Image-based multiplex immune profiling of cancer tissues: translational implications. A report of the International Immuno-oncology Biomarker Working Group on Breast Cancer.

Recent advances in the field of immuno-oncology have brought transformative changes in the management of cancer patients. The immune profile of tumours has been found to have key value in predicting disease prognosis and treatment response in various cancers. Multiplex immunohistochemistry and immunofluorescence have emerged as potent tools for the simultaneous detection of multiple protein biomarkers in a single tissue section, thereby expanding opportunities for molecular and immune profiling while preserving tissue samples. By establishing the phenotype of individual tumour cells when distributed within a mixed cell population, the identification of clinically relevant biomarkers with high-throughput multiplex immunophenotyping of tumour samples has great potential to guide appropriate treatment choices. Moreover, the emergence of novel multi-marker imaging approaches can now provide unprecedented insights into the tumour microenvironment, including the potential interplay between various cell types. However, there are significant challenges to widespread integration of these technologies in daily research and clinical practice. This review addresses the challenges and potential solutions within a structured framework of action from a regulatory and clinical trial perspective. New developments within the field of immunophenotyping using multiplexed tissue imaging platforms and associated digital pathology are also described, with a specific focus on translational implications across different subtypes of cancer. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Spatial analyses of immune cell infiltration in cancer: current methods and future directions: A report of the International Immuno-Oncology Biomarker Working Group on Breast Cancer.

Modern histologic imaging platforms coupled with machine learning methods have provided new opportunities to map the spatial distribution of immune cells in the tumor microenvironment. However, there exists no standardized method for describing or analyzing spatial immune cell data, and most reported spatial analyses are rudimentary. In this review, we provide an overview of two approaches for reporting and analyzing spatial data (raster versus vector-based). We then provide a compendium of spatial immune cell metrics that have been reported in the literature, summarizing prognostic associations in the context of a variety of cancers. We conclude by discussing two well-described clinical biomarkers, the breast cancer stromal tumor infiltrating lymphocytes score and the colon cancer Immunoscore, and describe investigative opportunities to improve clinical utility of these spatial biomarkers. © 2023 The Pathological Society of Great Britain and Ireland.

Pitfalls in machine learning-based assessment of tumor-infiltrating lymphocytes in breast cancer: A report of the International Immuno-Oncology Biomarker Working Group on Breast Cancer

The clinical significance of the tumor-immune interaction in breast cancer is now established, and tumor-infiltrating lymphocytes (TILs) have emerged as predictive and prognostic biomarkers for patients with triple-negative (estrogen receptor, progesterone receptor, and HER2-negative) breast cancer and HER2-positive breast cancer. How computational assessments of TILs might complement manual TIL assessment in trial and daily practices is currently debated. Recent efforts to use machine learning (ML) to automatically evaluate TILs have shown promising results. We review state-of-the-art approaches and identify pitfalls and challenges of automated TIL evaluation by studying the root cause of ML discordances in comparison to manual TIL quantification. We categorize our findings into four main topics: (1) technical slide issues, (2) ML and image analysis aspects, (3) data challenges, and (4) validation issues. The main reason for discordant assessments is the inclusion of false-positive areas or cells identified by performance on certain tissue patterns or design choices in the computational implementation. To aid the adoption of ML for TIL assessment, we provide an in-depth discussion of ML and image analysis, including validation issues that need to be considered before reliable computational reporting of TILs can be incorporated into the trial and routine clinical management of patients with triple-negative breast cancer. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Small lymphocytic lymphoma and lung malignancy coincidence in a male patient: a case report and literature review.

Lung carcinoma management secondary to chronic lymphocytic leukemia could be quite challenging. We report a case of a 60-year-old male with several co-morbidities, who presented with shortness of breath and persistent cough. A chest imaging showed a right pleural effusion and complete white-out of the right chest cavity. A computed tomography scan revealed consolidation of the right upper lobe with a 6-cm lesion in hilum with complete occlusion of right lobe bronchus. The patient underwent a video-assisted thoracoscopic surgery, drainage of pleural effusion and pleural and lung biopsy. Talc pleurodesis as well as a flexible bronchoscopy of the endobronchial lesion was performed. Histopathological examination showed a small B-cell lymphoma of the right pleura and an invasive non-small cell carcinoma of the right lung. Dual neoplasms are challenging in terms of diagnosing, and they usually require a multidisciplinary team for the right treatment strategy, including surgery and chemotherapy.

The challenging management of a giant intrathoracic desmoid tumour: a case report.

Desmoid tumours are rare, locally aggressive neoplasms exhibiting high tendency for recurrence, even after complete resection. Only 1 in 5 of them originates from the chest wall, usually measuring less than 10 cm at diagnosis. Herein, we report the case of a woman presenting with symptoms of gradual lung compression by a giant desmoid tumour occupying the entire hemithorax. She underwent complete surgical resection of the tumour and chest wall reconstruction. She had disease recurrence 15 months later and currently remains under regular follow-up. The management of intrathoracic desmoid tumours is challenging because they are usually not diagnosed until they become large enough to cause compression symptoms. While medical management is the primary modality of treatment, surgery could be considered in selected cases where significant symptoms arise, and the functional status is impaired secondary to the tumour. Adjuvant radiotherapy to minimise the risk of local recurrence should also be considered.

Cystic fibrohistiocytic tumour of the lung presenting with recurrent pneumothoraces: a case report.

Cystic fibrohistiocytic tumour of the lung is a very rare pathological entity that occurs either as a primary pulmonary neoplasm or as a metastasis from skin lesions called cellular fibrous histiocytomas. Herein, we present the case of a 19-year old man with a history of recurrent pneumothoraces who was managed surgically and was eventually diagnosed with cystic fibrohistiocytic tumour of the lung. Clinicians should include this disease in the differential diagnosis of pulmonary cystic lesions and be aware of its association with cellular fibrous histiocytoma. Reporting of more cases is warranted to further elucidate the natural course of the disease and optimise its management.

Pleuroparenchymal Fibroelastosis: A Review of Histopathologic Features and the Relationship Between Histologic Parameters and Survival.

Pleuroparenchymal fibroelastosis (PPFE) is now a defined clinicopathologic entity in the updated 2013 ATS/ERS classification of idiopathic interstitial pneumonias (IIPs), which has led to a significant increase in cases being diagnosed at our institution. We have therefore reviewed 43 PPFE cases (58 biopsies in total) to assess whether any clinical or histopathologic features provide prognostic information. A semiquantatitive grading system was used to assess extent of fibroblastic foci, intra-alveolar fibroelastosis, visceral pleural fibrosis, chronic inflammation in areas of fibrosis, vascular fibrointimal thickening, and presence of granulomas. Other patterns of interstitial lung disease were also noted, if present. All biopsies showed intra-alveolar fibroelastosis, fibroblastic foci at the leading edge of fibrosis and chronic inflammation within areas of fibrosis, 91% showed vascular fibrointimal thickening of vessels, 73% showed pleural fibrosis, and 35% showed granulomas. Ten cases showed a coexistent IIP (5 showed usual interstitial pneumonia, 5 showed features of hypersensitivity pneumonitis). There was no significant correlation with mortality and severity of histologic parameters, other than a significant decrease in mortality in PPFE with coexistent granulomas, after adjusting for age and gender (hazard ratio, 0.27; P=0.049). Male gender was also associated with an increased risk of mortality, after adjusting for age (hazard ratio, 4.8; P=0.045). PPFE is more common than previously thought, not infrequently showing coexistent pathology, specifically usual interstitial pneumonia and granulomatous lung disease, our data suggesting the latter may have prognostic significance.

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.

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.

Restrictive allograft syndrome and idiopathic pleuroparenchymal fibroelastosis: do they really have the same histology?

AIMS: Restrictive allograft syndrome (RAS) and idiopathic pleuroparenchymal fibroelastosis (IPPFE) are two different diseases reported to share the same histology. RAS relates to chronic allograft dysfunction in lung transplantation, with IPPFE being a rare condition in native lungs. Our aim is to compare their histologies alongside biopsies of usual interstitial pneumonia (UIP), to determine if there are differences that might help to elucidate the pathogenesis. METHODS AND RESULTS: We selected four postmortem allograft lungs from patients who developed a clear clinical RAS pattern, five biopsies diagnosed as IPPFE, five UIP biopsies and five sections of normal lung. Histopathological features were described without knowledge of clinical and radiological features. Both RAS allografts and IPPFE biopsies showed intra-alveolar fibrosis and elastosis (IAFE), but RAS allografts also showed concomitant obliterative bronchiolitis, vascular lymphoplasmacytic inflammation within fibrointimal thickening, less fibroblastic foci (FF) at the advancing edge of the fibrosis (one against 14.4 FF in 2 mm2 ) and a slight reduction of the capillary network compared to UIP (P = 0.07) and controls (P = 0.06). The main differences seen in UIP were the lack of IAFE and the presence of honeycomb change. CONCLUSIONS: RAS and PPFE histopathology both show IAFE, but display various differences, particularly in their vascular morphology that may allow further understanding of pathogenesis.

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.