Endoscopic follow-up of low-grade precancerous bronchial lesions in high-risk patients: long-term results of the SELEPREBB randomised multicentre trial.

BACKGROUND: 3-9% of low-grade preinvasive bronchial lesions progress to cancer. This study assessed the usefulness of an intensive bronchoscopy surveillance strategy in patients with bronchial lesions up to moderate squamous dysplasia. METHODS: SELEPREBB (ClinicalTrials.gov NCT00213603) was a randomised study conducted in 17 French centres. After baseline lung computed tomography (CT) and autofluorescence bronchoscopy (AFB) to exclude lung cancer and bronchial severe squamous dysplasia or carcinoma in situ (CIS), patients were assigned to standard surveillance (arm A) with CT and AFB at 36 months or to intensive surveillance (arm B) with AFB every 6 months. Further long-term data were obtained with a median follow-up of 4.7 years. RESULTS: 364 patients were randomised (A: 180, B: 184). 27 patients developed invasive lung cancer and two developed persistent CIS during the study, with no difference between arms (OR 0.63, 95% CI 0.20-1.96, p=0.42). Mild or moderate dysplasia at baseline bronchoscopy was a significant lung cancer risk factor both at 3 years (8 of 74 patients, OR 6.9, 95% CI 2.5-18.9, p<0.001) and at maximum follow-up (16 of 74 patients, OR 5.9, 95% CI 2.9-12.0, p<0.001). Smoking cessation was significantly associated with clearance of bronchial dysplasia on follow-up (OR 0.12, 95% CI 0.01-0.66, p=0.005) and with a reduced risk of lung cancer at 5 years (OR 0.15, 95% CI 0.003-0.99, p=0.04). CONCLUSION: Patients with mild or moderate dysplasia are at very high risk for lung cancer at 5 years, with smoking cessation significantly reducing the risk. Whereas intensive bronchoscopy surveillance does not improve patient outcomes, the identification of bronchial dysplasia using initial bronchoscopy maybe useful for risk stratification strategies in lung cancer screening programmes.

Vascular Ehlers-Danlos syndrome (vEDS): CT and histologic findings of pleural and lung parenchymal damage.

OBJECTIVES: To describe CT features of lung involvement in patients with vascular Ehlers-Danlos syndrome (vEDS), a rare genetic condition caused by pathogenic variants within the COL3A1 gene, characterized by recurrent arterial, digestive, and pulmonary events. MATERIAL AND METHODS: All consecutive vEDS patients referred to the national tertiary referral center for vEDS, between 2004 and 2016, were included. Chest CT scans obtained during the initial vascular work-up were reviewed retrospectively by two chest radiologists for lung involvement. Five surgical samples underwent histologic examination. RESULTS: Among 136 enrolled patients (83 women, 53 men; mean age 37 years) with molecularly confirmed vEDS, 24 (17.6%) had a history of respiratory events: 17 with pneumothorax, 4 with hemothorax, and 3 with hemoptysis that required thoracic surgery in 11. CT scans detected lung parenchymal abnormalities in 78 (57.3%) patients: emphysema (mostly centrilobular and paraseptal) in 44 (32.3%), comparable for smokers and non-smokers; clusters of calcified small pulmonary nodules in 9 (6.6%); and cavitated nodules in 4 (2.9%). Histologic examination of surgical samples found arterial abnormalities, emphysema with alveolar ruptures in 3, accompanied by diffuse hemorrhage and increased hemosiderin resorption. CONCLUSION: In vEDS patients, identification of lung parenchymal abnormalities is common on CT. The most frequently observed CT finding was emphysema suggesting alveolar wall rupture which might facilitate the diagnostic screening of the disease in asymptomatic carriers of a genetic COL3A1 gene mutation. The prognostic value and evolution of these parenchymal abnormalities remain to be evaluated. KEY POINTS: • Patients with vEDS can have lung parenchymal changes on top of or next to thoracal vascular abnormalities and that these changes can be present in asymptomatic cases. • The presence of these parenchymal changes is associated with a slightly higher incidence of respiratory events (although not statistically significant). • Identification of the described CT pattern by radiologists and chest physicians may facilitate diagnostic screening.

Comprehensive Molecular and Pathologic Evaluation of Transitional Mesothelioma Assisted by Deep Learning Approach: A Multi-Institutional Study of the International Mesothelioma Panel from the MESOPATH Reference Center.

INTRODUCTION: Histologic subtypes of malignant pleural mesothelioma are a major prognostic indicator and decision denominator for all therapeutic strategies. In an ambiguous case, a rare transitional mesothelioma (TM) pattern may be diagnosed by pathologists either as epithelioid mesothelioma (EM), biphasic mesothelioma (BM), or sarcomatoid mesothelioma (SM). This study aimed to better characterize the TM subtype from a histological, immunohistochemical, and molecular standpoint. Deep learning of pathologic slides was applied to this cohort. METHODS: A random selection of 49 representative digitalized sections from surgical biopsies of TM was reviewed by 16 panelists. We evaluated BAP1 expression and CDKN2A (p16) homozygous deletion. We conducted a comprehensive, integrated, transcriptomic analysis. An unsupervised deep learning algorithm was trained to classify tumors. RESULTS: The 16 panelists recorded 784 diagnoses on the 49 cases. Even though a Kappa value of 0.42 is moderate, the presence of a TM component was diagnosed in 51%. In 49% of the histological evaluation, the reviewers classified the lesion as EM in 53%, SM in 33%, or BM in 14%. Median survival was 6.7 months. Loss of BAP1 observed in 44% was less frequent in TM than in EM and BM. p16 homozygous deletion was higher in TM (73%), followed by BM (63%) and SM (46%). RNA sequencing unsupervised clustering analysis revealed that TM grouped together and were closer to SM than to EM. Deep learning analysis achieved 94% accuracy for TM identification. CONCLUSION: These results revealed that the TM pattern should be classified as non-EM or at minimum as a subgroup of the SM type.

In situ BCL2 expression is an independent prognostic factor in HIV-associated DLBCL, a LYMPHOVIR cohort study.

The prognostic value of cell of origin (COO) classification and BCL2 expression is not well established in diffuse large B-cell lymphoma (DLBCL) patients with human immunodeficiency virus (HIV) infection in the recent era. Phenotypic patterns were determined by immunohistochemistry (IHC) of pathological samples from patients with HIV-associated DLBCL prospectively enrolled in the French AIDS and Viral Hepatitis CO16 Lymphovir cohort between 2008 and 2015. Molecular subgroup classification into germinal centre B-cell (GCB) and non-GCB subtypes was determined using the Hans algorithm. Among 52 samples of systemic DLBCL subjected to centralized pathological analysis, 25 of the 42 tested for BCL2 expression were positive. Samples were further classified into GCB (n = 19) and non-GCB (n = 16) subtypes and 17 remained unclassified. In multivariable analysis, BCL2 expression was an independent pejorative prognostic biomarker [4-year progression-free survival (PFS): 52% for BCL2+ vs. 88% for BCL2- , P = 0·02] and tended to reduce 4-year overall survival (OS) (63% for BCL2+ vs. 88% for BCL2- , P = 0·06). The difference between CGB and non-GCB subtypes on PFS and OS did not reach significance (4-year PFS: 79% for GCB vs. 53% for non-GCB, P = 0·24 and 4-year OS: 78% for GCB vs. 69% for non-GCB, P = 0·34). BCL2 expression determined by IHC is an independent pejorative prognostic biomarker in HIV-associated DLBCL in the recent era. This supports the investigation of new therapeutic strategies in patients with BCL2 expression.

Pulmonary hyalinizing granuloma: a multicenter study of 5 new cases and review of the 135 cases of the literature.

Pulmonary hyalinizing granuloma (PHG) is a rare disease characterized by single or multiple benign lung nodules mimicking lung neoplasma. Histologic analysis reveals homogenous hyaline lamellae, usually surrounded by collection of plasma cells, lymphocytes and histiocytes in a perivascular distribution. The clinical and radiological findings have been described in small series, but the long-term outcomes have rarely been reported. The objectives were to describe the clinical, radiological and outcomes of PHG in new cases and through a literature review. Patients with PHG were found by a multicenter search among French departments of internal medicine, pulmonology and anatomo-pathology. Review of the literature was made through the National Library of Medicine's MEDLINE database using keywords "hyalinizing granuloma." Five news cases and 135 cases of the literature were found. There were 82 men and 57 women, mean age at the diagnosis 44.6 years (15-83). Patients were frequently asymptomatic (n = 39, 27.4 %). The nodule was unique in 37 cases (28.9 %) and multiple in 91 cases (71.1 %). 18FDG PET scan revealed hypermetabolism of the nodule in 9/15 cases (60 %). A systemic disease was associated in 65 cases (mainly mediastinal and retroperitoneal fibrosis, autoimmune, tumoral or infectious disease or thromboembolism). The outcomes were evaluated in 73 patients when follow-up was available: 14 patients had a surgical resection of the nodule. Forty-five patients did not receive any immunosuppressive drug. Among these patients, 2 improved, 29 were stable and 14 worsened. Corticosteroids were used as a monotherapy in 19 patients and led to radiological improvement in 8 cases, stabilization in 8 cases and worsening in 3 cases. Five patients were treated with corticosteroids and at least one immunosuppressive drug and 4 patients improved. PHG is a rare benign disease, mimicking lung neoplasma, frequently associated with systemic diseases.

Semantic Integrative Digital Pathology: Insights into Microsemiological Semantics and Image Analysis Scalability.

Being able to provide a traceable and dynamic second opinion has become an ethical priority for patients and health care professionals in modern computer-aided medicine. In this perspective, a semantic cognitive virtual microscopy approach has been recently initiated, the MICO project, by focusing on cognitive digital pathology. This approach supports the elaboration of pathology-compliant daily protocols dedicated to breast cancer grading, in particular mitotic counts and nuclear atypia. A proof of concept has thus been elaborated, and an extension of these approaches is now underway in a collaborative digital pathology framework, the FlexMIm project. As important milestones on the way to routine digital pathology, a series of pioneer international benchmarking initiatives have been launched for mitosis detection (MITOS), nuclear atypia grading (MITOS-ATYPIA) and glandular structure detection (GlaS), some of the fundamental grading components in diagnosis and prognosis. These initiatives allow envisaging a consolidated validation referential database for digital pathology in the very near future. This reference database will need coordinated efforts from all major teams working in this area worldwide, and it will certainly represent a critical bottleneck for the acceptance of all future imaging modules in clinical practice. In line with recent advances in molecular imaging and genetics, keeping the microscopic modality at the core of future digital systems in pathology is fundamental to insure the acceptance of these new technologies, as well as for a deeper systemic, structured comprehension of the pathologies. After all, at the scale of routine whole-slide imaging (WSI; ∼0.22 µm/pixel), the microscopic image represents a structured 'genomic cluster', enabling a naturally structured support for integrative digital pathology approaches. In order to accelerate and structure the integration of this heterogeneous information, a major effort is and will continue to be devoted to morphological microsemiology (microscopic morphology semantics). Besides insuring the traceability of the results (second opinion) and supporting the orchestration of high-content image analysis modules, the role of semantics will be crucial for the correlation between digital pathology and noninvasive medical imaging modalities. In addition, semantics has an important role in modelling the links between traditional microscopy and recent label-free technologies. The massive amount of visual data is challenging and represents a characteristic intrinsic to digital pathology. The design of an operational integrative microscopy framework needs to focus on scalable multiscale imaging formalism. In this sense, we prospectively consider some of the most recent scalable methodologies adapted to digital pathology as marked point processes for nuclear atypia and point-set mathematical morphology for architecture grading. To orchestrate this scalable framework, semantics-based WSI management (analysis, exploration, indexing, retrieval and report generation support) represents an important means towards approaches to integrating big data into biomedicine. This insight reflects our vision through an instantiation of essential bricks of this type of architecture. The generic approach introduced here is applicable to a number of challenges related to molecular imaging, high-content image management and, more generally, bioinformatics.

Plasmodium falciparum full life cycle and Plasmodium ovale liver stages in humanized mice.

Experimental studies of Plasmodium parasites that infect humans are restricted by their host specificity. Humanized mice offer a means to overcome this and further provide the opportunity to observe the parasites in vivo. Here we improve on previous protocols to achieve efficient double engraftment of TK-NOG mice by human primary hepatocytes and red blood cells. Thus, we obtain the complete hepatic development of P. falciparum, the transition to the erythrocytic stages, their subsequent multiplication, and the appearance of mature gametocytes over an extended period of observation. Furthermore, using sporozoites derived from two P. ovale-infected patients, we show that human hepatocytes engrafted in TK-NOG mice sustain maturation of the liver stages, and the presence of late-developing schizonts indicate the eventual activation of quiescent parasites. Thus, TK-NOG mice are highly suited for in vivo observations on the Plasmodium species of humans.

Comparative analysis of primary tumour and matched metastases in colorectal cancer patients: evaluation of concordance between genomic and transcriptional profiles.

PURPOSE: Focal and temporal tumour heterogeneity can represent a major challenge for biology-guided therapies. This study proposes to investigative molecular discrepancies between primary colorectal cancer (CRC) samples and matched metastases. EXPERIMENTAL DESIGN: Surgical samples from primary and matched metastatic tissues from 13 CRC patients along with their adjacent normal tissue were evaluated. A mutational analysis was performed using a targeted Next Generation Sequencing assay (Foundation Medicine) with a focus on known recurrent somatic mutations as surrogate of key oncogenic events. Gene expression analysis was also performed to investigate transcriptional discrepancies. RESULTS: Among the 26 samples, 191 mutations were identified including mutations in APC (13 pts), TP53 (11 pts), and KRAS (7 pts). Global concordance rate for mutations was 78% between primary and metastatic tumours and raised to 90% for 12 known recurrent mutations in CRC. Differential gene expression analysis revealed a low number of significantly variant transcripts between primary and metastatic tumours once the tissue effect was taken into account. Only two pathways (ST_ADRENERGIC, PID_REELINPATHWAY) were differentially up-regulated in metastases among 17 variant pathways. A common profile in primary and metastatic tumours revealed conserved pathways mostly involved in cell cycle regulation. Only two pathways were significantly down regulated compared to normal control, including regulation of autophagy (KEGG_REGULATION_OF_AUTOPHAGY). CONCLUSION: These results suggest that profiles of primary tumour can identify key alterations present in matched CRC metastases at first metastatic progression. Gene expression analysis identified mainly conserved pathways between primary tumour and matched liver metastases.

Mitosis detection in breast cancer histological images An ICPR 2012 contest.

INTRODUCTION: In the framework of the Cognitive Microscope (MICO) project, we have set up a contest about mitosis detection in images of H and E stained slides of breast cancer for the conference ICPR 2012. Mitotic count is an important parameter for the prognosis of breast cancer. However, mitosis detection in digital histopathology is a challenging problem that needs a deeper study. Indeed, mitosis detection is difficult because mitosis are small objects with a large variety of shapes, and they can thus be easily confused with some other objects or artefacts present in the image. We added a further dimension to the contest by using two different slide scanners having different resolutions and producing red-green-blue (RGB) images, and a multi-spectral microscope producing images in 10 different spectral bands and 17 layers Z-stack. 17 teams participated in the study and the best team achieved a recall rate of 0.7 and precision of 0.89. CONTEXT: Several studies on automatic tools to process digitized slides have been reported focusing mainly on nuclei or tubule detection. Mitosis detection is a challenging problem that has not yet been addressed well in the literature. AIMS: Mitotic count is an important parameter in breast cancer grading as it gives an evaluation of the aggressiveness of the tumor. However, consistency, reproducibility and agreement on mitotic count for the same slide can vary largely among pathologists. An automatic tool for this task may help for reaching a better consistency, and at the same time reducing the burden of this demanding task for the pathologists. SUBJECTS AND METHODS: Professor Frιdιrique Capron team of the pathology department at Pitiι-Salpκtriθre Hospital in Paris, France, has selected a set of five slides of breast cancer. The slides are stained with H and E. They have been scanned by three different equipments: Aperio ScanScope XT slide scanner, Hamamatsu NanoZoomer 2.0-HT slide scanner and 10 bands multispectral microscope. The data set is made up of 50 high power fields (HPF) coming from 5 different slides scanned at ×40 magnification. There are 10 HPFs/slide. The pathologist has annotated all the mitotic cells manually. A HPF has a size of 512 µm × 512 µm (that is an area of 0.262 mm (2) , which is a surface equivalent to that of a microscope field diameter of 0.58 mm. These 50 HPFs contain a total of 326 mitotic cells on images of both scanners, and 322 mitotic cells on the multispectral microscope. RESULTS: Up to 129 teams have registered to the contest. However, only 17 teams submitted their detection of mitotic cells. The performance of the best team is very promising, with F-measure as high as 0.78. However, the database we provided is by far too small for a good assessment of reliability and robustness of the proposed algorithms. CONCLUSIONS: Mitotic count is an important criterion in the grading of many types of cancers, however, very little research has been made on automatic mitotic cell detection, mainly because of a lack of available data. A main objective of this contest was to propose a database of mitotic cells on digitized breast cancer histopathology slides to initiate works on automated mitotic cell detection. In the future, we would like to extend this database to have much more images from different patients and also for different types of cancers. In addition, mitotic cells should be annotated by several pathologists to reflect the partial agreement among them.

Automated mitosis detection using texture, SIFT features and HMAX biologically inspired approach.

CONTEXT: According to Nottingham grading system, mitosis count in breast cancer histopathology is one of three components required for cancer grading and prognosis. Manual counting of mitosis is tedious and subject to considerable inter- and intra-reader variations. AIMS: The aim is to investigate the various texture features and Hierarchical Model and X (HMAX) biologically inspired approach for mitosis detection using machine-learning techniques. MATERIALS AND METHODS: We propose an approach that assists pathologists in automated mitosis detection and counting. The proposed method, which is based on the most favorable texture features combination, examines the separability between different channels of color space. Blue-ratio channel provides more discriminative information for mitosis detection in histopathological images. Co-occurrence features, run-length features, and Scale-invariant feature transform (SIFT) features were extracted and used in the classification of mitosis. Finally, a classification is performed to put the candidate patch either in the mitosis class or in the non-mitosis class. Three different classifiers have been evaluated: Decision tree, linear kernel Support Vector Machine (SVM), and non-linear kernel SVM. We also evaluate the performance of the proposed framework using the modified biologically inspired model of HMAX and compare the results with other feature extraction methods such as dense SIFT. RESULTS: The proposed method has been tested on Mitosis detection in breast cancer histological images (MITOS) dataset provided for an International Conference on Pattern Recognition (ICPR) 2012 contest. The proposed framework achieved 76% recall, 75% precision and 76% F-measure. CONCLUSIONS: Different frameworks for classification have been evaluated for mitosis detection. In future work, instead of regions, we intend to compute features on the results of mitosis contour segmentation and use them to improve detection and classification rate.

Liver biopsy analysis has a low level of performance for diagnosis of intermediate stages of fibrosis.

BACKGROUND & AIMS: There is controversy about the performance of noninvasive tests such as FibroTest in diagnosing intermediate stages of fibrosis. We investigated whether this controversy results from limitations of biopsy analysis for intermediate-stage fibrosis and inappropriate determination of the standard area under the receiver-operator characteristic curve (AUROC). METHODS: To determine whether biopsy has a lower diagnostic performance for fibrosis stage F2 (few septa) vs F1 (fibrosis without septa), compared with its performance for F1 vs F0 or F4 vs F3, we determined the fibrotic areas of large surgical samples collected from 20 consecutive patients with chronic liver disease or normal liver tissue that surrounded tumors. We analyzed digitized images of 27,869 virtual biopsies of increasing length and also analyzed data from 6500 patients with interpretable FibroTest results who also underwent biopsy analysis. RESULTS: The overall performance of biopsy analysis (by Obuchowski measure) increased with biopsy length from 0.885 for 5-mm to 0.912 for 30-mm samples (P < .0001). The performance of biopsy was lower for the diagnosis of F2 vs F1 samples (weighted AUROC [wAUROC] = 0.505) than for F1 vs F0 (wAUROC = 0.773; 53% difference; P < .0001) or F4 vs F3 (wAUROC = 0.700; 39% difference; P < .0001), even when 30-mm biopsy samples were used. The performance of FibroTest was also lower for the diagnosis of F2 vs F1 samples (wAUROC = 0.512) than for F1 vs F0 samples (wAUROC = 0.626; 22% difference; P < .0001) or F4 vs F3 (wAUROC = 0.628; 23% difference; P < .0001). However, the FibroTest had smaller percentage differences among wAUROC values than biopsy. CONCLUSIONS: Biopsy has a low level of diagnostic performance for fibrosis stages F2 and F1. The recommendation for biopsy analysis, instead of a validated biomarker panel such as FibroTest, for the diagnosis of intermediate stages of fibrosis is therefore misleading.

Mandibular cuniculatum carcinoma: apropos of 3 cases and literature review.

BACKGROUND: Cuniculatum carcinoma is a well-differentiated form of squamous cell carcinoma that shares histologic characteristics with papillary squamous cell carcinoma and verrucous carcinoma. Cuniculatum carcinoma usually occurs on the plantar region, and only 16 cases involving the oral cavity have been described in the literature. METHODS: The authors have reported 3 cases of mandibular cuniculatum carcinoma. All of the patients were in a great deal of pain. Histologic diagnosis was difficult due to the presence of few cellular atypies. Clinical criteria, osseous lysis, and the coexistence of multiple intraosseous well-differentiated, hyperkeratotic papillomatous lesions with few cellular atypies sign the diagnosis. RESULTS: No local recurrence has been reported after treatment with radical surgery alone. CONCLUSION: The diagnosis is often delayed. Although cuniculatum carcinoma displays aggressive behavior locally, lymph node infiltration and metastasis are rare. The therapy of choice is surgical removal with free margins, after which the prognosis is excellent.

Clinical significance of intratumoral CD8+ regulatory T cells in prostate carcinoma.

OBJECTIVE: To explore Foxp3, a member of the forkhead box family of transcription factors, which is a major gene for regulatory T (Treg) cell development of CD4+CD25+ or CD8+CD25+ phenotype. STUDY DESIGN: We constructed tissue microarrays from 82 patients after radical prostatectomy (RP). Three cores of neoplastic tissue and 3 from normal/inflammatory tissue were taken. Sections were immunostained for Foxp3 and CD8. Numbers of Foxp3 and CD8 positive cells were counted. Serum prostate-specific antigen levels before and after RP, Gleason score (GS), surgical margin status and pathologic stage were available. RESULTS: Among 82 patients aged 55-76 years (mean 66.1, SD +/- 5.8), 64 (78%) were staged pT2 and 18 (22%) pT3. Twenty-nine patients (35%) had positive margins, 24 (29%) increasing prostate-specific antigen levels (biochemical relapse) 6 months to 2 years (SD +/- 24.8 months) after RP. GS was distributed as follows: 41 (50%) patients with GS 6 (3+3), 34 (41%) with GS 7 [19 (3+4) and 15 (4+3)], 7 (9%) with GS > or = 8. In tumor cores, Foxp3 and CD8 counts correlated (p = 0.012). Foxp3 counts also correlated with biochemical relapse (p = 0.04). CONCLUSION: Treg cells were more common in cancer than in benign prostatic tissue. There are links between Foxp3 and CD8+ cells and between Foxp3 positive cells and biochemical relapse. Patients with prostate cancer show an immunosuppressive regulatory profile, including nonresponsive Tregs. It would be important to find mechanisms to target these cells for successful immunotherapy.

Pulmonary involvement in Erdheim-Chester disease: a single-center study of thirty-four patients and a review of the literature.

OBJECTIVE: Erdheim-Chester disease (ECD) is a rare form of non-Langerhans' cell histiocytosis that may present with pulmonary involvement. We undertook the current study to evaluate the characteristic features of pulmonary involvement in ECD, in the largest single-center series of patients reported to date. METHODS: We performed a retrospective study of the characteristics of 34 consecutive patients with biopsy-proven ECD who were referred to the internal medicine department of Pitié-Salpêtrière Hospital between 1981 and November 2008. RESULTS: Data were obtained from 23 men and 11 women. The median age at the time of diagnosis was 53.7 years (range 16-73 years), and the median followup was 3.5 years (1.4-5.3 years). Eight patients (24%) had pulmonary symptoms. High-resolution computed tomography (HRCT) scans of the chest revealed involvement of lung parenchyma in 18 patients (53%) and of the pleura in 14 patients (41%). Bronchoalveolar lavage fluid analysis revealed the presence of an opalescent aspirate in all the patients studied. Treatment with corticosteroids and/or interferon-α (IFNα) resulted in a marked improvement of the pulmonary lesions in only a single patient. Comparison of the survival between patients with and those without pulmonary involvement yielded no significant difference between the groups (P = 0.82). CONCLUSION: Pulmonary involvement in ECD has been overlooked in previous studies. HRCT reveals typical lesions in most patients. There is no clear response of these lesions to corticosteroids and IFNα. The overall prognosis of the disease is poor, but pulmonary involvement does not appear to be a major prognostic factor in ECD.