Elaine Borg

Inflammatory myofibroblastic tumour of the lung: a reactive lesion or a true neoplasm?

Inflammatory myofibroblastic tumour (IMT) of the lung represents an extremely rare type of inflammatory pseudo tumor that appears most commonly in children and young individuals. There has been an ongoing controversy whether an IMT is a reactive lesion or a true neoplasm making the further management extremely challenging. Purpose of the paper is through a literature review to highlight the existence of this rare tumour along with its key features and the management options available.

Mucins MUC5B and MUC5AC in Distal Airways and Honeycomb Spaces: Comparison among Idiopathic Pulmonary Fibrosis/Usual Interstitial Pneumonia, Fibrotic Nonspecific Interstitial Pneumonitis, and Control Lungs

Although the pathogenesis of idiopathic pulmonary fibrosis (IPF) remains elusive (1), one of the most intriguing aspects concerns the possible role of mucins. A strong association has been reported between the promoter polymorphism rs35705950 of MUC5B and the occurrence of familial/sporadic IPF (2–10), as well as with a more benign disease course (10, 11). Overexpression of MUC5B and of the other main airway mucin, MUC5AC, has been described in IPF lungs (12, 13), but the level of expression in other types of pulmonary fibrosis is unknown. In this study, we compare MUC5B and MUC5AC expression among IPF, idiopathic nonspecific interstitial pneumonitis (i-NSIP), systemic sclerosis–associated NSIP (SSc-NSIP), and control lungs. Some of the results of this study have been previously reported in the form of an abstract (14). Surgical lung biopsies from 23 patients with IPF/usual interstitial pneumonia (UIP) (17 men; mean6 SD age, 596 10 yr; 16 ever-smokers), 18 with i-NSIP (10 men; mean, age 466 23 yr; 11 ever-smokers), and 15 with SSc-NSIP (4 men; mean age, 526 11 yr; 11 ever-smokers) and normal lung tissue peripheral to resected cancer from 10 smoker and 10 nonsmoker control subjects (11 men; mean age, 686 14 yr) were selected from the Royal Brompton Hospital pathology archive with ethical approval. No significant differences in FVC, diffusing capacity of the lung for carbon monoxide (DLCO), or composite physiologic index (15) were observed between the different fibrotic patterns with the exception of patients with SSc-NSIP, characterized by a significantly higher DLCO (FVC, 796 22, 796 15, and 786 26% of the predicted value, respectively, in IPF, SSc-NSIP, and i-NSIP; DLCO, 516 9, 586 8, and 486 15% of the predicted value; composite physiologic index, 416 10, 386 7, 476 14). Sequential sections were immunolabeled with MUC5Band MUC5ACspecific antibodies (MUC5AC, Clone 45M1; Biocare Ltd., Concord, CA; and MUC5B, clone sc-20119, Santa Cruz Biotechnology, Dallas, TX; 1:100 dilution for both). Distal airways were defined as airways with no cartilage support or glandular elements, surrounded by smooth muscle bands and characterized by an undulating epithelium. Honeycomb cysts were defined as mucuscontaining areas with a less-wrinkled epithelium compared with the distal airways and surrounded by fibrosis (Figure 1). In each biopsy, three distal airways, and in the case of UIP biopsies, three honeycomb cysts, were evaluated. In each area, quantification of the proportion of MUC5Band MUC5AC-positive cells, respectively, was evaluated in six randomly selected fields, each containing 100 airway (or honeycomb cyst, as appropriate) epithelial cells, by an observer blinded to clinical details (C.C.). Positive cells were defined as brown-stained elements, a sign of the antibody reaction with MUC5B or MUC5AC. Preliminary experiments showed that this sample size minimized the coefficient of variation and that the manual readings did correlate well with image analysis (ImageJ Threshold Color plugin), with absolute intraclass correlation coefficients of 0.81 (95% confidence interval, 0.71–0.87) for MUC5AC and 0.72 (95% confidence interval, 0.57–0.81) for MUC5B. To compare manual counts of MUC5B and MUC5AC staining across patterns, multilevel mixed-effects linear regression was performed, using a model in which patients were analyzed as random effect variables, with airways (or honeycomb cysts) and fields nested into patients (Stata 12, College Station, TX). In IPF/UIP distal airways, the proportion of MUC5B cells was more than twofold higher compared with control, i-NSIP, and SSc-NSIP distal airways (P, 0.0001 for all comparisons), even after adjustment for age, sex, and smoking status on multivariate analysis, whereas the proportion of MUC5B cells in honeycomb cysts was similar to control airways (Table 1 and Figure 1). No significant differences were observed in MUC5B expression between distal airways of SSc-NSIP, i-NSIP, and controls. In contrast, the proportion of MUC5AC epithelial cells in IPF/UIP distal airways was similar to control biopsies, whereas both i-NSIP and SSc-NSIP distal airways were characterized by significantly lower percentages of MUC5ACpositive cells (P, 0.001 vs. controls and UIP), even after adjustment for age, sex, and smoking history. In IPF/UIP honeycomb cysts, the proportion of MUC5AC-positive cells was significantly lower than in distal airways of control biopsies (P = 0.004). The higher expression of MUC5B in IPF/UIP distal airways when compared with control lungs is in keeping with the findings of Seibold and colleagues (12). However, we did not observe increased expression of MUC5AC in IPF/UIP distal airways compared with controls as described by Seibold and colleagues, a discrepancy that could at least partially be related to differing staining techniques. The relative sensitivity of immunofluorescence, used by Seibold and colleagues, and immunoperoxidase, used in this study, in analyzing mucin staining in formalin-fixed paraffin-embedded lung biopsies is not known, but it may be that sensitivity differs between the two techniques. In summary, we report that MUC5B overexpression appears to be specific to IPF/UIP, with twice the number of MUC5B cells seen in IPF/UIP distal airways compared with idiopathic and SScassociated fibrotic NSIP patterns. Further, the distal airways, rather than honeycomb cysts, appear to be the primary site of MUC5B overexpression in IPF lungs. Although we did not assess whether this was related to the MUC5B variant rs35705950, an association between the single-nucleotide polymorphism and overexpression of MUC5B in the distal airways, but not in honeycomb cysts of IPF lungs, was reported by Nakano and colleagues (16), This research project was supported by the European Respiratory Society, with a short-term fellowship grant awarded to C.C., and by the National Institute of Health Respiratory Disease Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust.

Sclerosing hemangioma of the lung showing strong FDG avidity on PET scan: Case report and review of the current literature.

Sclerosing Hemangioma is a rare lung tumor with polymorphic histologic features that usually occurs in middle aged women. Based on many immunohistochemical and ultrastructural studies, it is most probably derived from undifferentiated respiratory epithelial cells. Symptoms are usually due to enlargement of the tumor and compression of the surrounding tissues. Occurrence of multiple lesions or metastasis is extremely rare although some authors consider sclerosing hemangioma as a potentially low grade malignancy tumor. It usually presents with low to moderate uptake on FDG PET imaging. We present a case of sclerosing hemangioma with strong FDG avidity on PET scan in a 41 year old lady with history of haemoptysis. A full review of the literature on this topic was performed.

Mediastinal hemangioendothelioma: Case report and review of the literature

Background Epithelioid haemangioendothelioma (EHE) is a rare low-grade vascular neoplasm that can arise in the lung, liver, soft tissues or, less commonly, bone. Due to its low prevalence of less than one in a million and its non-specific clinical features, EHE is often misdiagnosed and managed inappropriately. Here we discuss the case of a 58 year-old gentleman with mediastinal EHE and review existing literature on pulmonary EHE (PEH). Case history A 58 year-old gentleman presented to our outpatient Clinic with chest discomfort and palpitations. A whole-body FDG-CT-PET showed an FDG-avid single 6.3cm nodule in the superior anterior mediastinum which was fully excised by robotic approach. Histology showed a nodular structure with clusters of epithelioid and spindled cells with a low proliferative index and mitotic count, suspended in a sclerotic stroma. Immunohistochemistry staining was positive for CD3 and CD34, confirming endothelial lineage, and SMA, identifying smooth muscle clusters. Discussion PEH typically presents in young Caucasian women, either incidentally as multiple small pulmonary nodules on CT or with respiratory symptoms that include cough, dyspnoea, chest pain and occasionally pleural effusions. Aetiology and prognosis remain unclear, although indicators of poor prognosis include the presence of respiratory symptoms, male gender, older age and multi-organ disease. Diagnosis is difficult and PEH is often misidentified as chronic granulomatous disease, amyloidosis or other malignancy of the lung. Histological features suggestive of PEH include nodules of hypocellular sclerotic stroma containing spindle-shaped tumour cells with abundant eosinophilic cytoplasm, vacuoles containing erythrocytes and low mitotic counts. CD31, CD34 and Fli-1 positive immunohistochemistry is strongly indicative of epithelioid lineage. There is no standard treatment for PEH but curative resection is the preferred treatment option where possible, with chemotherapy being used as adjuvant treatment or in widespread inoperable disease. Conclusion This case report outlines the clinicopathological features that are characteristic of EHE with the hope of facilitating correct and early diagnosis in the future.

IgG4 related lung disease extending to the thoracic vertebrae

IgG4-related disease (IgG4-RD) is a fibroinflammatory condition that can affect practically every organ. Although it was first identified in pancreas and salivary glands, major organs like liver, biliary tree, kidney, thyroid glands and lungs are commonly involved, sometimes resulting in organ failure. We describe a case of an 41-year-old man presented with back pain after a rotator cuff injury. A Computed Tomography (CT) revealed incidentally a right lower lobe paravertebral lesion extending across the T5 and T6 vertebral levels and invading into the adjacent pleural surface. The laboratory findings and the CT guided biopsy were inconclusive. Morphological and immunohistochemical findings after a lung biopsy by video-assisted thoracic surgery (VATS) were suggestive to IgG4-related lung disease (IgG4-RLD), which was confirmed with high serum levels of IgG4. This represents the first case of a IgG4-RLD lesion located in the mediastinum and extending to the adjacent pleural surface and vertebrae and should be included in the differential diagnosis of posterior mediastinal masses.

Key Features in the Management of Pulmonary Carcinosarcoma

Pulmonary carcinosarcoma represents a category of extremely rare tumours accounting for 0.1% of all lung malignancies. It is defined as a poorly differentiated non-small-cell carcinoma that contains a component of sarcoma or sarcoma-like elements. These biphasic tumours typically have a poor prognosis due to late diagnosis and early metastases. Preoperative tissue diagnosis is usually difficult due to the heterogeneity of the tumour, with biopsies often just reflecting one element of the tumour. By means of a case illustration and review of the literature, we discuss the optimal management of patients with pulmonary carcinosarcoma.

The challenging management of lung choriocarcinoma

The purpose of this paper is to highlight the existence and the management of lung choriocarcinoma (CCA), a rare category of lung tumors. We present a 42-year-old female that presented to our department with a PET positive lesion in the left upper lobe and a history of pregnancy 6 months prior to onset of symptoms. CT guided biopsy was inconclusive for diagnosis and the patient underwent a left thoracotomy and lingula sparing upper lobectomy. Histology revealed CCA of the lung and subsequently blood results confirmed the elevated b-HCG. CCA of the lung is a clinical entity that should be considered in the differential diagnosis of lung lesions in women after pregnancy.

S22 Bap1 expression and treatment outcomes in malignant pleural mesothelioma in a prospective uk based clinical trial

Objectives Genomic studies of malignant pleural mesothelioma (MPM) have identified frequent mutations in the nuclear deubiquitinase BRCA Associated Protein 1 (BAP1). Previous studies have identified 100% correlation between BAP1 nuclear staining and wild type BAP1 status, pointing to immunohistochemistry (IHC) as a reliable technique to detect BAP1 molecular status. The objective of this study is to assess BAP1 expression and infer molecular status using IHC in a cohort from a prospective UK based clinical trial (MSO1). Furthermore, we aim to evaluate the effect of BAP1 status on treatment outcomes. Methods BAP1 expression was evaluated by IHC in 79 biopsies independently by two consultant histopathologists. Cases were considered positive (wild type BAP1) if strong nuclear staining was present and negative (mutant BAP1) if absent. Results Assessment of BAP1 expression was concordant in 77 of 79 cases (97%). BAP1 expression was negative in 66 of these 77 cases (86%). Patient characteristics and the effect of BAP1 expression on treatment outcomes are in Table 1. Conclusions BAP1 expression was negative in 86% of MPM tumours suggesting a high frequency of BAP1 mutations in this UK cohort. No significant differences in clinical characteristics or outcomes were noted between cases with positive or negative BAP1 expression overall. When analysed by treatment subgroup, there was a trend towards a survival benefit in cases with negative BAP1 expression (BAP1 mutants) in the ASC plus vinorelbine arm, but no statistically significant difference in outcomes within any treatment arm. We plan to further validate our findings by correlating BAP1 expression directly with BAP1 molecular status in this cohort using laser capture microdissection and sequencing. Abstract 22 Table 1 Clinical characteristics and clinical outcomes Nuclear BAP1 IHC positive (n=11) Nuclear BAP1 IHC negative (n=66) p-value Gender (M=male) M: 100% M: 91% 0.30 Median age at diagnosis (years) 69.5 66.0 0.94 Histology 0.57 Epithelioid 82% 89% Biphasic 18% 9% Sarcomatoid 0% 3% Median overall survival from diagnosis (months) All 21.0 23.3 0.22 Active symptom control (ASC) 24.3 25.0 0.62 ASC+vinorelbine 12.8 22.8 0.11 ASC+mitomycin, vinblastine, cisplatin 15.7 19.4 0.69

An unusual late onset of pulmonary alveolar microlithiasis: A case report and literature review

Pulmonary alveolar microlithiasis (PAM) is an uncommon genetic disorder associated with alveolar cell injury. This injury is caused in most cases by inactivating mutations in SLC34A2 gene, which is responsible for the production of a sodium-dependent phosphate co-transporter. The dysfunction or deficiency of this transporter leads to the aggregation of local phosphate intra-alveolarly and formation of microliths. Most of the patients are asymptomatic at the time of the diagnosis but as the disease progress it leads to fatal respiratory or cardiac failure. We describe a case of a 63-year-old man referred to our department for a surgical lung biopsy. He has been symptomatic for one year with progressive shortness of breath and deteriorating exercise tolerance. The imaging was suggestive of extensive interstitial bilateral lung disease. Histological findings after the lung biopsy by video-assisted thoracic surgery (VATS) established the diagnosis of pulmonary alveolar microlithiasis. His sister suffered from the same disease and passed away at the age of 54. It is remarkably rare for PAM to have such a late onset with a previous normal X-ray and only a few cases have been reported worldwide.

S6 MMP12 and LMO7, two key players on opposite sides of early lung squamous cell carcinoma development

Background Our laboratory has a unique cohort of patients with pre-invasive lung squamous cell carcinoma (SqCC) lesions, within which there is a clear discrepancy between the prevalence of pre-invasive lesions and the incidence of lung cancer, suggesting that not all pre-invasive lesions progress to cancer. Using gene expression microarrays we identified 1846 genes significantly differentially expressed between progressive and regressive pre-invasive SqCC lesions. The macrophage metalloelastase MMP12 gene was found to be highly expressed in progressive lesions, and we hypothesised that it plays a role in epithelial-to-mesenchymal transition (EMT). Conversely, the actin binding protein LIM-domain only 7 (LMO7) gene was highly expressed in regressive lesions, and we postulated that it may be protective against EMT due to its role in the maintenance of epithelial architecture. Initial studies using three SqCC cell lines (A431, H357 and H376) with MMP12-shRNA knockdown showed a significant decrease in migration and invasion compared to non-silencing shRNA controls. LMO7-shRNA knockdown in HBECS was found to significantly increase migration. The aim of this study is to further characterise the function and signalling of MMP12 and LMO7 in lung SqCC development. Methods Eight-week-old NOD/SCID mice were used for tumorigenesis experiments. Adhesion assays were carried out to assess the roles of MMP12-knockdown or LMO7-overexpression on cell adhesion. Cell signalling mechanisms were assessed using western blotting, qPCR and immunostaining. Results We observed that MMP12-knockdown decreases tumorigenicity in an immunocompromised mouse model. Both A431- and H357 MMP12-knockdown cells produced significantly smaller tumours compared with non-silencing shRNA cells. We found that MMP12-knockdown decreases cell adhesion, which is currently being further investigated along with effects on integrin signalling pathways. Levels of EMT markers were assessed in MMP12-knockdown and LMO7 overexpressing cells using qPCR, western blotting and immunostaining. Results indicate that higher MMP12 expression is associated with a mesenchymal phenotype, whereas higher LMO7 expression is associated with an epithelial phenotype. Conclusions Our results suggest that MMP12 is a key driver of migration and invasion in SqCC and its high expression may contribute to EMT, whereas LMO7 is a putative tumour suppressor with a crucial role in maintaining epithelial cell architecture. MMP12 and LMO7 may be potential early stage therapeutic markers for lung cancer.