RESUMEN
Rationale: Early pathogenesis of lung adenocarcinoma (LUAD) remains largely unknown. We found that, relative to wild-type littermates, the innate immunomodulator Lcn2 (lipocalin-2) was increased in normal airways from mice with knockout of the airway lineage gene Gprc5a (Gprc5a-/-) and that are prone to developing inflammation and LUAD. Yet, the role of LCN2 in lung inflammation and LUAD is poorly understood.Objectives: Delineate the role of Lcn2 induction in LUAD pathogenesis.Methods: Normal airway brushings, uninvolved lung tissues, and tumors from Gprc5a-/- mice before and after tobacco carcinogen exposure were analyzed by RNA sequencing. LCN2 mRNA was analyzed in public and in-house data sets of LUAD, lung squamous cancer (LUSC), chronic obstructive pulmonary disease (COPD), and LUAD/LUSC with COPD. LCN2 protein was immunohistochemically analyzed in a tissue microarray of 510 tumors. Temporal lung tumor development, gene expression programs, and host immune responses were compared between Gprc5a-/- and Gprc5a-/-/Lcn2-/- littermates.Measurements and Main Results:Lcn2 was progressively elevated during LUAD development and positively correlated with proinflammatory cytokines and inflammation gene sets. LCN2 was distinctively elevated in human LUADs, but not in LUSCs, relative to normal lungs and was associated with COPD among smokers and patients with LUAD. Relative to Gprc5a-/- mice, Gprc5a-/-/Lcn2-/- littermates exhibited significantly increased lung tumor development concomitant with reduced T-cell abundance (CD4+) and richness, attenuated antitumor immune gene programs, and increased immune cell expression of protumor inflammatory cytokines.Conclusions: Augmented LCN2 expression is a molecular feature of COPD-associated LUAD and counteracts LUAD development in vivo by maintaining antitumor immunity.
Asunto(s)
Adenocarcinoma del Pulmón/inmunología , Antineoplásicos/inmunología , Lipocalina 2/genética , Lipocalina 2/inmunología , Neoplasias Pulmonares/inmunología , Enfermedad Pulmonar Obstructiva Crónica/sangre , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Animales , Biomarcadores/sangre , Femenino , Regulación de la Expresión Génica , Humanos , Lipocalina 2/sangre , Masculino , Ratones , ARN MensajeroRESUMEN
BACKGROUND: The role of radiotherapy in metastatic renal cell carcinoma is controversial. We prospectively tested the feasibility and efficacy of radiotherapy to defer systemic therapy for patients with oligometastatic renal cell carcinoma. METHODS: This single-arm, phase 2, feasibility trial was done at one centre in the USA (The MD Anderson Cancer Center, Houston, TX, USA). Patients (aged ≥18 years) with five or fewer metastatic lesions, an Eastern Cooperative Oncology Group status of 0-2, and no more than one previous systemic therapy (if this therapy was stopped at least 1 month before enrolment) without limitations on renal cell carcinoma histology were eligible for inclusion. Patients were treated with stereotactic body radiotherapy (defined as ≤5 fractions with ≥7 Gy per fraction) to all lesions and maintained off systemic therapy. When lesion location precluded safe stereotactic body radiotherapy, patients were treated with hypofractionated intensity-modulated radiotherapy regimes consisting of 60-70 Gy in ten fractions or 52·5-67·5 Gy in 15 fractions. Additional rounds of radiotherapy were allowed to treat subsequent sites of progression. Co-primary endpoints were feasibility (defined as all planned radiotherapy completed with <7 days unplanned breaks) and progression-free survival. All efficacy analyses were intention-to-treat. Safety was analysed in the as-treated population. A second cohort, with the aim of assessing the feasibility of sequential stereotactic body radiotherapy alone in patients with low-volume metastatic disease, was initiated and will be reported separately. This study is registered with ClinicalTrials.gov, NCT03575611. FINDINGS: 30 patients (six [20%] women) were enrolled from July 13, 2018, to Sept 18, 2020. All patients had clear cell histology and had a nephrectomy before enrolment. All patients completed at least one round of radiotherapy with less than 7 days of unplanned breaks. At a median follow-up of 17·5 months (IQR 13·2-24·6), median progression-free survival was 22·7 months (95% CI 10·4-not reached; 1-year progression-free survival 64% [95% CI 48-85]). Three (10%) patients had severe adverse events: two grade 3 (back pain and muscle weakness) and one grade 4 (hyperglycaemia) adverse events were observed. There were no treatment-related deaths. INTERPRETATION: Sequential radiotherapy might facilitate deferral of systemic therapy initiation and could allow sustained systemic therapy breaks for select patients with oligometastatic renal cell carcinoma. FUNDING: Anna Fuller Foundation, the Cancer Prevention and Research Institute of Texas (CPRIT), and the National Cancer Institute.
Asunto(s)
Carcinoma de Células Renales/radioterapia , Neoplasias Renales/radioterapia , Radioterapia de Intensidad Modulada/mortalidad , Anciano , Carcinoma de Células Renales/epidemiología , Carcinoma de Células Renales/patología , Estudios de Factibilidad , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Renales/epidemiología , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Pronóstico , Tasa de Supervivencia , Texas/epidemiologíaRESUMEN
Invasive mucinous adenocarcinoma (IMA) of the lung is a unique variant of lung adenocarcinoma. Aberrant mucin expression is associated with cancer development and metastasis. However, the clinicopathological significance of mucin expression in IMA is not fully understood. Herein, we evaluated the clinicopathological, immunohistochemical, and molecular characteristics of 70 IMA tumors. EGFR, KRAS, GNAS, and TP53 mutations were assessed by PCR-based sequencing. Next-generation sequencing was used to assess cases without EGFR/KRAS mutations. A NanoString-based screening for fusions was performed in all IMAs without mitogenic driver mutations. Expression of mucins (MUC1, MUC2, MUC4, MUC5AC, and MUC6) was evaluated by immunohistochemistry and categorized as follows: negative (<10% of tumor cells), patchy expression (<90% of tumor cells), or diffuse expression (≥90% of tumor cells). Immunohistochemical testing for transcription factors (TTF-1, CDX2, HNF1ß, HNF3α, HNF3ß, and HNF4α) was also performed. As expected, KRAS mutations were the most common (in 67% of cases), followed by small numbers of other alterations. Patchy or diffuse expression of MUC1, MUC2, MUC4, MUC5AC, and MUC6 was observed in 52% or 6%, 3% or 0%, 30% or 3%, 26% or 73%, and 59% or 27% of cases, respectively. Furthermore, all IMAs were generally positive for HNF1ß (100%), HNF3α (100%), HNF3ß (100%), and HNF4α (99%) but were positive less often for TTF-1 (6%) and CDX2 (9%). Overall, there was no significant correlation between mucin expression and transcription factor expression. Unexpectedly, diffuse expression of MUC6 was significantly associated with KRAS-wild-type tumors (p = 0.0008), smaller tumor size (p = 0.0073), and tumors in female patients (p = 0.0359) in multivariate analyses. Furthermore, patients with tumors exhibiting diffuse MUC6 expression had significantly favorable outcomes. Notably, none of these patients died of the disease. Our data suggested that diffuse expression of MUC6 defines a distinct clinicopathological subset of IMA characterized by wild-type KRAS and possibly less aggressive clinical course.
Asunto(s)
Adenocarcinoma Mucinoso/enzimología , Biomarcadores de Tumor/análisis , Neoplasias Pulmonares/enzimología , Mucina 6/análisis , Adenocarcinoma Mucinoso/genética , Adenocarcinoma Mucinoso/patología , Adenocarcinoma Mucinoso/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Cromograninas/genética , Análisis Mutacional de ADN , Receptores ErbB/genética , Femenino , Subunidades alfa de la Proteína de Unión al GTP Gs/genética , Humanos , Inmunohistoquímica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/cirugía , Masculino , Persona de Mediana Edad , Mutación , Invasividad Neoplásica , Pronóstico , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteína p53 Supresora de Tumor/genéticaRESUMEN
AIMS: In the evolving era of precision medicine, increasing emphasis is placed on detecting molecular alterations driving the development of specific cancers and targeting them with matched therapies that can yield the best outcomes for patients. Lung adenocarcinomas with uncommon actionable alterations, including MET exon 14 skipping (METex14), ERBB2 and BRAF mutations, are rare and poorly characterised cancers. METHODS AND RESULTS: To more clearly understand the histopathological features of lung adenocarcinoma with uncommon actionable alterations, we compared the histological features of 678 cases with mitogenic driver alterations from 996 surgically resected lung adenocarcinomas. Genomic data from our cohort revealed METex14, ERBB2 and BRAF mutations in 13, 16 and 15 cases, respectively. Patients who had lung adenocarcinoma with METex14 were often elderly females. Histological features such as clear cell features (23%), hyaline globules (31%) and nuclear pleomorphism (39%) were the most frequently identified in METex14-positive cases; among those, three cases (23%) had tumour cells with bizarre giant or multilobulated nuclei. Additionally, the micropapillary pattern was the most frequently identified in ERBB2-mutated lung adenocarcinoma (31%). Lung adenocarcinoma with BRAF mutations tended to be less invasive, and the BRAF V600E mutation was identified in only one case with lepidic adenocarcinoma. Immunohistochemically, all METex14, ERBB2 and BRAF-positive tumours, except for invasive mucinous adenocarcinoma, were positive for thyroid transcription factor 1 (TTF-1). CONCLUSIONS: Our data from Japanese patients showed that lung adenocarcinoma with METex14 had unique clinicopathological characteristics: tumour cells with marked nuclear pleomorphism, hyaline globules and expression of TTF-1 in elderly women who never or lightly smoked.
Asunto(s)
Adenocarcinoma del Pulmón , Proteínas Proto-Oncogénicas c-met/genética , Factor Nuclear Tiroideo 1/metabolismo , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Genómica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Hialina/citología , Neoplasias Pulmonares/patología , Persona de Mediana Edad , Mutación , Proteínas Proto-Oncogénicas c-met/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Factor Nuclear Tiroideo 1/genéticaRESUMEN
BACKGROUND: Targeted therapies based on the molecular and histological features of cancer types are becoming standard practice. The most effective regimen in lung cancers is different between squamous cell carcinoma (SCC) and adenocarcinoma (AD). Therefore a precise diagnosis is crucial, but this has been difficult, particularly for poorly differentiated SCC (PDSCC) and AD without a lepidic growth component (non-lepidic AD). Biomarkers enabling a precise diagnosis are therefore urgently needed. METHODS: Cap Analysis of Gene Expression (CAGE) is a method used to quantify promoter activities across the whole genome by determining the 5' ends of capped RNA molecules with next-generation sequencing. We performed CAGE on 97 frozen tissues from surgically resected lung cancers (22 SCC and 75 AD), and confirmed the findings by immunohistochemical analysis (IHC) in an independent group (29 SCC and 45 AD). RESULTS: Using the genome-wide promoter activity profiles, we confirmed that the expression of known molecular markers used in IHC for SCC (CK5, CK6, p40 and desmoglein-3) and AD (TTF-1 and napsin A) were different between SCC and AD. We identified two novel marker candidates, SPATS2 for SCC and ST6GALNAC1 for AD, as showing comparable performance and complementary utility to the known markers in discriminating PDSCC and non-lepidic AD. We subsequently confirmed their utility at the protein level by IHC in an independent group. CONCLUSIONS: We identified two genes, SPATS2 and ST6GALNAC1, as novel complemental biomarkers discriminating SCC and AD. These findings will contribute to a more accurate diagnosis of NSCLC, which is crucial for precision medicine for lung cancer.
RESUMEN
BACKGROUND: Thymic squamous cell carcinoma and type B3 thymoma are primary neoplasms of the anterior mediastinum that are sometimes difficult to differentiate from one another histologically. However, only a few immunohistochemical markers are available for the differential diagnosis. The purpose of this study was to discover a novel marker for differentiating between thymic squamous cell carcinoma and type B3 thymoma. METHODS: We used histological samples of thymic carcinomas (n = 26) and type B3 thymomas (n = 38) which were resected between 1986 and 2017. To search for candidates of differential markers, gene expression levels were evaluated in samples using promoter analysis by cap analysis of gene expression (CAGE) sequencing. RESULTS: Promoter level expression of CALML5 genes was significantly higher in thymic carcinomas than in type B3 thymomas. We further validated the results of the CAGE analysis in all 26 thymic carcinomas and 38 type B3 thymomas by immunohistochemistry (IHC). CALML5 was strongly expressed in the cytoplasm in 19 of 26 cases with thymic carcinoma, whereas positivity at the protein level was shown in two of 38 type B3 thymomas. Thus, the sensitivity (73.1%) and specificity (94.7%) of CALML5 as markers for immunohistochemical diagnosis of thymic carcinoma were extremely high. CONCLUSION: We identified CALML5 as a potential marker for differentiating thymic squamous cell carcinoma from type B3 thymoma. It is assumed that future clinical use of CALML5 may improve the diagnostic accuracy of differentiating between these two diseases.
Asunto(s)
Carcinoma de Células Escamosas , Timoma , Neoplasias del Timo , Humanos , Biomarcadores de Tumor/análisis , Carcinoma de Células Escamosas/patología , Inmunohistoquímica , Timoma/patología , Neoplasias del Timo/patologíaRESUMEN
OBJECTIVES: Programmed death ligand 1 and 2 (PD-L1 and PD-L2) bind programmed death 1 (PD-1). PD-L1 is an established predictive biomarker of response to immunotherapies targeting PD-1 and PD-L1 in lung adenocarcinoma (LUAD). However, the clinical relevance of PD-L2 expression in patients with LUAD remains unclear; we aimed to examine this aspect using LUAD specimens. MATERIALS AND METHODS: PD-L2 expression status was immunohistochemically evaluated in 980 surgically resected LUAD specimens. PD-L2 expression status was classified based on the tumor proportion score (TPS) as negative (<1%), weakly positive (1-49%), or strongly positive (≥50%). Correlations between PD-L2 and PD-L1 expression status, clinicopathological features, driver oncogene alterations (EGFR, KRAS, ALK, ROS1, and RET), and prognosis were also analyzed. RESULTS: PD-L2 expression was negative in 720 (73%) of 980 LUADs, weakly positive in 190 (19%), and strongly positive in 70 (7%). The concordance rate between PD-L1 and PD-L2 expression was 60%. Male sex, smokers, tumors > 3 cm in size, high-grade tumors, tumors without EGFR mutation or ALK fusion, and tumors with KRAS mutation were more common in patients with PD-L2-positive tumors (TPS ≥ 1%) than in patients with PD-L2-negative tumors (TPS < 1%). PD-L2 expression was not associated with overall survival (OS) or relapse-free survival (RFS). However, positive PD-L2 expression tended to be associated with better OS/RFS in PD-L1-positive patients and worse OS/RFS in PD-L1-negative patients. CONCLUSIONS: PD-L2-positive LUADs showed biologically aggressive characteristics. PD-L2 expression status was not associated with survival outcomes, but tended to show contrasting prognostic impacts based on PD-L1 expression status.
Asunto(s)
Adenocarcinoma del Pulmón , Adenocarcinoma , Neoplasias Pulmonares , Proteína 2 Ligando de Muerte Celular Programada 1/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/cirugía , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/cirugía , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Biomarcadores de Tumor/metabolismo , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/cirugía , Masculino , Recurrencia Local de Neoplasia , Receptor de Muerte Celular Programada 1/metabolismo , Proteínas Tirosina Quinasas/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Proteínas Tirosina Quinasas Receptoras/genéticaRESUMEN
OBJECTIVES: Programmed death-ligand 1 (PD-L1) expression is a predictive biomarker of response to immunotherapies targeting programmed death-1/PD-L1 in advanced-stage lung adenocarcinoma. The aim of this study was to investigate the associations between PD-L1 expression and clinicopathological features, prognosis, and driver oncogene alterations in patients with lung adenocarcinoma. MATERIALS AND METHODS: We evaluated PD-L1 expression in 1,005 surgically resected lung adenocarcinoma specimens, by immunohistochemistry using the 22C3 antibody. PD-L1 positivity was defined based on the proportion of stained tumor cells (TPS) on tissue microarrays: <1% (negative), 1-49% (weakly positive), and ≥ 50% (strongly positive). Correlations between PD-L1 expression and clinicopathological features, prognosis, and driver oncogene (EGFR, KRAS, ALK, ROS1, and RET) alterations in lung adenocarcinoma were analyzed. RESULTS: PD-L1 expression was negative in 726 (72%) of 1,005 tumors, weakly positive in 161 (16%), and strongly positive in 118 (12%). Male sex, smoking, elevated serum carcinoembryonic antigen levels, advanced pathological stages, high-grade tumors, predominantly solid tumors, tumors with lymphatic permeation or vascular or pleural invasion, tumors without EGFR mutations, and tumors with KRAS mutations were more common in patients with PD-L1-positive tumors (TPS ≥ 1%) than in those with PD-L1-negative tumors (TPS < 1%). PD-L1 positivity was not associated with ALK, ROS1, or RET fusion status. Although PD-L1 positivity was associated with poor overall survival and poor relapse-free survival in all patients, this was not statistically significant after adjusting for prognostic factors in the multivariate analysis. In the subgroup analysis according to driver oncogene alterations, PD-L1 positivity was associated with poor relapse-free survival only in patients with EGFR-mutated tumors. CONCLUSION: Surgically resected lung adenocarcinomas with increased PD-L1 expression were biologically aggressive tumors that frequently occurred in male smokers. PD-L1 expression and its prognostic significance differed according to driver oncogene alterations.
Asunto(s)
Adenocarcinoma del Pulmón , Antígeno B7-H1/metabolismo , Neoplasias Pulmonares , Adenocarcinoma del Pulmón/genética , Quinasa de Linfoma Anaplásico/genética , Antígeno B7-H1/genética , Biomarcadores de Tumor , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/cirugía , Masculino , Recurrencia Local de Neoplasia , Oncogenes , Pronóstico , Proteínas Tirosina Quinasas/genética , Proteínas Proto-Oncogénicas/genéticaRESUMEN
The novel coronavirus SARS-CoV-2 is the causative agent of the COVID-19 pandemic. Severely symptomatic COVID-19 is associated with lung inflammation, pneumonia, and respiratory failure, thereby raising concerns of elevated risk of COVID-19-associated mortality among lung cancer patients. Angiotensin-converting enzyme 2 (ACE2) is the major receptor for SARS-CoV-2 entry into lung cells. The single-cell expression landscape of ACE2 and other SARS-CoV-2-related genes in pulmonary tissues of lung cancer patients remains unknown. We sought to delineate single-cell expression profiles of ACE2 and other SARS-CoV-2-related genes in pulmonary tissues of lung adenocarcinoma (LUAD) patients. We examined the expression levels and cellular distribution of ACE2 and SARS-CoV-2-priming proteases TMPRSS2 and TMPRSS4 in 5 LUADs and 14 matched normal tissues by single-cell RNA-sequencing (scRNA-seq) analysis. scRNA-seq of 186,916 cells revealed epithelial-specific expression of ACE2, TMPRSS2, and TMPRSS4. Analysis of 70,030 LUAD- and normal-derived epithelial cells showed that ACE2 levels were highest in normal alveolar type 2 (AT2) cells and that TMPRSS2 was expressed in 65% of normal AT2 cells. Conversely, the expression of TMPRSS4 was highest and most frequently detected (75%) in lung cells with malignant features. ACE2-positive cells co-expressed genes implicated in lung pathobiology, including COPD-associated HHIP, and the scavengers CD36 and DMBT1. Notably, the viral scavenger DMBT1 was significantly positively correlated with ACE2 expression in AT2 cells. We describe normal and tumor lung epithelial populations that express SARS-CoV-2 receptor and proteases, as well as major host defense genes, thus comprising potential treatment targets for COVID-19 particularly among lung cancer patients.
RESUMEN
Little is known of the geospatial architecture of individual cell populations in lung adenocarcinoma (LUAD) evolution. Here, we perform single-cell RNA sequencing of 186,916 cells from five early-stage LUADs and 14 multiregion normal lung tissues of defined spatial proximities from the tumors. We show that cellular lineages, states, and transcriptomic features geospatially evolve across normal regions to LUADs. LUADs also exhibit pronounced intratumor cell heterogeneity within single sites and transcriptional lineage-plasticity programs. T regulatory cell phenotypes are increased in normal tissues with proximity to LUAD, in contrast to diminished signatures and fractions of cytotoxic CD8+ T cells, antigen-presenting macrophages, and inflammatory dendritic cells. We further find that the LUAD ligand-receptor interactome harbors increased expression of epithelial CD24, which mediates protumor phenotypes. These data provide a spatial atlas of LUAD evolution, and a resource for identification of targets for its treatment. SIGNIFICANCE: The geospatial ecosystem of the peripheral lung and early-stage LUAD is not known. Our multiregion single-cell sequencing analyses unravel cell populations, states, and phenotypes in the spatial and ecologic evolution of LUAD from the lung that comprise high-potential targets for early interception.This article is highlighted in the In This Issue feature, p. 2355.
Asunto(s)
Adenocarcinoma del Pulmón/patología , Linfocitos T CD8-positivos , Neoplasias Pulmonares/patología , Microambiente Tumoral , Humanos , Análisis de la Célula IndividualRESUMEN
The extensive clinical applications of next-generation sequence analyzers have made uncommon and compound EGFR mutations more prevalent than previously described. However, clinicopathological impacts of compound EGFR mutations in lung adenocarcinoma remain unclear. We earlier examined the presence of compound EGFR mutations primarily in the cis allele by EGFR exon sequencing and droplet digital polymerase chain reaction in 462 completely resected EGFR-mutated adenocarcinomas of the lung and identified 64 tumors with compound mutations. We evaluated clinicopathological characteristics of lung adenocarcinomas with compound EGFR mutations in comparison with cases with common or uncommon single mutations. Among 64 compound EGFR mutations, L858R/E709G (9%) was the most frequent mutation type, followed by L858R/S768I (8%), L858R/T790M (8%), and L858R/L833V (6%). We observed both single and compound mutations frequently in women, never or light smokers; their adenocarcinomas showed thyroid transcription factor-1 immunoreactivity. In contrast, compound mutations were significantly associated with lymph node metastases (p = 0.0242; single vs. compound cases) and the presence of tumor cells with clear cytoplasm (p = 0.0014; single vs. compound cases). Furthermore, patients with compound mutations had significantly poorer prognoses than cases with single EGFR mutations (p = 0.043). Overall, clinicopathological features of common, uncommon, and compound EGFR mutations are similar; however, tumors with compound mutations may be characterized by aggressive behavior and histological findings of clear cell features.
Asunto(s)
Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Adulto , Anciano , Anciano de 80 o más Años , Receptores ErbB/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , MutaciónRESUMEN
We have previously shown that galectin-4 expression is an independent predictor for lymph node metastasis and serves as an adverse prognostic indicator in patients with acinar adenocarcinoma of the lung. In contrast, thyroid transcription factor-1 (TTF-1) expression in non-small cell lung carcinoma has been shown to be associated with a favorable prognosis. In the present study, 208 cases of acinar adenocarcinoma of the lung and 36 cases with distant metastatic lesions of lung adenocarcinoma were immunohistochemically examined for expression of galectin-4 and TTF-1 to elucidate their correlation with clinicopathological factors. TTF-1 expression was observed in 145 cases (69.7%) and associated with smaller tumor size, infrequent pleural invasion, and lower TNM stage. Galectin-4 expression was observed in 86 cases (41.3%). Furthermore, galectin-4-positive carcinoma cells and TTF-1-positive carcinoma cells existed exclusively within the same lesion. Expressions of TTF-1 and galectin-4 were favorable and adverse prognostic factors, respectively. Approximately 40% (15/36 cases) of lung adenocarcinoma at the distant metastatic sites were immunohistochemically negative for TTF-1. Four out of five galectin-4-positive metastatic lesions were negative for TTF-1. We found an inverse correlation between galectin-4 and TTF-1 expressions in acinar adenocarcinoma, and this phenomenon was also found to be present in metastatic sites. These findings suggest that we should not exclude the possibility of metastatic adenocarcinoma of the lung, even if the tumor cells are immunohistochemically negative for TTF-1 in the primary unknown tumor, because aggressive lung adenocarcinomas often lack TTF-1 expression.
Asunto(s)
Adenocarcinoma/patología , Biomarcadores de Tumor/análisis , Galectina 4/biosíntesis , Neoplasias Pulmonares/patología , Factor Nuclear Tiroideo 1/biosíntesis , Adenocarcinoma/mortalidad , Adenocarcinoma del Pulmón , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Galectina 4/análisis , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Factor Nuclear Tiroideo 1/análisisRESUMEN
Adipophilin, a lipid droplet-associated protein that regulates lipid droplet structure and formation, is expressed in a wide variety of tumors. The aims of this study were to evaluate the frequency and distribution pattern of adipophilin expression in gastric epithelial neoplasia and to correlate these variables with clinicopathological features and the mucin phenotype. We retrospectively examined 159 cases of gastric epithelial neoplasia, which were classified according to the Vienna classification system as 52 noninvasive low-grade adenoma (category 3), 65 noninvasive high-grade neoplasia (category 4), and 42 invasive neoplasia (category 5). Immunohistochemistry for adipophilin was performed, and phenotypic marker expression was determined by immunohistostaining with MUC2, MUC5AC, CD10, MUC6, and villin. Adipophilin was expressed in 41 of the 52 (79 %) category 3 cases, in 42 of the 65 (65 %) category 4 cases, and in 23 of the 42 (55 %) category 5 cases. Expression of adipophilin was only present in lesions with complete or incomplete intestinal phenotypes. Adipophilin was expressed more frequently in the surface epithelium in category 3, whereas there was a stepwise increase in cryptal staining of adipophilin from category 3 to category 5. In conclusion, adipophilin expression is closely related to the intestinal differentiation of the tumor. The pattern of immunostaining for adipophilin might be a useful new marker for discriminating adenomas from adenocarcinomas.
Asunto(s)
Adenocarcinoma , Adenoma/patología , Diferenciación Celular/fisiología , Neoplasias Gástricas/patología , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Diagnóstico Diferencial , Femenino , Humanos , Inmunohistoquímica/métodos , Intestinos/patología , Masculino , Persona de Mediana Edad , Fenotipo , Estómago/patología , Neoplasias Gástricas/metabolismoRESUMEN
The prognostic value of BRAF V600E and TERT promoter mutation in papillary thyroid carcinoma (PTC) is controversial. We examined alterations in BRAF V600E and TERT promoter by PCR-direct sequencing in PTC of 144 Japanese patients. Alternative lengthening of telomeres was examined as another mechanism of telomere maintenance by immunohistochemical staining for ATRX and DAXX. Of the clinicopathological characteristics, regional lymph node metastasis, extra-thyroid extension, multifocality/intrathyroidal spread, and advanced stage (III/V) were associated with shorter disease-free survival rate (DFSR). TERT promoter mutation was found in eight patients (6 %), and this was significantly associated with total thyroidectomy, multifocality/intrathyroidal spread, lymph node metastasis and advanced stage. The BRAF V600E mutation was found in 53 patients (38.2 %) but was not associated with any clinicopathological factors. TERT mutations were not correlated with BRAF V600E mutation status. TERT mutation-positive tumors (TERT+) showed lower DFSR than BRAF V600E -mutation-positive tumors (BRAF V600E +), and TERT+/BRAF V600E + tumors showed lower DFSR than BRAF V600E + tumors. No cases showed loss of ATRX/DAXX expression by immunohistochemistry. TERT promoter mutations showed a lower prevalence in our series and appeared to be associated with aggressive behavior. In PTCs, telomerase activation by TERT promoter mutation might be more important than alternative lengthening of telomeres.
Asunto(s)
Carcinoma Papilar/genética , Carcinoma/diagnóstico , Carcinoma/genética , Predisposición Genética a la Enfermedad , Mutación/genética , Regiones Promotoras Genéticas , Telomerasa/genética , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/genética , Adulto , Carcinoma/metabolismo , Carcinoma Papilar/patología , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunohistoquímica/métodos , Masculino , Persona de Mediana Edad , Pronóstico , Proteínas Proto-Oncogénicas B-raf/genética , Cáncer Papilar Tiroideo , Neoplasias de la Tiroides/metabolismoRESUMEN
Lymphangioleiomyomatosis (LAM), a rare progressive disease that almost exclusively affects women, is characterized by pulmonary cysts and neoplastic proliferation of smooth muscle-like cells (LAM cells). Airflow obstruction is a physiologic consequence that is commonly observed in LAM and has been attributed to narrowing of peripheral airways. However, histopathologic examinations of the entire airway have been precluded by the limited availability of such specimens. Here, we used explanted lung tissues from 30 LAM patients for a thorough histologic analysis with a special emphasis on the bronchi. We found bronchial involvement by LAM cells and lymphatics in all patients examined. Furthermore, a moderate to severe degree of chronic inflammation (73%), goblet cell hyperplasia (97%), squamous cell metaplasia (83%) of the epithelium, and thickening of basal lamina (93%) were identified in the bronchi. Because LAM cells are transformed by the functional loss of the TSC genes leading to a hyperactivated mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, we confirmed the expression of phospho-p70S6K, phospho-S6, phospho-4E-BP1, and vascular endothelial growth factor (VEGF)-D in LAM cells from all of the patients examined. In contrast, no protein expression of hypoxia-inducible factor 1α, a downstream molecule indicative of mTORC1 activation and leading to VEGF production, was detected in any patient. Our study indicates that late-stage LAM patients commonly have bronchi involved by the proliferation of both LAM cells and lymphatics and that chronic inflammation complicated their disease. Furthermore, the up-regulation of hypoxia-inducible factor 1α, a common event in mTORC1-driven tumor cells, does not occur in LAM cells and plays no role in VEGF-D expression in LAM cells.
Asunto(s)
Biomarcadores de Tumor/análisis , Bronquios/química , Bronquios/patología , Proliferación Celular , Neoplasias Pulmonares/química , Neoplasias Pulmonares/patología , Linfangioleiomiomatosis/metabolismo , Linfangioleiomiomatosis/patología , Vasos Linfáticos/química , Vasos Linfáticos/patología , Proteínas Adaptadoras Transductoras de Señales/análisis , Adulto , Biomarcadores de Tumor/genética , Western Blotting , Bronquios/cirugía , Proteínas de Ciclo Celular , Femenino , Humanos , Hiperplasia , Subunidad alfa del Factor 1 Inducible por Hipoxia/análisis , Inmunohistoquímica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/cirugía , Linfangioleiomiomatosis/genética , Linfangioleiomiomatosis/cirugía , Vasos Linfáticos/cirugía , Diana Mecanicista del Complejo 1 de la Rapamicina , Persona de Mediana Edad , Complejos Multiproteicos/análisis , Fosfoproteínas/análisis , Fosforilación , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteínas Quinasas S6 Ribosómicas 70-kDa/análisis , Transducción de Señal , Serina-Treonina Quinasas TOR/análisis , Factor D de Crecimiento Endotelial Vascular/análisis , Factor D de Crecimiento Endotelial Vascular/genética , Adulto JovenRESUMEN
Appendiceal mucinous tumors (AMTs) are classified as low-grade appendiceal mucinous neoplasms (LAMNs) or mucinous adenocarcinomas (MACs), although their carcinogenesis is not well understood. As somatic activating mutations of GNAS are considered to be characteristic of LAMNs while TP53 mutations have been shown to be specific to MACs, MACs are unlikely to result from transformation of LAMNs. However, emerging evidence also shows the presence of GNAS mutations in MACs. We examined 16 AMTs (11 LAMNs and 5 MACs) for genetic alterations of GNAS, KRAS, BRAF, TP53, CTNNB1, and TERT promoter in order to elucidate the possibility of a shared genetic background in the two tumor types. Extensive histological examination revealed the presence of a low-grade component in all cases of MAC. GNAS mutations were detected in two LAMNs and in one MAC, although the GNAS mutation in this MAC was a nonsense mutation (Q227X) expected not to be activating mutation. TP53 mutations were detected in three LAMNs; they were frequently detected in MACs. KRAS mutations were detected in three LAMNs and three MACs, and CTNNB1 mutations were detected in two LAMNs. KRAS mutation and activating mutation of GNAS occurred exclusively in AMTs. BRAF and TERT mutations were not detected. Overexpression of p53 was observed in only two MACs, and p53 immunostaining clearly discriminated the high-grade lesion from a low-grade component in one. These findings suggest that p53 overexpression plays an important role in the carcinogenesis of AMTs and that, in addition to mutations of GNAS, KRAS and TP53 alterations might be shared by AMTs, thus providing evidence for the possible progression of LAMNs to MAC.
Asunto(s)
Adenocarcinoma Mucinoso/genética , Neoplasias del Apéndice/genética , Biomarcadores de Tumor/genética , Subunidades alfa de la Proteína de Unión al GTP Gs/genética , Mutación , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteína p53 Supresora de Tumor/genética , Adenocarcinoma Mucinoso/química , Adenocarcinoma Mucinoso/patología , Adenocarcinoma Mucinoso/terapia , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias del Apéndice/química , Neoplasias del Apéndice/patología , Neoplasias del Apéndice/terapia , Biomarcadores de Tumor/análisis , Cromograninas , Análisis Mutacional de ADN , Femenino , Predisposición Genética a la Enfermedad , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Fenotipo , Valor Predictivo de las Pruebas , Regiones Promotoras Genéticas , Telomerasa/genética , Proteína p53 Supresora de Tumor/análisis , beta Catenina/genéticaRESUMEN
A case of prenatally diagnosed, giant cord hemangioma is reported, which was accompanied by the elevation of maternal serum alpha-fetoprotein (MS-AFP) and human chorionic gonadotropin (MS-hCG) levels. A 30-year-old woman without a previous history of gravida or para, presented with intermittent abdominal pain at 26 weeks of gestation. Doppler studies showed the fetus developing heart failure as the tumor grew larger. Caesarian section was performed at 29 weeks of gestation. Macroscopic examination of the placenta revealed a 17.0 × 10.0 × 7.0 cm tumor localized at the placental end of the umbilical cord. Microscopically, the tumor was composed of small arborizing vessels proliferating in the myxoid background, and the tumor cells were positive for AFP by immunohistochemistry. Extramedullary hematopoiesis was seen in the tumor vascular channels. The present case is one of the largest umbilical cord hemangiomas reported in the literature, and the first hemangioma case with MS-hCG elevation, extramedullary hematopoiesis, and positive AFP staining in the cord hemangioma. Its clinical course and detailed pathological findings are presented along with a review of the related literature.
Asunto(s)
Gonadotropina Coriónica/sangre , Hemangioma/patología , Complicaciones Neoplásicas del Embarazo/patología , Cordón Umbilical/patología , Adulto , Femenino , Hematopoyesis Extramedular , Humanos , Inmunohistoquímica , Embarazo , alfa-Fetoproteínas/biosíntesisRESUMEN
The impact of NGFI-A binding protein 2 (NAB2)-signal transducer and activator of transcription 6 (STAT6) fusion on the biological behavior and the mechanism of acquisition of malignant phenotype in solitary fibrous tumor (SFT) is not well understood. We examined variations of the NAB2-STAT6 fusion gene in 40 cases of SFT using formalin-fixed, paraffin-embedded tissues and secondary genetic alterations of tumor protein p53 (TP53),, platelet-derived growth factor receptor, ß polypeptide (PDGFRB), and telomerase reverse transcriptase (TERT) promoters. These gene variations were compared with the clinicopathological features. The 2-year and 5-year disease-free survival rates (DFSRs) were 91% and 83%, respectively. All 40 samples demonstrated nuclear staining for STAT6, including CD34-negative cases. Moreover, p53-positive staining was associated with a lower DFSR and was significantly associated with higher Ki-67 label index, higher mitotic rate (mitosis, >4/high-power field), and the presence of nuclear atypia/pleomorphism. NAB2-STAT6 fusions were detected in all of the cases; the NAB2 exon 4-STAT6 exon 2, the most common genotype, appeared in 18 cases, which was associated with thoracic tumor location and the less aggressive phenotype. In contrast, tumors with NAB2 exon 6-STAT6 exon 16/18 demonstrated an aggressive phenotype. Mutations in TP53 and PDGFRB were detected in 2 and 3 cases respectively, and these occurred in a mutually exclusive fashion. TERT promoter hot spot mutations were observed in 5 cases, which were associated with shorter DFSR. Two dedifferentiated SFT cases harbored both TP53 and TERT promoter mutations. TP53 mutations, which result in its overexpression, in combination with TERT promoter mutations seem to play an important role in the dedifferentiation process.
Asunto(s)
Biomarcadores de Tumor/genética , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Proteínas Represoras/análisis , Factor de Transcripción STAT6/análisis , Tumores Fibrosos Solitarios/genética , Tumores Fibrosos Solitarios/patología , Adulto , Anciano , Anciano de 80 o más Años , Secuencia de Bases , Biomarcadores de Tumor/análisis , Biopsia , Supervivencia sin Enfermedad , Femenino , Fusión Génica/genética , Genes p53/genética , Humanos , Inmunohistoquímica , Antígeno Ki-67/análisis , Antígeno Ki-67/genética , Masculino , Persona de Mediana Edad , Mutación , Clasificación del Tumor , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Polimorfismo Genético , Pronóstico , Proteínas Represoras/genética , Factor de Transcripción STAT6/genética , Tumores Fibrosos Solitarios/químicaRESUMEN
Solitary fibrous tumors (SFTs), initially observed in the pleura, were later found to develop in almost any extrapleural site. Dedifferentiation within SFTs, a rare phenomenon, was characterized only recently, although it was previously described in soft tissue and bone tumors. We report a case of dedifferentiated SFT arising in the right pleura of a 69-year-old man. Computed tomography revealed a huge mass in the thoracic cavity. The tumor contained an area with a high degree of calcification and was heterogeneously enhanced. Macroscopically, the resected tumor was 175×145×135 mm in size. Morphologically and immunohistochemically, this was comprised of a typical SFT juxtaposed to a high-grade component including an osteosarcomatous component. These were sharply demarcated by thin fibrous septa. Furthermore, NAB2-STAT6 fusion transcripts were detected by reverse-transcriptase polymerase chain reaction in both conventional and high-grade components, supporting the concept of a dedifferentiation process in this tumor.
Asunto(s)
Tumores Fibrosos Solitarios/patología , Neoplasias Torácicas/patología , Anciano , Desdiferenciación Celular , Humanos , Inmunohistoquímica , Masculino , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Cavidad Torácica/patologíaRESUMEN
Solitary fibrous tumors (SFTs), initially observed in the pleura, were later found to develop in almost any extrapleural site. Dedifferentiation within SFTs was characterized only recently. We report a case of dedifferentiated SFT arising within the pelvis of a 70-year-old Japanese woman. Macroscopically, the resected tumor measured 17 × 17 × 13 cm. Histologically, the tumor displayed distinct heterologous osteosarcomatous and chondrosarcomatous components on a background of conventional SFT. Immunohistochemistry uncovered a loss of CD34 expression in the dedifferentiated area, whereas the nuclear expression of signal transducer and activator of transcription-6 (STAT6) and NGFI-A-binding protein 2 (NAB2) was maintained in both components. The p53 mutation 158 CGC > CAC (A158H) was found only in the dedifferentiated component. Furthermore, a fusion gene of NAB2(exon6)-STAT6(exon18) was detected in both the conventional and dedifferentiated components. The patient died of the disease 4 months after surgery. This case identifies a possible role of p53 dysfunction in the dedifferentiation process of SFT as reported in other sarcomas.