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Background: The present article is an English-language version of the French National Diagnostic and Care Protocol, a pragmatic tool to optimize and harmonize the diagnosis, care pathway, management and follow-up of lymphangioleiomyomatosis in France., Methods: Practical recommendations were developed in accordance with the method for developing a National Diagnosis and Care Protocol for rare diseases of the Haute Autorité de Santé and following international guidelines and literature on lymphangioleiomyomatosis. It was developed by a multidisciplinary group, with the help of patient representatives and of RespiFIL, the rare disease network on respiratory diseases., Results: Lymphangioleiomyomatosis is a rare lung disease characterised by a proliferation of smooth muscle cells that leads to the formation of multiple lung cysts. It occurs sporadically or as part of a genetic disease called tuberous sclerosis complex (TSC). The document addresses multiple aspects of the disease, to guide the clinicians regarding when to suspect a diagnosis of lymphangioleiomyomatosis, what to do in case of recurrent pneumothorax or angiomyolipomas, what investigations are needed to make the diagnosis of lymphangioleiomyomatosis, what the diagnostic criteria are for lymphangioleiomyomatosis, what the principles of management are, and how follow-up can be organised. Recommendations are made regarding the use of pharmaceutical specialties and treatment other than medications., Conclusion: These recommendations are intended to guide the diagnosis and practical management of pulmonary lymphangioleiomyomatosis., Competing Interests: Declaration of Competing Interest Vincent COTTIN has no conflict of interest to disclose in relation with the content of the manuscript. Elodie BLANCHARD has no conflict of interest to disclose in relation with the content of the manuscript. Mallorie KERJOUAN declares research fees paid by Pfizer and Novartis to her institution. Romain LAZOR has no conflict of interest to disclose in relation with the content of the manuscript. Martine REYNAUD-GAUBERT has no conflict of interest to disclose in relation with the content of the manuscript. Romain LAZOR has no conflict of interest to disclose in relation with the content of the manuscript. Camille TAILLE declares consulting fees paid to her by Novartis. Yurdagül UZUNHAN has no conflict of interest to disclose in relation with the content of the manuscript. Lidwine WEMEAU has no conflict of interest to disclose in relation with the content of the manuscript. Claire ANDREJAK has no conflict of interest to disclose in relation with the content of the manuscript. Dany BAUD has no conflict of interest to disclose in relation with the content of the manuscript. Philippe BONNIAUD has no conflict of interest to disclose in relation with the content of the manuscript. Pierre-Yves BRILLET has no conflict of interest to disclose in relation with the content of the manuscript. Alain CALENDER has no conflict of interest to disclose in relation with the content of the manuscript. Lara CHALABREYSSE has no conflict of interest to disclose in relation with the content of the manuscript. Isabelle COURT-FORTUNE has no conflict of interest to disclose in relation with the content of the manuscript. Nicolas DESBAILLETS has no conflict of interest to disclose in relation with the content of the manuscript. Gilbert FERRETTI has no conflict of interest to disclose in relation with the content of the manuscript. Anne GUILLEMOT has no conflict of interest to disclose in relation with the content of the manuscript. Laurane HARDELIN has no conflict of interest to disclose in relation with the content of the manuscript. Marianne KAMBOUCHNER has no conflict of interest to disclose in relation with the content of the manuscript. Violette LECLERC (deceased). Mathieu LEDERLIN has no conflict of interest to disclose in relation with the content of the manuscript. Marie-Claire MALINGE has no conflict of interest to disclose in relation with the content of the manuscript. Alain MANCEL has no conflict of interest to disclose in relation with the content of the manuscript. Sylvain MARCHAND-ADAM declares consulting fees paid by Novartis. Jean-Michel MAURY has no conflict of interest to disclose in relation with the content of the manuscript. Jean-Marc NACCACHE has no conflict of interest to disclose in relation with the content of the manuscript. Mouhamad NASSER has no conflict of interest to disclose in relation with the content of the manuscript. Hilario NUNES has no conflict of interest to disclose in relation with the content of the manuscript. Gaële PAGNOUX has no conflict of interest to disclose in relation with the content of the manuscript. Grégoire PRÉVOT has no conflict of interest to disclose in relation with the content of the manuscript. Christine ROUSSET-JABLONSKI has no conflict of interest to disclose in relation with the content of the manuscript. Olivier ROUVIERE has no conflict of interest to disclose in relation with the content of the manuscript. Salim SI-MOHAMED has no conflict of interest to disclose in relation with the content of the manuscript. Renaud TOURAINE has no conflict of interest to disclose in relation with the content of the manuscript. Julie TRACLET has no conflict of interest to disclose in relation with the content of the manuscript. Ségolène TURQUIER has no conflict of interest to disclose in relation with the content of the manuscript. Stéphane VAGNARELLI has no conflict of interest to disclose in relation with the content of the manuscript. Kaïs AHMAD has no conflict of interest to disclose in relation with the content of the manuscript., (Copyright © 2023 SPLF and Elsevier Masson SAS. All rights reserved.)

In locally advanced non-small-cell lung cancer (NSCLC), mediastinal staging is the cornerstone of the therapeutic decision and echoendoscopy is the most practiced exam to assess the lymph node involvement. We describe a rare case of endobronchial involvement by cells originating from a metastatic lymph node after endobronchial ultrasound (EBUS). A 64-year-old man was diagnosed with a squamous cell lung cancer with mediastinal nodal involvement proven by EBUS. The patient received neoadjuvant chemotherapy with partial response and was scheduled for a lobectomy. Before surgery, a fibroscopy was performed which demonstrated a 1-cm polypoid lesion settled on the internal face of the main right bronchus corresponding to the EBUS puncture site. The histological analysis confirmed tumoral cell in this lesion. The patient was rejected for surgery and undergo chemoradiation. This case highlights the need for a careful endoscopic control before surgical resection in case of prior positive EBUS followed by an interval of time.

Aims: The association between lung cancer and idiopathic pulmonary fibrosis (IPF) is well known, but the significance of this association is poorly understood. Bronchiolar honeycomb cysts have been proposed as possible precursors for the development of carcinoma, but limited evidence in support of this hypothesis is available. The aim of this study was to investigate this hypothesis analysing a series of carcinomas arising in IPF by immunohistochemistry., Methods and Results: Thirty-three lung carcinomas arising in patients with IPF were analysed with a panel of immunohistochemical markers. The antibodies included those against pneumocyte markers [thyroid transcription factor 1 (TTF1), napsin-A, and surfactant protein A], the goblet cell marker mucin 5AC, markers of basal/squamous cell differentiation [cytokeratin (CK) 5/6 and ΔN-p63], and markers related to enteric differentiation (CDX2, mucin 2, CK20, and villin). A series of 100 consecutive lung adenocarcinomas arising in smokers without IPF were investigated as controls. All carcinomas arising in IPF patients were peripherally located on imaging analysis. The diagnoses were: eight squamous cell carcinomas, 20 adenocarcinomas, three small-cell carcinomas (including one composite small-cell carcinoma and adenocarcinoma), and two large-cell carcinomas. Among adenocarcinomas, a 'pneumocyte' profile (TTF1/napsin-A/SPA1-triple-positive) was observed in seven of 20 (35% versus 84% in non-IPF controls, P = 0.0001). The remaining 13 adenocarcinomas (65%) showed rare histotypes: four invasive mucinous adenocarcinomas (20% in IPF patients versus 1% in non-IPF controls, P = 0.002), seven tumours (35%) that were characterized by variable expression of markers of enteric differentiation, and two tumours (10%) that showed a peculiar basaloid component., Conclusions: The immunohistochemical characterization of carcinomas arising in IPF patients shows striking divergence from that in non-IPF smokers. The prevalence of rare entities showing bronchiole-related markers is in line with the hypothesis that these tumours arise from transformed small airways in honeycomb lung areas where abnormal bronchiolar proliferation takes place., (© 2017 John Wiley & Sons Ltd.)

Lymph vessels play an important role in tumor progression. Pulmonary adenocarcinomas, accounting for half of non-small-cell lung carcinomas, compose a spectrum of histological types, exclusively or without a lepidic growth pattern (LGP) along preserved interalveolar septa. In that context, this study was designed to investigate the lymphatic vascular pattern associated with LGP and the concomitant invasive component of pulmonary adenocarcinomas. Using the D2-40 monoclonal antibody as a marker of lymphatic endothelial cells, the lymphatic vessel density (LVD) and vessel-area fraction (LVAF) were morphometrically analyzed in four adenocarcinomas in situ (AIS) and the LGP of eight invasive adenocarcinomas (LPIA), and compared with their invasive pattern (IPIA). LVD in AIS (2.1 ± 0.7 mm(-2)) and LPIA (2.4 ± 1 mm(-2)) were significantly lower than that in IPIA (14.9 ± 13.6 mm(-2)) (p=0.001). Moreover, the lymphatic vascular pattern in LGP was similar to that of normal lung, with isolated small lymphatic vessels within the interalveolar septa. Our results showing the scarcity of lymphatics in LGP suggest an absence of septal lymphangiogenesis associated with the LGP pattern in lung adenocarcinomas, which could explain, at least partially, the better prognosis observed in tumors with exclusive or predominant lepidic spread compared with other subtypes.

Introduction: Investigation of the role of vascular endothelial growth factor-C (VEGF-C) and VEGF receptor-3 (VEGFR-3) in non-small-cell lung cancer (NSCLC) has mainly focused on lymph node (LN) metastasis related to lymphangiogenesis. However, the coexpression of VEGF-C/VEGFR-3 by tumour cells can independently play an important role. The present study was therefore designed to evaluate VEGF-C/VEGFR-3 coexpression in tumour cells from the primary tumour and corresponding LN metastases., Methods: VEGF-C and VEGFR-3 expression in cancer cells were evaluated by immunohistochemistry in 92 NSCLC samples and 45 metastatic LNs. Ki67 expression and mitotic index (MI) in tumours and clinicopathological data were analysed concurrently., Results: VEGFR-3 and VEGF-C expression were observed in 42% and 74% of tumours, respectively. Concurrent expression of VEGF-C and VEGFR-3, observed in 39% of tumours, was significantly associated with a higher proliferation rate and a higher incidence of LN metastases. VEGF-C expression in tumour cells was observed in 100% of metastatic LN and VEGF-C/VEGFR-3 coexpression was observed in 71% of metastatic LN. Finally, concurrent expression of VEGF-C/VEGFR-3 in the primary tumour was associated with poor disease-free survival on univariate analysis., Conclusion: In NSCLC cancer cells, VEGF-C/VEGFR-3 coexpression suggests an autocrine/paracrine loop responsible for a high proliferation rate in tumour cells. As VEGF-C/VEGFR-3 coexpression is very frequent in metastatic LN tumour cells, it can be hypothesised that this coexpression participates in the growth of LN metastasis.

The aim of the current study was to seek evidence for a correlation between mediators present in lung cancer micro-environments and subsets of dendritic cells (DCs) infiltrating these tumours. Immunohistochemistry and recently available antibodies were used to define the phenotype of DCs present in surgical biopsies from 12 patients with lung carcinomas, and the local expression of chemokines potentially involved in the recruitment of these cells was evaluated, both at mRNA and protein levels. Real-time PCR was used to analyse the expression of mRNA coding for cytokines known to influence the maturation of DCs in vitro. Different subsets of myeloid DCs were present in lung cancers, but no plasmocytoid DCs were identified. Both Langerhans cells and CD1a+/Langerin cells were interspersed among tumour cells, in numbers that were correlated to the amounts of CC chemokine ligand 20 produced in these tumours. In most specimens, DC-specific intercellular adhesion molecule-grabbing nonintegrin-positive DCs were also present at the periphery of the tumour beds. No DC-lysosomal associated membrane protein-positive DCs were identified and CD83+ DCs were rarely present in the tumour stroma. All tumours expressed interleukin (IL)-10, transforming growth factor-beta and vascular endothelial growth factor, whereas IL-12 was virtually absent. Thus, various types of dendritic cells infiltrate lung carcinomas and display an immature phenotype, presumably because of the inhibitory cytokine micro-environment.

Metastatic lymph nodes (LNs) are the major prognostic factor in resected non small cell lung carcinoma (NSCLC). However, almost 50% of pN0 patients relapse, suggesting metastatic cells undetected by current staging procedures. A combination of markers [cytokeratins 19 and 7 (CK19, CK7) and mucin type 1 (MUC1) mRNAs] was therefore evaluated by real-time RT-PCR in order to detect occult cancer cells. Forty-three NSCLC tumor samples, 4 micrometastatic, 6 metastatic and 84 histologically negative mediastinal LNs from 19 patients with NSCLC were evaluated as well as blood mononuclear cells from 29 healthy volunteers and 17 benign LNs. When tested on cell lines, RT-PCR was particularly efficient for evaluation of CK19, CK7 and MUC1 mRNA expression. All tumor samples were positive for at least 1 marker and 74% of samples were positive for all 3 markers. CK7 and CK19 mRNA were not detected in benign LN and blood cells from healthy donors in contrast with MUC1 mRNA. Only CK7 and CK19 mRNA were therefore used for evaluation of mediastinal LNs: the 6 histologically metastatic and the 4 micrometastatic LNs were positive for at least one marker. Among the 84 histologically negative LNs, 6 (7%) were positive for at least one marker, potentially changing the stage of 2 out of 19 patients. In conclusion, in our feasibility study, parallel molecular detection of CK19 and CK7 mRNA can be considered a specific diagnostic tool for the assessment of microscopic lymphatic spread. Its prognostic impact remains to be evaluated in a prospective study., ((c) 2005 Wiley-Liss, Inc.)

We present practice guidelines for the examination of lung specimens removed for cancer, and pulmonary biopsies performed for interstitial lung diseases. In addition, we propose a standardized form for the reporting of lung cancer. This approach takes place in looking for better quality and should facilitate the use of the morphologic data, particularly in multicentric studies.

Introduction: Less than 2 per 1,000 meningiomas are complicated by extra-cranial metastases. These are most often found in the lung parenchyma, liver or lymph nodes. They almost always occur in anaplastic meningiomas (grade III according to OMS) and much more rarely in atypical meningiomas (grade II)., Case Report: We report a case of pleural metastases from a primary frontal atypical meningioma with no other extra-cranial spread., Conclusion: Poorly differentiated meningioma presents many morphological and immuno-histochemical similarities to malignant mesothelioma. For this reason the diagnosis of pleural metastase from a meningioma cannot be made without knowledge of the primary meningeal tumour and its histological type.

Endometrial stromal sarcoma (ESS) is a rare neoplasm, mainly observed in premenopausal women. We describe two women 44 and 34 years old at the time ESS diagnosis, who developed lung metastases 3 and 6 years, respectively, after initial treatment: hysterectomy without (case 1) or with oophorectomy (case 2), followed by hormone replacement therapy (HRT) for the latter. Their estrogen (ER) and progesterone receptors (PR) were analyzed biochemically in metastatic lung tissue, yielding respective concentrations of ER 242 and 184, and PR 910 and 100 fmol/mg of cytosol protein. Both patients started treatment with the aromatase inhibitor aminoglutethimide (500 mg qid) after surgery for the first patient and after stopping HRT for the second. Under aromatase-inhibitor therapy, both patients achieved a complete response, patient 1 remains disease- free with 14+ years of follow-up, and patient 2 with 7+ years. Our data suggest that an aromatase inhibitor may be an effective treatment for ESS. Furthermore, routine ER and PR analyses could be useful to predict the response to hormonal therapy in ESS.

Background: The association between interstitial lung disease (ILD) and an increased risk of developing lung cancer has been reported. The goal of this retrospective study was to determine the outcome of lung cancer resection among patients with ILD., Methods: Between January 1979 and March 1999, 27 patients with both lung cancer and ILD were identified. Seven patients with poor pulmonary function tests or distant metastases underwent medical treatment and were excluded from this study. Twenty patients treated by surgical resection were analyzed., Results: Various types of ILD such as sarcoidosis (n = 7), idiopathic interstitial pneumonia (n = 4), histiocytosis X (n = 4), pneumoconiosis (n = 4), and amiodarone-induced ILD (n = 1) were observed. Tumors were located in the peripheral part of the lung in 16 cases. The most frequent tumor cell types were squamous and adenocarcinoma. The resections consisted of lobectomy (n = 16), bilobectomy (n = 1), and pneumonectomy (n = 3). Most cancers were stage I (n = 10) or II (n = 6). There was no postoperative death. The postoperative course was uneventful in 16 cases. The majority of patients (70%) did not experience respiratory insufficiency during the follow-up period. The actuarial 2-year and 5-year survival rates were, respectively, 83.5% and 66.4%., Conclusions: In this series, the long-term survival of patients who had lung cancer resection appeared to be not affected by the association with ILD. This could be explained by an adequate preoperative selection based on pulmonary function tests and a preferential choice for lobectomies. Thus, surgical resection should be offered to properly selected patients with lung cancer and underlying ILD.

K-ras activation by point mutation in codon 12 has been reported in lung adenocarcinomas in various models of experimental lung tumours induced by chemical carcinogens. The hypothesis of the presence of cells containing K-ras mutation in non neoplastic bronchial carina, the main site of impaction of airborne contaminants, was investigated by evaluating concurrent lung tumour and non-neoplastic proximal bronchial carinae from 19 patients with lung adenocarcinomas. The restriction fragment length polymorphism enriched PCR method used can detect one mutant allele among 10(3) normal alleles. A mutation was detected in 42% of lung adenocarcinoma samples. No mutation was detected in either tumour or bronchial carinae in nine patients (47%). K-ras mutation was detected in the lung tumour but not in bronchial carinae in four patients (21%), in both the lung tumour and bronchial carinae in four other patients (21%). In two patients (11%), K-ras mutation was detected in at least one bronchial carina, but not in the lung tumour. Mutations of codon 12, confirmed by sequencing analysis of ten samples, were G to T transversion, mostly TGT and GTT in bronchial carinae and lung tumours. Our data show that activated K-ras by point mutation can be present in non-neoplastic bronchial carina mucosa even when no mutation is detected in tumour samples.

Ki-ras activation by point mutation on codon 12 has been reported in non-small-cell lung carcinomas and in various models of experimental lung tumours induced by chemical carcinogens. The cellular targets for carcinogenic compounds of tobacco smoke are usually considered to be the cells of the bronchial mucosa or alveolar epithelium. However, little is known about preneoplastic events in bronchopulmonary carcinogenesis. The hypothesis of the presence of widespread target cells containing Ki-ras mutation was investigated by evaluating concurrent neoplastic and non-neoplastic bronchial and alveolar samples from 51 patients with non-small-cell lung carcinomas. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method used can detect one cell with a mutation on codon 12 among 10(2) normal cells. In tumour samples, a mutation was detected in 20% of adenocarcinomas, but in none of the adenosquamous or squamous cell carcinomas. No mutation was detected in the non-neoplastic bronchial or parenchymal samples. When using an enriched PCR-RFLP method detecting one mutated allele among 10(3) normal alleles a mutation was detected in 23% of adenocarcinomas. In conclusion, Ki-ras activation by mutation on codon 12 was not observed in non-neoplastic bronchial or parenchymal tissues in patients with bronchopulmonary cancers and does not appear to be a genetic event present in non-malignant epithelial target cells exposed to tobacco smoke.

The authors having prepared for a case of pulmonary lymphangioleiomatosis point out the diagnostic boundaries of this condition with benign metastasizing intravenous leiomyomas of the uterus, pulmonary localisation of Bourneville's tuberous sclerosis and the important aetio pathologic role of sex hormones. Finally they deal with the therapeutic management and the various uses of hormones to inhibit oestrogenic activity.