RESUMEN
The increase in the detection rate of synchronous multiple primary lung cancer (MPLC) has posed remarkable clinical challenges due to the limited understanding of its pathogenesis and molecular features. Here, comprehensive comparisons of genomic and immunologic features between MPLC and solitary lung cancer nodule (SN), as well as different lesions of the same patient, were performed. Compared with SN, MPLC displayed a lower rate of EGFR mutation but higher rates of BRAF, MAP2K1, and MTOR mutation, which function exactly in the upstream and downstream of the same signaling pathway. Considerable heterogeneity in T cell receptor (TCR) repertoire exists among not only different patients but also among different lesions of the same patient. Invasive lesions of MPLC exhibited significantly higher TCR diversity and lower TCR expansion than those of SN. Intriguingly, different lesions of the same patient always shared a certain proportion of TCR clonotypes. Significant clonal expansion could be observed in shared TCR clonotypes, particularly in those existing in all lesions of the same patient. In conclusion, this study provided evidences of the distinctive mutational landscape, activation of oncogenic signaling pathways, and TCR repertoire in MPLC as compared with SN. The significant clonal expansion of shared TCR clonotypes demonstrated the existence of immune commonality among different lesions of the same patient and shed new light on the individually tailored precision therapy for MPLC.
Asunto(s)
Neoplasias Pulmonares , Mutación , Neoplasias Primarias Múltiples , Receptores de Antígenos de Linfocitos T , Humanos , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Neoplasias Primarias Múltiples/inmunología , Neoplasias Primarias Múltiples/genética , Neoplasias Primarias Múltiples/patología , Masculino , Femenino , Persona de Mediana Edad , AncianoRESUMEN
PURPOSE: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare malignancy associated with an overall poor prognosis. We aimed to investigate the immune profile of cHCC-CCA and determine its impact on disease outcome. EXPERIMENTAL DESIGN: We performed a multicenter study of 96 patients with cHCC-CCA. Gene expression profile was analyzed using nCounter PanCancer IO 360 Panel. Densities of main immune cells subsets were quantified from digital slides of IHC stainings. Genetic alterations were investigated using targeted next-generation sequencing. RESULTS: Two main immune subtypes of cHCC-CCA were identified by clustering analysis: an "immune-high" (IH) subtype (57% of the cases) and an "immune-low" (IL) subtype (43% of the cases). Tumors classified as IH showed overexpression of genes related to immune cells recruitment, adaptive and innate immunity, antigen presentation, cytotoxicity, immune suppression, and inflammation (P < 0.0001). IH cHCC-CCAs also displayed activation of gene signatures recently shown to be associated with response to immunotherapy in patients with HCC. Quantification of immunostainings confirmed that IH tumors were also characterized by higher densities of immune cells. Immune subtypes were not associated with any genetic alterations. Finally, multivariate analysis showed that the IH subtype was an independent predictor of improved overall survival. CONCLUSIONS: We have identified a subgroup of cHCC-CCA that displays features of an ongoing intratumor immune response, along with an activation of gene signatures predictive of response to immunotherapy in HCC. This tumor subclass is associated with an improved clinical outcome. These findings suggest that a subset of patients with cHCC-CCA may benefit from immunomodulating therapeutic approaches.
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Neoplasias de los Conductos Biliares/inmunología , Neoplasias de los Conductos Biliares/terapia , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/terapia , Colangiocarcinoma/inmunología , Colangiocarcinoma/terapia , Inmunoterapia , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/terapia , Neoplasias Primarias Múltiples/inmunología , Neoplasias Primarias Múltiples/terapia , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de los Conductos Biliares/diagnóstico , Neoplasias de los Conductos Biliares/genética , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/genética , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/genética , Femenino , Predicción , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Masculino , Persona de Mediana Edad , Neoplasias Primarias Múltiples/diagnóstico , Neoplasias Primarias Múltiples/genética , Resultado del TratamientoRESUMEN
Many studies support a stepwise continuum of morphologic changes between atypical adenomatous hyperplasia (AAH) and lung adenocarcinoma (ADC). Here we characterized gene expression patterns and the association of differentially expressed genes and immune tumor microenvironment behaviors in AAH to ADC during ADC development. Tumor tissues from nine patients with ADC and synchronous multiple ground glass nodules/lesions (GGN/Ls) were analyzed using RNA sequencing. Using clustering, we identified genes differentially and sequentially expressed in AAH and ADC compared to normal tissues. Functional enrichment analysis using gene ontology terms was performed, and the fraction of immune cell types was estimated. We identified up-regulated genes (ACSL5 and SERINC2) with a stepwise change of expression from AAH to ADC and validated those expressions by quantitative PCR and immunohistochemistry. The immune cell profiles revealed increased B cell activities and decreased natural killer cell activities in AAH and ADC. A stepwise change of differential expression during ADC development revealed potential effects on immune function in synchronous precursors and in tumor lesions in patients with lung cancer.
Asunto(s)
Adenocarcinoma del Pulmón/genética , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/genética , Neoplasias Primarias Múltiples/genética , Estudios de Asociación Genética , Genoma Humano , Humanos , Hiperplasia , Inmunidad , Mutación/genética , Neoplasias Primarias Múltiples/inmunología , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , RNA-Seq , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: Diagnosing and treating patients with multiple primary lung cancers (MPLCs) bring challenges to the clinic, and the preliminary evidence has revealed unsatisfying outcomes after targeted therapy and immunotherapy. Therefore, we surveyed genomic profiles of MPLCs and their possible associations with tumor mutation burden (TMB), programmed death-ligand 1 (PD-L1), and the immune cell infiltration landscape. MATERIALS AND METHODS: A total of 112 patients with MPLCs with surgically resected 294 tumors were eligible, and 255 tumors were sequenced using a 1021-gene panel. Immunohistochemistry staining was performed to evaluate the levels of PD-L1 and the density of CD3+/CD8+ tumor-infiltrating lymphocytes (TILs), and CD68+/CD163+ tumor-associated macrophages (TAMs) at the central tumor and invasive margin, and immunotypes were generated based on those variables. RESULTS: MPLCs often occur simultaneously in non-smoker women younger than 60 years and manifest as ground-glass opacities, adenocarcinoma, and stage I lung lesions. The most frequently mutated genes in the 255 tumors were EGFR (56%), ERBB2 (12%), TP53 (12%), BRAF (11%), RBM10 (11%), and KRAS (9%). We found 87 (77.7%) patients with diverse genomic profiles, and 61 (54.5%) who shared at least one putative driver gene between different tumors presented more aggressive tumors. The median TMB was 1.92 mutations/Mb, and high-TMB (≥3) lesions often harbored EGFRL858R/KRASG12C/RBM10/TP53/LRP1B mutations or wild-type ERBB2. Only 8.1% of patients and 3.9% of lesions were positive for PD-L1 on tumor cells, and this positivity was more frequent in LRP1B/TP53-mutant tumors. EGFRL858R/RBM10/TP53 mutations were positively associated with specific immune cells and an inflamed immunotype, but ERBB2 mutations were negatively correlated. TMB, CD3+TILs, and CD68+/CD163+ TAMs presented with significant heterogeneity among paired tumors (all kappa <0.2), but PD-L1 and CD8 +TILs were more uniformly present in tumor pairs. CONCLUSION: MPLCs are driven by different molecular events and often exhibit low TMB, low PD-L1, and a heterogeneous immune infiltration landscape. Specific genomic profiles are associated with TMB and the tumor immune microenvironmental landscape in MPLCs. Our findings can help to guide MPLCs diagnoses and to identify patient populations that may benefit from immunotherapy and targeted therapy.
Asunto(s)
Antígeno B7-H1/metabolismo , Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Mutación , Neoplasias Primarias Múltiples/inmunología , Microambiente Tumoral , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/inmunología , Adenocarcinoma del Pulmón/metabolismo , Adenocarcinoma del Pulmón/patología , Antígeno B7-H1/genética , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunoterapia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Neoplasias Primarias Múltiples/genética , Neoplasias Primarias Múltiples/metabolismo , Neoplasias Primarias Múltiples/patología , Macrófagos Asociados a Tumores/inmunologíaRESUMEN
The experimental model of synchronous multiple primary malignant tumors (MPMT) was created. B16/F10 melanoma (0.5 ml of suspension diluted 1:20 in saline) and sarcoma 45 (0.5 million tumor cells in 0.5 ml saline) were simultaneously subcutaneously inoculated to male BALB/c nude mice. In the model of synchronous MPMT, the tumors appeared faster by 2.4 times and had greater volumes: melanoma by 2.2 times and sarcoma by 3.2 times; melanoma metastasized into sarcoma in 71.4% cases; the survival of mice with MPMT was lower. The altered dynamics of malignant growth in the MPMT model is based on the mutual influence of tumors, which results in the exchange of "structural information".
Asunto(s)
Neoplasias Pulmonares/patología , Melanoma Experimental/patología , Trasplante de Neoplasias/métodos , Neoplasias Primarias Múltiples/patología , Enfermedades de Inmunodeficiencia Primaria/patología , Neoplasias Cutáneas/patología , Animales , Línea Celular Tumoral , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Masculino , Melanoma Experimental/genética , Melanoma Experimental/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias Primarias Múltiples/genética , Neoplasias Primarias Múltiples/inmunología , Enfermedades de Inmunodeficiencia Primaria/genética , Enfermedades de Inmunodeficiencia Primaria/inmunología , Ratas , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/inmunologíaRESUMEN
BACKGROUND: To explore the genetic and immunophenotyping heterogeneities between patients with intrapulmonary metastasis (IPM) or multiple primary lung cancer (MPLC). METHODS: Whole exome sequencing (WES) and transcriptome sequencing (RNA-seq) were performed on the tissue and blood samples of IPM and MPLC patients to comprehensively analyze the clonal evolution, molecular typing and immunophenotyping. RESULTS: There was no significant difference in genetic mutation, tumor mutational burden (TMB) value and mutant allele tumor heterogeneity (MATH) value between IPM and MPLC patients. Notably, the loss of heterozygosity (LOH) of human leukocyte antigen (HLA) appeared in all IPM patients, while there was also no significant difference between the two groups. In addition, expression of immune checkpoint-related genes including CTLA-4, BTLA, TIGIT and HAVCR2 in the MPLC group was significantly higher than those in IPM group. At the same time, 86 differentially expressed genes (DEGs) were observed between IPM and MPLC patients with transcriptome sequencing, of which 56 DEGs were upregulated and 30 were downregulated in the IPM group compared with the MPLC group. The cluster analysis revealed that the 86 DEGs could be distinguished in IPM and MPLC samples. Moreover, only the infiltration levels of CD56dim natural killer cells in the IPM group was significantly higher than that in the MPLC group, and the infiltration levels of the remaining 27 immune cell subsets were similar in both groups. CONCLUSIONS: IPM and MPLC are roughly similar in genetic and immune characteristics indicating that genomics alone may not be able to effectively distinguish between IPM and MPLC, which still needs to be comprehensively evaluated with clinical manifestations, imaging, and pathological characteristics.
Asunto(s)
Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Neoplasias Primarias Múltiples/genética , Neoplasias Primarias Múltiples/inmunología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/inmunología , Humanos , Neoplasias Pulmonares/patología , Neoplasias Primarias Múltiples/patología , Secuenciación del ExomaRESUMEN
The phenomenon of multiple primary malignant tumors (MPMT) is characterized by the presence of several primary neoplasms in the same patient. An experimental model of MPMT with one dominating tumor was developed. Female BALB/c nude mice received simultaneous subcutaneous inoculation of Guerin's carcinoma (5×105 tumor cells in 0.5 ml saline) and B16/F10 melanoma (0.5 ml suspension diluted 1:20 with saline). Control females received transplantation of either melanoma or carcinoma alone in the same doses and volumes. In animals with MPMT model, tumors appeared 3-fold faster than after isolated transplantation of melanoma or Guerin's carcinoma and were larger by 7.5 and 2.2 times, respectively; the survival of mice with MPMT was lower. Guerin's carcinoma in the MPMT model metastasized to melanoma and almost completely suppressed its growth. Thus, a MPMT model was created with carcinoma suppressing the malignant growth of melanoma.
Asunto(s)
Carcinoma/patología , Melanoma Experimental/patología , Neoplasias Primarias Múltiples/patología , Enfermedades de Inmunodeficiencia Primaria/patología , Neoplasias Urológicas/patología , Animales , Carcinoma/inmunología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Femenino , Inyecciones Subcutáneas , Melanoma Experimental/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Trasplante de Neoplasias , Neoplasias Primarias Múltiples/inmunología , Enfermedades de Inmunodeficiencia Primaria/inmunología , Ratas , Factores de Tiempo , Carga Tumoral , Neoplasias Urológicas/inmunologíaRESUMEN
Background: As an emerging therapy with a promising efficacy, immunotherapy has been widely used in the treatment of solid tumors and hematologic malignancies. This clinical study compares the efficacy of tislelizumab, a domestic immune checkpoint inhibitor (ICI), to that of sorafenib when used as a first-line therapeutic option in hepatocellular carcinoma (HCC), and the concurrence of HCC and non-Hodgkin's lymphoma (NHL) is rare, especially in the treatment of ICIs. Case presentation: A 61-year-old patient presenting with primary HCC and indolent B-cell lymphoma had a partial clinical response to tislelizumab for his primary HCC. Besides, we described a phenomenon of pseudo-progression and delayed diagnosis of his lymphoma during a long course of treatment. Conclusion: Tislelizumab, an immunotherapeutic option with a favorable efficacy and toxicity, can be used to manage double primary tumors. However, studies should aim to elucidate the probable mechanisms of this therapy. Pseudo-progression and separation remission make the treatment of double primary tumors even more challenging, which calls for additional caution in patients undergoing immunotherapy to avoid misdiagnosis and, therefore, begin early appropriate interventions.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Linfoma de Células B/tratamiento farmacológico , Neoplasias Primarias Múltiples/tratamiento farmacológico , Carcinoma Hepatocelular/diagnóstico por imagen , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/metabolismo , Humanos , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/metabolismo , Linfoma de Células B/diagnóstico por imagen , Linfoma de Células B/inmunología , Linfoma de Células B/metabolismo , Masculino , Persona de Mediana Edad , Neoplasias Primarias Múltiples/diagnóstico por imagen , Neoplasias Primarias Múltiples/inmunología , Neoplasias Primarias Múltiples/patología , Resultado del TratamientoRESUMEN
PURPOSE: We compared upper tract urothelial carcinoma (UTUC) and bladder urothelial carcinoma (BUC) in same-patient metachronous UTUC and synchronous UTUC and BUC using next-generation sequencing. MATERIALS AND METHODS: Consecutive untreated same-patient samples of UTUC and BUC were macrodissected from unstained formalin-fixed, paraffin-embedded slides after quality control. Samples were divided into 4 groups: 1) UTUC-metachronous BUC, 2) BUC-metachronous UTUC, 3) synchronous UTUC-BUC, 4) UTUC without BUC. Exclusions were inadequate clinical data or histological tumor purity <30%. Whole transcriptome RNA sequencing was performed. After quality assessment, gene expression clusters using unsupervised hierarchical consensus clustering and correlation with pertinent clinicopathologic variables, a prior RNASeq data set and other published data were performed. RESULTS: RNAseq was performed on 95 samples (UTUC=61, BUC=34) from 40 untreated patients. Unsupervised consensus clustering segregated the tumors into 2 clusters that were enriched with BASE47 basal-like or luminal-like gene expression. Almost two-thirds (61.9%) of Group 2 tumors were basal-like, while the majority of Groups 1, 3, 4 (80.6%, 70.0% and 69.6%, respectively) were luminal-like (p=0.017). Further analyses revealed that the differences in basal-like and luminal-like gene expression were associated with differential fibroblast and immune cell gene expression signatures. In all, 87.5% of metachronous tumors maintained subtype membership. CONCLUSIONS: Gene expression analysis of same-patient metachronous UTUC-BUC suggests that the majority of mUTUC developing after BUC appear more basal-like, while synchronous and initial UTUC tumors appear luminal-like. Metachronous tumors largely maintain molecular subtype membership of the initial tumor regardless of chronologic development or anatomical origin.
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Carcinoma de Células Transicionales/diagnóstico , Neoplasias Renales/diagnóstico , Neoplasias Primarias Múltiples/diagnóstico , Neoplasias Primarias Secundarias/diagnóstico , Neoplasias Ureterales/diagnóstico , Neoplasias de la Vejiga Urinaria/diagnóstico , Anciano , Biomarcadores de Tumor/genética , Carcinoma de Células Transicionales/genética , Carcinoma de Células Transicionales/inmunología , Carcinoma de Células Transicionales/cirugía , Femenino , Regulación Neoplásica de la Expresión Génica/inmunología , Humanos , Riñón/inmunología , Riñón/patología , Riñón/cirugía , Neoplasias Renales/genética , Neoplasias Renales/inmunología , Neoplasias Renales/cirugía , Masculino , Neoplasias Primarias Múltiples/genética , Neoplasias Primarias Múltiples/inmunología , Neoplasias Primarias Múltiples/cirugía , Neoplasias Primarias Secundarias/genética , Neoplasias Primarias Secundarias/inmunología , Neoplasias Primarias Secundarias/cirugía , RNA-Seq , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Uréter/inmunología , Uréter/patología , Uréter/cirugía , Neoplasias Ureterales/genética , Neoplasias Ureterales/inmunología , Neoplasias Ureterales/cirugía , Vejiga Urinaria/inmunología , Vejiga Urinaria/patología , Vejiga Urinaria/cirugía , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/inmunología , Neoplasias de la Vejiga Urinaria/cirugíaRESUMEN
Multiple primary lung cancer (MPLC) remains a tough challenge to diagnose and treat. Although neoadjuvant immunotherapy has shown promising results in early stage non-small cell lung cancer, whether such modality can benefit all primary lesions remains unclear. Herein, we performed integrated multiomics analysis in one patient with early stage MPLC with remarkable tumor shrinkage in a solid nodule and no response in two subsolid nodules after treatment with three cycles of neoadjuvant pembrolizumab. Genomic heterogeneity was observed among responding nodules with high levels of infiltrating CD8+ and CD68+ immune cells. Substantially downregulated human leukocyte antigen (HLA)-related genes and impaired T lymphocyte function were observed in non-responding nodules. A larger proportion of infiltrating tissue resident memory T cells (Trm) along with high T cell receptor repertoire clonality in responding nodules were validated as predictive and prognostic biomarkers in multiple cancer types using external public datasets. These results suggested that neoadjuvant programmed death 1 (PD-1)/programmed death ligand 1 inhibitors alone may not be an optimal therapeutic strategy for MPLC due to disparities in genomic alterations and immune microenvironment among different lesions. Additionally, we postulate that increased infiltration of Trm may be a unique marker of early immune responses to PD-1 blockade.
Asunto(s)
Adenocarcinoma del Pulmón/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Genómica , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunoterapia , Neoplasias Pulmonares/tratamiento farmacológico , Nódulos Pulmonares Múltiples/tratamiento farmacológico , Terapia Neoadyuvante , Neoplasias Primarias Múltiples/tratamiento farmacológico , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/inmunología , Anciano , Quimioterapia Adyuvante , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Nódulos Pulmonares Múltiples/genética , Nódulos Pulmonares Múltiples/inmunología , Neoplasias Primarias Múltiples/genética , Neoplasias Primarias Múltiples/inmunología , RNA-Seq , Factores de Tiempo , Transcriptoma , Resultado del Tratamiento , Microambiente Tumoral/inmunologíaRESUMEN
An 88-year-old Inuit man from Northern Canada presented with an extensive skin rash associated with numerous violaceous skin nodules on his palms and lower extremities. Biopsy of a skin nodule revealed Kaposi's sarcoma (KS), a human herpesvirus 8 (HHV8)-associated malignancy, whereas biopsy of the erythematous skin showed an atypical infiltrate of CD4-positive T-cells that, together with TCR gene rearrangement and presence of clonal T-cells in peripheral blood by flow cytometry, was consistent with a T-cell lymphoma, mycosis fungoides (MF) subtype. Serology was negative for HIV and HTLV-I/II and no immunodeficiency syndrome was identified. The patient was successfully treated with an oral retinoid for KS, and with topical hydrocortisone and ultraviolet B (UVB) phototherapy for MF. This case highlights the existence of HHV8-related lesions in native persons of Northern Canada, and also that MF-induced immunosuppression combined with immunosenescence may play a role in the development of non-HIV-related KS.
Asunto(s)
Inuk , Micosis Fungoide/patología , Neoplasias Primarias Múltiples/patología , Sarcoma de Kaposi/patología , Neoplasias Cutáneas/patología , Acitretina/uso terapéutico , Administración Cutánea , Anciano de 80 o más Años , Antiinflamatorios/uso terapéutico , Herpesvirus Humano 8 , Humanos , Hidrocortisona/uso terapéutico , Huésped Inmunocomprometido , Inmunosenescencia , Masculino , Micosis Fungoide/inmunología , Micosis Fungoide/terapia , Neoplasias Primarias Múltiples/inmunología , Neoplasias Primarias Múltiples/terapia , Sarcoma de Kaposi/tratamiento farmacológico , Sarcoma de Kaposi/etnología , Sarcoma de Kaposi/inmunología , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/terapia , Terapia Ultravioleta/métodosRESUMEN
BACKGROUND: Combination immune checkpoint inhibitor (ICI) therapy has become the mainstay in cancer treatment, and the various antitumor effects of ICIs are being observed. Synchronous multiple primary lung cancers (SMPLCs), which simultaneously involve tumors of different histologies, are often encountered in clinical settings. In standard lung cancer treatment, an anticancer drug, usually a platinum-based drug, is administered, and this first treatment provides some antitumor effect. Thus, the initial administration of platinum-based anticancer agent may mask the detection of SMPLCs. The following case represents different antitumor effects on two different primary lung lesions during treatment with ICIs. CASE PRESENTATION: A 72-year-old man was referred to our hospital for an abnormal chest shadow, and computed tomography showed masses in the left lower and right upper lungs. Transbronchial lung biopsy from the left lung tumor revealed an adenocarcinoma. Following the administration of pembrolizumab (200 mg/body over 3 weeks) as monotherapy, the tumor in the left lung rapidly reduced in size. However, the tumor in the right upper lung continued to grow. Finally, his disease was diagnosed as SMPLCs of adenocarcinoma and small cell lung cancer. CONCLUSION: Bilateral lung lesions considered to be intrapulmonary metastases have completely different responses to ICI treatment. It is necessary to consider a diagnosis of SMPLCs if lesions with different responses to antitumor therapy are observed.
Asunto(s)
Adenocarcinoma del Pulmón/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Primarias Múltiples/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Adenocarcinoma del Pulmón/diagnóstico , Adenocarcinoma del Pulmón/inmunología , Adenocarcinoma del Pulmón/patología , Anciano , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Biopsia , Diagnóstico Diferencial , Resistencia a Antineoplásicos , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Pulmón/diagnóstico por imagen , Pulmón/inmunología , Pulmón/patología , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Masculino , Neoplasias Primarias Múltiples/diagnóstico , Neoplasias Primarias Múltiples/inmunología , Neoplasias Primarias Múltiples/patología , Carcinoma Pulmonar de Células Pequeñas/diagnóstico , Carcinoma Pulmonar de Células Pequeñas/inmunología , Carcinoma Pulmonar de Células Pequeñas/patología , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
OBJECTIVE: To determine the tumor genomic, immunologic expression, and risk factors of treatment outcomes for patients with double head and neck squamous cell carcinoma (HNSCC) and esophageal squamous cell carcinoma (ESCC). METHODS: We reviewed patients with double HNSCC and ESCC between 1995 and 2014. The TP53 genomic mutation, CD8+ tumor infiltrating lymphocytes (TIL) and tumor programmed cell death ligand 1 (PD-L1) expression of paired HNSCC and ESCC were analyzed. RESULTS: A total of 116 patients (57 metachronous and 59 synchronous) were included. There were 88 (75.86%) patients with HNSCC and 80 (68.97%) with ESCC harboured TP53 disruptive mutation. Nearly 106 (91.38%) patients had different clonality of TP53 mutation in paired HNSCC and ESCC. The immunologic expression of synchronous and metachronous patients was significantly different. Compared to the metachronous patients, the synchronous patients had significantly higher HNSCC CD8+ TIL (p = 0.03), ESCC CD8+ TIL (p < 0.001), HNSCC PD-L1+ tumor proportion score (TPS, p = 0.04), and ESCC PD-L1+ TPS (p = 0.04). Furthermore, among the synchronous patients, the immunologic expression between HNSCC and ESCC was significantly correlated. The CD8+ TIL and PD-L1 TPS had strongly (r = 0.63, p < 0.0001) and moderately (r = 0.42, p = 0.001) positive correlations, respectively. Finally, advanced stage (III/IV) HNSCC was a significant factor for disease-free (p = 0.03) and overall survival (p = 0.005). CONCLUSION: In patients with double HNSCC and ESCC, nearly all HNSCC and ESCC were of multicentric origin. For the synchronous patients, there was more adaptive immune resistance in HNSCC and ESCC. The immunologic expression between paired HNSCC and ESCC was also significantly correlated.
Asunto(s)
Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Genes p53/genética , Neoplasias de Cabeza y Cuello , Mutación/genética , Neoplasias Primarias Múltiples , Carcinoma de Células Escamosas de Cabeza y Cuello , Antígeno B7-H1/metabolismo , Linfocitos T CD8-positivos/citología , Supervivencia sin Enfermedad , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/inmunología , Neoplasias Esofágicas/mortalidad , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/inmunología , Carcinoma de Células Escamosas de Esófago/mortalidad , Femenino , Técnicas de Genotipaje , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/inmunología , Neoplasias de Cabeza y Cuello/mortalidad , Humanos , Neoplasias Hipofaríngeas/genética , Neoplasias Hipofaríngeas/inmunología , Inmunidad Celular , Linfocitos Infiltrantes de Tumor/citología , Masculino , Persona de Mediana Edad , Neoplasias Primarias Múltiples/genética , Neoplasias Primarias Múltiples/inmunología , Neoplasias Primarias Múltiples/mortalidad , Fenotipo , Estudios Retrospectivos , Factores de Riesgo , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/mortalidad , Neoplasias de la Lengua/genética , Neoplasias de la Lengua/inmunología , Resultado del TratamientoRESUMEN
Recently, there have been a few reports of rituximab (RTX)-induced Crohn's disease, but there is no literature available on successful long-term treatment and the clinical outcome of this condition. We retrospectively analyzed the clinical data of a rare case of Crohn's disease induced by RTX administered as induction and prolonged maintenance therapy of a follicular lymphoma, diagnosed synchronously with a gastric signet ring cells carcinoma, treated at our hospital.
Asunto(s)
Antiinflamatorios/uso terapéutico , Antineoplásicos Inmunológicos/efectos adversos , Enfermedad de Crohn/inmunología , Rituximab/efectos adversos , Budesonida/uso terapéutico , Carcinoma de Células en Anillo de Sello/diagnóstico , Carcinoma de Células en Anillo de Sello/tratamiento farmacológico , Carcinoma de Células en Anillo de Sello/inmunología , Enfermedad de Crohn/inducido químicamente , Enfermedad de Crohn/diagnóstico , Enfermedad de Crohn/tratamiento farmacológico , Quimioterapia Combinada/métodos , Humanos , Quimioterapia de Inducción/efectos adversos , Quimioterapia de Inducción/métodos , Linfoma Folicular/diagnóstico , Linfoma Folicular/tratamiento farmacológico , Linfoma Folicular/inmunología , Quimioterapia de Mantención/efectos adversos , Quimioterapia de Mantención/métodos , Masculino , Mesalamina/uso terapéutico , Persona de Mediana Edad , Neoplasias Primarias Múltiples/diagnóstico , Neoplasias Primarias Múltiples/tratamiento farmacológico , Neoplasias Primarias Múltiples/inmunología , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/inmunología , Resultado del TratamientoRESUMEN
Primary effusion lymphoma is a rare, clinically aggressive large B-cell neoplasm universally associated with human herpesvirus 8 that occurs in the setting of immune compromise. It is classically described as a lymphomatous effusion occurring within body cavities. Recently, however, solid tumor masses, and rarely an intravascular form, have been described. We report a case of a cutaneous intravascular primary effusion lymphoma occurring within ectatic vascular spaces of a Kaposi sarcoma skin lesion in a human immunodeficiency virus-positive adult. Human herpesvirus 8 immunohistochemistry was positive in the nuclei of the Kaposi sarcoma spindled cells as well as within large intravascular plasmacytoid cells. This unusual case highlights the importance of careful assessment of the nature of human herpesvirus 8-positive staining cells in an otherwise typical Kaposi sarcoma. A careful search for dual pathology in immune-compromised patients as well as the importance of histologic assessment of skin lesions in human immunodeficiency virus-positive patients is also highlighted.
Asunto(s)
Herpesvirus Humano 8/aislamiento & purificación , Linfoma de Efusión Primaria/diagnóstico , Neoplasias Primarias Múltiples/diagnóstico , Sarcoma de Kaposi/diagnóstico , Neoplasias Cutáneas/diagnóstico , Adulto , Angiomatosis Bacilar/diagnóstico , Angiomatosis Bacilar/inmunología , Fármacos Anti-VIH/efectos adversos , Biopsia , Diagnóstico Diferencial , Resultado Fatal , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Humanos , Huésped Inmunocomprometido , Inmunohistoquímica , Linfoma de Efusión Primaria/inmunología , Linfoma de Efusión Primaria/patología , Linfoma de Efusión Primaria/virología , Neoplasias Primarias Múltiples/inmunología , Neoplasias Primarias Múltiples/patología , Neoplasias Primarias Múltiples/virología , Sarcoma de Kaposi/inmunología , Sarcoma de Kaposi/patología , Sarcoma de Kaposi/virología , Piel/irrigación sanguínea , Piel/patología , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/virologíaAsunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Huésped Inmunocomprometido , Leucemia Linfocítica Crónica de Células B/inmunología , Neoplasias Primarias Múltiples/inmunología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Neoplasias Cutáneas/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/uso terapéutico , Carcinoma de Células Escamosas/patología , Quimioterapia Adyuvante , Humanos , Masculino , Recurrencia Local de Neoplasia/tratamiento farmacológico , Nivolumab/uso terapéutico , Inducción de Remisión , Cuero Cabelludo/patología , Neoplasias Cutáneas/patologíaRESUMEN
PURPOSE: In breast cancer, FoxP3-positive tumor-infiltrating lymphocytes (FoxP3+ TILs) vary depending on lymph node status, histological grade, and subtype. All these studies have compared the numbers of FoxP3+ TILs among different hosts, but recruitment of FoxP3+ TILs might depend on each individual's immune environment and each tumor's biological characteristics. In the present study, FoxP3+ TIL numbers were investigated in patients with synchronous bilateral breast cancer (SBBC) to determine the factors that affect FoxP3+ TIL recruitment in the same anti-tumor immune environment. METHODS: Patients diagnosed with SBBC who underwent curative surgery at two institutions were enrolled in this study. Patients who underwent primary systemic therapy or who were diagnosed with ductal carcinoma in situ or who had distant metastases at diagnosis were excluded. The average numbers of Foxp3+ TILs were determined from the scores of five high-power microscopic fields (HPF). The associations between Foxp3+ TIL numbers and the clinicopathological features of bilateral breasts in a single individual were examined. RESULTS: Nuclear grade (NG) (p = 0.007) and subtype (p = 0.03), but not size (p = 0.18) and axillary lymph node (p = 0.23) were significantly associated with increase of FoxP3 + TIL numbers by univariate analysis. Further, only NG was a statistically significant clinicopathological factor for change in the number of FoxP3+ TILs by multivariate analysis (p = 0.046) CONCLUSIONS: There was no relationship between FoxP3+ TIL numbers and cancer progression as reflected in tumor size and axillary lymph node in patients with SBBC. Aggressive biological factors, especially high NG, were significantly related to enhanced recruitment of FoxP3+ TILs.
Asunto(s)
Neoplasias de la Mama/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Neoplasias Primarias Múltiples/inmunología , Microambiente Tumoral/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Axila , Mama/inmunología , Mama/patología , Mama/cirugía , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Progresión de la Enfermedad , Femenino , Factores de Transcripción Forkhead/metabolismo , Humanos , Ganglios Linfáticos/patología , Recuento de Linfocitos , Linfocitos Infiltrantes de Tumor/metabolismo , Mastectomía , Persona de Mediana Edad , Clasificación del Tumor , Neoplasias Primarias Múltiples/patología , Neoplasias Primarias Múltiples/cirugía , Estudios RetrospectivosRESUMEN
BACKGROUND & AIMS: The presence of multifocal tumors, developed either from intrahepatic metastasis (IM) or multicentric occurrence (MO), is a distinct feature of hepatocellular carcinoma (HCC). Immunogenomic characterization of multifocal HCC is important for understanding immune escape in different lesions and developing immunotherapy. METHODS: We combined whole-exome/transcriptome sequencing, multiplex immunostaining, immunopeptidomes, T cell receptor (TCR) sequencing and bioinformatic analyses of 47 tumors from 15 patients with HCC and multifocal lesions. RESULTS: IM and MO demonstrated distinct clonal architecture, mutational spectrum and genetic susceptibility. The immune microenvironment also displayed spatiotemporal heterogeneity, such as less T cell and more M2 macrophage infiltration in IM and higher expression of inhibitory immune checkpoints in MO. Similar to mutational profiles, shared neoantigens and TCR repertoires among tumors from the same patients were abundant in IM but scarce in MO. Combining neoantigen prediction and immunopeptidomes identified T cell-specific neoepitopes and achieved a high verification rate in vitro. Immunoediting mainly occurred in MO but not IM, due to the relatively low immune infiltration. Loss of heterozygosity of human leukocyte antigen (HLA) alleles, identified in 17% of multifocal HCC, hampered the ability of major histocompatibility complex to present neoantigens, especially in IM. An integrated analysis of Immunoscore, immunoediting, TCR clonality and HLA loss of heterozygosity in each tumor could stratify patients into 2 groups based on whether they have a high or low risk of recurrence (p = 0.038). CONCLUSION: Our study comprehensively characterized the genetic structure, neoepitope landscape, T cell profile and immunoediting status that collectively shape tumor evolution and could be used to optimize personalized immunotherapies for multifocal HCC. LAY SUMMARY: Immunogenomic features of multifocal hepatocellular carcinoma (HCC) are important for understanding immune-escape mechanisms and developing more effective immunotherapy. Herein, comprehensive immunogenomic characterization showed that diverse genomic structures within multifocal HCC would leave footprints on the immune landscape. Only a few tumors were under the control of immunosurveillance, while others evaded the immune system through multiple mechanisms that led to poor prognosis. Our study revealed heterogeneous immunogenomic landscapes and immune-constrained tumor evolution, the understanding of which could be used to optimize personalized immunotherapies for multifocal HCC.
Asunto(s)
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/inmunología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/inmunología , Neoplasias Primarias Múltiples/genética , Neoplasias Primarias Múltiples/inmunología , Escape del Tumor , Adulto , Anciano , Anciano de 80 o más Años , Antígenos de Neoplasias/genética , Biomarcadores de Tumor/genética , Linfocitos T CD8-positivos/inmunología , Femenino , Predisposición Genética a la Enfermedad , Antígenos HLA/genética , Humanos , Linfocitos Infiltrantes de Tumor/inmunología , Masculino , Persona de Mediana Edad , Mutación , Recurrencia Local de Neoplasia , Receptores de Antígenos de Linfocitos T/genética , Transcriptoma , Secuenciación del ExomaRESUMEN
BACKGROUND: Intraorbital and intracerebral cavernous malformation (CM) lesions are considered independent entities. Purely cerebral CMs have variable biology with recent evidence depicting inflammation as an important player and a risk factor for aggressiveness. We describe a case of concomitant left intraaxial and extraaxial CMs, linked by the ipsilateral basal vein, where the extraaxial component has developed an aggressive behavior. CASE DESCRIPTION: A 35-year-old female patient presented with a rapid and progressive exophthalmos and loss of vision on the left eye. Cranial magnetic resonance and angiography examinations demonstrated a left craniofacial CM and large intraorbital component. The lesion was connected through a large basal vein to a cerebral intraventricular CM. Transconjunctival resection showed typical findings of CM. A complete histopathology and immunostaining analysis was performed and revealed a clear acute lymphomononuclear reaction with a predominant immune cellular inflammation. CONCLUSIONS: A case of intraorbital and extracranial cavernomatous mass, connected to a cerebral intraventricular CM through a large basal vein, has presented with an aggressive course. A complete histopathologic and immunohistochemical analysis of the orbital mass has pictured a clear immune-cellular inflammatory reaction adding to the amounting evidence of association between inflammation and site aggressiveness in the setting of CMs.
Asunto(s)
Venas Cerebrales/diagnóstico por imagen , Neoplasias del Ventrículo Cerebral/diagnóstico por imagen , Hemangioma Cavernoso del Sistema Nervioso Central/diagnóstico por imagen , Neoplasias Primarias Múltiples/diagnóstico por imagen , Neoplasias Orbitales/diagnóstico por imagen , Adulto , Linfocitos B/inmunología , Linfocitos B/patología , Angiografía Cerebral , Femenino , Hemangioma Cavernoso del Sistema Nervioso Central/inmunología , Hemangioma Cavernoso del Sistema Nervioso Central/patología , Hemangioma Cavernoso del Sistema Nervioso Central/cirugía , Humanos , Inflamación/inmunología , Inflamación/patología , Macrófagos/inmunología , Macrófagos/patología , Imagen por Resonancia Magnética , Neoplasias Primarias Múltiples/inmunología , Neoplasias Primarias Múltiples/patología , Neoplasias Primarias Múltiples/cirugía , Neoplasias Orbitales/inmunología , Neoplasias Orbitales/patología , Neoplasias Orbitales/cirugía , Células Plasmáticas/inmunología , Células Plasmáticas/patologíaRESUMEN
BACKGROUND: Pleomorphic dermal sarcoma is the cutaneous variant of undifferentiated pleomorphic sarcoma. It is a rare malignancy of unclear histogenesis; it is a diagnosis of exclusion that requires extensive use of immunohistochemistry to rule out other malignancies. Pleomorphic dermal sarcoma typically presents as a solitary tumor in sun-exposed areas and may have unpredictable clinical behavior, with some tumors associated with metastasis and death. CASE PRESENTATION: We present an unusual case of multifocal pleomorphic dermal sarcoma arising in the areas of alpha-1-antitrypsin deficiency panniculitis in a lung transplant patient. Our patient was a 58-year-old white woman whose initial presentation was consistent with alpha-1-antitrypsin deficiency panniculitis. She then developed extensive multifocal, bleeding, and ulcerated nodules in the areas of the panniculitis. A skin biopsy was consistent with a diagnosis of pleomorphic dermal sarcoma. Her immunosuppressive regimen was decreased, and she was treated with liposomal doxorubicin 40 mg/m2 every 3 weeks with some initial improvement in the size of her tumors. However, soon after beginning therapy, she developed pneumonia and septic shock and ultimately died from multi-organ failure. CONCLUSIONS: We hypothesize that chronic, multifocal inflammation in the skin in the setting of immunosuppression led to simultaneous, malignant transformation in numerous skin lesions. We discuss the challenges of diagnosing pleomorphic dermal sarcoma, therapeutic options, and stress the need for multidisciplinary management of these cases.