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Abstract: We report the case of an 18-month-old boy with a large heterogeneous and lobulated soft-tissue mass, filling completely the right nasal cavity and anterior ethmoid, displacing the nasal septum, eroding the lamina papyracea, compressing the orbit and extending to the endocranium. There were multiple intralesional foci of calcification. The tumor was completely removed via an endonasal endoscopic approach. The definitive histopathologic diagnosis was that of a nasal chondromesenchymal hamartoma (NCMH). This is an exceedingly rare benign tumor of the upper respiratory tract that shares similarities to the mesenchymal hamartoma arising from the chest wall in neonates. Moreover as some NCMHs are associated with a “pleuropulmonary blastoma”, they can be part of the heredofamilial disease complex associated with PPB and linked to mutations of gene DICER1. [Copyright &y& Elsevier]

Clin Microbiol Infect 2010; 16: 671–675 The present study aimed to validate ThermoFisher’s (Thermo Fisher Scientific, Runcorn, Cheshire, UK) Papspin (PS) for human papillomavirus (HPV) testing by in-house PCR and by the Hybrid Capture II (HC2) assay and to compare the results with those obtained using Specimen Transport Medium (STM) (Digene Diagnostics, Gaithersburg, MD, USA). Forty-five patients underwent conization for known lesions ranging from atypical squamous cells of undetermined significance (ASC-US) with high-risk HPV (hr-HPV) to high-grade squamous intraepithelial lesion (H-SIL/CIN2+) or adenocarcinoma. Two negative controls were included: one patient with post-menopausal bleeding and another from whom an inflammatory cervical sample was taken without conization. Prior to conization, a gynaecologist collected two cervical samples, fixed in PS or STM, from each patient. All but four cases were tested for panHPV (GP5+/GP6+) and specific hr-HPV subtypes (HPV16, 18, 31,33) by PCR using both media and all were processed for HC2. This study demonstrates that both HPV detection techniques work with PS, showing a specificity of 78.3% for HC2 and 92.8% for PCR compared to 83.8% for HC2 and 92% for PCR using STM. The efficacy of detecting HPV in PS-preserved H-SIL/CIN2+ was very high (96% for PCR using PS and 86% for HC2 using PS), which was in the same range as for PCR using STM, and which was only slightly lower than for HC2 using STM (96% and 89%, respectively). The differences were not statistically significant. It is concluded that ThermoFisher’s PS is a valid liquid-based cytology medium for cervical samples, convenient for HPV testing by PCR with GP5+/GP6+ primers and by the HC2 assay. [ABSTRACT FROM AUTHOR]

Post-infectious bronchiolitis obliterans (PIBO) forms a chronic obstructive lung disease in children following a severe viral respiratory infection. Subsequent dysanaptic lung growth, with differential development of the alveolar compartment over the airway compartment, was clinically described, but remains elusive. We therefore performed a detailed 3D airway characterization in PIBO compared to bronchiolitis obliterans syndrome (BOS) after lung transplantation and discarded donor lungs. Explant lungs from matched adult patients who underwent lung transplantation for end-stage PIBO (n=5), redo lung transplantation patients with end-stage BOS (n=5), and discarded donor lungs (n=5) were included. Lungs were air-inflated and frozen in fumes of liquid nitrogen. Ex vivo computed tomography (CT) scans (resolution 700 µm) were obtained and used for radiologic scoring and semi-automated 3D airway segmentation. Next, frozen lungs were sampled on matched locations (n=4/lung) and scanned with microCT (resolution 10 µm). Radiologic scoring indicated more airway wall thickening (p=0.079), bronchial dilatation (p=0.087), and pleural thickening (p=0.071) in PIBO vs BOS. The number of airways per generation was similar between groups (p=0.53), but airway diameters were increased in PIBO (generation 6-11) and in BOS lungs (generation 7-10) compared to controls, without differences between PIBO and BOS. Significantly more airways ended in BO lesions in BOS vs PIBO (p=0.016, mean 25.60% vs 12.60%), although the size of the BO lesions was increased in PIBO vs BOS (p=0.032, median 27.23mm³ vs 5.01mm³). Subsequent micro CT assessment revealed a significant lower number of terminal bronchioles (TB) in PIBO (p=0.0009, PIBO: mean 3131 TB/lung, BOS: 8360 TB/lung, controls: 10342 TB/lung), although diameters of TB were similar across groups (p=0.37). In addition, alveolar spaces tended to be larger in PIBO (p=0.070). 3D micro CT analysis confirmed that in BOS, BO lesions are only segmental with preserved TBs, while in PIBO, the airway is completely lost following the obstruction. PIBO lungs displayed a more than two-fold decrease in TB compared to BOS, with fewer but larger BO lesions and non-reopening of airways distal from BO. Our findings provide potential pathophysiologic evidence of dysanaptic lung growth in PIBO. [ABSTRACT FROM AUTHOR]

Donor organ shortage, in combination with a 70% decline rate of offered donor lungs, results in significant wait list mortality and time with poor quality of life. Assessing donor lungs for transplant suitability is based on donors' history, gas exchange, chest X-ray, bronchoscopy, and in situ visual inspection; but donor lung acceptance remains subjective. We performed an in depth histopathologic and radiologic assessment of retrieved but unused donor lungs. We assessed 62 donor lungs not used for transplantation for various reasons between 2010 and 2019. These lungs were air-inflated, frozen, scanned with computed tomography, systematically sampled on 4 different locations, assessed macroscopically and microscopically by two experienced lung pathologists and by an experienced thoracic radiologist, all blinded for the reason of decline. Reasons for non-use are summarized in the figure. Thirty-nine (63%) lungs were not used for allograft-related reasons. In 13/39 (33%) lungs, the reason for decline could not be confirmed by histologic assessment (emboli, n=7; pneumonia, n=3; contusion, n=2; emphysema, n=1), in an additional 8/39 (21%) lungs, histologic abnormalities were only considered focal and mild (emphysema, n=5; pneumonia, n=3). In 16/39 (41%) lungs, radiology could not confirm the reason for decline. Twenty-three (37%) of 62 unused donor lungs were not transplanted due to extra pulmonary causes, of which 3 (13%) lungs displayed severe histologic abnormalities (pneumonia, n=2; emphysema, n=1), in addition to mild emphysema in 9 (39%) lungs and mild bronchopneumonia in 1 lung (4%). Radiology revealed ground-glass opacities in 8/23 (35%) and emphysema in 4/23 (17%) of these donor lungs. Histologic and radiologic assessment of unused donor lungs revealed substantial discrepancy with the clinical reason for decline. Prior chest CT imaging and frozen sections in selected cases might contribute to adequate donor assessment and augment current yield of donor lungs. [ABSTRACT FROM AUTHOR]

Abstract: Bacillary angiomatosis is an infection caused by Bartonella, which has first been described in human immunodeficiency virus (HIV)–infected patients. We report an unusually located lesion, in a totally asymptomatic kidney transplant recipient. The diagnosis was strongly suggested based on the iconography and our histological analysis, but was not confirmed using polymerase chain reaction (PCR) and immunohistochemical studies. We illustrate our difficult way to the diagnosis as well as the course of the disease and our therapeutic strategy. [Copyright &y& Elsevier]

• Discordant ALK immunohistochemistry positive (IHC) FISH negative NSCLC occurs at low frequency. • Not all locally performed ALK IHC and FISH test were centrally confirmed. • Prognosis of concordant ALK IHC and FISH positive NSCLC is similar as literature. • Prognosis of validated discordant ALK IHC positive FISH negative NSCLC is significantly lower. • In NSCLC a positive ALK IHC screentest should be followed by ALK FISH. Metastasized non-small cell lung cancer (NSCLC) with an anaplastic lymphoma kinase (ALK) rearrangement is usually sensitive to a range of ALK-tyrosine kinase inhibitors. ALK-positive NSCLC have been identified in pivotal phase III trials with fluorescence in situ hybridization (ALK FISH+). These tumors are also expressing the fusion product (ALK immunohistochemistry (IHC)+). However, discrepant cases occur, including ALK IHC + FISH-. The aim of this study was to collect ALK IHC + cases and compare within this group response to crizotinib treatment of ALK FISH + cases with ALK FISH- cases. In this European prospective multicenter research study patients with Stage IV ALK IHC + NSCLC treated with crizotinib were enrolled. Tumor slides were validated centrally for ALK IHC and ALK FISH. Registration of 3523 ALK IHC tests revealed a prevalence of 2.7% (n = 94) ALK IHC + cases. Local ALK FISH analysis resulted in 48 concordant (ALK IHC+/FISH+) and 16 discordant (ALK IHC+/FISH-) cases. Central validation revealed 37 concordant and 7 discordant cases, 5 of which had follow-up. Validation was hampered by limited amount of tissue in biopsy samples. The PFS at 1 year for ALK concordant and discordant was 58% and 20%, respectively (HR = 2.4; 95% CI: 0.78–7.3; p = 0.11). Overall survival was significantly better for concordant cases than discordant cases after central validation (HR=4.5; 95% CI= 1.2–15.9; p=0.010. ALK IHC + FISH- NSCLC is infrequent and associated with a worse outcome on personalized treatment. A suitable predictive testing strategy may be to screen first with IHC and then confirm with FISH instead of considering ALK IHC equivalent to ALK FISH according to the current guidelines. [ABSTRACT FROM AUTHOR]

We report a case of crizotinib effectiveness in a heavily pretreated patient with a metastatic NSCLC initially considered IHC-positive and FISH-negative for ALK rearrangement. After repeated analyses of tumor samples, borderline ALK FISH-positivity (18.5% positive cells) was demonstrated. [ABSTRACT FROM AUTHOR]

Donor-transmitted vascular tumors are a rare complication after lung transplantation. A 35-year-old woman underwent bilateral lung transplantation for primary ciliary dyskinesia. Three years post-transplant, a nodule in the right upper lung lobe was detected on routine computer tomography. Wedge resection showed a hemangioma. One year later, two new lung nodules, as well as two liver lesions appeared, and vascular lesions without signs of malignancy were diagnosed on laparoscopic liver biopsies. After switching from tacrolimus to sirolimus, the volume of the lesions significantly decreased. However, two years later, mixed solid tissue lesions developed in both ovaries, while the lung and liver lesions gradually increased in volume again. Histological examination after bilateral salpingectomy was compatible with bilateral angiosarcoma. Tumor analysis by haplotyping and human leukocyte antigen typing showed mixed donor-chimerism, proving that the tumoral lesions in the lungs and ovaries were of donor origin. In retrospect, the donor became brain death following brain surgery complications for a previously biopsy-proven cerebral hemangioma, which is believed to have been a precursor lesion of this vascular malignancy. Our case highlights a unique course of donor-related angiosarcoma, finally diagnosed 6 years after lung transplantation. Donor-origin of tumors detected in solid organ recipients should always be suspected in case of uncommon disease course or histology, and proper tissue-based diagnosis using sensitive techniques should be pursued, given the possible implications for treatment and outcome of other organ recipients in case of multi-organ donation. [ABSTRACT FROM AUTHOR]

Connective tissue growth factor (CTGF) is an important mediator in several fibrotic diseases, including lung fibrosis. We investigated CTGF expression in chronic lung allograft dysfunction (CLAD) and pulmonary graft-versus-host disease (GVHD) by analyzing CTGF expression in broncho-alveolar lavage (BAL) fluid, plasma and lung tissue. Sixty matched lung transplant patients were included (stable, n=20; bronchiolitis obliterans syndrome (BOS), n=20, restrictive allograft syndrome (RAS), n=20). CTGF expression was analyzed in BAL 3m post-transplant, 1y post-transplant, and at CLAD diagnosis or 2y post-transplant for stable patients. Explant lung tissue of CLAD (BOS, n=20; RAS, n=20), pulmonary GHVD (n=9), and discarded donor lungs (n=20) was immunohistochemically stained for CTGF. BAL CTGF protein expression was significantly higher at 3m post-transplant in patients who later developed RAS compared to stable or BOS patients (ANOVA p=0.028); while CTGF expression was similar at 1y post-transplant (ANOVA p=0.20). At CLAD diagnosis, CTGF expression was significantly increased in RAS compared to stable (p=0.0007) and BOS (p=0.042). Serial analysis revealed no difference in CTGF values between time points for stable and BOS patients (ANOVA p=0.84, p=0.92), whereas CTGF levels were significantly higher in RAS at CLAD diagnosis compared to 1y post-transplant (ANOVA p=0.029). CTGF plasma values were similar between BOS, RAS, and stable (ANOVA p=0.74). Immunohistochemistry revealed a higher percentage and intensity of CTGF positive respiratory epithelial cells in BOS and RAS lungs compared to controls (ANOVA p<0.0001), without significant difference between BOS and RAS (p=0.47). There was consistent strong CTGF positivity in BO lesions. CTGF expression in endothelial cells was significantly higher in BOS and RAS compared to controls (p=0.011 and p=0.0005). Fibroblasts in fibrotic regions of RAS were strongly CTGF positive. Pulmonary GVHD displayed similar CTGF staining as in CLAD. Higher CTGF expression is present in BAL from RAS patients at CLAD diagnosis. Lung tissue CTGF expression is increased in end-stage RAS, BOS and pulmonary GVHD. Our results suggest a potential role for CTGF in CLAD, especially RAS, and pulmonary GVHD, which warrants further investigation of CTGF and its potential therapeutic modulation in these conditions. [ABSTRACT FROM AUTHOR]

Background To investigate the safety and activity of cetuximab in the pre-operative treatment of squamous cell carcinoma of the head and neck (SCCHN). Patients and methods Cetuximab was administered for 2 weeks before surgery to 33 treatment-naïve patients selected for primary surgical treatment. Tumour biopsies, 2-[fluorine-18]-fluoro-2-deoxy-d-glucose positron emission tomography (18FDG-PET) and imaging were carried out at baseline and before surgery. The primary aim of the study was safety and the secondary aims included metabolical, radiological and pathological tumour response. Five untreated patients were included as controls. Results Cetuximab given 24 h before surgery was safe. Ninety percent of patients had 18FDG-PET partial response (EORTC guideline) in the cetuximab group versus 0% in the control group. Delta maximal standardized uptake values (ΔSUVmax) were correlated with tumour cellularity on the surgical specimens (P < 0.0001). For patients with ΔSUVmax less than −25% or less than −50%, Ki67 was significantly decreased by cetuximab (P = 0.01 and 0.003). Cetuximab induced down-regulation of pEGFR (P = 0.0004) and pERK (P = 0.003). Conclusions Short-course pre-operative administration of cetuximab is safe and shows a high rate of 18FDG-PET response. 18FDG-PET response was correlated with residual tumour cellularity suggesting that 18FDG-PET deserves further investigation as a potential early marker of cetuximab activity in SCCHN. [ABSTRACT FROM PUBLISHER]

Purpose Chronic pulmonary graft versus host disease (cpGvHD) is a diverse and underestimated complication following allogenic hematopoietic stem cell transplantation (alloHCT). We aimed to compare the airway architecture with chronic lung allograft dysfunction (CLAD) after lung transplantation (LTx). Methods Inflated explant lungs from cpGvHD patients, retrieved at lung transplantation, were compared to lungs with CLAD following LTx and unused donor lungs as controls, matched according to age and gender, using a combination of CT, whole lung microCT (80µm resolution), tissue microCT (10µm resolution) and histopathology (n=6 per group), aiming to quantify histopathologic findings in (small) airways. Results Following alloHCT, 3 patients presented as BOS and 3 patients showed interstitial changes and restriction. CT analysis demonstrated a strong similarity between BOS after LTx and post- alloHCT, evidenced by a similar airway count compared to controls but severe (>50%) airway obstruction from generation 7, with whole lung microCT demonstrating that 70.8% of the airways ended in obstruction (figure). Further analysis indicated that bronchioles either collapsed or accumulated matrix along a segment of the airway (figure). In patients with restriction and interstitial changes following alloHCT, the degree of airway obstruction was lower compared to BOS post-alloHCT, but similar to RAS post-LTx, showing a lower proportion of airway obstruction (±35%), decreased number of terminal bronchioles per lung (p<0.01) and parenchymal fibrosis (p<0.01) as evidenced by microCT analysis. Conclusion We observed similarities in airway pathology in chronic pulmonary GvHD and CLAD following LTx, suggesting similar pathophysiological mechanisms. [ABSTRACT FROM AUTHOR]

Purpose Bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS), have been identified as main phenotypes of chronic lung allograft dysfunction (CLAD), however patients can change phenotype. We aimed to describe incidence, prognosis, radiology, pulmonary function and pathology in this mixed group of CLAD. Methods We retrospectively assessed the chest CT-scans of all double lung patients transplanted between 2001 and 2015 with a FEV1 decline >20% of baseline. The diagnosis of RAS was made using a decline in TLC>10% compared to baseline or a decline in FVC>20% compared to baseline. A mixed group of CLAD was defined as patients developing a TLC or FVC decline with persistent CT opacities after initial CLAD diagnosis (without TLC or FVC drop) or vice versa. Results 44% of the patients developed CLAD (268/608) of which 77 developed persistent CT opacities (29%). 45 patients were immediately diagnosed with RAS. We found twenty-seven patients with a mixed phenotype of CLAD (25 BOS to RAS, 2 RAS to BOS). In 5 patients persistent pleuroparenchymal opacities were found without an additional decrease in FVC or TLC. The median time between CLAD and mixed diagnosis was 2Y (IQR 0.9-4.8Y). Median survival after CLAD diagnosis was longer in the mixed group compared to the RAS group (4.3Y vs 1.17, p=0.0052), however survival after the appearance of opacities was similar in both groups (p=0.39). We found significantly more emphysema patients in the mixed group (p=0.0062), with a lower FEV1 (p<0.0001) and lower FEV1/FVC (p=0.0002) at diagnosis. In the mixed group, TLC was decreased by 10% in all patients, while the FVC was only decreased in a minority of the patients (36%). Radiology at diagnosis in the mixed group showed a significant apical predominance of the opacities, whereas there was no specific preponderance of CT opacities in the RAS group (p=0.0029). Pathology of explant specimens at autopsy or redo-transplantation showed a predominant pattern of organising pneumonia in the RAS group (55% vs 22%, p=0.13) and pleuroparenchymal fibro-elastosis in the mixed group (67% vs 40%; p=0.25). Conclusion We demonstrated that 35% of patients showed a mixed phenotype of CLAD, which showed difference in survival, demographics, pulmonary function, radiology and pathology compared to RAS patients. [ABSTRACT FROM AUTHOR]

Purpose Acute fibrinous and organizing pneumonia (AFOP) after lung transplantation has recently gained attention as it may result in a rapid decline in respiratory function and death; or chronic lung allograft dysfunction (CLAD) in patients surviving the acute onset. We investigated the effect of fibrin deposition and organizing pneumonia (OP) in transbronchial biopsies (TBB) from lung transplant patients on graft survival and CLAD-free survival. Methods We reviewed all pathology reports of TBB obtained from 468 patients who underwent lung transplantation in the University Hospital Leuven between 2011 and 2017 (follow-up until 9/2018). The presence of intra-alveolar fibrin deposition or OP was assessed and defined as early (< 3 months) or late (> 3 months). CLAD was defined as a persistent FEV1 decline (<80%); restrictive allograft syndrome (RAS) was defined by an additional >10% decline in total lung capacity and the presence of persistent radiological opacities. Results The presence of early and late fibrin deposition or OP was detected in 23 (5%) and 28 (6%) patients, respectively. CLAD was diagnosed in 107 (22.9%) of 468 patients (median time to CLAD = 2.90y, IQR [1.41-4.78]), in 4 of 23 patients (17.4%) with early fibrin or OP (1 RAS +), and in 16 of 28 patients (57.1%) with late fibrin or OP (12 RAS +). CLAD-free survival was significantly lower in patients with late fibrin or OP (p<0.0001, median survival 2.64y) compared to patients without or with early fibrin or OP (median survival >7.68y and >7.64y, respectively). The presence of late fibrin or OP significantly increased the risk of later RAS (OR: 13.31; CI [3.871 - 40.2], p<0.0001), whereas early fibrin or OP showed no correlation with RAS (p=0.57). Similarly, graft survival was significantly lower in patients with late fibrin or OP (p=0.0008, median survival 4.46y) compared to patients without or with early fibrin or OP (median survival >7.81y and >7.77y, respectively). Patients with late fibrin or OP mostly died from CLAD (n=10, 9 RAS +), humoral rejection (n=2), sepsis (n=1), or tuberculosis (n=1). Conclusion The pathologist should actively search for fibrin and OP in TBB, as it is associated with worse prognosis and a high risk of subsequent CLAD development, specifically RAS. This indicates that the presence of late fibrin and OP in TBB could be an early pathologic manifestation of later RAS development. [ABSTRACT FROM AUTHOR]