Search

Adult recurrence of infantile myofibromatosis is exceptional. Here, we report the case of a 23-year-old woman with a late recurrence of infantile myofibromatosis revealed by spontaneous pneumothorax. The chest computed tomography scan found both cavitary and nodular bilateral pulmonary lesions. In infancy, she had multicentric myofibromatosis with digestive, cutaneous, and bone involvement, spontaneously regressive before the age of 15 months. Histological analysis of lung samples showed identical findings as from the cutaneous biopsy performed in infancy, confirming the recurrence of infantile myofibromatosis as pulmonary metastasis. New biopsy and long-term follow-up are highly recommended in the management of such cases., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Annals of Thoracic Medicine.)

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 mm 2 . 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., Competing Interests: Disclosure Where authors are identified as personnel of the International Agency for Research on Cancer/WHO, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer/WHO. The rest of the authors declare no conflict of interest., (Copyright © 2024 World Health Organization. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Meningiomas are the most common type of primary central nervous system tumors. In about 80% cases, these tumors are benign and grow very slowly, but the remainder 20% can unlock higher proliferation rates and become malignant. In this study we examined two miRs, miR-16 and miR-519, and evaluated their role in tumorigenesis and cell growth in human meningioma., Methods: A cohort of 60 intracranial grade 1 and grade 2 human meningioma plus 20 healthy meningeal tissues was used to quantify miR-16 and miR-519 expressions. Cell growth and dose-response assays were performed in two human meningioma cell lines, Ben-Men-1 (benign) and IOMM-Lee (aggressive). Transcriptomes of IOMM-lee cells were measured after both miR-mimics transfection, followed by integrative bioinformatics to expand on available data., Results: In tumoral tissues, we detected decreased levels of miR-16 and miR-519 when compared with arachnoid cells of healthy patients (miR-16: P=8.7e-04; miR-519: P=3.5e-07). When individually overexpressing these miRs in Ben-Men-1 and IOMM-Lee, we observed that each showed reduced growth (P<0.001). In IOMM-Lee cell transcriptomes, downregulated genes, among which ELAVL1/HuR (miR-16: P=6.1e-06; miR-519:P=9.38e-03), were linked to biological processes such as mitotic cell cycle regulation, pre-replicative complex, and brain development (FDR<1e-05). Additionally, we uncovered a specific transcriptomic signature of miR-16/miR-519-dysregulated genes which was highly enriched in HuR targets (>6-fold; 79.6% of target genes)., Discussion: These results were confirmed on several public transcriptomic and microRNA datasets of human meningiomas, hinting that the putative tumor suppressor effect of these miRs is mediated, at least in part, via HuR direct or indirect inhibition., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hergalant, Casse, Oussalah, Houlgatte, Helle, Rech, Vallar, Guéant, Vignaud, Battaglia-Hsu and Gauchotte.)

Background: ALK , ROS1 and RET rearrangements occur, respectively, in 5%, 2%, and 1% non-small cell lung cancers (NSCLC). ALK and ROS1 fusion proteins detection by immunohistochemistry (IHC) has been validated for rapid patient screening, but ROS1 fusions need to be confirmed by another technique and no RET IHC test is available for clinical use., Research Design and Methods: We report herein the usefulness of the HTG EdgeSeq Assay, an RNA extraction-free test combining a quantitative nuclease protection assay with NGS, for the detection of ALK , ROS1 and RET fusions from 'real-life' small NSCLC samples. A total of 203 FFPE samples were collected from 11 centers. They included 143 rearranged NSCLC (87 ALK , 39 ROS1 , 17 RET ) and 60 ALK - ROS1 - RET negative controls., Results: The assay had a specificity of 98% and a sensitivity for ALK , ROS1 and RET fusions of 80%, 94% and 100% respectively. Among the 19 HTG-assay false negative samples, the preanalytical conditions were identified as the major factors impacting the assay efficiency., Conclusions: Overall, the HTG EdgeSeq assay offers comparable sensitivities and specificity than other RNA sequencing techniques, with the advantage that it can be used on very small and old samples collected multicentrically.

Malignant pleural mesothelioma (MPM) is an aggressive cancer with rising incidence and challenging clinical management. Through a large series of whole-genome sequencing data, integrated with transcriptomic and epigenomic data using multiomics factor analysis, we demonstrate that the current World Health Organization classification only accounts for up to 10% of interpatient molecular differences. Instead, the MESOMICS project paves the way for a morphomolecular classification of MPM based on four dimensions: ploidy, tumor cell morphology, adaptive immune response and CpG island methylator profile. We show that these four dimensions are complementary, capture major interpatient molecular differences and are delimited by extreme phenotypes that-in the case of the interdependent tumor cell morphology and adapted immune response-reflect tumor specialization. These findings unearth the interplay between MPM functional biology and its genomic history, and provide insights into the variations observed in the clinical behavior of patients with MPM., (© 2023. The Author(s).)

Background: 3-9% of low-grade preinvasive bronchial lesions progress to cancer. This study assessed the usefulness of an intensive bronchoscopy surveillance strategy in patients with bronchial lesions up to moderate squamous dysplasia., Methods: SELEPREBB (ClinicalTrials.gov NCT00213603) was a randomised study conducted in 17 French centres. After baseline lung computed tomography (CT) and autofluorescence bronchoscopy (AFB) to exclude lung cancer and bronchial severe squamous dysplasia or carcinoma in situ (CIS), patients were assigned to standard surveillance (arm A) with CT and AFB at 36 months or to intensive surveillance (arm B) with AFB every 6 months. Further long-term data were obtained with a median follow-up of 4.7 years., Results: 364 patients were randomised (A: 180, B: 184). 27 patients developed invasive lung cancer and two developed persistent CIS during the study, with no difference between arms (OR 0.63, 95% CI 0.20-1.96, p=0.42). Mild or moderate dysplasia at baseline bronchoscopy was a significant lung cancer risk factor both at 3 years (8 of 74 patients, OR 6.9, 95% CI 2.5-18.9, p<0.001) and at maximum follow-up (16 of 74 patients, OR 5.9, 95% CI 2.9-12.0, p<0.001). Smoking cessation was significantly associated with clearance of bronchial dysplasia on follow-up (OR 0.12, 95% CI 0.01-0.66, p=0.005) and with a reduced risk of lung cancer at 5 years (OR 0.15, 95% CI 0.003-0.99, p=0.04)., Conclusion: Patients with mild or moderate dysplasia are at very high risk for lung cancer at 5 years, with smoking cessation significantly reducing the risk. Whereas intensive bronchoscopy surveillance does not improve patient outcomes, the identification of bronchial dysplasia using initial bronchoscopy maybe useful for risk stratification strategies in lung cancer screening programmes., Competing Interests: Conflict of interest: All authors report payment for study completion to participating institutions from the French Ministry of Health (PHRC National). In addition, within the 36 months prior to manuscript submission: S. Lachkar reports consulting fees and payment or honoraria from Olympus, Fuji and TSC; payment or honoraria from Merck Sharp & Dohme; and participation on a data safety monitoring or advisory board for Boston Scientific. P. Hofman reports consulting fees, payment or honoraria and participation on data safety or advisory boards from AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Roche, Pfizer, Bayer, Novartis, Illumina, Thermo Fisher, AbbVie, Biocartis and Lilly. G. Zalcman reports consulting fees from Bristol Myers Squibb and AstraZeneca, paid to their institution, and support for attending meetings or travel from AstraZeneca (ASCO 2019), Bristol Myers Squibb (ESMO 2018 and 2019) and AbbVie (ASCO 2019). All other authors declare no additional competing interests., (Copyright ©The authors 2022. For reproduction rights and permissions contact permissions@ersnet.org.)

Introduction: Histologic subtypes of malignant pleural mesothelioma are a major prognostic indicator and decision denominator for all therapeutic strategies. In an ambiguous case, a rare transitional mesothelioma (TM) pattern may be diagnosed by pathologists either as epithelioid mesothelioma (EM), biphasic mesothelioma (BM), or sarcomatoid mesothelioma (SM). This study aimed to better characterize the TM subtype from a histological, immunohistochemical, and molecular standpoint. Deep learning of pathologic slides was applied to this cohort., Methods: A random selection of 49 representative digitalized sections from surgical biopsies of TM was reviewed by 16 panelists. We evaluated BAP1 expression and CDKN2A (p16) homozygous deletion. We conducted a comprehensive, integrated, transcriptomic analysis. An unsupervised deep learning algorithm was trained to classify tumors., Results: The 16 panelists recorded 784 diagnoses on the 49 cases. Even though a Kappa value of 0.42 is moderate, the presence of a TM component was diagnosed in 51%. In 49% of the histological evaluation, the reviewers classified the lesion as EM in 53%, SM in 33%, or BM in 14%. Median survival was 6.7 months. Loss of BAP1 observed in 44% was less frequent in TM than in EM and BM. p16 homozygous deletion was higher in TM (73%), followed by BM (63%) and SM (46%). RNA sequencing unsupervised clustering analysis revealed that TM grouped together and were closer to SM than to EM. Deep learning analysis achieved 94% accuracy for TM identification., Conclusion: These results revealed that the TM pattern should be classified as non-EM or at minimum as a subgroup of the SM type., (Copyright © 2020. Published by Elsevier Inc.)

The percentage of sarcomatoid component has an impact on prognosis in patients with biphasic malignant pleural mesothelioma. Recent study showed that the transitional pattern similar to sarcomatoid component of malignant mesothelioma has negative prognostic significance. Practice guidelines recommend quantification of sarcomatoid component despite poor diagnostic reproducibility of biphasic mesothelioma among thoracic pathologists. The aim of this study was to determine the interobserver agreement in the quantification of sarcomatoid component, and in the diagnosis of a transitional component in the biphasic malignant mesothelioma. Thirteen experts in thoracic pathology reviewed the representative H&E and cytokeratin whole-slide images of the 54 biphasic mesotheliomas, without knowledge of BAP1 or p16 deletion status, and completed the survey of 25 questions. The overall interobserver agreement in the assessment of the percentage of the sarcomatoid component in 25% increments was good (wK = 0.62). Excellent agreement was present in 14 of 54 cases (26%), and 3 cases were unanimously scored. Excellent agreement was reached for the cases with 0-24% and > 75% of the sarcomatoid component.The most commonly used criteria for the diagnosis of sarcomatoid component were malignant spindle cells, frank sarcomatoid features and high N/C ratio. The overall interobserver agreement for transitional pattern was fair (wK = 0.40). Unanimous opinion about the absence of transitional pattern was observed in only one case. At least 70% agreement regarding the presence of transitional pattern was observed in 12 cases, with the rest of the cases showing a wide range of disagreement. Morphologic characteristics that favor transitional pattern over non-transitional include sheet-like growth of cohesive, plump, elongated epithelioid cells with well-defined cell borders and a tendency to transition into spindle cells. Our study defined precise morphologic criteria that may be used in the differential diagnosis between transitional pattern and other mesothelioma subtypes including sarcomatoid and epithelioid.

Denosumab, an antibody directed against receptor activator of nuclear factor-κB ligand (RANKL), has recently been introduced in the treatment strategy of giant cell tumor of bone. In this study, we assessed the tumor changes induced by denosumab in a national multicentric series of 35 cases (French Bone Pathology Group network-ResOs). Tissue specimens collected before and after denosumab treatment were investigated for RANKL, H3.3 G34W, p63, and Ki-67 expression, and for H3F3A mutation. These parameters were put in correspondance with clinical and radiologic presentation to identify prognostic factors, and more specifically, predictive markers of an optimal histologic response to denosumab, identified as a ≥50% loss in giant cells with fibrosis and ossification. The main changes in posttreatment specimens showed an induction of ossification (P=2.10), an increased fibrosis (P=3.10), and a major decrease in giant cells (P=6.10). No significant change in mononuclear tumor cell density and in patterns of expression of RANKL (P=0.061) and H3.3 G34W was observed (P=0.061). An optimal histologic response to denosumab treatment was associated with an enhanced progression-free survival (P=0.010 in univariate analyses; P=0.040 in multivariate analyses). The initial number of giant cells was predictive of the histologic response to treatment (P=0.016). In summary, denosumab treatment induced radical changes in the tumor. The histologic response, despite the absence of objective regression of the mononuclear cells, was associated with an enhanced progression-free survival. Greater numbers of giant cells represented the only predictive indication of an optimal histologic response to denosumab treatment.

Introduction: Molecular and immunologic breakthroughs are transforming the management of thoracic cancer, although advances have not been as marked for malignant pleural mesothelioma where pathologic diagnosis has been essentially limited to three histologic subtypes., Methods: A multidisciplinary group (pathologists, molecular biologists, surgeons, radiologists, and oncologists), sponsored by European Network for Rare Adult Solid Cancers/International Association for the Study of Lung Cancer, met in 2018 to critically review the current classification., Results: Recommendations include: (1) classification should be updated to include architectural patterns and stromal and cytologic features that refine prognostication; (2) subject to data accrual, malignant mesothelioma in situ could be an additional category; (3) grading of epithelioid malignant pleural mesotheliomas should be routinely undertaken; (4) favorable/unfavorable histologic characteristics should be routinely reported; (5) clinically relevant molecular data (programmed death ligand 1, BRCA 1 associated protein 1 [BAP1], and cyclin dependent kinase inhibitor 2A) should be incorporated into reports, if undertaken; (6) other molecular data should be accrued as part of future trials; (7) resection specimens (i.e., extended pleurectomy/decortication and extrapleural pneumonectomy) should be pathologically staged with smaller specimens being clinically staged; (8) ideally, at least three separate areas should be sampled from the pleural cavity, including areas of interest identified on pre-surgical imaging; (9) image-acquisition protocols/imaging terminology should be standardized to aid research/refine clinical staging; (10) multidisciplinary tumor boards should include pathologists to ensure appropriate treatment options are considered; (11) all histologic subtypes should be considered potential candidates for chemotherapy; (12) patients with sarcomatoid or biphasic mesothelioma should not be excluded from first-line clinical trials unless there is a compelling reason; (13) tumor subtyping should be further assessed in relation to duration of response to immunotherapy; and (14) systematic screening of all patients for germline mutations is not recommended, in the absence of a family history suspicious for BAP1 syndrome., Conclusions: These multidisciplinary recommendations for pathology classification and application will allow more informative pathologic reporting and potential risk stratification, to support clinical practice, research investigation and clinical trials., (Copyright © 2019 International Association for the Study of Lung Cancer. All rights reserved.)

Introduction: PELICAN ("Partager Efficacement en Laboratoire les Informations des Comptes rendus ANatomopathologiques") is a software, which generates standardized reports, and allows to automatically create a database. It has been used in central nervous system tumor pathology at the University Hospital of Nancy since 2014. The purpose of this article was to illustrate the use of this application for meningiomas, with a first statistical evaluation., Materials and Methods: The export of data included all cases of meningiomas recorded in the PELICAN application until July 2018. The PELICAN application is a Microsoft Excel file containing a software, written in Visual Basic for Applications, and used by the pathologist to create the report. The main clinical data were collected from the Hérault Register census form. Follow-up was systematically reported for atypical meningiomas., Results: Two hundred and ninety-five meningiomas were analyzed, including 250 grade I meningiomas, 42 grade II meningiomas, and 3 grade III meningiomas. Grade II meningiomas were characterized by a significantly higher proportion of men (P=0.002) and dural infiltration (P<0.001), a significant increase in the Ki-67 index (P<0.0001), and a significant decrease in progesterone receptor expression (P<0.001). In atypical meningiomas, a Ki-67 index of more than 20 % was significantly correlated with a shorter progression-free survival (P=0.032)., Conclusion: The PELICAN software is an easy-to-use tool that allows to generate standardized reports and feed a database, opening very interesting perspectives from an epidemiological and scientific point of view., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Gross examination is an essential step for pathological report of a surgical sample. It includes the description of the surgical specimen and their disease(s), the precise and exhaustive sampling of tumoral and adjacent tumoral tissue areas. This examination requires a good knowledge of the updated pTNM classification. Pathologists from the PATTERN group have collaborated with thoracic surgeons, under the auspices of the Sociéte française de pathologie, to propose guidelines for resected specimen management. This approach fits into the context of the elaboration of structured pathological report proposed by the société française de pathologie, which is necessary for a standardized management of patients., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Background: Malignant Pleural Mesothelioma (MPM) is an aggressive disease related to asbestos exposure, with no effective therapeutic options., Methods: We undertook unsupervised analyses of RNA-sequencing data of 284 MPMs, with no assumption of discreteness. Using immunohistochemistry, we performed an orthogonal validation on a subset of 103 samples and a biological replication in an independent series of 77 samples., Findings: A continuum of molecular profiles explained the prognosis of the disease better than any discrete model. The immune and vascular pathways were the major sources of molecular variation, with strong differences in the expression of immune checkpoints and pro-angiogenic genes; the extrema of this continuum had specific molecular profiles: a "hot" bad-prognosis profile, with high lymphocyte infiltration and high expression of immune checkpoints and pro-angiogenic genes; a "cold" bad-prognosis profile, with low lymphocyte infiltration and high expression of pro-angiogenic genes; and a "VEGFR2+/VISTA+" better-prognosis profile, with high expression of immune checkpoint VISTA and pro-angiogenic gene VEGFR2. We validated the gene expression levels at the protein level for a subset of five selected genes belonging to the immune and vascular pathways (CD8A, PDL1, VEGFR3, VEGFR2, and VISTA), in the validation series, and replicated the molecular profiles as well as their prognostic value in the replication series., Interpretation: The prognosis of MPM is best explained by a continuous model, which extremes show specific expression patterns of genes involved in angiogenesis and immune response., (Copyright © 2018. Published by Elsevier B.V.)

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.

Introduction: The detection of a ROS1 rearrangement in advanced and metastatic lung adenocarcinoma (LUAD) led to a targeted treatment with tyrosine kinase inhibitors with favorable progression-free survival and overall survival of the patients. Thus, it is mandatory to screen for the ROS1 rearrangement in all these patients. ROS1 rearrangements can be detected using break-apart fluorescence in situ hybridization (FISH), which is the gold standard; however, ROS1 immunohistochemistry (IHC) can be used as a screening test because it is widely available, easy and rapid to perform, and cost-effective., Methods: We evaluated the diagnostic accuracy and interpathologist agreement of two anti-ROS1 IHC clones, SP384 (Ventana, Tucson, Arizona) and D4D6 (Cell Signaling, Danvers, Massachusetts), in a training cohort of 51 positive ROS1 FISH LUAD cases, and then in a large validation cohort of 714 consecutive cases of LUAD from six routine molecular pathology platforms., Results: In the two cohorts, the SP384 and D4D6 clones show variable sensitivity and specificity rates on the basis of two cutoff points greater than or equal to 1+ (all % tumor cells) and greater than or equal to 2+ (>30% stained tumor cells). In the validation cohort, the D4D6 yielded the best accuracy for the presence of a ROS1 rearrangement by FISH. Interpathologist agreement was moderate to good (interclass correlation 0.722-0.874) for the D4D6 clone and good to excellent (interclass correlation: 0.830-0.956) for the SP384 clone., Conclusions: ROS1 IHC is an effective screening tool for the presence of ROS1 rearrangements. However, users must be acutely aware of the variable diagnostic performance of different anti-ROS1 antibodies before implementation into routine clinical practice., (Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Current histoprognostic parameters and prognostic scores used in paragangliomas and pheochromocytomas do not adequately predict the risk of metastastic progression and survival. Here, using a series of 147 cases of paraganglioma and pheochromocytoma, we designed and evaluated the potential of a new score, the COPPS (COmposite Pheochromocytoma/paraganglioma Prognostic Score), by taking into consideration three clinico-pathological features (including tumor size, necrosis, and vascular invasion), and the losses of PS100 and SDHB immunostain to predict the risk of metastasis. We compared also the performance of the COPPS with several presently used histoprognostic parameters in risk assessment of these tumors. A PASS score (Pheochromocytoma of the Adrenal gland Scaled Score) ≥ 6 was significantly associated with the occurrence of metastases (P < 0.0001) and shorter PFS (P = 0.013). In addition, both MCM6 and Ki-67 LI correlated with worse PFS (P = 0.004 and P < 0.0001, respectively), and MCM6, but not Ki-67, was significantly higher in metastatic group (P = 0.0004). Loss of PS100 staining correlated with the occurrence of metastasis (P < 0.0001) and shorter PFS (P < 0.0001). At a value of greater or equal to 3, the COPPS correlated with shorter PFS (P < 0.0001), and predicted reproducibly (weighted Kappa coefficient, 0.863) the occurrence of metastases with a sensitivity of 100.0% and specificity of 94.7%. It thus surpassed those found for either PASS, SDHB, MCM6, or Ki-67 alone. In conclusion, while validation is still necessary in independent confirmatory cohorts, COPPS could be of great potential for the risk assessment of metastasis and progression in paragangliomas and pheochromocytomas.

Introduction: PELICAN (« Partager Éfficacement en Laboratoire les Informations des Comptes rendus ANatomopathologiques ») is a software which generates standardized reports and, in parallel, allows to automatically create a database that can be used for research purpose. This application has been used in our laboratory since 2014 for central nervous system tumors. The aim of this work was to extend it to another type of tumor, lung cancer., Materials and Methods: The content of the pathology reports was previously defined using various standards (Société Française de Pathologie, Institut National du Cancer, WHO Classification 2015, …). A double codification was used with SNOMED and ADICAP codes. The PELICAN application is a Microsoft Excel file containing a software specifically developed for pathology laboratories, written in Visual Basic for Applications and respecting the CDA-R2 standard., Results: After definition of the software specifications, a beta-version was installed in February 2018. After various updates, the 3.19 version was installed in July 2018. Almost all lung cancer surgical pathology reports are now generated with the PELICAN software; a total of 56 reports were validated at the time of writing this manuscript. The medical time for the generation of the report was globally the same or decreased for some pathologists. The secretarial time was greatly reduced., Conclusion: The PELICAN software is an easy to use tool that allows to generate standardized reports in pulmonary pathology and to feed a database that can be easily used for statistical purposes., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Background: Well-differentiated papillary mesothelioma of the peritoneum (WDPMP) is a rare entity. Questions regarding management are still being debated as no more than 50 cases have been reported in the literature., Objective: We aimed to analyze the clinical, therapeutic, and prognostic data of patients with WDPMP from the RENAPE observational registry., Patients and Methods: All patients diagnosed with WDPMP and prospectively included in the RENAPE national registry between 2010 and 2018 were also included in our study. Expert pathologists from the RENA-PATH group confirmed all cases. All clinical, therapeutic, postoperative, and prognostic data were extracted and analyzed., Results: We report on 56 patients with a mean age of 52 years (range 21-74). WDPMP was incidentally diagnosed during imaging or surgery in 16% and 36% of patients, respectively, and an association with synchronous malignancy was found in 18% of patients. Nine lesions showed discrete signs of fatty invasion. The median Peritoneal Cancer Index was 11 (range 0-33). Eleven patients were treated with definitive excision, 4 were treated with cytoreductive surgery (CRS) only, 37 were treated with CRS and hyperthermic intraperitoneal chemotherapy (HIPEC), and 2 were treated with CRS plus HIPEC plus early postoperative intraperitoneal chemotherapy. CRS was considered to be complete in 90% of cases. One patient died postoperatively and 16 patients (31%) faced postoperative complications. The median disease-free survival was 144 months; Four patients relapsed, with a median period of 27 months. No prognostic factors could be identified., Conclusions: Our analysis confirms the favorable prognosis of WDPMP. CRS and HIPEC could be a therapeutic option for diffuse, symptomatic, and/or recurrent disease.

Background: The purpose of this study was to describe the pathology of the different compartments in endoscopic resection of nasal intestinal-type adenocarcinomas (ITACs) and its relationships with oncologic outcomes., Methods: This retrospective study included all patients endoscopically operated for nasal ITACs, followed by radiotherapy in the majority of cases, between 2004 and 2014. The surgery systematically separated 3 compartments: ethmoid lateral mass, olfactory cleft, and anterior cranial fossa (in cases with skull-base invasion) to analyze their pathological "focal" or "massive" invasion by the tumor., Results: Sixty-seven patients (aged 69.2 ± 9.8 years) were included. Twenty-nine patients (43.3%) had only pathological focal invasion. At 61.0 ± 41.7 months of mean follow-up, the recurrence rates were 34.2% in the group with massive invasion and 10.3% in the group with focal invasion (P = .023). The disease-specific death rate had a tendency to be higher in the group with massive invasion (23.7% vs 6.9% for the group with focal invasion; P = .097). By Kaplan-Meier analysis, the 5-year disease-specific survival rate was better in the group with focal invasion than the group with massive invasion (P = .01). The 5-year overall survival was not different between the 2 groups (47.4% and 65.5% for focal invasion and massive invasion respectively; P = .14)., Conclusion: Compartmentalized endoscopic resection, combined with postoperative radiotherapy, is one way to operate on nasal ITACs with good oncologic outcomes., (© 2018 Wiley Periodicals, Inc.)

Introduction: The 2015 WHO classification of tumors categorized malignant mesothelioma into epithelioid, biphasic (BMM), and sarcomatoid (SMM) for prognostic relevance and treatment decisions. The survival of BMM is suspected to correlate with the amount of the sarcomatoid component. The criteria for a sarcomatoid component and the interobserver variability between pathologists for identifying this component are not well described. In ambiguous cases, a "transitional" (TMM) subtype has been proposed but was not accepted as a specific subtype in the 2015 WHO classification. The aims of this study were to evaluate the interobserver agreement in the diagnosis of BMM, to determine the nature and the significance of TMM subtype, and to relate the percentage of sarcomatoid component with survival. The value of staining for BRCA-1-associated protein (BAP1) and CDKN2A(p16) fluorescence in situ hybridization (FISH) were also assessed with respect to each of the tumoral components., Methods: The study was conducted by the International Mesothelioma Panel supported by the French National Cancer Institute, the network of rare cancer (EURACAN) and in collaboration with the International Association for the Study of Lung Cancer (IASLC). The patient cases include a random group of 42 surgical biopsy samples diagnosed as BMM with evaluation of SMM component by the French Panel of MESOPATH experts was selected from the total series of 971 BMM cases collected from 1998 to 2016. Fourteen international pathologists with expertise in mesothelioma reviewed digitally scanned slides (hematoxylin and eosin - stained and pan-cytokeratin) without knowledge of prior diagnosis or outcome. Cases with at least 7 of 14 pathologists recognizing TMM features were selected as a TMM group. Demographic, clinical, histopathologic, treatment, and follow-up data were retrieved from the MESOBANK database. BAP1 (clone C-4) loss and CDKN2A(p16) homozygous deletion (HD) were assessed by immunohistochemistry (IHC) and FISH, respectively. Kappa statistics were applied for interobserver agreement and multivariate analysis with Cox regression adjusted for age and gender was performed for survival analysis., Results: The 14 panelists recorded a total of 544 diagnoses. The interobserver correlation was moderate (weighted Kappa = 0.45). Of the cases originally classified as BMM by MESOPATH, the reviewers agreed in 71% of cases (385 of 544 opinions), with cases classified as pure epithelioid in 17% (93 of 544), and pure sarcomatoid in 12% (66 of 544 opinions). Diagnosis of BMM was made on morphology or IHC alone in 23% of the cases and with additional assessment of IHC in 77% (402 of 544). The median overall survival (OS) of the 42 BMM cases was 8 months. The OS for BMM was significantly different from SMM and epithelioid malignant mesothelioma (p < 0.0001). In BMM, a sarcomatoid component of less than 80% correlated with a better survival (p = 0.02). There was a significant difference in survival between BMM with TMM showing a median survival at 6 months compared to 12 months for those without TMM (p < 0.0001). BAP1 loss was observed in 50% (21 of 42) of the total cases and in both components in 26%. We also compared the TMM group to that of more aggressive patterns of epithelioid subtypes of mesothelioma (solid and pleomorphic of our large MESOPATH cohort). The curve of transitional type was persistently close to the OS curve of the sarcomatoid component. The group of sarcomatoid, transitional, and pleomorphic mesothelioma were very close to each other. We then considered the contribution of BAP1 immunostaining and loss of CDKN2A(p16) by FISH. BAP1 loss was observed in 50% (21 of 41) of the total cases and in both component in 27% of the cases (11 of 41). There was no significant difference in BAP1 loss between the TMM and non-TMM groups. HD CDKN2A(p16) was detected in 74% of the total cases with no significant difference between the TMM and non-TMM groups. In multivariate analysis, TMM morphology was an indicator of poor prognosis with a hazard ratio = 3.2; 95% confidence interval: 1.6 - 8.0; and p = 0.003 even when compared to the presence of HD CDKN2A(p16) on sarcomatoid component (hazard ratio = 4.5; 95% confidence interval: 1.2 - 16.3, p = 0.02)., Conclusions: The interobserver concordance among the international mesothelioma and French mesothelioma panel suggests clinical utility for an updated definition of biphasic mesothelioma that allows better stratification of patients into risk groups for treatment decisions, systemic anticancer therapy, or selection for surgery or palliation. We also have shown the usefulness of FISH detection of CDKN2A(p16) HD compared to BAP1 loss on the spindle cell component for the separation in ambiguous cases between benign florid stromal reaction from true sarcomatoid component of biphasic mesothelioma. Taken together our results further validate the concept of transitional pattern as a poor prognostic indicator., (Copyright © 2018 International Association for the Study of Lung Cancer. All rights reserved.)

Background: The prognosis of lung cancer remains poor; only 20% of patients can undergo surgery. N2 non-small cell lung cancer (NSCLC) is a heterogeneous disease. We conducted a retrospective study to analyze the impact of N2 location on survival., Methods: This study included 342 NSCLC with N2 involvement between 1988 and 2014. Patient-related data were collected through the CRB biobank and included demographic, therapeutic, and survival data. Survival was analyzed according to Kaplan-Maier method. Cox's regression analysis and analysis of variance (ANOVA) were used to determine factors significantly associated with survival., Results: The population average age was 61.6 years; 82.2% were men, a majority were former smokers (87.1%), and 45.3% had adenocarcinoma. The main prognostic factors were male gender (p = 0.01), number of nodes (p < 0.0001), and tumor size (p < 0.0001). N2 disease had a poor survival (16 months) compared with N0 (32 months) and N1 (21.1 months) disease (p < 0.0001). The patients with involvement of station 4 (survival = 17.8 months) seemed to have a prognosis between those with station 7 (survival = 10.5 months) and N1 (survival = 22.6 months), p = 0.0005., Conclusions: N2 location has a prognostic impact in surgically NSCLC, and station 4 involvement has a better prognostic than station 7.

Lung cancer is the leading cause of cancer death in France with low response rates to conventional chemotherapy. Nevertheless, new therapies have emerged recently, among which PD1 immune checkpoint inhibitors (ICI), such as nivolumab (OPDIVO ® , Bristol-Myers Squibb) and pembrolizumab (KEYTRUDA ® , Merck & Co), or PD-L1 ICI, such as atezolizumab (TECENTRIQ ® , Genentech), durvalumab (IMFINZI ® , Astra-Zeneca), and avelumab (BAVENCIO ® , EMD Serono). The prescription of pembrolizumab for advanced stage non-small cell lung carcinoma (NSCLC) patients requires the demonstration of PD-L1 expression by tumor cells by immunohistochemistry (IHC) (minimum of 50% of positive tumor cells is required for first-line setting, and of 1% for second-line and beyond) and PD-L1 assay is now considered as a companion diagnostic tool for this drug. Numerous standardized PD-L1 assays performed on dedicated platforms have been validated in clinical trials, each antibody being associated to one specific PD1 or PD-L1 inhibitor. However, not all pathologists have access to the dedicated platforms and the high cost of these assays is still a limitation to their implementation; in addition, the small size of the NSCLC tumor samples does not allow to perform at the same time multiple assays for multiple drugs. The use of laboratory-developed tests seems feasible but their validation must guarantee the same sensitivities and specificities as standardized tests. In this context, the French group of thoracic pathologists PATTERN has teamed up with thoracic oncologists to provide recommendations on the indication, the critical technical steps and the interpretation of the PD-L1 IHC test to help pathologists to implement quickly and in the best conditions this new theranostic test., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Background: The prognostic value of exon 19 and 21 EGFR mutations in stage IV non-small cell lung cancer (NSCLC) is well established., Objective: We aimed to evaluate the prognostic value of the mutations in surgically resected NSCLC., Methods: We retrospectively reviewed data from 1798 surgically resected NSCLC adenocarcinomas between 2007 and 2017 in three departments of thoracic surgery (Nancy/Strasbourg, France, and Torino, Italy) for whom mutational status was known. Overall survival (OS) was evaluated using log-rank and Cox proportional hazard models., Results: EGFR exon 19 deletion was observed in 108 patients (55.1%) and exon 21 L858R mutations were observed in 88 patients (44.9%). In stage I, the median OS was not significantly different between exons 19 and 21 (p = 0.54), while, in stage II, the median OS reached 65 months [95% confidence interval (CI) 41.67-88.33] for exon 19 mutations and decreased to 48 months for exon 21 mutations (95% CI 44.21-51.79; p = 0.027). In multivariate analysis, exon 19 deletion remained a favorable prognostic factor [hazard ratio (HR) 0.314, 95% CI 0.098-0.997; p = 0.05]. In stage III, the median OS reached 66 months (95% CI 44.67-87.32) for exon 19 mutations and decreased to 32 months for exon 21 mutations (95% CI 29.86-34.14; p = 0.03). In multivariate analysis, exon 19 deletion remained a significantly favorable prognostic factor (HR 0.165, 95% CI 0.027-0.999; p = 0.05)., Conclusion: The prognostic value of EGFR exon 19 and 21 mutations appears to be different according to disease stage in surgically resected NSCLC.

Minichromosome maintenance complex component 6 (MCM6) is involved in initiating DNA replication and is upregulated during licensed G0 phase of the cell cycle. This early expression permits its labeling of more proliferating cells than those by Ki-67. Here using a cohort of 89 endometrioid adenocarcinoma, we report findings made on the prognostic value of MCM6 based on immunohistochemical labeling index (LI) of the protein in comparison with that of Ki67 as no such information is currently available. Additionally, we examined the prognostic values of these markers based on their mRNA expression using a cohort of uterine corpus endometrial carcinoma (UCEC, n = 307) taken from The Cancer Genome Atlas (TCGA) database. Our evidence indicated the presence of a positive correlation between the LI of MCM6 and the histological grade of endometrioid endometrial adenocarcinoma (grade I, 66.7%; grade II, 75.3%; grade III, 81.4%; p < 0.001) and an inverse correlation between the LI of MCM6 and the overall and progression-free survival (p = 0.02 for both). The LI of Ki-67 correlated with grade (p < 0.001), but not survival. The MCM6 and Ki-67 inter-observer intra-class correlation coefficients were excellent: 0.84 (95% confidence interval, 0.83-0.91) and 0.84 (0.77-0.90), respectively. For in silico analyses of the TCGA cohort, both univariate and multivariate Cox analyses (p = 0.003 and p = 0.03, respectively) revealed high MCM6 mRNA Z-scores associated with reduced overall survival. This association was absent for Ki-67. MCM6 is thus a highly reproducible marker of poor prognosis in endometrial cancer. Evaluation of MCM6 should thus be considered in daily practice for risk stratification.

Purpose: Adrenocortical lesions are characterized through imaging, hormonal and histopathological analysis. Our aim was to compare the radiological features of adrenocortical lesions with their cortisol-secreting status and histopathological Weiss score., Methods: Seventy five patients operated between 2004 and 2016 in the University Hospital of Nancy for either adrenocortical carcinomas (ACC) or adrenocortical adenomas (ACA) were enrolled in this study. We collected cortisol parameters, Computed Tomography (CT) scans (unenhanced density, wash-out (WO) analysis) and 18 F-Fluorodeoxyglucose positron emission tomography/computed tomography ( 18 F-FDG PET/CT) datas. The histopathological Weiss score ultimately differentiates ACA (score ≤ 2) from ACC (score ≥ 3). One-way ANOVA, Fisher's exact and unpaired t tests were used for statistical analysis with significancy reached at p < 0.05., Results: There were 23 ACC and 52 ACA with 40 patients (53%) who had an autonomous secretion of cortisol. On CT scan, ACC were larger compared to ACA (108 vs. 37 mm, p < 0.0001). A roughly similar proportion of cortisol-secreting (22/25) and non-secreting (15/19) ACA were atypical (i.e., unenhanced density value ≥ 10 Hounsfield Units [HU]), however 85% of cortisol-secreting vs. 40% of non-secreting ACA were classified as benigns by the relative WO analysis (p = 0.08). Likewise, there was a trend for a higher 18 F-FDG uptake in cortisol-secreting ACA compared to non-secreting ACA (p = 0.053)., Conclusions: The relative adrenal WO analysis consolidates the benign nature of an ACA, especially in case of cortisol oversecretion, a condition known to compromise the diagnostic accuracy of the 10 HU unenhanced CT attenuation threshold.

Purpose: Prophylactic radiotherapy to prevent procedure-tracts metastases from malignant pleural mesothelioma remains controversial and clinical practice varies. The purpose was to assess the efficacy of local radiotherapy in a single fraction of 10Gy in preventing malignant seeding at intervention pleural site in patients with malignant pleural mesothelioma., Material and Methods: This is a retrospective cohort study, including patients with histological confirmed malignant pleural mesothelioma treated by prophylactic irradiation to prevent interventional site metastases with a unique fraction of 10Gy with 6 to 18MeV, from January 1990 to December 2013 in the institut de cancérologie de Lorraine (Nancy, France)., Results: Ninety-one patients were treated by irradiation in intervention site, involving 120 intervention pleural sites, 91 thoracoscopies, 17 thoracotomies with chest drain and 12 CT or ultrasound guided needle biopsies. The median follow-up was 7 months (interquartile between 3 and 15 months). The overall survival was 43.5% at 12 months. The local progression free survival was 43.7% at 12 month. The incidence of local recurrence was 8% at 12 months. The median interval from radiotherapy to local recurrence was 4 months (2; 32). No grade II or higher toxicity was observed., Conclusion: Irradiation of pleural intervention sites with a single fraction of 10Gy is effective, well tolerated, simple, fast and cost effective., (Copyright © 2017 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.)

The promalignant effects of neurotensin (NTS) are sustained in many solid tumors, including hormone-dependent cancers. As the endometrium is also subjected to hormonal regulation, we evaluated the contribution of NTS to endometrial carcinogenesis. Neurotensin receptor 1 (NTSR1) expression and NTSR1 promoter methylation (HM450) were analyzed in 385 cases of endometrial carcinoma from The Cancer Genome Atlas (TCGA). Additionally, from a series of 100 endometrial carcinomas, and 66 benign endometrium samples, NTS and NTSR1 labeling was evaluated by immunohistochemistry. Using TCGA series, NTSR1 messenger RNA (mRNA) level was negatively correlated with overall survival (OS) and progression-free survival (PFS) (p = 0.0012 and p = 0.0116, respectively), and positively correlated with the grade (p = 0.0008). When including only endometrioid carcinomas, NTSR1 mRNA level continued to be negatively correlated with OS (log-rank: p < 0.0001) and PFS (log-rank: p = 0.002). A higher NTSR1 mRNA level was significantly associated with a loss of NTSR1 promoter methylation. Immunohistochemical expression of NTS and NTSR1 was significantly increased in adenocarcinoma (n = 100), as compared to benign endometrium (p < 0.001). NTSR1 expression was positively correlated with grade (p = 0.004). High immunohistochemical expression of cytoplasmic NTSR1 was significantly correlated with a shorter OS and PFS (p < 0.001 and p = 0.001, respectively). This correlation remained significant when excluding non-endometrioid subtypes (p = 0.04 and p = 0.02, respectively). In multivariate analysis, the expression of NTSR1 was an independent prognostic factor (p = 0.004). NTSR1 overexpression is a poor prognostic factor in endometrial cancer, highlighting the contribution of NTS in endometrial cancer progression and its uses as a prognostic marker, and as a potential therapeutic target.

Immunohistochemistry is used to distinguish sarcomatoid malignant mesotheliomas (SMM) from spindle cell and pleomorphic carcinomas (SPC) but there are no guidelines on how to interpret cases that show overlapping or equivocal immunohistochemical findings. A systematic literature review of the immunophenotype of these lesions was performed and the experience with 587 SMM and 46 SPC at MESOPATH was collected. Data were analyzed with Comprehensive Meta-Analysis 2.0 software (Biostat, Englewood, NJ). There were insufficient data to evaluate the differential diagnosis between SPC and localized SMM or peritoneal SMM. Meta-analysis showed considerable overlap in the immunophenotype of these neoplasms and significant data heterogeneity amongst many of the results. Survival data from MESOPATH patients showed no significant differences in overall survival between SMM and SPC patients. Best available evidence was used to formulate several evidence-based guidelines for the differential diagnosis between pleural SMM and SPC. These guidelines emphasize the need to correlate the histopathological findings with clinical and imaging information. Diffuse SMM can be diagnosed with certainty in the presence of malignant spindle cell pleural lesions showing immunoreactivity for cytokeratin and mesothelial markers and negative staining for epithelial markers. Criteria for the interpretation of various other combinations of immunoreactivity for cytokeratin and mesothelial and/or epithelial markers are proposed. Localized sarcomatoid mesotheliomas can only be diagnosed in the presence of spindle cell malignancies that exhibit immunoreactivity for cytokeratin and mesothelial markers and negative immunoreactivity for epithelial lesions, in patients that show no multifocal or diffuse pleural spread and no evidence for extrapleural lesions., (Copyright © 2017. Published by Elsevier Inc.)

HuR regulates cytoplasmic mRNA stability and translatability, and the HuR expression level has been shown to correlate with poor disease outcome in several cancer types; however, the prognostic value and potential pro-oncogenic properties of HuR in meningioma remain unclear. Thus, in the present study, we analysed 85 meningioma tissue samples to establish the relationship between HuR expression, tumour cell proliferation, and/or patient survival. In addition, we examined the anti-proliferative effects of HuR knockdown in two meningioma cell lines (IOMM-Lee and Ben-Men-1) and conducted transcriptome-wide analyses (IOMM-Lee cells) to elucidate the molecular consequences of HuR knockdown. The results of the present study showed HuR cytoplasmic expression to correlate positively with tumour grade (p = 1.2 × 10 -8 ) and negatively with progression-free and overall survival (p = 0.01) time in human meningioma tissues. In vitro, siHuR-induced HuR knockdown was shown to reduce the growth of both Ben-Men-1 (p = 2 × 10 -8 ) and IOMM-Lee (p = 4 × 10 -9 ) cells. Transcriptome analyses revealed HuR knockdown in IOMM-Lee cells to deregulate the HIF1A signalling pathway (p = 1.5 × 10 -6 ) and to up-regulate the expression of genes essential for the assembly of the cytoplasmic mRNA processing body, global genome nucleotide-excision repair, poly(A)-specific ribonuclease activity, the positive regulation of apoptosis and of cell cycle arrest, and the negative regulation of RNA splicing [p(FDR) < 0.001]. Interestingly, HuR knockdown under hypoxic culture conditions further potentiated the effects of HuR knockdown on cell growth, apoptosis, and HIF1A expression. We thus conclude that cytoplasmic HuR expression is a marker of poor prognosis in meningioma and that HuR is a promising potential therapeutic target for use in tumours refractory to standard therapies. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Doege-Potter syndrome is a paraneoplastic syndrome characterized by non-islet cell tumor hypoglycemia secondary to a solitary fibrous tumor. These tumors are rare and usually asymptomatic. The syndrome of hypoglycemia is seen in less than 5% of the cases, and the associated tumors are large with a high mitotic rate. The cause of hypoglycemia is related to insulin-like growth factors produced by these tumors called "big" IGF-2. Several biological tests can demonstrate the increase of "big" IGF-2 plasma levels confirming the diagnosis of non-islet cell tumor induced hypoglycemia. The diagnosis is suggested by imaging but diagnostic confirmation is provided by the surgery, which remains the treatment of choice. Resection in many cases is the cure leading to hypoglycemia resolution. Recurrences and malignant transformations are possible which imposes a long-term monitoring. We report a case with relapsed malignant pleural fibrous tumor for which the pathophysiological mechanism of hypoglycemia could be documented as a paraneoplastic syndrome., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Microvascular proliferation (MVP) is a hallmark of glioblastoma. Endothelial cell hypertrophy (ECH), also known as endothelial hyperplasia, is correlated with a shorter survival of patients with gliomas. However, the prognostic value of these 2 morphological features has not been studied in meningiomas. The aim of this study was to evaluate the prognostic value of angiogenesis in meningiomas, most notably ECH, MVP, and microvascular density, which were evaluated using immunohistochemistry with antibodies against CD34 and CD105 (a marker of neovascularization) in a series of 139 meningiomas. ECH, MVP, and CD105 immunoreactivity were significantly correlated with higher histological grades (p < 0.0001, p = 0.0004, and p = 0.0003, respectively). ECH and MVP but not CD105 immunoreactivities were significantly correlated with a shorter progression-free survival time (PFS) (p = 0.017, p = 0.021, and p = 0.137, respectively). In Cox multivariate analysis, ECH was an independent predictor of shorter PFS (p = 0.028). Therefore, ECH and MVP are markers of shorter PFS in meningiomas and are significantly correlated with grade. These findings give insight into the use of anti-angiogenic therapies. Further studies are needed to determine whether these markers could allow us to identify patients who could benefit from anti-angiogenic therapies., (© 2016 American Association of Neuropathologists, Inc. All rights reserved.)

Wound age evaluation is one of the most challenging issues in forensic pathology. In the first minutes or hours, standard histological examination may not determine whether the wound was inflicted in the pre- or post-mortem period. While red blood cell infiltration is classically considered as a sign of vital reaction, several studies have shown that extravasation of blood cells may also occur after death and cannot be used as a reliable marker in the diagnosis of wound vitality. Numerous studies about wound vitality are available in the literature. They have evaluated markers involved in coagulation or inflammation, using various methods such as enzymology, molecular biology or immunohistochemistry. In this update, we first introduce some methodological principles. Then, we review the main studies available in the literature. Immunohistochemistry seems to be the most valuable method, given its easy application and the possibility to analyse the localization of the molecules of interest. Some markers are promising, such as CD15, TNFα, IL-6, IL-1β, TGFα or TGFβ1. Prior to their application in daily practice, these early results need to be confirmed with other studies, conducted by independent teams and integrating multiple controls. Most notably, the antibodies have to be tested in numerous post-mortem wounds. Indeed, a critical risk of overexpression in post-mortem wounds is present. Some promising markers have been later invalidated because of post-mortem false positivity. Finally, optimal sensitivity and specificity values could probably be reached by combining several markers, validated by large groups of pre- and post-mortem wounds., (© The Author(s) 2015.)

Personalized medicine has gained increasing importance in clinical oncology, and several clinically important biomarkers are implemented in routine practice. In an effort to guarantee high quality of molecular testing in France, three subsequent external quality assessment rounds were organized at the initiative of the National Cancer Institute between 2012 and 2014. The schemes included clinically relevant biomarkers for metastatic colorectal (KRAS, NRAS, BRAF, PIK3CA, microsatellite instability) and non-small cell lung cancer (EGFR, KRAS, BRAF, PIK3CA, ERBB2), and they represent the first multigene/multicancer studies throughout Europe. In total, 56 laboratories coordinated by 28 regional molecular centers participated in the schemes. Laboratories received formalin-fixed, paraffin-embedded samples and were asked to use routine methods for molecular testing to predict patient response to targeted therapies. They were encouraged to return results within 14 calendar days after sample receipt. Both genotyping and reporting were evaluated separately. During the three external quality assessment rounds, mean genotype scores were all above the preset standard of 90% for all biomarkers. Participants were mainly challenged in case of rare insertions or deletions. Assessment of the written reports showed substantial progress between the external quality assessment schemes on multiple criteria. Several essential elements such as the clinical interpretation of test results and the reason for testing still require improvement by continued external quality assessment education., (Copyright © 2016 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Eccrine spiradenoma (ES) is a benign adnexal tumor predominantly located in the head and neck regions. Multiple neoplasms located on the scalp have been reported but never with a zosteriform configuration on the first trigeminal area., Case Report: We describe an original case report of a 75-year-old Caucasian man presenting multiple subcutaneous blue and purple nodules disseminated on the first left trigeminal dermatome. All the nodules appeared gradually on a one-year period. Biopsy revealed a nodular adnexal tumor in the dermis without malignant eccrine spiradenoma (MES) transformation. The surgical procedure was performed in a manner to protect the galea aponeurotica in the upper half on the first left trigeminal area. The frontalis muscle was raised with the surgical specimen in the lower half of the first trigeminal area. A split-thickness skin graft was applied on the surgical defect. Histological examination revealed multilobular well-defined tumors located in the dermis., Conclusion: The presence of multiple subcutaneous nodules in a trigeminal pattern should suggest a multiple localized zosteriform ES. The diagnosis is focused on clinical findings and the treatment is based on a large surgical excision. The histological examination is essential for not to fail a MES transformation., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

The precise distinction between adenocarcinoma and squamous cell carcinoma (SqCC) has become very important for determining the appropriate therapy for patients and more specifically to drive the use of tyrosine kinase inhibitors, pemetrexed, anti-VEGF monoclonal antibody and crizotinib. Squamous pearls and distinct intercellular bridges identify keratinizing SqCC. In non-keratinizing SqCC, immuno-histochemistry is required. Recent studies have shown p40 and TTF1 to be the two best markers of SqCC and adenocarcinoma respectively. Many morphological variants of SqCC have been described. Basaloid SqCC is a poorly differentiated epithelial tumor lacking squamous morphology but showing immuno-histochemical expression of squamous makers. The pronostic of basaloid carcinoma is considered poorer than that of other non-small cell lung cancers. Adenosquamous carcinoma shows components of both SqCC and adenocarcinoma. Both components must be clearly identified either on H&E or by immuno-histochemistry. The adenocarcinoma components justified a screening for gene rearrangements. Finally, the recent WHO classification of lung tumors did not change the criteria applying for the grading of preinvasive bronchial lesion., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

While investigating cohorts of unclassified sarcomas by RNA sequencing, we identified 19 cases with inactivation of SMARCA4, which encodes an ATPase subunit of BAF chromatin-remodeling complexes. Clinically, the cases were all strikingly similar, presenting as compressive mediastino-pulmonary masses in 30- to 35-year-old adults with a median survival time of 7 months. To help define the nosological relationships of these tumors, we compared their transcriptomic profiles with those of SMARCA4-mutated small-cell carcinomas of the ovary, hypercalcemic type (SCCOHTs), SMARCB1-inactivated malignant rhabdoid tumors (MRTs) and lung carcinomas (of which 10% display SMARCA4 mutations). Gene profiling analyses demonstrated that these tumors were distinct from lung carcinomas but related to MRTs and SCCOHTs. Transcriptome analyses, further validated by immunohistochemistry, highlighted strong expression of SOX2, a marker that supports the differential diagnosis of these tumors from SMARCA4-deficient lung carcinomas. The prospective recruitment of cases confirmed this new category of 'SMARCA4-deficient thoracic sarcomas' as readily recognizable in clinical practice, providing opportunities to tailor their therapeutic management.

Few studies on oncogenesis of chondrosarcoma (CS) are available in the literature. Our previously published experimental evidence suggests that while the C-propeptide of procollagen Iα1 (PC1CP), a component of cartilage, favors tumor progression, the C-propeptide of procollagen IIα1 (PC2CP) exerts antitumor properties. In this study, we analyzed expression of PC1CP and PC2CP by immunohistochemistry in a series of enchondromas and CS. Our retrospective series consisted of 88 cases, including 43 CSs, 34 enchondromas and 11 nontumor samples. Immunohistochemical staining for PC1CP and PC2CP was evaluated in the cytoplasm and in the extracellular matrix (ECM). Diffuse staining for PC1CP in ECM was significantly more frequent in tumor than in nontumor samples (32 % vs. 0 %; p = 0.03), and in CSs than in enchondromas (44 vs. 18 %; p = 0.02). ECM semiquantitative score was higher in tumors than in nontumor samples (p < 0.005) and higher in CSs than in enchondromas (p = 0.05). Staining for PC2CP in ECM was more frequently found in enchondromas than in CSs (59 vs. 33 %; p = 0.02). ECM semiquantitative score was higher in enchondromas than in CSs (p = 0.02). Diffuse staining for PC1CP in combination with absence of staining for PC2CP had 94 % specificity for CS but with a sensitivity of only 35 %. Expression of neither PC1CP nor PC2CP correlated with recurrence-free survival or occurrence of metastases. In conclusion, we show that the expression of PC1CP is higher and that of PC2CP lower in malignant cartilaginous tumors. These results support an oncogenic role of PC1CP and anti-oncogenic property of PC2CP in cartilaginous tumors.

Purpose: Glioma grading is necessary for prognostic evaluation and optimal treatment decisions. The aims of this study were to establish whether a correlation between F-FDOPA uptake with tumor grade was observed and to determine which of the SUV-derived indices was the best correlated., Patients and Methods: Thirty-one patients were retrospectively included (mean [SD] age, 36.8 [12.1] years) including 21 proven low-grade tumors due to histology, imaging, and clinical follow-up and 10 histologically proven high-grade tumors. Static PET acquisitions were postreconstructed between the 10th and 30th minute after injection of F-FDOPA. Regions of interest of 20 mm were applied to tumors, and isocontoured volumes were defined at levels of 50% and 80% of the peak intensity voxel. Background was quantified with 30-mm-diameter regions of interest on contralateral striatum and centrum semioval. Tumoral uptake was evaluated with the following SUV-derived indices: SUVmax, SUVmean, SUVmax, and SUVmean of isocontoured volume, tumor/striatum ratio (T/S), and tumor/normal brain ratio (T/N)., Results: All the SUV-derived indices tested were significantly correlated with tumor grade, considering low-grade and high-grade groups (P < 0.05), except for the SUVmean 50%. The 2 best-correlated indices were SUVmean T/N and SUVmean T/S, with correlation coefficients of 0.561 and 0.522, respectively. Receiver operating characteristic analysis defined optimal thresholds of 1.33 and 1 for sensitivity and specificity of 71% and 100% and 67% and 100%, respectively., Conclusions: F-FDOPA PET SUV-derived indices are routinely available information that enables accurate discrimination of low-grade and high-grade gliomas. The best-correlated indices were SUVmean T/N and SUVmean T/S with thresholds of 1.33 and 1.

Objectives: In non small cell lung carcinoma (NSCLC), earlier studies supported a prognostic value of intra-cytoplasmic HuR expression. HuR is a RNA binding protein previously shown to stimulate proliferation, but the link between HuR and proliferation in NSCLC has not yet been evaluated. The first objective of this study was to analyze the expression of HuR in a series of NSCLC and to correlate this to two proliferation markers, Ki-67 and MCM6. As potential post-transcriptional regulatory mechanisms for HuR expression, two miRNAs, miR16 and miR519, were also analyzed. Finally, because HuR methylation could be involved in its nucleocytoplasmic shuttling, the expression of methyl(R217)HuR and its relation to cancer survival were determined., Materials and Methods: Immunohistochemistry was used to evaluate the expression of HuR, methy(R217)HuR, Ki-67 and MCM6 in a series of 190 NSCLCs. The level of miR16 and miR519 was determined by qRT-PCR., Results: Higher cytoplasmic HuR staining was found in tumor vs. control paired normal lung (p<0.0001), but without correlation with survival. The level of methyl(R217)HuR was correlated both significantly with intra-cytoplasmic HuR staining (p<0.001), and overall survival (p=0.01). MCM6 correlated to a poorer overall survival (p<0.01). Both MCM6 and Ki-67 were positively correlated with HuR nuclear staining (p<0.0001 and p<0.001, respectively). On the contrary, MCM6 and Ki-67 correlated inversely to methyl(R217)HuR (p<0.001 and p=0.01, respectively). The levels of miR16 and miR519 were significantly lower in tumor tissue vs. paired normal lung (p<0.0001), but only miR519 correlated inversely to HuR expression (p=0.01)., Conclusion: While overall cytoplasmic HuR level was higher in tumor tissues, we found unexpectedly that methyl(R217)HuR was a marker of good prognosis. Furthermore, our data suggest that HuR level could be regulated by miR519. Finally, we demonstrated that Ki-67 and MCM6, both correlated with HuR, are valuable markers of poor prognosis in NSCLC., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)