinoma (CMBC) remains controversial. This systematic review evaluates the role of cutaneous metastasectomy in breast cancer and provides an overview of existing treatment types.
Assuntos
Neoplasias da Mama , Neoplasias Pulmonares , Metastasectomia , Neoplasias Cutâneas , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Feminino , Humanos , Neoplasias Pulmonares/cirurgiaRESUMO
BACKGROUND: Melanoma of unknown primary (MUP) accounts for approximately 3% of melanoma diagnoses. This study sought to evaluate treatment and outcomes for a modern MUP cohort. METHODS: A retrospective review of MUP was performed at a tertiary referral cancer center. RESULTS: Of 815 melanoma patients, 67 (8.2%) had MUP. Men were more likely to have MUP than women (67% vs. 55%; p = 0.04). The most common sites of MUP were lymph nodes (28%), visceral solid organs (25%), brain (16%), and skin/subcutaneous tissues (10%). Of the patients who underwent tumor genomic profiling, 52% harbored pathogenic BRAF mutations. Of the 24 patients who underwent multi-gene panel testing, all had pathogenic mutations and 21 (88%) had mutations in addition to or exclusive of BRAF, including 11 patients (46%) with telomerase reverse transcriptase promoter mutations. Checkpoint inhibitors (39%) and BRAF-MEK inhibitors (7%) were the most common first-line treatments. Upfront surgical resection was used for 25% of the MUP patients, and 12 of these resections were for curative intent. During a median follow-up period of 22.1 months, the median overall survival (OS) was not met for the patients with MUP isolated to lymph nodes. At 56.8 months, 75% of these patients were alive. The median OS was 37.4 months for skin/soft tissue MUP, 33.3 months for single solid organ viscera MUP, and 29.8 months for metastatic brain MUP. CONCLUSION: Multigene panel testing identified pathogenic mutations in all tested MUP patients and frequently identified targets outside BRAF. Despite advanced stage, aggressive multimodal therapy for MUP can be associated with 5-year OS and should be pursued for appropriate candidates.
Assuntos
Melanoma , Neoplasias Primárias Desconhecidas , Neoplasias Cutâneas , Feminino , Humanos , Linfonodos , Masculino , Melanoma/genética , Melanoma/terapia , Mutação , Neoplasias Primárias Desconhecidas/genética , Neoplasias Primárias Desconhecidas/terapia , Proteínas Proto-Oncogênicas B-raf/genética , Estudos Retrospectivos , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/terapiaRESUMO
We present the third reported case of a primary cutaneous marginal zone lymphoma (PCMZL) treated with doxycycline in a pediatric patient with negative serology for Borrelia burgdorferi. A 14-year-old boy presented with multiple asymptomatic erythematous papules and nodules on his extremities and trunk which biopsy confirmed to be PCMZL. He was started on doxycycline and experienced a near-complete response. Given the favorable side effect profile of doxycycline and the indolent nature of PCMZL, we believe doxycycline is a possible therapy for PCMZL pediatric patients who have widely disseminated cutaneous disease.
Assuntos
Linfoma de Zona Marginal Tipo Células B , Neoplasias de Tecido Conjuntivo , Neoplasias Cutâneas , Adolescente , Biópsia , Criança , Doxiciclina/uso terapêutico , Humanos , Linfoma de Zona Marginal Tipo Células B/tratamento farmacológico , Masculino , Neoplasias Cutâneas/tratamento farmacológicoRESUMO
BACKGROUND: BRAF inhibition has improved overall survival in patients with BRAF mutant melanoma, but this is associated with a range of known and predictable cutaneous side effects, including squamous cell carcinomas associated with RAS mutations. METHODS: We identified three severely dysplastic nevi, one atypical intraepidermal melanocytic proliferation, and four melanoma in situ lesions, newly arising in four patients undergoing treatment with vemurafenib. To characterize mutations in these atypical melanocytic lesions, we used a custom iPlex panel detecting 74 mutations in 13 genes known to play a role in melanoma pathogenesis. RESULTS: We identified an NRAS mutation at codon 61 (Q61R) and a rare BRAF exon 11 mutation (G466A) in atypical melanocytic lesions that arose in patients treated with vemurafenib. CONCLUSION: There appears to be development or accelerated growth of atypical melanocytic lesions in the setting of BRAF inhibition. Our results underscore the need for careful surveillance for melanocytic lesions in patients on BRAF inhibitor therapy and shed light on potential mechanisms for melanoma pathogenesis in the context of BRAF pathway blockade. Further studies are warranted to show a causal relationship.
Assuntos
Antineoplásicos/efeitos adversos , GTP Fosfo-Hidrolases/genética , Melanoma/tratamento farmacológico , Proteínas de Membrana/genética , Segunda Neoplasia Primária/genética , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/tratamento farmacológico , Vemurafenib/efeitos adversos , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Mutação , Segunda Neoplasia Primária/induzido quimicamente , Estudos Retrospectivos , Neoplasias Cutâneas/induzido quimicamente , Neoplasias Cutâneas/genética , Melanoma Maligno CutâneoRESUMO
BACKGROUND: Distinguishing types of lymphocytic scarring alopecia is often difficult because of the overlapping features. Recently, the presence of plasmacytoid dendritic cells (PDCs) in cutaneous lupus erythematosus (LE) was demonstrated and further shown to help distinguish lupus from other dermatoses.1-6 This study aims to determine if the presence and distribution of PDCs can aid in the diagnosis of scarring alopecia. METHODS: Cases of scarring alopecia due to chronic cutaneous lupus erythematosus (CCLE), lichen planopilaris (LPP) and central centrifugal cicatricial alopecia (CCCA) were examined histopathologically. A total of 45 total biopsies were evaluated and CD123 immunohistochemistry was performed on all samples. The relative percentage of PDCs, the presence of clusters and the distribution of CD123+ cells were noted. RESULTS: PDCs comprised a greater percentage of the infiltrate and were arranged in clusters in cases of CCLE vs. LPP or CCCA. In CCLE, the location of PDCs was perivascular, perifollicular, perieccrine and/or at the follicular junction. In LPP and CCCA, PDCs were mainly arranged as single, interstitial cells. CONCLUSIONS: Our findings suggest that the presence and arrangement of CD123+ PDCs may assist in the diagnosis of scarring alopecia. We anticipate this will be of value in diagnosing challenging cases of highly inflammatory scarring alopecia.
Assuntos
Alopecia/diagnóstico , Células Dendríticas/patologia , Subunidade alfa de Receptor de Interleucina-3/análise , Biomarcadores/análise , Cicatriz , Humanos , Imuno-Histoquímica , Estudos Retrospectivos , Sensibilidade e EspecificidadeRESUMO
T lymphocytes belong to 2 distinct sublineages that express either αß or γδ T-cell receptor (TCR) complex. Although malignancy is a great instigator of lineage infidelity, as exemplified by aberrant expression of numerous lineage markers in lymphoma cells, malignant T cells rarely coexpress αß and γδ TCR complexes. Similarly, only rare cases of CD4/CD8 double-positive primary cutaneous T-cell lymphoma have been reported. In this report, we describe a remarkable case of primary cutaneous T-cell lymphoma coexpressing αß and γδ TCR complexes, strong diffuse CD8, and a very restricted coexpression of CD4 and CD8. A 66-year-old man was referred to our center for treatment of a persistent eczematoid eruption of 6 years of duration. An initial biopsy demonstrated not only marked spongiosis, but also an epidermotropic population of CD4 small mature T cells with partial expression of CD8. The process remained indolent for another year, followed by an abrupt progression with development of plaques and tumors. Repeat biopsies of these lesions demonstrated a superimposed population of large anaplastic T cells extensively involving the dermis and epidermis. The large cells showed a strong uniform expression of CD3, CD8, CD45RA, CD5, granzyme, TIA1, perforin, TCR-ß, and TCR-γ and a weaker but unambiguous expression of CD4, CD25, CD2, and CD56. TCR gene rearrangement studies showed clonal rearrangements for TCR-ß and TCR-γ with identical peaks to those seen in the biopsy from a year earlier. The patient developed lymphadenopathy, with a biopsy showing nodal involvement by a morphologically and phenotypically identical neoplastic T-cell population. The disease showed partial response to systemic chemotherapy with development of new plaques, but these new lesions have regressed with radiation therapy.
Assuntos
Antígenos CD/análise , Linfoma Cutâneo de Células T/química , Linfoma Cutâneo de Células T/patologia , Receptores de Antígenos de Linfócitos T alfa-beta/análise , Receptores de Antígenos de Linfócitos T gama-delta/análise , Idoso , Granzimas/análise , Humanos , Masculino , Perforina/análise , Proteínas de Ligação a Poli(A)/análise , Antígeno-1 Intracelular de Células TRESUMO
Syringocystadenocarcinoma papilliferum (SCACP) is an extremely rare adnexal neoplasm, believed to arise in a preexisting nevus sebaceus of Jadassohn (NSJ) through a multistep progression process. This hypothetical process involves an NSJ giving rise to syringocystadenoma papilliferum, which then presumably undergoes malignant transformation in rare circumstances to give rise to SCACP in situ, which finally progresses to an invasive SCACP. Of the 30 SCACP cases reported so far, none have documented the process from a birthmark to the final invasive lesion, with histological evidence of each step, in a single tumor. Here, the authors report just such a case. A 74-year-old man presented with a recently enlarging birthmark on the scalp. Excisional biopsy showed an invasive SCACP, in the background of SCACP in situ, syringocystadenoma papilliferum, and NSJ. Furthermore, this tumor showed a concurrent pigmented trichoblastoma and histological evidence of lymphovascular invasion, events that have not been documented with SCACP. Interestingly, all these component lesions were present on a single histological section of this solitary tumor. Regional lymph node metastasis, a rare occurrence in SCACP, was also present in this remarkable case. The authors discuss the implications of these findings in light of the review of relevant literature.
Assuntos
Carcinoma in Situ/patologia , Cistadenocarcinoma Papilar/patologia , Neoplasias de Cabeça e Pescoço/patologia , Nevo Sebáceo de Jadassohn/patologia , Couro Cabeludo , Neoplasias Cutâneas/patologia , Siringoma/patologia , Idoso , Transformação Celular Neoplásica , Cistadenocarcinoma Papilar/secundário , Humanos , Metástase Linfática , Masculino , Invasividade NeoplásicaRESUMO
Therapy related acute lymphoblastic leukemia (t-ALL) of B cell origin is rare and constitutes approximately 2% of all ALL. Previously compiled data on the complete cytogenetic analysis of 48 t-B-ALL cases suggested that MLL rearrangement at 11q23 gene locus is the most common abnormality. Philadelphia chromosome (Ph) and a normal karyotype were reported as the second and third most common karyotypes, respectively. We investigated cytogenetic karyotypes of six t-B-ALL cases with a pre-B cell immunophenotype. Ph + t-B-ALL was noted in four of six patients previously treated with radiation and/or chemotherapy. In addition, one case demonstrated MLL rearrangement at 11q23 locus while one case demonstrated normal cytogenetic karyotype. Five of the six t-B-ALL patients had persistent leukemia following initiation of chemotherapy for secondary leukemia with survival ranging from 10 to 21 months. To our knowledge, only fourteen patients with Ph + t-B-ALL have been described in the literature. In the current study, three of four cases with Ph + t-B-ALL were associated with treated breast carcinoma while one patient was treated for Hodgkin lymphoma. All four patients had undergone radiation therapy. The results may indicate a plausible association between Ph+t-B-ALL and prior radiation exposure.
Assuntos
Rearranjo Gênico/genética , Histona-Lisina N-Metiltransferase/genética , Proteína de Leucina Linfoide-Mieloide/genética , Segunda Neoplasia Primária/patologia , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Idoso , Neoplasias da Mama/genética , Cromossomos Humanos Par 11/genética , Análise Citogenética/métodos , Feminino , Humanos , Imunofenotipagem/métodos , Cariotipagem , Masculino , Pessoa de Meia-Idade , Segunda Neoplasia Primária/diagnóstico , Segunda Neoplasia Primária/genética , Translocação Genética/genéticaRESUMO
Porokeratoses are acquired and hereditary disorders of keratinization that share a distinctive lesion characterized by raised keratotic borders corresponding histologically to an angled column of parakeratotic cells, called a cornoid lamella. Although a precise mechanistic explanation is lacking, ultraviolet radiation and immunosuppressed states are considered causally-associated with most cases of acquired porokeratosis. Hepatitis C virus (HCV) infection has been proposed as a link between the immunosuppressed states and development of acquired porokeratosis. Among the various recognized clinical entities that constitute this group, rare cases of hyperkeratotic variants have been described that may pose a diagnostic challenge. Herein we describe a remarkable case of the hyperkeratotic variant of porokeratosis that occurred in a patient with known HIV and HCV infections and a coexisting therapy-related immunosuppressed state. We also provide a review of the relevant literature.
Assuntos
Síndrome da Imunodeficiência Adquirida/complicações , Hepatite C/complicações , Hospedeiro Imunocomprometido , Poroceratose/imunologia , Artrite Psoriásica/complicações , Artrite Psoriásica/tratamento farmacológico , Humanos , Imunossupressores/efeitos adversos , Masculino , Pessoa de Meia-Idade , Poroceratose/complicaçõesAssuntos
Granuloma/patologia , Melanoma/patologia , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Neoplasias Cutâneas/patologia , Diagnóstico Diferencial , Granuloma/diagnóstico , Granuloma/cirurgia , Humanos , Masculino , Melanoma/cirurgia , Pessoa de Meia-Idade , Cirurgia de Mohs/métodos , Monitorização Fisiológica , Metástase Neoplásica , Reoperação , Medição de Risco , Neoplasias Cutâneas/cirurgiaRESUMO
The Grainy head-like 3 (Grhl3) gene encodes a transcription factor that plays essential roles in epidermal morphogenesis during embryonic development, with deficient mice exhibiting failed skin barrier formation, defective wound repair, and loss of eyelid fusion. Despite sharing significant sequence homology, overlapping expression patterns, and an identical core consensus DNA binding site, the other members of the Grhl family (Grhl1 and -2) fail to compensate for the loss of Grhl3 in these processes. Here, we have employed diverse genetic models, coupled with biochemical studies, to define the inter-relationships of the Grhl factors in epidermal development. We show that Grhl1 and Grhl3 have evolved complete functional independence, as evidenced by a lack of genetic interactions in embryos carrying combinations of targeted alleles of these genes. In contrast, compound heterozygous Grhl2/Grhl3 embryos displayed failed wound repair, and loss of a single Grhl2 allele in Grhl3-null embryos results in fully penetrant eyes open at birth. Expression of Grhl2 from the Grhl3 locus in homozygous knock-in mice corrects the wound repair defect, but these embryos still display a complete failure of skin barrier formation. This functional dissociation is due to unexpected differences in target gene specificity, as both GRHL2 and GRHL3 bind to and regulate expression of the wound repair gene Rho GEF 19, but regulation of the barrier forming gene, Transglutaminase 1 (TGase1), is unique to GRHL3. Our findings define the mechanisms underpinning the unique and cooperative roles of the Grhl genes in epidermal development.
Assuntos
Proteínas de Ligação a DNA/metabolismo , Epiderme/embriologia , Morfogênese/fisiologia , Fenótipo , Proteínas Repressoras/metabolismo , Fatores de Transcrição/metabolismo , Animais , Primers do DNA/genética , Proteínas de Ligação a DNA/genética , Ensaio de Desvio de Mobilidade Eletroforética , Epiderme/ultraestrutura , Técnicas de Introdução de Genes , Imuno-Histoquímica , Hibridização In Situ , Camundongos , Microscopia Eletrônica de Varredura , Proteínas Repressoras/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição/genética , Transglutaminases/metabolismo , Cicatrização/fisiologiaRESUMO
Invasive aspergillosis (IA) is a serious fungal infection that primarily affects patients with prolonged and profound neutropenia, and compromised cell-mediated immunity. Aspergillosis of the oesophagus and gastrointestinal tract is uncommon but seen in advanced cases of disseminated IA. However, it is difficult to diagnose antemortem due to the poor specificity of the symptoms and the absence of characteristic imaging findings. Therefore, the reported cases of gastrointestinal aspergillosis have been associated with high morbidity and mortality, and frequently diagnosed postmortem. Here we present a successful outcome in a patient with relapsed and refractory multiple myeloma who had presented with febrile neutropenia, cough and dysphagia, and was diagnosed with disseminated IA comprising of pulmonary and oesophageal involvement. This case highlights the need for a high index of suspicion and the importance of invasive procedures for histopathology and molecular diagnostics to ensure an early diagnosis and therapeutic intervention.
Assuntos
Aspergilose , Infecções Fúngicas Invasivas , Aspergilose Pulmonar Invasiva , Mieloma Múltiplo , Aspergilose/complicações , Aspergilose/diagnóstico , Aspergilose/tratamento farmacológico , Esôfago , Humanos , Infecções Fúngicas Invasivas/complicações , Aspergilose Pulmonar Invasiva/complicações , Aspergilose Pulmonar Invasiva/diagnóstico , Aspergilose Pulmonar Invasiva/tratamento farmacológico , Mieloma Múltiplo/complicações , Mieloma Múltiplo/diagnósticoRESUMO
Primary cutaneous CD30+ T-cell lymphoproliferative disorders are the second most common cutaneous lymphomas. According to the World Health Organization, CD30+ T-cell lymphoproliferative disorders include primary cutaneous anaplastic large cell lymphoma (C-ALCL) and lymphomatoid papulosis (LyP) as well as borderline lesions. C-ALCL and LyP are thought to represent two ends of a spectrum of diseases that have different clinical presentations, clinical courses, and prognoses in their classic forms but share the same histology of medium to large CD30+ atypical lymphoid cell infiltrates. Because the behavior of these entities is different clinically and prognostically, we aim to search for oncogenic genomic variants using whole-exome sequencing that drive the development of LyP and C-ALCL. Clinical information, pathology, immunohistochemistry, and T-cell rearrangements on six cases of LyP and five cases of C-ALCL were reviewed to confirm the rendered diagnosis before whole-exome sequencing of all specimens. Both LyP and C-ALCL had recurrent alterations in epigenetic modifying genes affecting histone methylation and acetylation (SETD2, KMT2A, KMT2D, and CREBBP). However, they also harbor unique differences with mutations in signal transducer and activator of transcription gene STAT3 of the Jak/signal transducer and activator of transcription pathway and EOMES, a transcription factor involved in lymphocyte development, only noted in C-ALCL specimens. Genomic characterization of LyP and C-ALCL in this series confirms the role of multiple pathways involved in the biology and development of these lymphomatous processes. The identification of similar aberrations within the epigenetic modifying genes emphasizes common potential development mechanisms of lymphomagenesis within lymphoproliferative disorders being shared between LyP and C-ALCL; however, the presence of differences may account for the differences in clinical course.
RESUMO
Primary neurulation in mammals has been defined by distinct anatomical closure sites, at the hindbrain/cervical spine (closure 1), forebrain/midbrain boundary (closure 2), and rostral end of the forebrain (closure 3). Zones of neurulation have also been characterized by morphologic differences in neural fold elevation, with non-neural ectoderm-induced formation of paired dorso-lateral hinge points (DLHP) essential for neural tube closure in the cranial and lower spinal cord regions, and notochord-induced bending at the median hinge point (MHP) sufficient for closure in the upper spinal region. Here we identify a unifying molecular basis for these observations based on the function of the non-neural ectoderm-specific Grainy head-like genes in mice. Using a gene-targeting approach we show that deletion of Grhl2 results in failed closure 3, with mutants exhibiting a split-face malformation and exencephaly, associated with failure of neuro-epithelial folding at the DLHP. Loss of Grhl3 alone defines a distinct lower spinal closure defect, also with defective DLHP formation. The two genes contribute equally to closure 2, where only Grhl gene dosage is limiting. Combined deletion of Grhl2 and Grhl3 induces severe rostral and caudal neural tube defects, but DLHP-independent closure 1 proceeds normally in the upper spinal region. These findings provide a molecular basis for non-neural ectoderm mediated formation of the DLHP that is critical for complete neuraxis closure.
Assuntos
Proteínas de Ligação a DNA/genética , Tubo Neural/embriologia , Fatores de Transcrição/genética , Animais , Proteínas de Ligação a DNA/metabolismo , Embrião de Mamíferos/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Camundongos , Camundongos Transgênicos , Tubo Neural/crescimento & desenvolvimento , Defeitos do Tubo Neural/genética , Fatores de Transcrição/metabolismoRESUMO
The neural tube defects (NTDs) spina bifida and anencephaly are widely prevalent severe birth defects. The mouse mutant curly tail (ct/ct) has served as a model of NTDs for 50 years, even though the responsible genetic defect remained unrecognized. Here we show by gene targeting, mapping and genetic complementation studies that a mouse homolog of the Drosophila grainyhead (grh) gene, grainyhead-like-3 (Grhl3), is a compelling candidate for the gene underlying the curly tail phenotype. The NTDs in Grhl3-null mice are more severe than those in the curly tail strain, as the Grhl3 alleles in ct/ct mice are hypomorphic. Spina bifida in ct/ct mice is folate resistant, but its incidence can be markedly reduced by maternal inositol supplementation periconceptually. The NTDs in Grhl3-/- embryos are also folate resistant, but unlike those in ct/ct mice, they are resistant to inositol. These findings suggest that residual Grhl3 expression in ct/ct mice may be required for inositol rescue of folate-resistant NTDs.
Assuntos
Proteínas de Ligação a DNA/deficiência , Ácido Fólico/farmacologia , Inositol/farmacologia , Defeitos do Tubo Neural/etiologia , Defeitos do Tubo Neural/prevenção & controle , Fatores de Transcrição/deficiência , Animais , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/fisiologia , Resistência a Medicamentos , Epitélio/patologia , Feminino , Humanos , Camundongos , Camundongos Knockout , Camundongos Mutantes Neurológicos , Defeitos do Tubo Neural/genética , Defeitos do Tubo Neural/patologia , Proteínas Nucleares , Fenótipo , Gravidez , Fatores de Transcrição/genética , Fatores de Transcrição/fisiologiaRESUMO
Extrapulmonary small cell carcinoma (EPSCC) is a rare and aggressive clinical entity that can involve a variety of anatomic locations, including the gastrointestinal tract. Involvement of the gastrointestinal tract is associated with a particularly poor prognosis with patients often presenting with widespread dissemination on initial clinical presentation or rapidly progressing to systemic disease from locoregional involvement. Primary small cell carcinoma of the anal canal is extremely rare, with limited published case reports in the literature. As a result, management of this disease is not well defined, and outcomes are poor with high rates of disease relapse. We report a patient with locally advanced anal small cell carcinoma after presenting with irregular bowel movements, changes in stool caliber, and rectal bleeding for two months and achieved a durable complete response to concurrent chemoradiation with cisplatin and etoposide followed by consolidation chemotherapy and discuss our current understanding of this disease. Specifically, we review the epidemiology, risk factors, clinical course, the treatment strategies over the past two decades, and prognosis for EPSCC. Finally, we conclude our discussion by reviewing the rationale of our treatment regimen and the potential role and benefit of consolidation therapy in the management of this rare and aggressive disease.
RESUMO
In locally advanced basal cell carcinoma (BCC) patients who are not surgical candidates and where radiation therapy (RT) alone would offer lower control rates, the combination of vismodegib and RT delivered concurrently may potentially improve outcomes compared to single modality treatment. The current study presents a case of very advanced, multifocal BCC who received concurrent vismodegib and RT. The patient initially came in with four large primary areas of disease including the left preauriculum, right shoulder, chest wall and right lateral ankle. All sites achieved a clinical complete response, with a pathologic complete response at the right shoulder. The ankle lesion did not require RT and continues to have a clinical complete response. The findings from our case report support several other cases with similar efficacy when vismodegib and RT are combined.
RESUMO
Squamous cell carcinoma in situ (SCCIS) is a prevalent precancerous lesion that can progress to cutaneous squamous cell carcinoma. Although SCCIS is common, its pathogenesis remains poorly understood. To better understand SCCIS development, we performed laser captured microdissection of human SCCIS and the adjacent epidermis to isolate genomic DNA and RNA for next-generation sequencing. Whole-exome sequencing identified UV-signature mutations in multiple genes, including NOTCH1-3 in the epidermis and SCCIS and oncogenic TP53 mutations in SCCIS. Gene families, including SLFN genes, contained UV/oxidative-signature disruptive epidermal mutations that manifested positive selection in SCCIS. The frequency and distribution of NOTCH and TP53 mutations indicate that NOTCH mutations may precede TP53 mutations. RNA sequencing identified 1,166 differentially expressed genes; the top five enriched gene ontology biological processes included (i) immune response, (ii) epidermal development, (iii) protein phosphorylation, (iv) regulation of catalytic activity, and (v) cytoskeletal regulation. The NEURL1 ubiquitin ligase, which targets Notch ligands for degradation, was upregulated in SCCIS. NEURL1 protein was found to be elevated in SCCIS suggesting that increased levels could represent a mechanism for downregulating Notch during UV-induced carcinogenesis. The data from DNA and RNA sequencing of epidermis and SCCIS provide insights regarding SCCIS formation.
Assuntos
Carcinoma in Situ/etiologia , Carcinoma de Células Escamosas/etiologia , Epiderme/efeitos da radiação , Exoma , Perfilação da Expressão Gênica , Neoplasias Induzidas por Radiação/etiologia , Neoplasias Cutâneas/etiologia , Carcinogênese/genética , Carcinoma in Situ/genética , Carcinoma de Células Escamosas/genética , Genes p53 , Humanos , Mutação , Neoplasias Induzidas por Radiação/genética , Receptores Notch/genética , Análise de Sequência de RNA , Neoplasias Cutâneas/genética , Raios UltravioletaRESUMO
PURPOSE OF REVIEW: Primary cutaneous CD30+ T-cell lymphoproliferative disorders (CD30+ LPDs) are the second most common cutaneous lymphomas after mycosis fungoides and Sezary syndrome. They include primary cutaneous anaplastic large cell lymphoma (pcALCL), lymphomatoid papulosis (LyP), and borderline lesions. The purpose of this literature review is to consolidate the available evidence on the primary cutaneous CD30+ LPD in order to define the tools for correct diagnosis and appropriate treatment. RECENT FINDINGS: The current body of knowledge regarding the clinical features, histopathologic changes, recently described genetic alterations, and therapeutic options will be covered in this comprehensive review. Primary cutaneous CD30+ LPD represent rare cutaneous lymphomas that have significant histologic overlap within the defined group as well as with other neoplastic and reactive entities. The importance of differentiating these entities is crucial, as each one has a different clinical course and prognosis.
Assuntos
Antígeno Ki-1/imunologia , Linfoma Anaplásico Cutâneo Primário de Células Grandes , Papulose Linfomatoide , Transtornos Linfoproliferativos , Neoplasias Cutâneas , Diagnóstico Diferencial , Humanos , Linfoma Anaplásico Cutâneo Primário de Células Grandes/genética , Linfoma Anaplásico Cutâneo Primário de Células Grandes/imunologia , Linfoma Anaplásico Cutâneo Primário de Células Grandes/terapia , Papulose Linfomatoide/genética , Papulose Linfomatoide/imunologia , Papulose Linfomatoide/terapia , Transtornos Linfoproliferativos/genética , Transtornos Linfoproliferativos/imunologia , Transtornos Linfoproliferativos/terapia , Valor Preditivo dos Testes , Prognóstico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/terapiaRESUMO
PURPOSE: Elevation of L-2-hydroxylgutarate (L-2-HG) in renal cell carcinoma (RCC) is due in part to reduced expression of L-2-HG dehydrogenase (L2HGDH). However, the contribution of L-2-HG to renal carcinogenesis and insight into the biochemistry and targets of this small molecule remains to be elucidated. EXPERIMENTAL DESIGN: Genetic and pharmacologic approaches to modulate L-2-HG levels were assessed for effects on in vitro and in vivo phenotypes. Metabolomics was used to dissect the biochemical mechanisms that promote L-2-HG accumulation in RCC cells. Transcriptomic analysis was utilized to identify relevant targets of L-2-HG. Finally, bioinformatic and metabolomic analyses were used to assess the L-2-HG/L2HGDH axis as a function of patient outcome and cancer progression. RESULTS: L2HGDH suppresses both in vitro cell migration and in vivo tumor growth and these effects are mediated by L2HGDH's catalytic activity. Biochemical studies indicate that glutamine is the predominant carbon source for L-2-HG via the activity of malate dehydrogenase 2 (MDH2). Inhibition of the glutamine-MDH2 axis suppresses in vitro phenotypes in an L-2-HG-dependent manner. Moreover, in vivo growth of RCC cells with basal elevation of L-2-HG is suppressed by glutaminase inhibition. Transcriptomic and functional analyses demonstrate that the histone demethylase KDM6A is a target of L-2-HG in RCC. Finally, increased L-2-HG levels, L2HGDH copy loss, and lower L2HGDH expression are associated with tumor progression and/or worsened prognosis in patients with RCC. CONCLUSIONS: Collectively, our studies provide biochemical and mechanistic insight into the biology of this small molecule and provide new opportunities for treating L-2-HG-driven kidney cancers.