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.

[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.

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.

MUC5AC mucin release from human airways in vitro: effects of indomethacin and Bay X1005.

BACKGROUND: Increased secretion of mucus is a hallmark of many respiratory diseases and contributes significantly to the airflow limitation experienced by many patients. While the current pharmacological approach to reducing mucus and sputum production in patients is limited, clinical studies have suggested that drugs which inhibit the cyclooxygenase and/or 5-lipoxygenase enzymatic pathways may reduce secretory activity in patients with airway disease. AIM: This study was performed to investigate the effects of indomethacin (cyclooxygenase inhibitor) and Bay x 1005 (5-lipoxygenase inhibitor) on MUC5AC release from human airways in vitro. METHODS: An immunoradiometric assay was used to determine the quantities of MUC5AC present in the biological fluids derived from human airways in vitro. The measurements were made with a mixture of eight monoclonal antibodies (MAbs; PM8) of which the 21 M1 MAb recognized a recombinant M1 mucin partially encoded by the MUC5AC gene. RESULTS: The quantities of MUC5AC detected in the biological fluids derived from human bronchial preparations were not modified after treatment with indomethacin (cyclooxygenase inhibitor) and/or an inhibitor of the 5-lipoxygenase metabolic pathway (BAY x 1005). CONCLUSION: These results suggest that the cyclooxygenase and 5-lipoxygenase metabolic pathways play little or no role in the release of MUC5AC from human airways.

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.

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.

Actinomycosis and other bronchopulmonary infections with bacterial granules.

Pulmonary infections with formation of bacterial granules are rare. We reviewed the clinical and pathologic data from 18 cases diagnosed using surgical specimens in our department during the last 10 years. Three clinicopathologic forms were observed: endobronchial infections complicating tuberculous sequelae or bronchiectases (n = 7), tumor-like lesions (n = 8), and diffuse pneumonia (n = 3). The two latter forms contrasted with the former by a male predominance, association with general debilitating conditions and inflammatory syndrome, and pathologically by smaller granules often located in parenchymal abscesses or excavations. The pathologic examination of the bacteria forming the granules permitted the diagnoses of actinomycosis (n = 10), botryomycosis (n = 7), or nocardiosis (n = 1). The latter case corresponded to an endobronchial infection. Both actinomycosis and botryomycosis were encountered in every clinicopathologic form. At present, pulmonary actinomycosis and related infections rarely seems to present with chest wall invasion. On the contrary, purely endobronchial forms represented a large proportion of our cases. Cultures are often difficult and the clinical appearance is not specific. However, pathologic examination with special stains must indicate the type of involved microorganism.

Basal secretion of lysozyme from human airways in vitro.

The aim of this study was to examine the basal release of lysozyme from isolated human lung tissues. Measurements of lysozyme in the fluids derived from lung preparations were performed using a rate-of-lysis assay subsequent to acidification of the biological samples. Lysozyme released from bronchial preparations into fluids was greater than that observed for parenchymal tissues. The lysozyme quantities detected in bronchial fluids were not modified by removal of the surface epithelium. Furthermore, the quantities of lysozyme in bronchial fluids was correlated with the size of the bronchial preparations. These results suggest that the lysozyme was principally secreted by the human bronchi (submucosal layer) rather than by parenchyma tissues and that a greater release was observed in the proximal airways.

Frozen section diagnosis and surgical biopsy of lymph nodes, tumors and pseudotumors of the mediastinum.

OBJECTIVE: Our experience with the use of frozen section (FS) was reviewed in order to assess its interest and limits, during minimally aggressive mediastinal surgery for staging of lung carcinomas and biopsy of primary lesions. METHODS: The retrospective study was based on a series of 420 consecutive mediastinal biopsies with FS performed through cervicotomy (n = 12), mediastinoscopy (n = 345), mediastinotomy (n = 43), manubriotomy (n = 13) or videothoracoscopy (n = 7), in 417 patients, aged 8-86 years (mean: 52.5 +/- 15.6). The FS diagnoses were compared with the final diagnoses and consequences of the FS analyses were analyzed. RESULTS: Biopsies with FS had a 99.4% (351/353) efficiency rate for a precise definitive diagnosis (excluding normal lymph nodes). However, two patients required a second operation: one for typing a lymphoma and the other to correct a FS misdiagnosis of small cell carcinoma on a crushed normal lymph node. The sensitivity for detection of carcinoma lymph node metastases was 99% (200/202). The two false negative FS diagnoses, including one post-chemotherapy, were related to micrometastases. There were 46 correct FS diagnoses of non-metastatic lymph node which were followed by an immediate thoracotomy during the same anesthesia, for benign lung lesions (n = 9) or for carcinomas (n = 37), including 30 lung carcinomas that were immediately resected and proved to have no mediastinal involvement (n = 24), or only a limited involvement in a non-biopsied site (n = 6). In the 51 cases of primary mediastinal tumors excluding carcinomas, FS indicated a resectable lesion with a sensitivity of 87.5% (7/8) and a specificity of 97.7% (43/44). Five lesions were immediately resected: one Castleman's disease, one intrathoracic goiter, two of six thymomas and a Hodgkin's disease, which was diagnosed as thymoma on FS. An invasive thymoma was resected during a second operation after a FS diagnosis of carcinoma. FS had a sensitivity of 100% in the 62 cases of sarcoidosis and a sensitivity of 90% in the 20 cases of infectious lesions. One of the 18 cases of tuberculosis and an infectious pseudo-tumor of the anterior mediastinum had no microbiologic study because of FS diagnoses of tumor necrosis and lymphoma. CONCLUSIONS: FS efficiently secures the adequacy of the samples and guides the surgeon's decision making for the resection of lung carcinomas, but is less effective for a precise diagnosis of some primary mediastinal lesions, which may have close histologic appearances.

Radical resection of radiation-induced sarcoma of the chest wall: report of 15 cases.

BACKGROUND: Surgical management of radiation-induced sarcoma of the chest wall remains difficult because of its impressive local aggressiveness. METHODS: Between 1987 and 1995, 15 patients (median age, 58 years) underwent radical resection of radiation-induced sarcoma of the chest wall. This type of tumor was defined as a metachronous, histologically different neoplasm in the irradiated field of the original tumor. Ten patients had a history of primary breast cancer and 5 patients, Hodgkin's disease. The median delivered radiation dose to the primary tumor area was 45 Gy, and the median interval between radiotherapy and diagnosis of sarcoma was 14 years. Seven tumors were located on the sternum, three on the lateral chest wall, and five in the thoracic outlet. Four total and three partial sternectomies, three lateral chest wall resections and five resections of tumors in the thoracic outlet (three first-rib resections) were performed. Seven patients required stabilization of the chest wall with prosthetic material. Soft tissue reconstruction was carried out with either muscle flaps and skin advancement in 9, musculocutaneous flaps in 4, or skin flaps alone in 2 patients. RESULTS: One patient died 3 months after total sternectomy of respiratory failure. Two patients (13.3%) had a local complication: sepsis after sternectomy in 1 and cutaneous necrosis in 1. Local recurrence occurred in 7 patients after a median interval of 10 months. Two of them died, and 4 underwent a repeat resection, 3 of whom are still alive. Four patients died of systemic recurrence. With a median follow-up of 30 months, overall 5-year survival and 5-year disease-free survival rates were 48% and 27%, respectively. CONCLUSION: Despite poor long-term disease-free survival, radical resection of radiation-induced sarcoma of the chest wall is justified on the basis of low postoperative morbidity and the lack of other available therapies.

Thymic neuroendocrine carcinoma (carcinoid): a clinicopathologic study of fourteen cases.

The medical records and histologic documents of 14 patients treated at our institution for a thymic carcinoid tumor were reviewed. There were 3 women and 11 men with an age range from 35 to 71 years. One patient had a multiple endocrine neoplasia syndrome; another had a neurofibromatosis. Twelve tumors were revealed by local symptoms and two were asymptomatic. One patient had Cushing's syndrome that appeared secondarily and was related to metastases. Tumors ranged from 6 to 20 cm and had the characteristic histologic appearance of atypical carcinoid tumor. Immunohistochemical evaluations were done. Tumors were positive for cytokeratin (92%), neuroendocrine markers (100%), and p53 oncoprotein (29%). S-100 protein antibody revealed numerous sustentacular cells in one case. Overall survival was 46% and 31% at 3 and 5 years, respectively. However, all patients died of the disease within 109 months as a result of local progression (n = 5), local relapse (n = 3), distant metastases (n = 8), or a combination of these reasons. Median survival was 71, 30, and 5 months for patients who had total resection (n = 4), partial resection (n = 5), or simple biopsy (n = 4), respectively (p = 0.023). In conclusion, thymic carcinoid tumors can be considered thymic neuroendocrine carcinomas because of their malignant behavior and histologic appearance of atypical carcinoid tumors. Complete surgical resection offers the best hope for long-term survival.

Large bilateral pulmonary artery aneurysms in Behçet's disease: rupture of the contralateral lesion after aneurysmorrhaphy.

An 18-year-old man presented with Behçet's disease and two large bilateral pulmonary artery aneurysms. The day following aneurysmorrhaphy of the right aneurysm, a massive hemoptysis led to death. Postmortem examination disclosed rupture of the left aneurysm in a segmental bronchus. The aneurysms had inflammatory walls and were associated with organized pulmonary arterial thromboses and endomyocardial fibrosis of the right ventricle. Our case report highlights the surgical risk of rupture of associated arterial lesions, certainly related to per- and postoperative pulmonary arterial pressure variations.

Maximal preservation time of tracheal allografts. The Paris-Sud University Lung Transplantation Group.

BACKGROUND: Our objective was to study the maximal preservation time of directly revascularized tracheal allografts in immunosuppressed piglets. METHODS: Donor grafts were flushed with Euro-Collins solution (65 mL/kg at 4 degrees C) by simultaneous inferior thyroid artery and bronchial artery perfusion through a 15-cm aortic segment and heterotopically implanted on their own vascular pedicle after 3 (group 1), 6 (group 2), 15 (group 3), and 24 (group 4) hours of static storage in Euro-Collins solution at 4 degrees C (n = 5 each). The animals were observed for 4 weeks after transplantation and then sacrificed. Histologic evaluation of the tracheal allografts was routinely done using specimens from open biopsies. RESULTS: The overall length of tracheal grafts was 12.4 +/- 0.6 cm, and this variable was not significantly different between the four groups. Graft exocrine (mucous secretion) function began 1.3 +/- 0.5 days after transplantation in groups 1 through 3 but was absent in all group 4 grafts (p < 0.0001). All grafts in groups 1 through 3 were viable at the time of sacrifice and showed little discernible intergroup and intragroup histologic and functional (tracheal smooth muscle contraction and relaxation) variations except for a significantly higher (p < 0.001) incidence of rejection in group 3 allografts. In contrast, all grafts in group 4 became completely necrotic 4 days after transplantation (p < 0.001) despite full patency of all the vascular anastomoses. CONCLUSIONS: These results demonstrate that tracheal allografts may be safely preserved for as long as 15 hours and that longer periods of ischemia are likely to result in irreversible allograft damage.

Extramedullary hematopoietic tumors of the posterior mediastinum related to asymptomatic refractory anemia.

Two asymptomatic paravertebral thoracic masses occurred in a 65-year-old patient with isolated macrocytosis. The largest one measured 8 cm and was surgically resected with a presumptive diagnosis of schwannoma. This thoracic mass was hemorrhagic, encapsulated, and composed of fat and hematopoietic tissue. While extramedullary hematopoietic tumors usually occur in patients with severe chronic hemolytic anemia, our report suggests that such lesions must be considered in the differential diagnosis of posterior mediastinal mass in patients without clinical evident anemia.