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Background: Allogeneic stem cell transplant (allo-SCT) is a mainstay of treatment for acute myeloid leukemia (AML). Its success depends largely on response of donor T lymphocytes against leukemia cells, known as graft-vs-leukemia (GvL) effect. A key potential driver of GvL is immune response to mutation-derived neoantigens. Previous studies in solid tumors have demonstrated enhanced immunogenicity of frameshift (FS)-derived peptides vs. those from non-synonymous single nucleotide variants (SNVs). We therefore hypothesized that AML cases bearing FS mutations in leukemia-associated genes would be more immunogenic than those with only other types of mutations (non-FS), and thus benefit more from allo-SCT via more robust GvL. Methods: We identified AML patients who had undergone allo-SCT between 2010 and 2022 and had next-generation sequencing data available on diagnostic specimens using a 42-gene hot spot panel. We compared the impact of tumor mutations present at diagnosis on overall survival and relapse-free survival based on FS versus non-FS status. Results: Ninety-five AML allo-SCT patients were identified. We observed superior relapse-free survival (P = 0.038, hazard ratio (HR): 0.24) and borderline superior overall survival (P = 0.058, HR: 0.55) post-transplant in de novo AML patients, who had at least one FS mutation (other than NPM1) in one of the 42 assessed genes versus those with only non-FS mutations. Conclusions: Our findings suggest that FS-mutated AML cases may benefit more from allo-SCT than those with only non-FS mutations, possibly due to increased generation of immunogenic neoepitopes. If validated in an expanded study, incorporation of somatic FS mutation status in AML could improve patient selection algorithms for bone marrow transplant and thereby lead to superior outcomes.
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Recursive partitioning of healthy consortia led to the development of the Clonal Hematopoiesis Risk Score (CHRS) for clonal haematopoiesis (CH); however, in the practical setting, most cases of CH are diagnosed after patients present with cytopenias or related symptoms. To address this real-world population, we characterize the clinical trajectories of 94 patients with CH and distinguish CH harbouring canonical DNMT3A/TET2/ASXL1 mutations alone ('sole DTA') versus all other groups ('non-sole DTA'). TET2, rather than DNMT3A, was the most prevalent mutation in the real-world setting. Sole DTA patients did not progress to myeloid neoplasm (MN) in the absence of acquisition of other mutations. Contrastingly, 14 (20.1%) of 67 non-sole DTA patients progressed to MN. CHRS assessment showed a higher frequency of high-risk CH in non-sole DTA (vs. sole DTA) patients and in progressors (vs. non-progressors). RUNX1 mutation conferred the strongest risk for progression to MN (odds ratio [OR] 10.27, 95% CI 2.00-52.69, p = 0.0053). The mean variant allele frequency across all genes was higher in progressors than in non-progressors (36.9% ± 4.62% vs. 24.1% ± 1.67%, p = 0.0064). This analysis in the post-CHRS era underscores the natural history of CH, providing insight into patterns of progression to MN.
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Hematopoyesis Clonal , Proteínas de Unión al ADN , Dioxigenasas , Mutación , Humanos , Hematopoyesis Clonal/genética , Masculino , Femenino , Persona de Mediana Edad , Anciano , Proteínas de Unión al ADN/genética , ADN Metiltransferasa 3A , Adulto , Anciano de 80 o más Años , Progresión de la Enfermedad , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Represoras/genética , ADN (Citosina-5-)-Metiltransferasas/genéticaRESUMEN
CONTEXT.: Syringocystadenocarcinoma papilliferum (SCACP) is a rare adnexal carcinoma and the malignant counterpart of syringocystadenoma papilliferum (SCAP), which is commonly located on the head and neck and may arise in association with a nevus sebaceus. RAS mutations have been identified in both SCAP and nevus sebaceus. OBJECTIVE.: To evaluate the clinicopathologic and molecular features of SCACPs, which have not been previously explored. DESIGN.: We obtained 11 SCACPs from 6 institutions and reviewed the clinicopathologic features. We also performed molecular profiling using next-generation sequencing. RESULTS.: The cohort comprised 6 women and 5 men with ages ranging from 29 to 96 years (mean, 73.6 years). The neoplasms occurred on the head and neck (n = 8; 73%) and extremities (n = 3; 27%). Three tumors possibly arose in a nevus sebaceus. A total of 4 cases showed at least carcinoma in situ (adenocarcinoma, n = 3; squamous cell carcinoma [SCC], n = 1), and 7 cases were invasive (SCC, n = 5; mixed adenocarcinoma + SCC, n = 2). A total of 8 of 11 cases (73%) had hot spot mutations consisting of HRAS (n = 4), KRAS (n = 1), BRAF (n = 1), TP53 (n = 4), ATM (n = 2), FLT3 (n = 1), CDKN2A (n = 1), and PTEN (n = 1). All 4 cases with HRAS mutations occurred on the head and neck, whereas the KRAS mutation occurred on the extremity. CONCLUSIONS.: RAS-activating mutations were detected in 50% of the cases, of which most (80%) involved HRAS and occurred on the head and neck, which shows overlapping features with SCAP, supporting that a subset may arise as a result of malignant transformation and likely an early oncogenic event.
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Adenocarcinoma , Carcinoma de Células Escamosas , Nevo , Neoplasias Cutáneas , Neoplasias de las Glándulas Sudoríparas , Masculino , Humanos , Femenino , Proteínas Proto-Oncogénicas p21(ras)/genética , Neoplasias de las Glándulas Sudoríparas/genética , Neoplasias de las Glándulas Sudoríparas/patología , Nevo/patología , Carcinoma de Células Escamosas/patología , Mutación , Neoplasias Cutáneas/patologíaRESUMEN
Anorectal ulcer with granulation tissue is typically associated with left-sided inflammatory bowel disease or infection. Due to emerging cases of Chlamydia proctitis, we aim to investigate the prevalence of Chlamydia infection using immunohistochemistry (IHC) in anorectal biopsies showing ulcer and granulation tissue. Seventy-seven patients including 60 males and 17 females with mean age of 51 years old were retrospectively identified in surgical pathology archives. Chlamydia IHC was validated with a monoclonal antibody on an index who was positive for Chlamydia by rectal swab nucleic acid amplification test (NAAT), then performed on formalin fixed and paraffin embedded (FFPE) tissue sections. Confirmative molecular test using real-time PCR was performed on DNA extractions of 14 IHC-positive and 14 IHC-negative FFPEs, 18 NAAT-positive, and 5 NAAT-negative cytology specimens. Chlamydia IHC showed strong intracytoplasmic or extracellular sphere morphology in 14 of 77 (18.2 %) FFPEs, including 11 of 60 (18.3 %) males and 3 of 17 (17.6 %) females (age 11-84 years). Eight of 14 (57.1 %) Chlamydia-IHC positive patients had known history of STDs, high-risk behavior, or immunosuppressive conditions. One of 14 (7.1 %) IHC-positive FFEP and 15 of 18 (83.3 %) NAAT-positive cytology cases were confirmed by real-time PCR. Chlamydia inclusions were detected in all 4 randomly selected NAAT and PCR-positive cytology specimens by IHC. Our data suggested that Chlamydia infection is more prevalent than we thought in patients with active proctitis and ulceration. Chlamydia IHC may be performed as a screening test in biopsies to facilitate early detection of this treatable proctitis in high-risk population.
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Infecciones por Chlamydia , Proctitis , Masculino , Femenino , Humanos , Persona de Mediana Edad , Niño , Adolescente , Adulto Joven , Adulto , Anciano , Anciano de 80 o más Años , Inmunohistoquímica , Úlcera/epidemiología , Estudios Retrospectivos , Prevalencia , Infecciones por Chlamydia/diagnóstico , Infecciones por Chlamydia/epidemiología , Proctitis/diagnóstico , Proctitis/epidemiología , Tejido de GranulaciónRESUMEN
TP53 aberrations constitute the highest risk subset of myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML). The International Consensus Classification questions the blast threshold between MDS and AML. In this study, we assess the distinction between MDS and AML for 76 patients with TP53 aberrations. We observed no significant differences between MDS and AML regarding TP53 genomics. Median overall survival (OS) was 223 days for the entire group, but prognostic discrimination within subgroups showed the most inferior OS (46 days) for AML with multihit allelic state plus TP53 variant allele frequency (VAF) > 50%. In multivariate analysis, unadjusted Cox models revealed the following variables as independent risk factors for mortality: AML (vs. MDS) (hazard ratio [HR]: 2.50, confidence interval [CI]: 1.4-4.4, p = 0.001), complex karyotype (HR: 3.00, CI: 1.4-6.1, p = 0.003), multihit status (HR: 2.30, CI 1.3-4.2, p = 0.005), and absence of hematopoietic cell transplant (HCT) (HR: 3.90, CI: 1.8-8.9, p = 0.0009). Clonal dynamic modeling showed a significant reduction in TP53 VAF with front-line hypomethylating agents. These findings clarify the impact of specific covariates on outcomes of TP53-aberrant myeloid neoplasms, irrespective of the diagnosis of MDS versus AML, and may influence HCT decisions.
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Lymphangiectasia, an anomalous dilation of lymphatic vessels first described in the 17th century, is frequently associated with chylous effusion, respiratory failure, and high mortality in young patients, yet the underlying molecular pathogenesis and effective treatments remain elusive. Here, we identify an unexpected causal link between MAPK activation and defective development of the lymphatic basement membrane that drives lymphangiectasia. Human pathological tissue samples from patients diagnosed with lymphangiectasia revealed sustained MAPK activation within lymphatic endothelial cells. Endothelial KRASG12D-mediated sustained MAPK activation in newborn mice caused severe pulmonary and intercostal lymphangiectasia, accumulation of chyle in the pleural space, and complete lethality. Pathological activation of MAPK in murine vasculature inhibited the Nfatc1-dependent genetic program required for laminin interactions, collagen crosslinking, and anchoring fibril formation, driving defective development of the lymphatic basement membrane. Treatment with ravoxertinib, a pharmacological inhibitor of MAPK, reverses nuclear-to-cytoplasmic localization of Nfatc1, basement membrane development defects, lymphangiectasia, and chyle accumulation, ultimately improving survival of endothelial KRAS mutant neonatal mice. These results reveal defective lymphatic basement membrane assembly and composition as major causes of thoracic lymphangiectasia and provide a potential treatment.
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Células Endoteliales , Vasos Linfáticos , Animales , Membrana Basal , Células Endoteliales/fisiología , Humanos , Sistema Linfático , Vasos Linfáticos/patología , Ratones , Piridonas , PirimidinasRESUMEN
TP53-aberrant myelodysplastic syndrome and acute myeloid leukemia have dismal outcomes. Here, we define the clinico-genomic landscape of TP53 disruptions in 40 patients and employ clonal dynamic modeling to map the mutational hierarchy against clinical outcomes. Most TP53 mutations (45.2%) localized to the L3 loop or LSH motif of the DNA-binding domain. TP53 disruptions had high co-occurrence with mutations in epigenetic regulators, spliceosome machinery, and cohesin complex and low co-occurrence with mutations in proliferative signaling genes. Ancestral and descendant TP53 mutations constituted measurable residual disease and fueled relapse. High mutant TP53 gene dosage predicted low durability of remission. The median overall survival (OS) was 280 days. Hypomethylating agent-based therapy served as an effective bridge to transplant, leading to improved median OS compared to patients who did not receive a transplant (14.7 vs. 5.1 months). OS was independent of the genomic location of TP53 disruption, which has implications for rational therapeutic design.
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Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Genes p53 , Perfil Genético , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Mutación , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/terapia , Proteína p53 Supresora de Tumor/genéticaAsunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Transformación Celular Neoplásica/metabolismo , Células Endoteliales/metabolismo , Hemangioendotelioma Epitelioide/metabolismo , Neoplasias Vasculares/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Antígenos CD/genética , Antígenos CD/metabolismo , Cadherinas/genética , Cadherinas/metabolismo , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Células Endoteliales/patología , Regulación Neoplásica de la Expresión Génica , Hemangioendotelioma Epitelioide/genética , Hemangioendotelioma Epitelioide/patología , Humanos , Ratones Transgénicos , Transducción de Señal , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Neoplasias Vasculares/genética , Neoplasias Vasculares/patología , Proteínas Señalizadoras YAPRESUMEN
Anal squamous cell carcinoma (SqCC) is a morphologically heterogeneous entity. Basaloid and non-keratinizing anal SqCC may be confused with other tumors including neuroendocrine carcinoma due to morphologic overlap, and expression of neuroendocrine markers is not well-studied in anal SqCC. Prompted by a case of anal SqCC that was initially misdiagnosed as neuroendocrine carcinoma on the basis of morphology and CD56 expression, we retrospectively examined the expression of neuroendocrine markers CD56, synaptophysin, and chromogranin in 48 cases of basaloid anal SqCC, with clinicopathologic correlation. HPV16 was identified in 46 cases, HPV33 in one case, and one case was HPV-negative. Three (6.3%) cases demonstrated CD56 expression, including two with diffuse and one with focal expression. Two CD56-positive cases demonstrated basaloid morphology with peripheral palisading and the other demonstrated adenoid cystic/cylindroma-like morphology. None of the cases showed significant synaptophysin or chromogranin expression. The three cases expressing CD56 were HPV16-positive, and one demonstrated a CTNNB1 mutation. There was no difference in clinicopathologic features including stage, outcome, or HPV status, between CD56-positive and negative groups. Our findings support that CD56 expression is infrequently expressed in anal SqCC and is not indicative of neuroendocrine differentiation in the absence of expression of more specific neuroendocrine markers such as synaptophysin and chromogranin. Pathologists should be aware that CD56 expression may occur in basaloid anal SqCC and is a diagnostic pitfall due to morphologic overlap with neuroendocrine carcinoma and other tumors including basal cell carcinoma.
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Canal Anal/patología , Antígeno CD56/metabolismo , Carcinoma Neuroendocrino/diagnóstico , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/metabolismo , Anciano , Biomarcadores de Tumor/metabolismo , Carcinoma Neuroendocrino/patología , Carcinoma de Células Escamosas/patología , Cromograninas/metabolismo , Errores Diagnósticos/prevención & control , Errores Diagnósticos/estadística & datos numéricos , Femenino , Estudios de Seguimiento , Papillomavirus Humano 16/aislamiento & purificación , Humanos , Inmunohistoquímica/métodos , Masculino , Persona de Mediana Edad , Mutación , Estadificación de Neoplasias/métodos , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/diagnóstico , Infecciones por Papillomavirus/virología , Estudios Retrospectivos , Sinaptofisina/metabolismo , beta Catenina/genéticaRESUMEN
BACKGROUND: Urine cytology can reliably diagnose high-grade urothelial carcinoma (HGUC) but not low-grade urothelial carcinoma (LGUC), and a more sensitive test is needed. Previously, a pilot study highlighted the possible diagnostic utility of next-generation sequencing (NGS) in identifying both LGUC and HGUC in urine cytology specimens. METHODS: Twenty-eight urine ThinPrep cytology specimens and preceding or subsequent bladder tumor biopsy/resection specimens obtained within 3 months were included in the study (LGUC, n = 15; HGUC, n = 13). A customized, bladder-specific NGS panel was performed; it covered 69 frequently mutated or altered genes in urothelial carcinoma (UC) that were reported by The Cancer Genome Atlas and the Catalogue of Somatic Mutations in Cancer. RESULTS: The sequencing results were compared between the urine cytology specimens and the corresponding bladder tumor biopsies/resections. TP53 was the most frequently identified mutation in HGUC cases (11 of 13 [85%]). PIK3CA and KDM6A were the most frequently identified mutations in LGUC: they occurred in 7 of 15 cases (47%) and in 6 of 15 cases (40%), respectively. Additional frequent mutations identified in the panel included ARID1A (n = 5), EP300 (n = 4), LRP1B (n = 3), ERBB2 (n = 2), STAG2 (n = 2), FGFR3 (n = 3), MLL (n = 2), MLL3 (n = 2), CREBBP1 (n = 1), RB1 (n = 1), and FAT4 (n = 1). Overall, the concordance between the cytology and surgical specimens was 75%. The sensitivity and specificity for identifying mutations in urine cytology specimens were 84% and 100%, respectively. CONCLUSIONS: A bladder-specific NGS panel increases the sensitivity and specificity of urine cytology's diagnostic utility in both low- and high-grade tumors and may serve as a noninvasive surveillance method in the follow-up of patients with UC harboring known mutations.
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Carcinoma de Células Transicionales/diagnóstico , Carcinoma de Células Transicionales/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Neoplasias de la Vejiga Urinaria/diagnóstico , Neoplasias de la Vejiga Urinaria/genética , Vejiga Urinaria/patología , Orina/citología , Anciano , Carcinoma de Células Transicionales/patología , Femenino , Humanos , Masculino , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
Squamous cell carcinoma (SqCC) is the most common malignancy of the anal canal, where it is strongly associated with HPV infection. Characteristic genomic alterations have been identified in anal SqCC, but their clinical significance and correlation with HPV status, pathologic features, and immunohistochemical markers are not well established. We examined the molecular and clinicopathologic features of 96 HPV-positive and 20 HPV-negative anal SqCC. HPV types included 89 with HPV16, 2 combined HPV16/HPV18, and 5 HPV33. HPV-positive cases demonstrated frequent mutations or amplifications in PIK3CA (30%; p = 0.027) or FBXW7 mutations (10%). HPV-negativity was associated with frequent TP53 (53%; p = 0.00001) and CDKN2A (21%; p = 0.0045) mutations. P16 immunohistochemistry was positive in all HPV-positive cases and 3/20 HPV-negative cases (p < 0.0001; sensitivity: 100%; specificity: 85%) and was associated with basaloid morphology (p = 0.0031). Aberrant p53 immunohistochemical staining was 100% sensitive and specific for TP53 mutation (p < 0.0001). By the Kaplan-Meier method, HPV-negativity, aberrant p53 staining, and TP53 mutation were associated with inferior overall survival (OS) (p < 0.0001, p = 0.0103, p = 0.0103, respectively) and inferior recurrence-free survival (p = 0.133, p = 0.0064, and p = 0.0064, respectively). TP53/p53 status stratified survival probability by HPV status (p = 0.013), with HPV-negative/aberrant p53 staining associated with the worst OS, HPV-positive/wild-type p53 with best OS, and HPV-positive/aberrant p53 or HPV-negative/wild-type p53 with intermediate OS. On multivariate analysis HPV status (p = 0.0063), patient age (p = 0.0054), T stage (p = 0.039), and lymph node involvement (p = 0.044) were independently associated with OS. PD-L1 expression (CPS ≥ 1) was seen in 30% of HPV-positive and 40% of HPV-negative cases, and PD-L1 positivity was associated with a trend toward inferior OS within the HPV-negative group (p = 0.064). Our findings suggest that anal SqCC can be subclassified into clinically, pathologically, and molecularly distinct groups based on HPV and TP53 mutation status, and p16 and p53 immunohistochemistry represent a clinically useful method of predicting these prognostic groups.
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Neoplasias del Ano/genética , Carcinoma de Células Escamosas/genética , Mutación , Infecciones por Papillomavirus/genética , Proteína p53 Supresora de Tumor/genética , Adulto , Neoplasias del Ano/patología , Neoplasias del Ano/virología , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/virología , Análisis Mutacional de ADN/métodos , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inmunofenotipificación , Masculino , Persona de Mediana Edad , Infecciones por Papillomavirus/patología , Infecciones por Papillomavirus/virología , PronósticoRESUMEN
INTRODUCTION: Cytology and cystoscopy are used to detect urothelial carcinoma (UC), but together they still fail to detect some UC cases and are not suitable for screening asymptomatic individuals. Mutations are present in more than 98% of UC, mutations have therapeutic significance, and they can be detected by next generation sequencing (NGS) in urine samples. We review the role of NGS in UC detection. MATERIALS AND METHODS: Comprehensive literature review on UC genetics, economics of NGS, and previous reports of UC detection by NGS. RESULTS: The raw costs of NGS have decreased to about 14,000 base pairs per penny, making it appear economically feasible to use NGS widely. Reported NGS assays fall short of predicted sensitivity. Decreased sensitivity is attributed to a low frequency of mutant alleles in many urine samples. Attempts to increase the percentage of mutant alleles, by using cell-free urinary DNA, or by using cell sorting and microfluidics, have been unsuccessful or remain unproven. However, cytologic examination can immediately enable NGS: Urine cytologies with sufficient proportions of abnormal cells could be directly triaged to NGS with high sensitivity for UC detection. For cases with a low proportion of abnormal cells, cytologically targeted microdissection of cells for NGS should maintain sensitivity and decrease sequencing costs. Cytologically targeted urothelial cells for NGS could allow a screening test for low grade UC. CONCLUSIONS: Cytology is immediately poised to allow NGS to improve the diagnosis of UC, allowing NGS to be an ancillary test for atypical cytologies, and potentially allowing a screening test for low-grade UC.
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Biomarcadores de Tumor/genética , Carcinoma/genética , Análisis Citogenético , Análisis Mutacional de ADN , Detección Precoz del Cáncer , Secuenciación de Nucleótidos de Alto Rendimiento , Mutación , Orina/citología , Neoplasias Urológicas/genética , Urotelio/patología , Biomarcadores de Tumor/orina , Carcinoma/patología , Carcinoma/orina , Humanos , Microscopía , Clasificación del Tumor , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Urinálisis , Neoplasias Urológicas/patología , Neoplasias Urológicas/orinaRESUMEN
Primary peritoneal serous carcinomas (PPSC) are exceedingly rare in male patients. Only a few cases were reported, and mostly with the limited immunophenotypical characterization. No molecular analysis of PPSC in males has been previously performed. We here describe another case of PPSC in a male patient. A comprehensive molecular analysis of the tumor revealed SF3B1 gene mutation as a possible driver.
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Human hepatic vascular cavernomas, the most common benign tumor of the liver, were described in the mid-1800s, yet the mechanisms for their formation and effective treatments remain unknown. Here, we demonstrate gain-of-function mutations in KRAS or BRAF genes within liver endothelial cells as a causal mechanism for hepatic vascular cavernomas. We identified gain-of-function mutations in KRAS or BRAF genes in pathological liver tissue samples from patients with hepatic vascular cavernomas. Mice expressing these human KRASG12D or BRAFV600E mutations in hepatic endothelial cells recapitulated the human hepatic vascular cavernoma phenotype of dilated sinusoidal capillaries with defective branching patterns. KRASG12D or BRAFV600E induced "zipper-like" contiguous expression of junctional proteins at sinusoidal endothelial cell-cell contacts, switching capillaries from branching to cavernous expansion. Pharmacological or genetic inhibition of the endothelial RAS-MAPK1 signaling pathway rescued hepatic vascular cavernoma formation in endothelial KRASG12D- or BRAFV600E-expressing mice. These results uncover a major cause of hepatic vascular cavernomas and provide a road map for their personalized treatment.
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Hígado/irrigación sanguínea , Hígado/patología , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Mutación/genética , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Uniones Adherentes/metabolismo , Adulto , Anciano de 80 o más Años , Animales , Comunicación Celular/efectos de los fármacos , Pérdida del Embrión/patología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Femenino , Mutación con Ganancia de Función/genética , Humanos , Hígado/efectos de los fármacos , Hígado/enzimología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/patología , Masculino , Ratones , Persona de Mediana Edad , Proteínas Quinasas Activadas por Mitógenos/metabolismoAsunto(s)
Leucemia Neutrofílica Crónica , Leucocitosis , Anciano de 80 o más Años , Femenino , Humanos , Leucemia Neutrofílica Crónica/tratamiento farmacológico , Leucemia Neutrofílica Crónica/genética , Leucemia Neutrofílica Crónica/metabolismo , Leucemia Neutrofílica Crónica/patología , Leucocitosis/tratamiento farmacológico , Leucocitosis/genética , Leucocitosis/metabolismo , Leucocitosis/patología , MutaciónRESUMEN
Mucous membrane plasmacytosis (MMP) is an uncommon variant of mucositis represented by a polyclonal plasma cell infiltration of mucosal tissue. Various clinical presentations in the upper airway have been reported ranging from erythematous mucosa to fungating masses. Histologic features include mucosal epithelial hyperplasia or psoriasiform changes with a dense submucosal infiltrate of polytypic plasma cells. Molecular studies for immunoglobulin gene rearrangement should be performed in all cases of MMP to rule out clonal neoplastic expansion of plasma cells. We present a case of MMP with over 15 years of clinical follow-up, emphasizing the relatively benign clinical course of this disorder.
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INTRODUCTION: Many pancreatic cystic lesions (PCL) are of neoplastic nature with potential to progress to pancreatic adenocarcinoma. Early stratification of patients to either clinical observation or surgical intervention can considerably increase the survival rate. Recent studies have shown the value of molecular analysis to current diagnostic modalities.The aim of this study is to evaluate the diagnostic improvement by utilizing multiple sequential cytologic and molecular cyst fluid analyses. MATERIALS AND METHODS: We prospectively evaluated 58 patients for whom multiple endoscopic ultrasound-guided fine-needle aspiration of cyst fluid specimens were available. Specimens were subjected to next generation sequencing to identify any recurrent gene mutations commonly found in PCL. The molecular findings were compared with cytologic and final diagnoses. RESULTS: Cytologic diagnoses were classified into 3 groups: non-diagnostic (first visit: 33.9%, cumulative: 15.8%, P = 0.03), negative (1st visit: 53.6%, cumulative: 56.1%, P = 0.85) and atypical/suspicious/positive (first visit: 12.5%, cumulative: 28.1%, P = 0.06). The mutational analyses were clustered into indeterminate/failure (first visit: 1.7%, cumulative: 0%), KRAS/GNAS/VHL group (first visit: 50.0%, cumulative: 53.4%) and any mutation (first visit: 50.0%, cumulative: 53.4%). Mutational analysis identifies up to 72% and 71% whereas cytologic analysis classified up to 46% and 63% of lesions correctly in first and multiple visits, respectively. CONCLUSIONS: The cytology and molecular analyses provide a complementary approach to patients with PCL. Power of molecular analysis in detection of a neoplastic lesion is significantly higher in one visit (P = 0.01) with comparable detection rates (P = 0.43) for both cytologic and molecular analyses after multiple visits.