Assessment of the current and emerging criteria for the histopathological classification of lung neuroendocrine tumours in the lungNENomics project.

BACKGROUND: Six thoracic pathologists reviewed 259 lung neuroendocrine tumours (LNETs) from the lungNENomics project, with 171 of them having associated survival data. This cohort presents a unique opportunity to assess the strengths and limitations of current World Health Organization (WHO) classification criteria and to evaluate the utility of emerging markers. PATIENTS AND METHODS: Patients were diagnosed based on the 2021 WHO criteria, with atypical carcinoids (ACs) defined by the presence of focal necrosis and/or 2-10 mitoses per 2 mm2. We investigated two markers of tumour proliferation: the Ki-67 index and phospho-histone H3 (PHH3) protein expression, quantified by pathologists and automatically via deep learning. Additionally, an unsupervised deep learning algorithm was trained to uncover previously unnoticed morphological features with diagnostic value. RESULTS: The accuracy in distinguishing typical from ACs is hampered by interobserver variability in mitotic counting and the limitations of morphological criteria in identifying aggressive cases. Our study reveals that different Ki-67 cut-offs can categorise LNETs similarly to current WHO criteria. Counting mitoses in PHH3+ areas does not improve diagnosis, while providing a similar prognostic value to the current criteria. With the advantage of being time efficient, automated assessment of these markers leads to similar conclusions. Lastly, state-of-the-art deep learning modelling does not uncover undisclosed morphological features with diagnostic value. CONCLUSIONS: This study suggests that the mitotic criteria can be complemented by manual or automated assessment of Ki-67 or PHH3 protein expression, but these markers do not significantly improve the prognostic value of the current classification, as the AC group remains highly unspecific for aggressive cases. Therefore, we may have exhausted the potential of morphological features in classifying and prognosticating LNETs. Our study suggests that it might be time to shift the research focus towards investigating molecular markers that could contribute to a more clinically relevant morpho-molecular classification.

Clinical and molecular practice of European thoracic pathology laboratories during the COVID-19 pandemic. The past and the near future.

BACKGROUND: This study evaluated the consequences in Europe of the COVID-19 outbreak on pathology laboratories orientated toward the diagnosis of thoracic diseases. MATERIALS AND METHODS: A survey was sent to 71 pathology laboratories from 21 European countries. The questionnaire requested information concerning the organization of biosafety, the clinical and molecular pathology, the biobanking, the workload, the associated research into COVID-19, and the organization of education and training during the COVID-19 crisis, from 15 March to 31 May 2020, compared with the same period in 2019. RESULTS: Questionnaires were returned from 53/71 (75%) laboratories from 18 European countries. The biosafety procedures were heterogeneous. The workload in clinical and molecular pathology decreased dramatically by 31% (range, 3%-55%) and 26% (range, 7%-62%), respectively. According to the professional category, between 28% and 41% of the staff members were not present in the laboratories but did teleworking. A total of 70% of the laboratories developed virtual meetings for the training of residents and junior pathologists. During the period of study, none of the staff members with confirmed COVID-19 became infected as a result of handling samples. CONCLUSIONS: The COVID-19 pandemic has had a strong impact on most of the European pathology laboratories included in this study. Urgent implementation of several changes to the organization of most of these laboratories, notably to better harmonize biosafety procedures, was noted at the onset of the pandemic and maintained in the event of a new wave of infection occurring in Europe.

Integrative and comparative genomic analyses identify clinically relevant pulmonary carcinoid groups and unveil the supra-carcinoids.

The worldwide incidence of pulmonary carcinoids is increasing, but little is known about their molecular characteristics. Through machine learning and multi-omics factor analysis, we compare and contrast the genomic profiles of 116 pulmonary carcinoids (including 35 atypical), 75 large-cell neuroendocrine carcinomas (LCNEC), and 66 small-cell lung cancers. Here we report that the integrative analyses on 257 lung neuroendocrine neoplasms stratify atypical carcinoids into two prognostic groups with a 10-year overall survival of 88% and 27%, respectively. We identify therapeutically relevant molecular groups of pulmonary carcinoids, suggesting DLL3 and the immune system as candidate therapeutic targets; we confirm the value of OTP expression levels for the prognosis and diagnosis of these diseases, and we unveil the group of supra-carcinoids. This group comprises samples with carcinoid-like morphology yet the molecular and clinical features of the deadly LCNEC, further supporting the previously proposed molecular link between the low- and high-grade lung neuroendocrine neoplasms.

[Ectopic thymic tissue and ectopic thymic tumors]. / Ektopien des Thymus und ektope Thymustumoren.

Ectopic thymic tissue outside its core position in the antero-superior mediastinum is quite common owing to the complexity of embryonal thymus development, whereby reported prevalence values (1 to 90%) are heavily dependent on the method of investigation and the intensity of the workup. The debated prevalence and relevance of ectopic thymic tissue and its accessibility underlie the ongoing discussion whether modern, minimally invasive thymectomy strategies can match the proven benefit of the radical transsternal thymectomy procedure for the treatment of Myasthenia gravis. In this context, the following article covers the etiology, prevalence, and location of normal-looking, reactive, and neoplastic ectopic thymic tissue. Furthermore, ectopic tissues and tumors inside or adjacent to the thymus are mentioned.

CD52, CD22, CD26, EG5 and IGF-1R expression in thymic malignancies.

BACKGROUND: Thymic epithelial tumours are rare cancers for which new treatment options are required. Identification of putative predictive markers is important for developing clinical trials. We studied the expression of five putative predictive biomarkers, potentially actionable by approved experimental drugs. METHODS: CD52, CD22, CD26, EG5, and IGF-1R expression were investigated by immunohistochemistry in formalin-fixed surgical samples of thymic epithelial tumour patients. All samples containing 10% positive epithelial tumour cells, independent of tumour cell intensity, were considered as positive. Correlation with histological subtype was performed. RESULTS: 106 surgical samples (89 thymomas, 12 thymic carcinoma, and 5 thymic neuroendocrine tumours) were evaluated. Overall, CD52, CD22, CD26, EG5 and IGF-1R expression was observed in 7%, 42%, 25%, 42% and 77% of samples, respectively. CD52 expression was more frequent in B2 and B3 thymoma. All TET subtypes stained for CD22, mainly AB thymoma (68%). CD26 expression also correlated with AB thymoma (68%), and A thymoma (50%) subtype, while IGFR1 was the most common marker expressed by thymic carcinoma samples (92%), followed by EG5 (60%). Only EG5 expression was significantly higher in thymic carcinomas than in thymomas (75% vs. 38%, p=0.026). CONCLUSIONS: Our data were consistent with a previous study of IGF-1R expression. Based on their expression, activity of agents targeting CD52, CD 22, CD26 and EG5 could be further explored in TET patients.

Bronchial Paraganglioma with SDHB Deficiency.

Though most paragangliomas arise as sporadic tumors, the recent advantages in the genetic screening revealed that about 30 % of paragangliomas are linked to hereditary mutations, such as those involving SDH genes. A 22-year-old woman carrying a left main bronchus tumor underwent surgery in our institution. Her past medical history included a GIST without KIT or PDGFRA mutation. The histological examination revealed a nested proliferation of medium-sized cells expressing neuroendocrine markers (chromogranin A and synaptophysin). The neoplastic cells failed to express SDHB gene product. These findings led us to the final diagnosis of bronchial paraganglioma in the setting of Carney-Stratakis syndrome. Bronchial paragangliomas are exceedingly rare tumors with polymorphous clinical presentation, and usually benign clinical course. Though most paragangliomas are sporadic, some tumors are associated with specific hereditary disease, especially those occurring in young patients or in combination with other neoplasms.

[Angiosarcoma mimicking recurrent pulmonary embolism]. / Un angiosarcome mimant une embolie pulmonaire récidivante.

INTRODUCTION: Pulmonary artery sarcoma is a rare disease with non-specific symptoms. The clinical and radiological presentation can mimic pulmonary embolism with chronic thromboembolic pulmonary hypertension. Management is essentially surgical but the prognosis remains poor. CASE REPORT: A patient presented with symptoms of pulmonary embolism. Despite vitamin K antagonist therapy, he suffered from extension of the endovascular defects and his pulmonary hypertension increased. Suspicious results of positron emission tomography suggested the diagnosis of pulmonary artery sarcoma that was confirmed by surgery. However, the outcome was unfavourable, leading to death of the patient. CONCLUSION: This case reinforces the idea that the clinical and tomodensitometric presentations of pulmonary arterial sarcoma and chronic thromboembolic pulmonary hypertension are similar. The positron emission tomography seems to be a key to distinguishing these two diagnoses.

Surgical management of thymic epithelial tumors in children: lessons from the French Society of Pediatric Oncology and review of the literature.

PURPOSE: We report the results of a French multicenter retrospective study based on a period of more than 30 years and a review of the literature in order to more clearly define the surgical approach and specific pediatric risk factors. METHODS: Clinical data of children comprising all histologic subtypes of thymic epithelial tumors (TET) treated between 1979 and 2009 in French pediatric oncology centers were retrospectively analyzed and discussed in the light of a review of all pediatric cases reported in the literature. RESULTS: Nine cases were identified, corresponding to five females and four males with a median age of 13 years (range: 7.5-17). Histologic subtypes were type AB (n = 1), type B (n = 5) and type C (n = 3). Treatment consisted of tumor resection (4 R0, 4 R1, 1 R2) via right anterior thoracotomy, posterolateral thoracotomy, left thoracoscopy, sternotomy and cervicosternotomy, and/or chemotherapy, mainly cyclophosphamide-doxorubicin-cisplatin (CAP; n = 5), and/or radiotherapy (n = 4). Two patients with TET type C died. All other patients are alive with a median follow-up of 4 years (range: 1.5-20). Review of a total of 93 pediatric cases reported in the literature showed statistically significant associations between less favorable histologic subtypes and male gender (P = 0.012), advanced Masaoka stage (P < 0.001) and quality of resection (P < 0.001) respectively. CONCLUSIONS: A review of the literature and our series identified several risk factors to take into account in the therapeutically decision. Complete resection through a sternotomy is highly recommended.

Prevention of hepatopulmonary syndrome and hyperdynamic state by pentoxifylline in cirrhotic rats.

Inhibition of tumour necrosis factor-alpha (TNF-alpha), levels of which are increased in the blood of cirrhotic rats, prevents hyperdynamic circulatory state, mainly by decreasing the vascular overproduction of nitric oxide. Hepatopulmonary syndrome, which is characterised by intrapulmonary vascular dilatation and increased alveolar to arterial oxygen tension difference (PA-a,O2), is mainly related to pulmonary over-production of NO by macrophages accumulated in lung vessels. Since TNF-alpha is a potent activator of macrophagic inducible nitric oxide synthase (NOS), the aim of this study was to investigate whether TNF-alpha inhibition prevented hepatopulmonary syndrome and hyperdynamic circulatory state in rats with cirrhosis. TNF-alpha was inhibited by 5 weeks of pentoxifylline (10 mg x kg body weigh(-1) x day(-1)) in rats with cirrhosis induced by common bile duct ligation. Cardiac output, pulmonary and systemic vascular resistance, PA-a,O2 and cerebral uptake of intravenous technetium-99m-labelled albumin macroaggregates (which reflects intrapulmonary vascular dilatation) were similar in sham- and pentoxifylline-treated cirrhotic rats. Blood TNF-alpha concentrations and pulmonary intravascular macrophage sequestration, as assessed by morphometric analysis and radioactive colloid uptake, were decreased with pentoxifylline. Pentoxifylline also prevented increases in aorta and lung NOS activities and inducible NOS expression. Thus pentoxifylline prevents development of hyperdynamic circulatory state and hepatopulmonary syndrome, probably by inhibiting the effects of tumour necrosis factor-alpha on vascular nitric oxide synthase and intravascular macrophages. These results support an important role for tumour necrosis factor-alpha in the genesis of hepatopulmonary syndrome.

[Pulmonary carcinosarcoma with jejunal metastasis: complete response to chemotherapy]. / Carcinosarcome pulmonaire avec métastase jéjunale et réponse complète à la chimiothérapie.

We report a case of pulmonary carcinosarcoma with jejunal metastasis. The lung is an exceptional localization for carcinosarcoma, a tumor with carcinomatous and sarcomatous components. These two components are closely related but well-defined morphologically and immunohistochemically. Risk of metastasis and local recurrence is high. Surgery is the treatment of choice for localized forms. Prognosis depends on the sarcomatous component which is usually sensitive to chemotherapy, with at least doxorubicin and ifosfamide. This rare case illustrates the potential for jejunal metastasis and complete response to chemotherapy, proven histologically at 33 months.

Fibroma and inflammatory myofibroblastic tumor of the heart.

Cardiac fibroma and inflammatory myofibroblastic tumor (IMT) of the heart are rare lesions occurring in young patients and having pathologic similarities. We compared the morphologic and immunohistochemical features of seven cardiac fibromas, including one biopsied at birth and removed 4 years later, and two IMTs of the heart diagnosed at Marie Lannelongue Surgical Center (Le Plessis Robinson, France) between 1980 and 1999. Cardiac fibromas occurred in five females and two males and were surgically biopsied (n = 2) or removed (n = 6) between the ages of 8 days to 31 years (mean 7 +/- 12 years). Inflammatory myofibroblastic tumors were removed in two male patients, aged 13 weeks and 1 year, both alive and well 9 months and 5 years after surgery, respectively. Fibromas were ventricular lesions measuring 3 to 10 cm (mean, 5.7 +/- 2.2 cm). They contained entrapped myocytes and wavy elastic fibers. Three cases contained calcifications. Spindle cells were monomorphic. Their nucleus had a thin chromatin without nucleolus. Mitoses and extramedullary hematopoiesis were only observed in fibromas from patients younger than 5 months (n = 5) while prominent collagen fibrosis was present in fibromas from patients older than 4 years (n = 3). Inflammatory myofibroblastic tumors were endocardial lesions measuring 2 and 2.5 cm. They were covered by fibrin. Spindle cells were larger than in fibromas. Their nucleus had obvious nucleoli. They were associated with numerous inflammatory cells in a variable amount of myxoid background. Occasional mitoses and foci of necrosis were present. Spindle cells in both fibromas and IMTs strongly expressed smooth-muscle actin and were negative for desmin, CD34, S-100 protein, and p53. Our study shows that IMT must be considered in the differential diagnosis of cardiac fibroma especially in cases of inflammatory syndrome, location outside the ventricular myocardium, or multinodular lesions. Morphologic analysis permits the correct diagnosis, while immunochemistry shows a myofibroblastic differentiation in both lesions.

Cholesterol crystal embolization demonstrated on GI biopsy.

OBJECTIVES: Cholesterol crystal embolism is a severe complication of atherosclerosis responsible for nonspecific cutaneous, renal, and, less often, digestive manifestations that may mimic other systemic diseases. METHODS: We reviewed retrospectively 10 patients with histologically proven cholesterol crystal emboli diagnosed by endoscopic GI biopsy. RESULTS: All patients had prior clinical manifestations of severe atherosclerosis and predisposing factors for cholesterol migration. They all had cutaneous manifestations of cholesterol crystal embolism, acute renal failure, and biological inflammatory syndrome. Digestive symptoms were found in the 10 patients: abdominal pain in eight, diarrhea in four, and GI bleeding in three. GI endoscopy ruled out specific digestive diseases, showing only a congestive or erosive mucosa. Histological diagnosis of cholesterol crystal emboli was based on gastric biopsy in nine patients, duodenal biopsy in four, colonic biopsy in three, and rectal biopsy in one, with six having positive biopsies on multiple sites. Outcome after the diagnosis of cholesterol crystal embolism was poor, with all patients requiring permanent hemodialysis. Death by atherosclerosis complications occurred in five patients. CONCLUSIONS: This cohort suggests that upper GI endoscopy may be helpful in demonstrating the presence of cholesterol crystal embolism, and that diagnosis of cholesterol crystal emboli on digestive tract biopsy indicates advanced systemic atherosclerosis disease of poor prognosis.

Prostacyclin modulation of contractions of the human pulmonary artery by cysteinyl-leukotrienes.

The contractile response to cysteinyl-leukotrienes was studied in isolated human pulmonary arterial rings. Concentration-response curves for leukotriene C(4) were significantly potentiated by the cyclooxygenase inhibitor indomethacin (1.7 microM) and after endothelial denudation. Measurements of 6-keto prostaglandin F(1alpha) showed that cysteinyl-leukotrienes stimulated the release of prostacyclin. A single concentration (1 microM) of either leukotriene C(4) or leukotriene D(4) resulted in both contraction and relaxation. Indomethacin abolished the relaxant phase and enhanced the amplitude of the contraction, supporting that cysteinyl-leukotriene-induced contractions of the human pulmonary artery may be functionally antagonised by the release of prostacyclin. The contractions induced by leukotriene C(4) were resistant to the two cysteinyl-leukotriene receptor antagonists MK 571 ((3-(-2(7-chloro-2-quinolinyl)ethenyl)phenyl)((3-(dimethylamino-3-oxo propyl)thio)methyl)thio propanoic acid, 1 microM) and BAY u9773 (6(R)-(4'-carboxyphenylthio)-5(S)-hydroxy-7(E),9(E), 11(Z)14(Z)-eicosatetrenoic acid, 3 microM), both in the absence and presence of indomethacin. These findings suggest a functional cysteinyl-leukotriene receptor in the human pulmonary artery with antagonist properties not previously described in human tissue.

[Primary biphasic synovial sarcoma of the pleura]. / Synovialosarcome biphasique primitif de la plèvre.

A 36-year-old man presented with a pleural tumor. The first pathologic analysis diagnosed biphasic pleural malignant mesothelioma. However, the atypical clinical course, the early development of lung metastases and a new reading of histologic documents led to the diagnosis of primary pleural synovial sarcoma. The literature review is limited, as only nine other cases have been reported to date. Chest pain is the only constant clinical feature. Misleading interpretation of histologic material is frequent (6 of 10 cases). Only a complete immuno-histochemical study confronted with the clinical course can lead to the correct diagnosis. Because the efficacy of chemotherapy and/or radiotherapy is poor, surgery remains the basis of treatment, whenever possible. Evolution is mainly intra-thoracic, with multiple local recurrences and lung metastases. Prognostic is poor, a survival rate is similar to that of primary pulmonary sarcomas.

ATP induced MUC5AC release from human airways in vitro.

BACKGROUND: Chronic airway diseases are often associated with marked mucus production, however, little is known about the regulation of secretory activity by locally released endogenous mediators. AIM: This investigation was performed to determine the release of MUC5AC mucin from human bronchial preparations using the purinergic agonists adenosine 5'-triphosphate (ATP) and uridine 5'-triphosphate (UTP). METHODS: Immunohistochemical and immunoradiometric assays (IRMA) were used to detect the MUC5AC mucin. Immunohistochemical analysis were performed using individual 1-13 M1 and 21 M1 MAbs recognizing a recombinant M1 mucin partially encoded by the MUC5AC gene. IRMA measurments were performed using a mixture of eight anti-M1 mucin MAbs (PM8), which included both 1-13 M1 and 21 M1 MAbs. Lysozyme and protein were also measured in the biological fluids derived from human bronchial preparations obtained from patients who had undergone surgery for lung carcinoma. RESULTS: The anti-M1 monoclonal antibodies labelled epithelial goblet cells. After challenge of human bronchial preparations with ATP, the goblet cells exhibited less staining. In contrast, UTP did not alter the immunolabelling of goblet cells. MUC5AC mucin in the bronchial fluids derived from ATP-challenged preparations was increased while UTP had no effect on release. ATP did not alter either the quantities of lysozyme or protein detected in the biological fluids. CONCLUSION: These results suggest that ATP may regulate epithelial goblet cell secretion of MUC5AC mucin from human airways in vitro.

Extraskeletal osteosarcoma of the mediastinum after treatment of a mediastinal germ-cell tumor.

Three years after four cycles of bleomycin, etoposide, and cisplatin (BEP) chemotherapy for a nonseminomatous germ-cell tumor of the mediastinum followed by complete resection of residual teratoma in a 21-year-old man, a mediastinal recurrence was diagnosed as an extraskeletal osteosarcoma. After unsuccessful chemotherapy and removal of the tumor, the patient died of cerebral metastases. Histologic transformation of the teratomatous components of nonseminomatous germ-cell tumors is an uncommon phenomenon showing a particular aspect of germ-cell tumor biology. We review the literature and discuss the pathogenesis concerning this subject.

M1/MUC5AC mucin released by human airways in vitro.

A series of monoclonal antibodies which bind to a mucin known as M1 (anti-M1 MAbs) have also been shown to detect the product of the human gene MUC5AC. The aim of this investigation was to determine the concentration of the M1 mucin in the surface epithelium of human bronchial preparations by means of immunohistochemistry and in the bronchial fluid derived from human airways by means of an immunoradiometric assay. Human bronchial ring preparations from the resection material of 20 patients were challenged with methacholine, leukotriene D4, or anti-immunoglobulin E. Experiments were performed in preparations with an intact epithelium as well as in tissues in which the epithelium had been mechanically removed. The anti-M1 MAbs stained the goblet cells in the epithelium intensely and there was also light and less uniform staining in the submucosa. The M1/MUC5AC mucin in the fluids secreted by the bronchial preparations was not modified during either the experimental protocol or stimulation with the different secretagogues. However, in preparations in which the epithelium had been removed, there was a significant reduction in the amount of M1/MUC5AC mucin detected. These data suggest that the M1/MUC5AC mucin detected in the biological fluids produced by human airways in vitro may be released constantly, and principally from the goblet cells in the epithelial layer.

Characterization of a pig-to-goat orthotopic lung xenotransplantation model to study beyond hyperacute rejection.

BACKGROUND: A pig-to-goat orthotopic lung xenograft model was developed to test whether depletion of goat xenoreactive antibodies against pig red blood cells would prolong pig lung xenograft survival. METHODS: Adult goats with anti-pig xenoreactive antibodies underwent left pneumonectomy followed by orthotopic transplantation of pig left lung (group 1) or immunodepletion of their xenoreactive antibodies by extracorporeal right pig lung perfusion before transplantation without (group 2) or with (group 3) complete clampage of the right pulmonary artery. In group 4, goat left lungs were orthotopically transplanted into pigs and served as negative controls (pig serum does not have anti-goat xenoreactive antibodies). Each study group included 5 animals. Immunosuppression in surviving recipients included cyclosporine and azathioprine. RESULTS: Group 1 recipients died 7 +/- 3 hours after xenograft reimplantation of severe pulmonary hypertension and dysfunction and vasogenic shock, with little evidence of histologic xenograft injury. Group 2 xenografts had a stable circulatory and respiratory function on reperfusion and survived 9 +/- 4 days. Group 3 animals also tolerated complete occlusion of the right pulmonary artery, and xenografts assured the total respiratory support for 4 +/- 1 days. After immunodepletion, goat serum showed no detectable titers of xenoreactive antibodies, which began to reappear by postoperative day 2, where xenografts showed histologic stigmata of acute (humoral and cellular-mediated) rejection that evolved to a complete xenograft necrose at death. Group 4 xenografts showed scattered features of acute rejection 5 +/- 1 days after the operation. CONCLUSIONS: Pig left lung xenografts can provide prolonged and complete respiratory support after depletion of goat xenoreactive antibodies, but they ultimately necrose once recipient xenoreactive antibodies return to pretransplantation values.

Prognostic factors and results after surgical treatment of primary sarcomas of the lung.

BACKGROUND: Primary sarcoma of the lung is a rare tumor. Our purpose was to study survival after resection and prognostic factors, which have been rarely reported. METHODS: In a 24-year period, we performed 20 complete resections and three exploratory thoracotomies only for primary lung sarcomas. One patient declined operation. Mean diameter of resected tumors was 9 cm (range, 4 to 18 cm). There were eight stage IB, eight stage IIB, one stage IIIA, and three stage IIIB. Sixty percent of patients with resected tumors received adjuvant therapy. Age, sex, resectability, tumor size, histologic cell type, stage, and adjuvant therapy were analyzed as predictors of survival. RESULTS: No postoperative deaths occurred. All 4 patients who had no resection died within 15 months. The 5- and 10-year actuarial survival after complete resection was 48%. The 5- and 10-year actuarial survival in stage IB was 83%, whereas the 4-year actuarial survival in stage IIB was 30% (p < 0.05). Complete resection and stage of disease were the sole significant prognostic factors. CONCLUSIONS: Complete resection of primary sarcoma of the lung, when feasible, can achieve prolonged survival, although almost half of the patients died of metastasis within 2 years of operation. Adjuvant therapy needs to be investigated.