Khoór, András

Abstract Background With recent advances in oncology, tyrosine kinase inhibitors like imatinib play a significant role in gastrointestinal stromal tumor (GIST) treatment but can cause rare pulmonary complications. When new respiratory symptoms arise after starting these agents, differentiating drug toxicity from other lung diseases is important for timely management. Case Presentation A 72-year-old man with GIST, recently started on imatinib, presented with acute dyspnea and hypoxia. His medical history included chronic obstructive pulmonary disease and a 40-pack-year smoking history. Chest CT revealed new bilateral interstitial infiltrates absent on imaging two months ago, prior to imatinib initiation. The differential diagnosis included imatinib-induced pneumonitis versus atypical infection. Bronchoscopy showed yellowish nodular mucosa throughout the trachea and bronchi, mucus plugging, and airway narrowing in the left lower lobe. Endobronchial biopsies demonstrated amyloid deposits consistent with tracheobronchial amyloidosis. The bronchoalveolar lavage was negative for infection and, therefore, corticosteroid therapy was initiated, resulting in clinical and radiographic improvement. The findings supported a diagnosis of imatinib-induced pneumonitis coexisting with tracheobronchial amyloidosis. Discussion This case highlights the diagnostic challenges when drug-induced pneumonitis occurs along with structural airway abnormalities. Tracheobronchial amyloidosis, although rare, can cause airway obstruction and coexist with inflammatory lung conditions. The temporal association with imatinib, exclusion of infection, and steroid responsiveness indicate imatinib-induced pneumonitis as the primary cause of the acute symptoms, with concurrent amyloid deposition contributing to airway pathology. Conclusion In patients developing new pulmonary symptoms after starting tyrosine kinase inhibitors, drug-induced pneumonitis should be strongly suspected. The coexistence of airway diseases such as tracheobronchial amyloidosis can complicate diagnosis and management, highlighting the need for thorough evaluation including bronchoscopy and tissue biopsy to guide treatment. This abstract is funded by: None

Aims Lymphangioleiomyomatosis (LAM) is a PEComa that primarily affects premenopausal women and is associated with the cystic destruction of the lung. Although smooth muscle and melanocytic markers can be helpful, histologic diagnosis of LAM remains challenging, especially in small biopsies. Glycoprotein non‐metastatic melanoma protein B (GPNMB) expression has recently been identified as a highly specific and sensitive immunohistochemical marker for PEComas. Nevertheless, only a few LAM cases have been studied so far. The aim of this study was to assess the utility of GPNMB immunohistochemistry as an ancillary marker in a larger cohort of LAM samples. Methods and results Immunohistochemistry for GPNMB was performed on cases of LAM ( N = 15), potential differential diagnostic mimics ( N = 30) and normal lung tissue ( N = 2). Immunohistochemistry was assessed using the H‐score method; an H‐score above 100 was considered ‘high’. All LAM cases showed strong cytoplasmic expression, with cell membrane accentuation in some areas. In contrast, differential diagnostic mimics were either negative or only weakly positive. Normal lung parenchyma was negative for GPNMB; however, weak‐to‐moderate expression was seen in alveolar macrophages in both the normal and diseased lung tissues in most cases. Considering only ‘high’ positivity, GPNMB immunohistochemistry showed 100% sensitivity and specificity for the diagnosis of LAM in our cohort. Conclusions Based on its 100% sensitivity and specificity, GPNMB appears to be a highly valuable immunohistochemical marker for the diagnosis of pulmonary LAM. Besides its diagnostic value, the membrane positivity of GPNMB on LAM cells may predict a response to glembatumumab vedotin, an antibody‐drug conjugate targeting GPNMB.

Abstract Rationale: Primary ciliary dyskinesia (PCD) is a heterogeneous, rare genetic disorder characterized by dysfunctional motile cilia. PCD pulmonary manifestations include impaired airway mucociliary clearance, mucus obstruction, recurrent infection, and bronchiectasis (BE). Notably, thoracic imaging studies indicate that alveolar atelectasis is more prevalent in children with PCD than in age-matched children with cystic fibrosis (CF). However, morphologic and molecular analyses of the site of initiation and progression of PCD airway disease and relationships to PCD alveolar disease have not been reported. In this study, we analyzed region-specific morphologic and molecular characterizations of airway epithelia and alveolar regions in PCD lungs excised at transplantation to address these questions. Methods: Nine PCD lungs and seven non-diseased control lungs were included in the morphometric studies. Bronchi and proximal and distal bronchioles were defined using unique morphologic structures, and distal airway secretory cell (DASC) markers were used to differentiate between proximal and distal bronchioles. Morphologic characteristics of airway epithelia and luminal mucus were quantitated by histology, immunohistochemistry, and RNA in situ hybridization. Spatial transcriptomic technologies (GeoMx) characterized region-specific transcript expression in three airway epithelial regions (bronchi, proximal bronchioles, and distal bronchioles), intraluminal mucus plugs, and alveolar regions of PCD compared to control lungs. Finally, pulmonary function data from a cohort of PCD subjects were analyzed to investigate correlations between alveolar morphologic findings and alveolar gas exchange function, i.e. diffusing capacity for carbon monoxide (DLCO). Results: PCD bronchi and proximal bronchioles exhibited ectasia, characterized by increased MUC5AC and MUC5B-producing cells, mucus plugs containing MUC5AC and MUC5B mucins infiltrated by neutrophils, and epithelial gene signatures associated with ectasia. In contrast, PCD distal bronchioles were not ectatic and exhibited MUC5B-dominant DASCs, mucus plugs containing selectively MUC5B mucin infiltrated by mixture of neutrophils and macrophages, and gene signatures suggestive of impaired ciliogenesis. Molecular analysis revealed upregulation of pathways associated with muco-inflammation, antimicrobial defense, and the innate immune system routinely in PCD airway epithelia. IL-1β gene signatures were observed in both PCD airway and alveolar epithelia, whereas interferon-stimulated gene signatures were restricted to airway epithelia. Transcriptomic and morphologic analyses suggested that PCD alveolar disease was initiated by distal bronchiolar obstruction, associated with chronic microatelectasis, progressive loss of alveolar epithelial type 2 (AT2) cells, and eventual non-resolving fibrosis. A significant percentage (28%) of people with PCD exhibited reduced DLCO. Conclusions: PCD airway disease is manifest by distinct profiles of proximal vs distal bronchiolar disease associated with microatelectatic and fibrotic alveolar disease.

Abstract Introduction Medullary thyroid cancer (MTC) is an uncommon malignancy arising from the C-cells of the thyroid gland. It makes up 2% of all thyroid cancers, with both familial and sporadic patterns noted. It is most commonly diagnosed in the fourth to sixth decade of life, with the lungs being a common site of metastasis. We present a case of metastatic MTC with a rare pulmonary presentation. Case Description The patient presented at the age of 28 after having a chronic complaint of stomach pain and diarrhea. Imaging of the abdomen revealed small nodules in the lower pulmonary fields. Dedicated imaging of the chest was subsequently ordered. This study was notable for an enlarged left lobe of the thyroid extending into the mediastinum with two large mediastinal lymph nodes. A fine-needle aspiration of the left neck lymph node was consistent with MTC and there were hematologic findings of elevated calcitonin and CEA. Testing for the RET proto-oncogene was negative. Pathology on total thyroidectomy confirmed the diagnosis, with further sampling identifying metastasis in the thoracic spine (T12). Initial therapy with pazopanib was commenced. After some time on stable therapy, the patient was noted to have waxing and waning pulmonary micro-nodularity associated with increase in his calcitonin levels. There was a finding of a miliary pattern of disease on chest imaging. The pulmonary service was consulted due to these findings in conjunction with sub-acute cough. Pulmonary biopsy was performed, with findings of nodular amyloidosis; Congo red stain highlighted amyloid deposition. Immunohistochemical studies were performed, revealing rare cell groups that were positive for calcitonin, CEA, CAM5.2, TTF-1, chromogranin, and synaptophysin. After further discussion with the Pathology service, the patient was given formal diagnosis of amyloid deposition of the Acal subtype due to metastatic medullary thyroid cancer. Discussion This case highlights a patient diagnosed with sporadic MTC, later found to have metastatic related pulmonary amyloid deposition. While local amyloid deposition can be seen in MTC, it is unusual to have diffuse parenchymal disease due todiffuse parenchymal disease due to distant deposition. There are only four other instances in the literature of a similar presentation. Amyloid deposition is associated with worse outcomes, but the patient had a good outcome with treatment by a tyrosine-kinase inhibitor.

Context.— Mesothelioma is an uncommon tumor that can be difficult to diagnose. Objective.— To provide updated, practical guidelines for the pathologic diagnosis of mesothelioma. Data Sources.— Pathologists involved in the International Mesothelioma Interest Group and others with expertise in mesothelioma contributed to this update. Reference material includes peer-reviewed publications and textbooks. Conclusions.— There was consensus opinion regarding guidelines for (1) histomorphologic diagnosis of mesothelial tumors, including distinction of epithelioid, biphasic, and sarcomatoid mesothelioma; recognition of morphologic variants and patterns; and recognition of common morphologic pitfalls; (2) molecular pathogenesis of mesothelioma; (3) application of immunohistochemical markers to establish mesothelial lineage and distinguish mesothelioma from common morphologic differentials; (4) application of ancillary studies to distinguish benign from malignant mesothelial proliferations, including BAP1 and MTAP immunostains; novel immunomarkers such as Merlin and p53; fluorescence in situ hybridization (FISH) for homozygous deletion of CDKN2A; and novel molecular assays; (5) practical recommendations for routine reporting of mesothelioma, including grading epithelioid mesothelioma and other prognostic parameters; (6) diagnosis of mesothelioma in situ; (7) cytologic diagnosis of mesothelioma, including use of immunostains and molecular assays; and (8) features of nonmalignant peritoneal mesothelial lesions.

Lung carcinoma is one of the most common cancer types for both men and women. Despite recent breakthroughs in targeted therapy and immunotherapy, it is characterized by a high metastatic rate, which can significantly affect quality of life and prognosis. Rictor (encoded by the RICTOR gene) is known as a scaffold protein for the multiprotein complex mTORC2. Among its diverse roles in regulating essential cellular functions, mTORC2 also facilitates epithelial–mesenchymal transition and metastasis formation. Amplification of the RICTOR gene and subsequent overexpression of the Rictor protein can result in the activation of mTORC2, which promotes cell survival and migration. Based on recent studies, RICTOR amplification or Rictor overexpression can serve as a marker for mTORC2 activation, which in turn provides a promising druggable target. Although selective inhibitors of Rictor and the Rictor-mTOR association are only in a preclinical phase, they seem to be potent novel approaches to reduce tumor cell migration and metastasis formation. Here, we summarize recent advances that support an important role for Rictor and mTORC2 as potential therapeutic targets in the treatment of lung cancer. This is a traditional (narrative) review based on Pubmed and Google Scholar searches for the following keywords: Rictor, RICTOR amplification, mTORC2, Rictor complexes, lung cancer, metastasis, progression, mTOR inhibitors.

Radiologists fulfill a vital role in the multidisciplinary care provided to patients with interstitial lung diseases and other diffuse parenchymal lung disorders. The diagnosis of interstitial lung diseases hinges on the consensus of clinical, radiology, and pathology medical subspecialists, but additional expertise from rheumatology, immunology, or hematology can be invaluable. The thin-section computed tomography (CT) features of lung involvement informs the diagnostic approach. Radiologists should be familiar with radiologic methods (including inspiratory/expiratory and prone imaging) and be well versed in the recognition of the CT features of fibrosis, assessment of the overall pattern of lung involvement, and classification according to the latest guidelines. We present a case-based review that highlights examples wherein CT features and subspecialist radiologist interpretation informed the multidisciplinary team consensus diagnosis and care pathways.

Key message Diffuse pulmonary meningotheliomatosis (DPM) is an ultra‐rare pulmonary disease characterized by innumerable bilateral minute meningothelial‐like nodules, sometimes presenting a characteristic ‘cheerio‐sign’ on imaging. Most patients with DPM are asymptomatic and experience no disease progression. Although little is known about its nature, DPM may be associated with pulmonary malignancies, mostly lung adenocarcinoma.