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Currently, the application of peritoneal washings as a diagnostic tool for endometrial cancer staging is not well defined. The case described aims to highlight the current ambiguity surrounding the use of peritoneal washings in clinical practice. A 69-year-old G3P3003 presented to her gynecologist with complaints of new-onset heavy vaginal bleeding. The patient sought an endometrial biopsy, which suggested serous endometrial intraepithelial carcinoma (EIC) focally suspicious for invasive carcinoma, with the involvement of polyps. Based on these results, a robotic-assisted total laparoscopic hysterectomy, bilateral salpingo-oophorectomy, bilateral sentinel lymph node dissection, and omentectomy were performed. Results from her final pathology exhibited a stage IA uterine serous carcinoma (USC) involving a polyp (4.2 cm in greatest dimension) with no myometrial or lymphovascular invasion, but washings were positive for adenocarcinoma. Based on her family history of malignancy, the patient underwent germline panel testing. The patient's somatic tumor testing demonstrated proficient DNA mismatch repair status, microsatellite stability, low tumor mutational burden (4 mut/Mb), low loss of heterozygosity (9%), amplification of the ERBB2 (HER2/neu) gene by both immunohistochemistry (3+, 20% positive) and fluorescence in-situ hybridization. Her tumor also had weakly positive estrogen receptor expression (1+, 10% positive); furthermore, some pathogenic variants in KRAS (c.37G>T), PIK3CA (c.263G>A), and TP53 (c.743G>A) were identified. Given the incongruent findings found with the positive peritoneal washing and negative lymph node involvement in addition to molecular testing, management for this patient was unclear. Ultimately, this case highlights a number of advances within the field of gynecological oncology but also emphasizes the persistent ambiguity and incongruency in the management of patients with early-stage high-risk histologies. Moving forward it will become increasingly important to be able to develop a more standardized process to assess how these diagnostic tools should inform prognosis and treatment plans.
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Understanding the distinct pathogenic mechanisms that culminate in allograft fibrosis and chronic graft failure is key in improving outcomes after solid organ transplantation. Here, we describe an F1 â parent orthotopic lung transplant model of restrictive allograft syndrome (RAS), a particularly fulminant form of chronic lung allograft dysfunction (CLAD), and identify a requisite pathogenic role for humoral immune responses in development of RAS. B6D2F1/J (H2-b/d) donor lungs transplanted into the parent C57BL/6J (H2-b) recipients demonstrated a spectrum of histopathologic changes, ranging from lymphocytic infiltration, fibrinous exudates, and endothelialitis to peribronchial and pleuroparenchymal fibrosis, similar to those noted in the human RAS lungs. Gene expression profiling revealed differential humoral immune cell activation as a key feature of the RAS murine model, with significant B cell and plasma cell infiltration noted in the RAS lung allografts. B6D2F1/J lung allografts transplanted into µMt-/- (mature B cell deficient) or activation-induced cytidine deaminase (AID)/secretory µ-chain (µs) double-KO (AID-/-µs-/-) C57BL/6J mice demonstrated significantly decreased allograft fibrosis, indicating a key role for antibody secretion by B cells in mediating RAS pathology. Our study suggests that skewing of immune responses determines the diverse allograft remodeling patterns and highlights the need to develop targeted therapies for specific CLAD phenotypes.
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Aloinjertos/inmunología , Aloinjertos/patología , Inmunidad Humoral/inmunología , Animales , Fibrosis , Rechazo de Injerto/inmunología , Pulmón/patología , Trasplante de Pulmón/métodos , Masculino , Ratones , Ratones Endogámicos C57BL , Trasplante de Órganos , FenotipoRESUMEN
Bronchopulmonary dysplasia (BPD) is usually seen in premature infants who require mechanical ventilation and oxygen therapy for acute respiratory distress. Although most patients wean from oxygen therapy by the ages of 2 to 3, rehospitalization for respiratory problems is common in these patients in adulthood. There have been few studies that document the long-term outcomes of BPD survivors and information about the pulmonary function and radiographic findings of adult BPD are limited. Data on pathologic features of adult BPD are scarce. Three adult patients who underwent recent lung transplantation for BPD from 2 institutions were identified. Clinical data including clinical presentation, chest radiographic images, pulmonary function tests, cardiac catheterization, and echocardiography were retrieved from the electronic medical records. Hematoxylin and eosin and selective elastic stained sections of the explant lungs were examined. CD31 immunohistochemical stain is performed on representative sections. All 3 cases had similar clinical and radiologic features including the history of prematurity and long-term mechanical ventilation after birth, hyperexpanded lungs with air trapping and mosaic attenuation on chest computed tomographic scan, severe obstructive changes on pulmonary function test, and pulmonary hypertension. Pathologic examination showed common features including enlarged and simplified alveoli, peribronchial, subpleural, and interlobular septal fibrosis, narrowing/obliteration of the small airways by elastosis and muscular hypertrophy, thickening of venous walls by fibromuscular hyperplasia, and bronchitis/bronchiolitis. Cholesterol granulomas were seen in 2 cases. The common pathologic findings in the lungs explain the clinical and radiologic findings. Future studies are warranted to further characterize the clinical and pathologic features of adult BPD to develop optimal management strategies for these patients.
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Displasia Broncopulmonar/patología , Displasia Broncopulmonar/cirugía , Trasplante de Pulmón , Pulmón/patología , Pulmón/cirugía , Adulto , Factores de Edad , Biopsia , Displasia Broncopulmonar/diagnóstico por imagen , Displasia Broncopulmonar/fisiopatología , Femenino , Humanos , Indiana , Pulmón/diagnóstico por imagen , Pulmón/fisiopatología , Masculino , Michigan , Sobrevivientes , Factores de Tiempo , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Adulto JovenRESUMEN
Histologic variants are uncommon but well reported amongst cases of prostatic adenocarcinoma, including those in the setting of hormonal and/or chemoradiation therapy and castration resistance. However, the spectrum of morphologic phenotypes and molecular alterations present in such histologic variants are still incompletely understood. Herein, we describe a case of metastatic prostatic adenocarcinoma with hormonal and chemoradiation therapy-associated differentiation, displaying a combination of squamous cell, small cell, and sarcomatoid elements. The morphologic, immunohistochemical, and molecular observations are discussed with attention given to the gene alterations present, including in TP53, NF1, AR, PTEN, and RB1. Finally, we will compare our findings with those observed in uncommonly reported similar cases so as to detail the molecular underpinnings of such processes which may carry therapeutic implications.
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Adenocarcinoma/patología , Neoplasias de la Próstata Resistentes a la Castración/patología , Adenocarcinoma/genética , Adenocarcinoma/terapia , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/efectos de la radiación , Quimioradioterapia , Células Epiteliales/patología , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/terapiaRESUMEN
Rationale: Evidence suggests damage to small airways is a key pathologic lesion in chronic obstructive pulmonary disease (COPD). Computed tomography densitometry has been demonstrated to identify emphysema, but no such studies have been performed linking an imaging metric to small airway abnormality.Objectives: To correlate ex vivo parametric response mapping (PRM) analysis to in vivo lung tissue measurements of patients with severe COPD treated by lung transplantation and control subjects.Methods: Resected lungs were inflated, frozen, and systematically sampled, generating 33 COPD (n = 11 subjects) and 22 control tissue samples (n = 3 subjects) for micro-computed tomography analysis of terminal bronchioles (TBs; last generation of conducting airways) and emphysema.Measurements and Main Results: PRM analysis was conducted to differentiate functional small airways disease (PRMfSAD) from emphysema (PRMEmph). In COPD lungs, TB numbers were reduced (P = 0.01); surviving TBs had increased wall area percentage (P < 0.001), decreased circularity (P < 0.001), reduced cross-sectional luminal area (P < 0.001), and greater airway obstruction (P = 0.008). COPD lungs had increased airspace size (P < 0.001) and decreased alveolar surface area (P < 0.001). Regression analyses demonstrated unique correlations between PRMfSAD and TBs, with decreased circularity (P < 0.001), decreased luminal area (P < 0.001), and complete obstruction (P = 0.008). PRMEmph correlated with increased airspace size (P < 0.001), decreased alveolar surface area (P = 0.003), and fewer alveolar attachments per TB (P = 0.01).Conclusions: PRMfSAD identifies areas of lung tissue with TB loss, luminal narrowing, and obstruction. This is the first confirmation that an imaging biomarker can identify terminal bronchial pathology in established COPD and provides a noninvasive imaging methodology to identify small airway damage in COPD.
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Obstrucción de las Vías Aéreas/diagnóstico por imagen , Biomarcadores , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Microtomografía por Rayos X/métodos , Adulto , Anciano , Anciano de 80 o más Años , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Hypersensitivity pneumonitis (HP) is an interstitial lung disease with a better prognosis, on average, than idiopathic pulmonary fibrosis (IPF). We compare survival time and pulmonary function trajectory in patients with HP and IPF by radiologic phenotype. METHODS: HP (n = 117) was diagnosed if surgical/transbronchial lung biopsy, BAL, and exposure history results suggested this diagnosis. IPF (n = 152) was clinically and histopathologically diagnosed. All participants had a baseline high-resolution CT (HRCT) scan and FVC % predicted. Three thoracic radiologists documented radiologic features. Survival time is from HRCT scan to death or lung transplant. Cox proportional hazards models identify variables associated with survival time. Linear mixed models compare post-HRCT scan FVC % predicted trajectories. RESULTS: Subjects were grouped by clinical diagnosis and three mutually exclusive radiologic phenotypes: honeycomb present, non-honeycomb fibrosis (traction bronchiectasis and reticulation) present, and nonfibrotic. Nonfibrotic HP had the longest event-free median survival (> 14.73 years) and improving FVC % predicted (1.92%; 95% CI, 0.49-3.35; P = .009). HP with non-honeycomb fibrosis had longer survival than IPF (> 7.95 vs 5.20 years), and both groups experienced a significant decline in FVC % predicted. Subjects with HP and IPF with honeycombing had poor survival (2.76 and 2.81 years, respectively) and significant decline in FVC % predicted. CONCLUSIONS: Three prognostically distinct, radiologically defined phenotypes are identified among patients with HP. The importance of pursuing a specific diagnosis (eg, HP vs IPF) among patients with non-honeycomb fibrosis is highlighted. When radiologic honeycombing is present, invasive diagnostic testing directed at determining the diagnosis may be of limited value given a uniformly poor prognosis.
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Alveolitis Alérgica Extrínseca/diagnóstico , Pulmón/diagnóstico por imagen , Pruebas de Función Respiratoria/métodos , Alveolitis Alérgica Extrínseca/mortalidad , Biopsia , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Pronóstico , Radiografía Torácica , Estudios Retrospectivos , Tasa de Supervivencia/tendencias , Tomografía Computarizada por Rayos X , Estados Unidos/epidemiologíaRESUMEN
High-resolution computed tomography (HRCT) may be useful for diagnosing hypersensitivity pneumonitis. Here, we develop and validate a radiological diagnosis model and model-based points score.Patients with interstitial lung disease seen at the University of Michigan Health System (derivation cohort) or enrolling in the Lung Tissue Research Consortium (validation cohort) were included. A thin-section, inspiratory HRCT scan was required. Thoracic radiologists documented radiological features.The derivation cohort comprised 356 subjects (33.9% hypersensitivity pneumonitis) and the validation cohort comprised 424 subjects (15.5% hypersensitivity pneumonitis). An age-, sex- and smoking status-adjusted logistic regression model identified extent of mosaic attenuation or air trapping greater than that of reticulation ("MA-AT>Reticulation"; OR 6.20, 95% CI 3.53-10.90; p<0.0001) and diffuse axial disease distribution (OR 2.33, 95% CI 1.31-4.16; p=0.004) as hypersensitivity pneumonitis predictors (area under the receiver operating characteristic curve 0.814). A model-based score >2 (1 point for axial distribution, 2 points for "MA-AT>Reticulation") has specificity 90% and positive predictive value (PPV) 74% in the derivation cohort and specificity 96% and PPV 44% in the validation cohort. Similar model performance is seen with population restriction to those reporting no exposure (score >2: specificity 91%).When radiological mosaic attenuation or air trapping are more extensive than reticulation and disease has diffuse axial distribution, hypersensitivity pneumonitis specificity is high and false diagnosis risk low (<10%), but PPV is diminished in a low-prevalence setting.
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Alveolitis Alérgica Extrínseca/diagnóstico por imagen , Pulmón/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Anciano , Alveolitis Alérgica Extrínseca/fisiopatología , Femenino , Humanos , Modelos Logísticos , Pulmón/fisiopatología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Sensibilidad y Especificidad , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing lung disease of unknown etiology. Inter-society consensus guidelines on IPF diagnosis and management outline radiologic patterns including definite usual interstitial pneumonia (UIP), possible UIP, and inconsistent with UIP. We evaluate these diagnostic categories as prognostic markers among patients with IPF. METHODS: Included subjects had biopsy-proven UIP, a multidisciplinary team diagnosis of IPF, and a baseline high-resolution computed tomography (HRCT). Thoracic radiologists assigned the radiologic pattern and documented the presence and extent of specific radiologic findings. The outcome of interest was lung transplant-free survival. RESULTS: IPF patients with a possible UIP pattern on HRCT had significantly longer Kaplan-Meier event-free survival compared to those with definite UIP pattern (5.21 and 3.57 years, respectively, p = 0.002). In a multivariable Cox proportional hazards model adjusted for baseline age, gender, %-predicted FVC, and %-predicted DLCO via the GAP Stage, extent of fibrosis (via the traction bronchiectasis score) and ever-smoker status, possible UIP pattern on HRCT (versus definite UIP) was associated with reduced hazard of death or lung transplant (HR = 0.42, CI 95% 0.23-0.78, p = 0.006). CONCLUSIONS: Radiologic diagnosis categories outlined by inter-society consensus guidelines is a widely-reported and potentially useful prognostic marker in IPF patients, with possible UIP pattern on HRCT associated with a favorable prognosis compared to definite UIP pattern, after adjusting for relevant covariates.
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Fibrosis Pulmonar Idiopática/diagnóstico por imagen , Pulmón/diagnóstico por imagen , Factores de Edad , Anciano , Monóxido de Carbono , Femenino , Humanos , Fibrosis Pulmonar Idiopática/mortalidad , Fibrosis Pulmonar Idiopática/patología , Fibrosis Pulmonar Idiopática/fisiopatología , Pulmón/patología , Pulmón/fisiopatología , Trasplante de Pulmón , Masculino , Persona de Mediana Edad , Análisis Multivariante , Modelos de Riesgos Proporcionales , Capacidad de Difusión Pulmonar , Radiografía Torácica , Estudios Retrospectivos , Factores Sexuales , Tasa de Supervivencia , Tomografía Computarizada por Rayos X , Capacidad VitalRESUMEN
Cystic trophoblastic tumor (CTT) is a rare testicular germ cell tumor (GCT) predominantly seen in post-chemotherapy patients. It is prognostically similar to teratoma and requires no additional chemotherapy in the absence of a nonteratomatous GCT component. We report a case of metastatic CTT in a patient with primary testicular teratoma without prior chemotherapy. Retroperitoneal lymph node metastases contained teratoma, embryonal carcinoma, and CTT. The CTT was ß-hCG positive and SALL4 negative by immunohistochemistry (IHC). CTT can arise in metastatic testicular GCT in treatment naïve patients. An important differential diagnosis is choriocarcinoma due to treatment implications, and SALL4 IHC may help.
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Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is caused by germline mutations in the FH gene, and is associated with increased incidence of leiomyomas and a potentially aggressive variant of renal cell carcinoma (HLRCC-associated RCC). Absent immunohistochemical expression of fumarate hydratase (FH) has previously been used to diagnose HLRCC-associated RCC, but immunohistochemical staining of leiomyomas is not standard practice. We performed immunohistochemistry (IHC) on whole sections from consecutive cutaneous leiomyomas from our archives to evaluate for both FH and succinate dehydrogenase B expression, in addition to clinicopathologic data collection and review of all hematoxylin and eosin-stained slides for blinded morphologic evaluation of features reported to be seen in HLRCC-associated uterine leiomyomas. Ninety-six cutaneous leiomyomas from 87 patients were identified; 12 of these specimens were from 7 patients with documented HLRCC. FH expression by IHC was absent in 9 specimens and retained in 85 specimens; 2 cases were equivocal with minimal FH expression. Seven of the 9 absent expression specimens were from patients with HLRCC, as were both of the equivocal specimens. The overall sensitivity and specificity of absent FH expression in leiomyomas for detection of patients with HLRCC were 70.0% and 97.6%, respectively. Inclusion of cases classified as equivocal increased sensitivity to 75.0%. Succinate dehydrogenase B expression was retained in 95 specimens and equivocal in 1 specimen. None of the evaluated morphologic features showed any association with leiomyomas in HLRCC. Loss of FH immunohistochemical expression in cutaneous leiomyomas is a sensitive and specific marker for detection of HLRCC, thus suggesting a role for prospective FH IHC in patients with these tumors to screen for HLRCC.
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Biomarcadores de Tumor/metabolismo , Fumarato Hidratasa/metabolismo , Leiomiomatosis/diagnóstico , Síndromes Neoplásicos Hereditarios/diagnóstico , Neoplasias Cutáneas/diagnóstico , Succinato Deshidrogenasa/metabolismo , Neoplasias Uterinas/diagnóstico , Adolescente , Adulto , Bases de Datos Factuales , Femenino , Humanos , Inmunohistoquímica , Leiomiomatosis/enzimología , Leiomiomatosis/patología , Masculino , Síndromes Neoplásicos Hereditarios/enzimología , Síndromes Neoplásicos Hereditarios/patología , Sensibilidad y Especificidad , Método Simple Ciego , Neoplasias Cutáneas/enzimología , Neoplasias Cutáneas/patología , Neoplasias Uterinas/enzimología , Neoplasias Uterinas/patologíaRESUMEN
Tissue fibrosis is the primary cause of long-term graft failure after organ transplantation. In lung allografts, progressive terminal airway fibrosis leads to an irreversible decline in lung function termed bronchiolitis obliterans syndrome (BOS). Here, we have identified an autocrine pathway linking nuclear factor of activated T cells 2 (NFAT1), autotaxin (ATX), lysophosphatidic acid (LPA), and ß-catenin that contributes to progression of fibrosis in lung allografts. Mesenchymal cells (MCs) derived from fibrotic lung allografts (BOS MCs) demonstrated constitutive nuclear ß-catenin expression that was dependent on autocrine ATX secretion and LPA signaling. We found that NFAT1 upstream of ATX regulated expression of ATX as well as ß-catenin. Silencing NFAT1 in BOS MCs suppressed ATX expression, and sustained overexpression of NFAT1 increased ATX expression and activity in non-fibrotic MCs. LPA signaling induced NFAT1 nuclear translocation, suggesting that autocrine LPA synthesis promotes NFAT1 transcriptional activation and ATX secretion in a positive feedback loop. In an in vivo mouse orthotopic lung transplant model of BOS, antagonism of the LPA receptor (LPA1) or ATX inhibition decreased allograft fibrosis and was associated with lower active ß-catenin and dephosphorylated NFAT1 expression. Lung allografts from ß-catenin reporter mice demonstrated reduced ß-catenin transcriptional activation in the presence of LPA1 antagonist, confirming an in vivo role for LPA signaling in ß-catenin activation.
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Comunicación Autocrina , Lisofosfolípidos/fisiología , Fibrosis Pulmonar/metabolismo , beta Catenina/metabolismo , Aloinjertos , Animales , Bronquiolitis Obliterante/metabolismo , Células Cultivadas , Colágeno/biosíntesis , Femenino , Rechazo de Injerto/metabolismo , Humanos , Pulmón/metabolismo , Pulmón/patología , Trasplante de Pulmón , Masculino , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Factores de Transcripción NFATC/metabolismo , Hidrolasas Diéster Fosfóricas/metabolismo , Receptores del Ácido Lisofosfatídico/metabolismo , Activación TranscripcionalRESUMEN
BACKGROUND: Surgical lung biopsy (SLB) is invasive and not possible in all patients with undiagnosed interstitial lung disease (ILD). We hypothesized that transbronchial biopsy (TBB) findings combined with clinical and high-resolution CT (HRCT) data leads to a confident diagnosis congruent to SLB and therefore avoids the need for SLB in some patients. METHODS: We evaluated 33 patients being investigated for suspected ILD who underwent HRCT, TBB, and SLB. First, clinicians, radiologists, and a pathologist reviewed the clinical information and HRCT and TBB findings. Clinicians were asked to provide a diagnosis and were also asked if SLB was needed for a more confident diagnosis. Subsequently, the clinical, HRCT, and SLB data were reviewed, and the same participants were asked to provide a final diagnosis. Clinician consensus and overall agreement between TBB- and SLB-based diagnoses were calculated. RESULTS: Four patients had definite usual interstitial pneumonia (UIP) on HRCT and would not be considered for biopsy using current guidelines. Of the 29 patients without a definitive HRCT diagnosis, the clinicians felt confident of the diagnosis (ie, would not recommend SLB) in six cases. In these cases, there was 100% agreement between TBB and SLB diagnoses. UIP was the most common diagnosis (n = 3) and was associated with an HRCT diagnosis of possible UIP/nonspecific interstitial pneumonia-like. Agreement was poor (33%) between TBB and SLB diagnoses when confidence in the TBB diagnosis was low. CONCLUSIONS: Information from TBB, when combined with clinical and HRCT data, may provide enough information to make a confident and accurate diagnosis in approximately 20% to 30% of patients with ILD.
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Biopsia/métodos , Broncoscopía/métodos , Enfermedades Pulmonares Intersticiales/patología , Pulmón/patología , Adulto , Anciano , Alveolitis Alérgica Extrínseca/diagnóstico por imagen , Alveolitis Alérgica Extrínseca/patología , Alveolitis Alérgica Extrínseca/fisiopatología , Bronquiolitis/diagnóstico por imagen , Bronquiolitis/patología , Bronquiolitis/fisiopatología , Estudios de Cohortes , Neumonía en Organización Criptogénica/diagnóstico por imagen , Neumonía en Organización Criptogénica/patología , Neumonía en Organización Criptogénica/fisiopatología , Femenino , Volumen Espiratorio Forzado , Humanos , Fibrosis Pulmonar Idiopática/diagnóstico por imagen , Fibrosis Pulmonar Idiopática/patología , Fibrosis Pulmonar Idiopática/fisiopatología , Pulmón/fisiopatología , Pulmón/cirugía , Enfermedades Pulmonares Intersticiales/diagnóstico por imagen , Enfermedades Pulmonares Intersticiales/fisiopatología , Masculino , Persona de Mediana Edad , Capacidad de Difusión Pulmonar , Estudios Retrospectivos , Tomografía Computarizada por Rayos X , Capacidad VitalRESUMEN
Respiratory involvement in Crohn's disease (CD) is a rare manifestation known to involve the large and small airways, lung parenchyma, and pleura. The clinical presentation is nonspecific, and diagnostic tests can mimic other pulmonary diseases, posing a diagnostic challenge and delay in treatment. We report a case of a 60-year-old female with a history of CD and psoriatic arthritis who presented with dyspnea, fever, and cough with abnormal radiological findings. Diagnostic testing revealed an elevated CD4:CD8 ratio in the bronchoalveolar lavage fluid, and cryoprobe lung biopsy results showed non-necrotizing granulomatous inflammation. We describe here the second reported case of pulmonary involvement mimicking sarcoidosis in Crohn's disease and a review of the literature on the approaches to making a diagnosis of CD-associated interstitial lung disease.
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Enfermedad de Crohn/complicaciones , Enfermedades Pulmonares Intersticiales/diagnóstico , Pulmón , Sarcoidosis Pulmonar/diagnóstico , Biopsia , Enfermedad de Crohn/diagnóstico , Diagnóstico Diferencial , Femenino , Humanos , Pulmón/diagnóstico por imagen , Pulmón/fisiopatología , Enfermedades Pulmonares Intersticiales/etiología , Enfermedades Pulmonares Intersticiales/patología , Enfermedades Pulmonares Intersticiales/fisiopatología , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pruebas de Función Respiratoria , Sarcoidosis Pulmonar/patología , Sarcoidosis Pulmonar/fisiopatología , Tomografía Computarizada por Rayos XRESUMEN
RATIONALE: The small conducting airways are the major site of airflow obstruction in chronic obstructive pulmonary disease and may precede emphysema development. OBJECTIVES: We hypothesized a novel computed tomography (CT) biomarker of small airway disease predicts FEV1 decline. METHODS: We analyzed 1,508 current and former smokers from COPDGene with linear regression to assess predictors of change in FEV1 (ml/yr) over 5 years. Separate models for subjects without and with airflow obstruction were generated using baseline clinical and physiologic predictors in addition to two novel CT metrics created by parametric response mapping (PRM), a technique pairing inspiratory and expiratory CT images to define emphysema (PRM(emph)) and functional small airways disease (PRM(fSAD)), a measure of nonemphysematous air trapping. MEASUREMENTS AND MAIN RESULTS: Mean (SD) rate of FEV1 decline in ml/yr for GOLD (Global Initiative for Chronic Obstructive Lung Disease) 0-4 was as follows: 41.8 (47.7), 53.8 (57.1), 45.6 (61.1), 31.6 (43.6), and 5.1 (35.8), respectively (trend test for grades 1-4; P < 0.001). In multivariable linear regression, for participants without airflow obstruction, PRM(fSAD) but not PRM(emph) was associated with FEV1 decline (P < 0.001). In GOLD 1-4 participants, both PRM(fSAD) and PRM(emph) were associated with FEV1 decline (P < 0.001 and P = 0.001, respectively). Based on the model, the proportional contribution of the two CT metrics to FEV1 decline, relative to each other, was 87% versus 13% and 68% versus 32% for PRM(fSAD) and PRM(emph) in GOLD 1/2 and 3/4, respectively. CONCLUSIONS: CT-assessed functional small airway disease and emphysema are associated with FEV1 decline, but the association with functional small airway disease has greatest importance in mild-to-moderate stage chronic obstructive pulmonary disease where the rate of FEV1 decline is the greatest. Clinical trial registered with www.clinicaltrials.gov (NCT 00608764).
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Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Sistema Respiratorio/fisiopatología , Femenino , Volumen Espiratorio Forzado/fisiología , Humanos , Pulmón/diagnóstico por imagen , Pulmón/fisiopatología , Masculino , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico por imagen , Sistema Respiratorio/diagnóstico por imagen , Espirometría , Tomografía Computarizada por Rayos XRESUMEN
The pulmonary apical cap (PAC) is a morphologically distinct type of unilateral or bilateral fibroelastotic scar involving the lung apices. Despite being relatively common and having been described more than a hundred years ago, it remains underappreciated as a unique diagnostic entity by clinicians, radiologists, and pathologists alike. Given the centrality of modern chest imaging in the workup of diseases of the lungs, it may be expected that the PAC will be biopsied with increasing frequency. As such, pathologists should be familiar with its presentation, appearance, and differential diagnosis. This article serves as a short overview of PAC and as a practical aid in its diagnosis for surgical pathologists.
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Cicatriz/patología , Enfermedades Pulmonares/diagnóstico , Neoplasias Pulmonares/diagnóstico , Pulmón/patología , Diagnóstico Diferencial , Humanos , Radiografía Torácica , Tomografía Computarizada por Rayos XRESUMEN
Bronchiolitis obliterans is the leading cause of chronic graft failure and long-term mortality in lung transplant recipients. Here, we used a novel murine model to characterize allograft fibrogenesis within a whole-lung microenvironment. Unilateral left lung transplantation was performed in mice across varying degrees of major histocompatibility complex mismatch combinations. B6D2F1/J (a cross between C57BL/6J and DBA/2J) (Haplotype H2b/d) lungs transplanted into DBA/2J (H2d) recipients were identified to show histopathology for bronchiolitis obliterans in all allogeneic grafts. Time course analysis showed an evolution from immune cell infiltration of the bronchioles and vessels at day 14, consistent with acute rejection and lymphocytic bronchitis, to subepithelial and intraluminal fibrotic lesions of bronchiolitis obliterans by day 28. Allografts at day 28 showed a significantly higher hydroxyproline content than the isografts (33.21 ± 1.89 versus 22.36 ± 2.33 µg/mL). At day 40 the hydroxyproline content had increased further (48.91 ± 7.09 µg/mL). Flow cytometric analysis was used to investigate the origin of mesenchymal cells in fibrotic allografts. Collagen I-positive cells (89.43% ± 6.53%) in day 28 allografts were H2Db positive, showing their donor origin. This novel murine model shows consistent and reproducible allograft fibrogenesis in the context of single-lung transplantation and represents a major step forward in investigating mechanisms of chronic graft failure.
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Bronquiolitis Obliterante/patología , Rechazo de Injerto/patología , Trasplante de Pulmón/efectos adversos , Pulmón/patología , Células Madre Mesenquimatosas/patología , Animales , Bronquiolitis Obliterante/etiología , Bronquiolitis Obliterante/inmunología , Modelos Animales de Enfermedad , Rechazo de Injerto/inmunología , Pulmón/inmunología , Linfocitos/inmunología , Linfocitos/patología , Macrófagos/inmunología , Macrófagos/patología , Células Madre Mesenquimatosas/inmunología , RatonesRESUMEN
OBJECTIVE: A panel of immunohistochemical (IHC) stains frequently used to subclassify non-small cell lung cancers (NSCLCs) includes napsin A, TTF-1, CK5/6, p40, and p63. The expression profiles of these stains in neuroendocrine tumors have not been systematically evaluated. METHOD: Sixty-eight resected pulmonary neuroendocrine tumors, including 52 typical carcinoids (TCs), eight atypical carcinoids (ACs), seven small cell carcinomas (SCLCs) and one large cell neuroendocrine carcinoma (LCNEC), were stained for napsin A, TTF-1, p63, p40, and CK5/6. Tumors were scored as positive (>1% tumor cells reactive) or negative, and percentage of reactive tumor cells was recorded. RESULTS: Napsin A, p63, p40, and CK5/6 were consistently negative in neuroendocrine tumors. TTF-1 was positive in 17 of 52 TCs, 4 of 8 ACs, 5 of 7 SCLCs, and 0 of 1 LCNECs. CONCLUSION: Pulmonary neuroendocrine tumors have a distinct but nonspecific profile on IHC panel commonly applied to subclassify NSCLCs. They are napsin A-/p40-/p63-/CK5/6-/TTF-1±. Recognizing this profile may have value in separating neuroendocrine tumors from NSCLCs.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias Pulmonares/metabolismo , Tumores Neuroendocrinos/metabolismo , Ácido Aspártico Endopeptidasas/metabolismo , Proteínas de Unión al ADN/metabolismo , Humanos , Epítopos Inmunodominantes/metabolismo , Inmunohistoquímica , Queratina-5/metabolismo , Queratina-6/metabolismo , Neoplasias Pulmonares/patología , Proteínas de la Membrana/metabolismo , Tumores Neuroendocrinos/patología , Fragmentos de Péptidos/metabolismo , Factores de TranscripciónRESUMEN
Rapid ("warm") autopsies of patients with advanced metastatic cancer provide invaluable insight into the natural history, pathobiology, and morphology of advanced and treatment-resistant tumors. Here, we report a rapid autopsy case of a hereditary leiomyomatosis and renal cell carcinoma (HLRCC) patient with advanced metastatic renal cell carcinoma (RCC)-the first such case described for either a primary renal tumor or HLRCC-related cancer. Mutations in the fumarate hydratase (FH) gene underlie HLRCC, a rare syndrome involving cutaneous and uterine leiomyomata and aggressive kidney tumors. Loss of heterozygosity at the wild-type FH gene locus results in profound cellular metabolic derangement, "pseudohypoxic" upregulation of hypoxia-inducible factor 1α (HIF-1α)-dependent transcription, and aberrant protein succination; these molecular changes drive oncogenesis of kidney tumors in HLRCC patients. The current index patient had a high-grade RCC with classic morphologic features of HLRCC, including large nuclei with prominent eosinophilic nucleoli and perinucleolar clearing. In addition, this patient's RCC demonstrated extensive sarcomatoid and rhabdoid features-morphologies not previously well described in HLRCC-associated kidney tumors. Here, we report the extent of metastatic dissemination and supplement this unique tumor morphology with mitochondrial enzyme histochemistry and extended immunohistochemical analysis. Tumor cells strongly expressed PAX8, vimentin, CD10, and the HIF target GLUT1 and showed increased nuclear p53 accumulation; the expression of other RCC markers was negative. We also detail microscopic tubular epithelial changes in the grossly uninvolved ipsilateral renal parenchyma and demonstrate sporadic, aberrant upregulation of the HIF targets GLUT1 and CAIX in dysplastic peritumoral tubules.
Asunto(s)
Autopsia/métodos , Carcinoma de Células Renales/secundario , Neoplasias Renales/patología , Leiomiomatosis/patología , Neoplasias Cutáneas/patología , Neoplasias Uterinas/patología , Biomarcadores de Tumor/análisis , Femenino , Humanos , Leiomiomatosis/metabolismo , Persona de Mediana Edad , Síndromes Neoplásicos Hereditarios , Neoplasias Cutáneas/metabolismo , Neoplasias Uterinas/metabolismoRESUMEN
⺠Young women with hypercalcemic type small cell ovarian cancer face a poor prognosis. ⺠Tumors respond to multi-agent chemotherapy, although rapid recurrence is typical. ⺠Using updated immunohistochemical staining patterns, this tumor can be identified.
RESUMEN
We use a case-based format to review 4 relatively common, diagnostic challenges in surgical pathology of nonneoplastic lung diseases. All cases are linked to virtual slides so that the reader can participate in a manner that simulates the breakout session held at the 2008 New Frontiers in Pathology course at the University of Michigan, from which, this material was excerpted. Brief clinical histories and a summary of radiologic findings are followed by a description of the pertinent histologic findings and a concise topic review, intended to focus on practical diagnostic considerations. Our goal is that readers gain a greater understanding of those features most helpful in recognizing usual interstitial pneumonia, Langerhans cell histiocytosis, aspiration pneumonia, and Wegener granulomatosis.