Publications by authors named "Francois Casteillo"

28 Publications

  • Page 1 of 1

Glioma Associated Microglia/Macrophages Distribution is Conserved in Glioblastoma Regrowth: A Morphometric Study.

Cancer Invest 2021 Jul 12:1-6. Epub 2021 Jul 12.

Department of Pathology, University Jean Monnet, Saint Etienne, France.

We compared the morphological aspect of glioblastoma-associated microglia/macrophages cells in 15 paired recurrent glioblastomas to check the ability of glioblastoma to recreate its microenvironment. The absolute number of GAMs is lower in normal tissue (21/mm) than in the isolated tumor cells area (100-112/mm) than in the solid tumor area (212-220/mm) ( < 0.01). The morphology of GAMs remained the same in each tumor area with a reduced covered area by cell processes (196 to 216/mm) than in normal tissue (708/mm) ( < 0.01). In paired tumors, GAMs morphology remained the same in successive resections and was not modified by the treatments.
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http://dx.doi.org/10.1080/07357907.2021.1944179DOI Listing
July 2021

Heterogeneity of PD-L1 expression in lung adenocarcinoma metastasis is related to histopathological subtypes.

Lung Cancer 2021 05 4;155:1-9. Epub 2021 Mar 4.

Centre Hospitalier Universitaire de Saint Etienne, Hôpital Nord, Department of Pathology, Avenue Albert Raimond, 42055 Saint Etienne, France; Corneal Graft Biology, Engineering, and Imaging Laboratory, BiiGC, EA2521, Federative Institute of Research in Sciences and Health Engineering, Faculty of Medicine, Jean Monnet University, Saint-Etienne, France.

Objectives: The heterogeneity of PD-L1 expression and its relationship with histopathological subtype has recently been shown on primary tumor but has not been evaluated on metastases. The aim of our work is to analyze PD-L1 expression within each histopathological pattern on resected metastases.

Material And Methods: 136 patients were included in this retrospective study. Immunohistochemistry was performed with 22C3 laboratory-developed test. The Tumor Proportion Score was evaluated on each subtype.

Results: The most frequent major histopathological subtype was solid (n = 69, 50.7 %), followed by acinar (n = 37, 27.2 %), micropapillary (n = 14, 10.3 %) and papillary (n = 10, 7.3 %). Mean percentage of PD-L1 expression for each subtype was at 28+/-4.8 % for solid subtype, 5.3+/-1.9 % for acinar subtype, 5+/-1.9 % for papillary subtype and 23.6+/-4.1 % for micropapillary subtype. Mean percentage of PD-L1 expression was different between solid pattern and acinar pattern (p < 0.001), solid pattern and papillary pattern (p = 0.007), micropapillary pattern and acinar pattern (p < 0.001) and micropapillary pattern and papillary pattern (p = 0.015).

Conclusion: To conclude, we have showed firstly that several patterns are present in metastases of lung adenocarcinoma, secondly that the evaluation of patterns and PD-L1 stain on different patterns is reproducible, thirdly that pattern heterogeneity is related to PD-L1 staining, fourthly that in metastatic lung adenocarcinoma with at least two patterns, solid and micropapillary subtypes have higher levels of PD-L staining, fifthly that PD-L1 heterogeneity between different patterns is not a rare event. These results might explain discrepancies of PD-L1 results between biopsies and surgical samples and the fact that some patients might respond to checkpoint inhibitors even though PD-L1 expression is low or absent.
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http://dx.doi.org/10.1016/j.lungcan.2021.02.032DOI Listing
May 2021

High endothelial venules are present in pharyngeal and laryngeal carcinomas and they are associated with better prognosis.

Pathol Res Pract 2021 Apr 18;220:153392. Epub 2021 Feb 18.

Departments of Pathology, North Hospital, University Hospital of St-Etienne, France.

Background: Tumors lymphocytic infiltration has prognostic and predictive value. However, the mechanisms involved in lymphocyte recruitment remain poorly characterized. High endothelial venules (HEV) are blood vessels specialized in lymphocyte recruitment, recently showing prognostic significance in some types of cancer. Their implications in laryngeal or pharyngeal cancer is largely unknown.

Aim Of The Study: To investigate the possible presence of HEVs in head and neck cancer.

Material And Methods: Oropharyngeal (n = 61), hypopharyngeal (n = 53) and laryngeal (n = 21) squamous cell carcinomas were immunohistochemically studied with the MECA-79 antibody, which specifically recognizes HEVs. Histological and clinical factors were correlated with HEVs' presence.

Results: HEVs were present in 34% of tumors, showing significant correlations with oropharyngeal localization, higher lymphocytic response, lower tumor budding, lower T status, absence of distant metastases and better overall and progression-free survival.

Conclusion: HEVs represent an important prognostic factor in head and neck cancer.
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http://dx.doi.org/10.1016/j.prp.2021.153392DOI Listing
April 2021

Mesothelial Cysts.

Am J Clin Pathol 2021 05;155(6):853-862

Pathology Department, University Hospital of Saint-Etienne, Saint-Etienne, France.

Objectives: Peritoneal mesothelial cysts have been reported under various terms, including benign cystic mesothelioma, usually in the form of case reports/series, whereas extraperitoneal cases are rarely reported. Our objective was to report the detailed characteristics of cystic lesions of the serosal cavities.

Methods: We retrospectively examined the clinicopathologic findings of a series of mesothelial cystic lesions (n = 79).

Results: Most cases (n = 68, 86%) concerned the peritoneum, whereas 11 (14%) concerned the pericardium. No pleural cases were found. A total of 51 (64.5%) lesions were solitary, whereas 28 (35.5%) were multiple. Peritoneal lesions harbored a plump eosinophilic mesothelium and a loose connective stroma, whereas pericardial lesions showed a cuboidal/flattened mesothelium, collagenous stroma, intense inflammation, and other tissue types, like adipose and muscle tissue. Solitary peritoneal lesions are usually extrapelvic and found in older patients incidentally during other surgeries, whereas multiple lesions are found in younger patients and usually in the pelvis. The lesions show a benign clinical course with rare recurrences but no malignant transformation.

Conclusions: Most mesothelial cysts are peritoneal and rarely pericardial. Peritoneal cysts differ from pericardial cysts. Peritoneal solitary lesions differ from multiple lesions, also suggesting their pathogenetic differences.
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http://dx.doi.org/10.1093/ajcp/aqaa189DOI Listing
May 2021

Incidental Detection of a Small Cell Lung Cancer by 18F-Choline PET/CT Performed for Recurrent Hyperparathyroidism After Parathyroidectomy.

Clin Nucl Med 2021 Feb;46(2):e109-e111

From the Departments of Nuclear Medicine.

Abstract: We report the case of a 64-year-old woman with musculoskeletal pain and elevated serum parathyroid hormone who had undergone parathyroidectomy for primary hyperparathyroidism 4 years earlier. An 18F-choline PET/CT scan was performed and incidentally showed an intense uptake in a right upper lobe pulmonary nodule and in the right hilar, mediastinal, and cervical lymph nodes. Histopathological analysis confirmed the diagnosis of a small cell lung cancer. Clinical symptoms and recurrent hyperparathyroidism were therefore consistent with a paraneoplastic syndrome. A complete metabolic response was achieved on 18F-FDG PET/CT scan after chemotherapy.
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http://dx.doi.org/10.1097/RLU.0000000000003246DOI Listing
February 2021

Brain metastasis PD-L1 and CD8 expression is dependent on primary tumor type and its PD-L1 and CD8 status.

J Immunother Cancer 2020 08;8(2)

Pathology, University Hospital of Saint-Etienne, Saint-Etienne, France.

Background: Brain metastases (Bmets) are frequent; however, limited data exist on the efficacy of immunotherapy in these lesions. The aims of the study were to analyze the immunohistochemical expressions of programmed death ligand 1 (PD-L1) and CD8 in Bmets and to compare them with their expressions in paired primary tumors, as well as correlate the results with clinicopathological features.

Methods: This is a retrospective study of 233 patients with Bmets and 111 paired primaries. Clinical, histological, and molecular data were recorded and compared with the immunohistochemical results of PD-L1 and CD8 expressions. The statistical analysis included χ test, Cramer's V test, factorial analyses of variance, simple regression analysis, and Kaplan-Meier analysis with log-rank product limit estimation.

Results: PD-L1 expression was found in 23.6% of Bmets and in 29.0% of primary tumors with concordant expression between them in 75.5% of cases. Bmets PD-L1 expression was associated with primary tumor PD-L1 expression and the primary tumor type. Significant CD8 peritumoral expression was found in 68.6% of Bmets and in 87.7% of primary tumors. CD8 expression was concordant between primary and metastatic tumors in 73.3% of cases. Bmets CD8 expression was associated with primary tumor CD8 expression and primary tumor type. PD-L1 expression was associated with CD8 expression in both primary and metastatic tumors. The concordance between primary and metastatic tumor PD-L1 expression was independent of all factors studied. The concordance between primary and metastatic CD8 expressions was marginally associated to the time of Bmets development. No prognostic role for PD-L1 and CD8 expression in Bmets was found.

Conclusion: PD-L1 and CD8 Bmets expressions are associated with the primary tumor type and its PD-L1 and CD8 expressions. No factor predicts the discordance for PD-L1 expression, while time to Bmets development is associated with CD8 expression discordance.
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http://dx.doi.org/10.1136/jitc-2020-000597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454240PMC
August 2020

Immune Escape Is an Early Event in Pre-Invasive Lesions of Lung Squamous Cell Carcinoma.

Diagnostics (Basel) 2020 Jul 21;10(7). Epub 2020 Jul 21.

Pathology Department, North Hospital, University Hospital of Saint Etienne, Avenue Albert Raimond, CEDEX 2, 42055 Saint Etienne, France.

Bronchial dysplasia is the pre-neoplastic lesion recognized for invasive squamous cell carcinoma. The mechanisms leading to invasive squamous cell carcinoma for this lesion are not fully known. Programmed Death-Ligand 1 (PD-L1) expression by the bronchial dysplasia neoplastic epithelium might suggest a response to immunotherapy. The objective of this work is to further characterize PD-L1 and CD8 expression in bronchial dysplasia and bronchial metaplasia compared to normal bronchial epithelium. Immunohistochemical analysis of PD-L1 and CD8 staining were characterized in bronchial dysplasia of 24 patients and correlated with clinical data. We also compared PD-L1 expression in dysplasia samples to 30 normal epithelium and 20 samples with squamous bronchial metaplasia. PD-L1 was never expressed in normal epithelium and in metaplastic epithelium whereas 37.5% of patients with bronchial dysplasia were stained by PD-L1 ( < 0.001). PD-L1 expression was not related to the degree of dysplasia or a medical history of invasive squamous cell carcinoma, while CD8 expression and its localization were related to medical history of squamous cell carcinoma ( = 0.044). Our results show that PD-L1 is expressed in roughly one third of patients with bronchial dysplasia and is not expressed in normal and metaplastic epithelium. This suggests that PD-L1 is expressed in preneoplastic lesions of squamous cell carcinoma.
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http://dx.doi.org/10.3390/diagnostics10070503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399898PMC
July 2020

Histopathological subtyping is a prognostic factor in stage IV lung adenocarcinoma.

Lung Cancer 2020 09 11;147:77-82. Epub 2020 Jul 11.

Department of Pathology, University Hospital of Saint Etienne, North Hospital, Avenue Albert Raimond, 42055 Saint Etienne CEDEX 2, France; Corneal Graft Biology, Engineering and Imaging Laboratory, BiiGC, Federative Institute of Research in Sciences and Health Engineering, Faculty of Medicine, Jean Monnet University, Saint-Etienne, EA2521, France. Electronic address:

Lung adenocarcinoma is a heterogeneous tumor made of different architectural patterns. These tumors are classified into subtypes according to the predominant pattern in the primary tumor because the predominant pattern is related to overall survival. The prognostic role of these subtypes in stage IV disease is not well known, and most lung adenocarcinomas are diagnosed at the stage of metastatic disease. We aimed to evaluate the prognostic role of histopathological subtypes in lung adenocarcinoma metastases in a retrospective study of 253 patients with clinical, histopathological and molecular data. The presence of the solid subtype was related to overall survival (p = 0.045); the median overall survival was 6.8 months (95 % confidence interval (95 %CI) 4.4-9.1) when present and 11.1 months (95 %CI 8.6-21.3) when absent. Thyroid transcription factor 1 (TTF-1) immunohistochemistry was related to overall survival (p < 0.001); the median overall survival was 11.2 months (95 %CI 8.4-17.7) when positive and 4 months (95 %CI 2.3-5.7) when negative. On multivariate analysis, the presence of the solid subtype (p = 0.0036, hazard ratio (HR) 1.55, 95 %CI 1.03-2.34), TTF-1 positivity (p = 0.044, HR 0.64, 95 %CI 0.42-0.98), age <60 years at the time of resection (p = 0.017, HR 1.89; 95 %CI 1.12-3.21), performance status <2 (p = 0.017, HR 0.57; 95 %CI 0.36-0.91), treatment by chemotherapy (p = 0.033, HR 0.54, 95 %CI 0.31-0.95), and treatment by tyrosine kinase inhibitor or immunotherapy (p = 0.013, HR 0.36, 95 %CI 0.17-0.81) were related to overall survival. The evaluation of architectural pattern in metastases in stage IV patients provides further information for physicians about patient prognosis. This information might be included in clinical trials in patients with stage IV lung adenocarcinoma.
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http://dx.doi.org/10.1016/j.lungcan.2020.07.010DOI Listing
September 2020

Clinical long-term outcome of non-specific pleuritis (NSP) after surgical or medical thoracoscopy.

J Thorac Dis 2020 May;12(5):2096-2104

Department of Pneumonology, University Hospital of Alexandroupolis, Alexandroupolis, Greece.

Background: Thoracoscopy, either "medical" or "surgical", is the gold standard to reveal the cause of pleural effusion by taking large biopsies. However, in some cases, the histology of pleural biopsies is inconclusive for a specific cause, describing a variable process of inflammation, encompassing for non-specific pleuritis (NSP). Questions are raised whether the surgical (or video-assisted thoracoscopic surgery, VATS) is doing better than the medical thoracoscopy (MT or pleuroscopy), but no direct comparison between the two techniques exist in the current bibliography. The aim of our retrospective study was to compare these two techniques to find whether there is any difference in the false negative cases of NSP.

Methods: We included in our study 295 patients with NSP, 179 patients who underwent VATS comparing to 116 patients who underwent MT for pleural effusion of initially undetermined cause, having a follow-up of at least one year. Analysis of patients' files, history, clinical examinations, further tests, and follow-up were recorded.

Results: The mean age of our patients was 58.5±19.1 and M/F gender was 216/79; no difference was observed between the two groups. The mean follow-up period was 47.3±20.7 months. After VATS, only one patient (0.55%) was finally diagnosed with pleural malignancy (false negative) while after MT 2 patients (1.7%). Negative predictive value for pleura-related malignancy for VATS was 0.994 and for MT 0.982.

Conclusions: In patients with histological diagnosis of NSP both VATS and MT showed similar and excellent results of false negative cases and negative predictive value in excluding malignant pleural disease.
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http://dx.doi.org/10.21037/jtd-19-3496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330408PMC
May 2020

Histopathological and molecular study for synchronous lung adenocarcinoma staging.

Virchows Arch 2020 Jun 4;476(6):835-842. Epub 2020 Jan 4.

Department of Pathology , University Hospital of Saint Etienne. North Hospital, Avenue Albert Raimond, 42055, Saint Etienne CEDEX 2, France.

The presence of multiple synchronous lung cancer with the same histopathological type for a patient is a common situation and an issue for staging. Pathological criteria exist to distinguish multiple primaries from intra-pulmonary metastases of the same tumor, but they lack standardization. We wondered how molecular analysis with a limited Next Generation Sequencing panel could bring further information for tumor staging in this setting. We analyzed 24 patients with a total of 50 tumor nodules (22 pairs, two triplets). We compared histopathological examination with molecular analysis. A total of 50 tumors were molecularly tested. Nucleoli size was associated with molecular analysis concordance (p = 0.047). The presence of lepidic component in any of the two larger tumors was associated with molecular analysis concordance (p = 0.012). For molecular analysis, the proportion of progression-free patients was at the limits of significance (p = 0.054) whereas the presence of lepidic component, architectural concordance, and the concordance of comprehensive histologic assessments was not related to progression-free survival. For two patients with a discordant TTF-1 immunohistochemistry, molecular analysis showed a different mutation. Our results show that a limited NGS panel brings supplementary data to classify synchronous lung adenocarcinoma in most patients. We show that molecular staging seems in accordance with progression-free survival. Histopathological examination alone might not be accurate enough to assess a correct staging for synchronous tumors. We also suggest that TTF-1 immunohistochemistry, for the rare discrepant cases, might be a surrogate to molecular analysis.
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http://dx.doi.org/10.1007/s00428-019-02736-0DOI Listing
June 2020

Persistent low body weight in humans is associated with higher mitochondrial activity in white adipose tissue.

Am J Clin Nutr 2019 09;110(3):605-616

Metabolic Health, Nestlé Research, EPFL Innovation Park, Lausanne, Switzerland.

Background: Constitutional thinness (CT) is a state of low but stable body weight (BMI ≤18 kg/m2). CT subjects have normal-range hormonal profiles and food intake but exhibit resistance to weight gain despite living in the modern world's obesogenic environment.

Objective: The goal of this study is to identify molecular mechanisms underlying this protective phenotype against weight gain.

Methods: We conducted a clinical overfeeding study on 30 CT subjects and 30 controls (BMI 20-25 kg/m2) matched for age and sex. We performed clinical and integrative molecular and transcriptomic analyses on white adipose and muscle tissues.

Results: Our results demonstrate that adipocytes were markedly smaller in CT individuals (mean ± SEM: 2174 ± 142 μm 2) compared with controls (3586 ± 216 μm2) (P < 0.01). The mitochondrial respiratory capacity was higher in CT adipose tissue, particularly at the level of complex II of the electron transport chain (2.2-fold increase; P < 0.01). This higher activity was paralleled by an increase in mitochondrial number (CT compared with control: 784 ± 27 compared with 675 ± 30 mitochondrial DNA molecules per cell; P < 0.05). No evidence for uncoupled respiration or "browning" of the white adipose tissue was found. In accordance with the mitochondrial differences, CT subjects had a distinct adipose transcriptomic profile [62 differentially expressed genes (false discovery rate of 0.1 and log fold change >0.75)], with many differentially expressed genes associating with positive metabolic outcomes. Pathway analyses revealed an increase in fatty acid oxidation ( P = 3 × 10-04) but also triglyceride biosynthesis (P = 3.6 × 10-04). No differential response to the overfeeding was observed in the 2 groups.

Conclusions: The distinct molecular signature of the adipose tissue in CT individuals suggests the presence of augm ented futile lipid cycling, rather than mitochondrial uncoupling, as a way to increase energy expenditure in CT individuals. We propose that increased mitochondrial function in adipose tissue is an important mediator in sustaining the low body weight in CT individuals. This knowledge could ultimately allow more targeted approaches for weight management treatment strategies. This trial was registered at clinicaltrials.gov as NCT02004821.
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http://dx.doi.org/10.1093/ajcn/nqz144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736451PMC
September 2019

Non-specific pleuritis: pathological patterns in benign pleuritis.

Pathology 2019 Jun 20;51(4):405-411. Epub 2019 Apr 20.

Department of Pneumonology and Thoracic Oncology, North Hospital, University Hospital of St-Etienne, France.

A pleural biopsy without granulomatous inflammation or tumour cells is interpreted as 'non-specific pleuritis' (NSP), a diagnosis without any specificity, often frustrating for physicians. However, varying histological features are found in NSPs with unknown significance. The aim of this study was to describe the detailed microscopic features of NSP and correlate them with the underlying aetiology. One hundred patients diagnosed with NSP after pleural biopsy were retrospectively evaluated. A benign cause of pleural effusion was attributed. Histological features evaluated were inflammation, fibrosis, vascular proliferation, haemorrhage, fibrin, oedema and mesothelial hyperplasia. A semi-quantitative scoring was applied. Bacterial-caused and autoimmune disease-associated NSPs showed a higher score followed by viral and drug-induced conditions, while pneumothorax and cardiac-induced NSPs showed a lower score (p<0.0001). The degree of fibrosis was higher in bacterial NSP, and the type of fibrosis was cellular in this group (p=0.006). Vascular proliferation differed between groups (p<0.0001), and was higher in bacterial NSP. Histological findings differ significantly between the varying aetiologies of NSP, and this may be used to suggest the cause of the effusion.
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http://dx.doi.org/10.1016/j.pathol.2019.01.007DOI Listing
June 2019

First Characterization with Ultrasound Contrast Agent of a Fibrovascular Polyp Before Its Endoscopic Resection: A Case Report (with Videos).

Clin Endosc 2019 Mar 5;52(2):186-190. Epub 2018 Oct 5.

Department of Hepatogastroenterology, University Hospital of Saint-Etienne, Saint-Priest en Jarez, France.

We described for the first time the contrast enhancement of a giant fibrovascular esophageal polyp using ultrasound contrast agent, Sonovue® (Bracco, Milan, Italy) during echoendoscopy. Fine Doppler was unsuccessful in showing vascularization due to the mobile characteristic of the tumor. In contrast, via Sonovue® , tissue microcirculation was highlighted inside the entire head of the polyp, leading to better appreciate the risk of bleeding related to its resection. In a second part, we showed the feasibility of classic polypectomy for this giant polyp (5×5 cm) without complication and results of control endoscopy at 3 months. The present case is summarized in a video.
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http://dx.doi.org/10.5946/ce.2018.083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453852PMC
March 2019

Pathologic Subtypes of Lung Adenocarcinoma Brain Metastasis Is a Strong Predictor of Survival After Resection.

Am J Surg Pathol 2018 12;42(12):1701-1707

Departments of Pathology.

Primary lung adenocarcinoma is classified according to predominant histopathologic architecture into lepidic, papillary, acinar, solid, and micropapillary subtypes. These subtypes are related to overall survival in primary lung adenocarcinoma. The main goal of our work was to evaluate the prognostic impact of this classification on surgical resection of brain adenocarcinoma metastases in 97 patients with surgically resected brain metastases of lung adenocarcinoma from 2008 to 2017. Histopathologic subtype is associated with overall survival (P=0.0085): 30.1±5.6 months for papillary-predominant pattern, 26.5±6.3 months for acinar-predominant pattern, 13.8±1.4 months for solid pattern, 11.6±10.1 for micropapillary pattern. A "low grade" group comprising acinar and papillary-predominant pattern tumors showed a longer overall survival (28.5±4.1 mo) when compared with high-grade-predominant pattern (solid and micropapillary patterns) (13.7±1.4 mo), P=0.0011. On multivariate analysis, age below 55 years at the time of resection (hazard ratio, 3.56; 95% confidence interval, 1.12-11.31) and groups of architectural patterns (hazard ratio, 4.25; 95% confidence interval, 1.83-9.9) were related to overall survival (P=0.031 and 0.00078, respectively). Predominant architectural pattern evaluated on the surgical specimen of brain metastasis is a major prognostic factor of overall survival in metastatic lung adenocarcinoma.
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http://dx.doi.org/10.1097/PAS.0000000000001161DOI Listing
December 2018

Fulminant hepatitis due to very severe sinusoidal obstruction syndrome (SOS/VOD) after autologous peripheral stem cell transplantation: a case report.

BMC Res Notes 2018 Jul 3;11(1):436. Epub 2018 Jul 3.

Department of Clinical Hematology, Institut de Cancérologie Lucien Neuwirth, 108 Bis Avenue Albert Raimond, 42270, Saint Priest en Jarez, France.

Background: Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (SOS/VOD), is a potentially fatal complication of allogeneic or autologous hematopoietic stem cell transplantation. A plethora of transplant and patient-related risk factors predispose to SOS/VOD and should be taken into account for prognosis assessment as well as for adequate therapeutic intervention.

Case Presentation: We describe the case of a mantle cell lymphoma patient who developed a fulminant hepatitis following oxaliplatin-containing intensive chemotherapy and autologous transplantation. This clinical manifestation was secondary to a very severe SOS/VOD. The patient did not exhibit the usual risk factors and presented a non-classical form with major cytolysis, thus puzzling SOS/VOD diagnosis in this context.

Conclusion: SOS has been previously reported after oxaliplatin-based chemotherapy regimens for colorectal cancers, in particular in patients with colorectal liver metastases. We therefore suspected a potential relationship with oxaliplatin-based regimen as a driver of SOS/VOD in a non-susceptible lymphoma patient. With regards to this case, clinicians and especially intensivists should be aware of this atypical presentation.
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http://dx.doi.org/10.1186/s13104-018-3533-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6029059PMC
July 2018

EGFR, KRAS, BRAF and HER2 testing in metastatic lung adenocarcinoma: Value of testing on samples with poor specimen adequacy and analysis of discrepancies.

Exp Mol Pathol 2017 12 22;103(3):306-310. Epub 2017 Nov 22.

University Hospital of Saint Etienne, North Hospital, Department of Pathology, Avenue Albert Raimond, 42055 Saint Etienne, CEDEX 2, France; Molecular Genetic Platform of Cancer of Saint Etienne, Avenue Albert Raimond, 42055 Saint Etienne, CEDEX 2, France.

Molecular testing on metastatic lung adenocarcinoma or on non-small cell non-squamous lung carcinoma often relies on small specimen. In this group of patient with poor specimen adequacy, we analyzed the rate of EGFR, KRAS, BRAF and HER2 mutations compared to their rate in optimal specimen. We analyzed discrepancies in molecular testing results in patients with iterative analysis on several samples. We performed a retrospective study of 1538 samples consecutively analyzed. 263/665 (39,5%) biopsies and 37/708 (5,2%) surgical specimens were considered as samples with poor specimen adequacy (p<0,0001). A lower tumor cell content was associated with a lower rate of KRAS mutation: 15,8% in samples with <10% of tumor cells or <100 tumor cells versus 29,8% in samples with >10% tumor cell and >100 tumor cells (p=0,001). KRAS mutational rate was at 11,1% in cytology specimens, significantly lower than in biopsy or surgical specimens respectively at 28,2% and 28,5% (p=0,0002). Tumor cell content was not associated with mutational rate for EGFR, BRAF and HER2 mutations. DNA quantity was not associated with mutational rate for EGFR, KRAS, BRAF and HER2. A discrepancy in molecular testing was found in 16 patients. For 5 patients there was also a discrepancy for TTF-1 expression. On the 11 without TTF-1 discrepancy, specimen adequacy was not fulfilled in 10 cases at least for tumor content. Discrepancies were found in the case of low cellularity, poor cell content or testing on cytological specimens. Tumor cell content is a crucial parameter for molecular analysis rather than the type of specimen or the DNA quantity. Discrepancies in molecular testing results are rare but might suggest the presence of another tumor type, the emergence of another clone or a molecular testing in a sample with low cell content.
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http://dx.doi.org/10.1016/j.yexmp.2017.11.013DOI Listing
December 2017

Eosinophilic Cells, Autoimplants, Degree of Cellular Proliferation, and Adenofibroma Pattern are Important Histologic Findings in Ovarian Borderline Tumors.

Int J Gynecol Pathol 2017 Sep;36(5):447-452

Departments of Pathology (G.K., M.V., F.H., M.P., F.C.) Obstetrics and Gynecology (C.C.), North Hospital, University Hospital of Saint-Etienne, Saint-Etienne, France.

Ovarian borderline tumors can show histologic features, such as different degrees of cellular proliferation, eosinophilic cells, autoimplants, and adenofibromatous architecture, the importance of which is not known. The aim of the study was to describe these features and correlate them with clinical characteristics. Eighty-three ovarian borderline tumors were studied for the aforementioned features. These were correlated with clinicopathologic features. Epithelial proliferation was associated with the T stage in serous tumors (P=0.0009), but not in mucinous tumors (P=0.97). It was positively associated with bilateral tumors (P=0.01) and the presence of autoimplants (P<0.0001). It was associated with the presence of eosinophilic cells, as tumors with extensive eosinophilic cells had a mean proliferation of 80.7%, for those with no such cells it was 23.8% (P<0.0001), and for those with a limited presence of eosinophilic cells it was 48.7% (P=0.03). Cellular proliferation was not associated with the size of the tumor. An adenofibromatous architecture was associated with unilateral tumors (P=0.02) and showed a trend (P=0.08) with regard to T stage in serous tumors. It was not associated with the size of the tumor. The presence of autoimplants was marginally associated (P=0.07) with bilateral tumors and it was not associated with the size of the tumor or the T stage. The presence of eosinophilic cells was not associated with the T stage, the size of the tumor, or bilateral tumors. The degree of epithelial proliferation, autoimplants, adenofibromatous architecture, and the presence of eosinophilic cells are important features in ovarian borderline tumors.
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http://dx.doi.org/10.1097/PGP.0000000000000361DOI Listing
September 2017

TTF-1-positive Metastatic Endometrioid Carcinoma: A Case Report and Review of Literature of a Potential Diagnostic Pitfall.

Appl Immunohistochem Mol Morphol 2020 01;28(1):e6-e9

Departments of Pathology.

A 75-year-old female patient, nonsmoker was addressed to our institution for a fracture of C5 vertebra with spinal cord compression by a tumor mass invading surrounding soft tissue. She had a previous history of breast ductal carcinoma and endometrioid carcinoma. Biopsy of the tumor mass showed a TTF-1-positive carcinoma. Molecular study showed a E545K mutation of PIK3CA. Lung imaging showed multiple nodules evocative of metastasis rather than a primitive tumor. Reviewing of slides of endometrioid carcinoma showed areas positive for TTF1, and the same E545K mutation was found in endometrial tumor. The final diagnosis was endometrioid metastatic carcinoma with aberrant TTF-1 expression. A subset of endometrial neoplasm expresses TTF-1, this situation might be confusing especially in case of metastatic disease.
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http://dx.doi.org/10.1097/PAI.0000000000000539DOI Listing
January 2020

PD-L1 expression in pleomorphic, spindle cell and giant cell carcinoma of the lung is related to TTF-1, p40 expression and might indicate a worse prognosis.

PLoS One 2017 3;12(7):e0180346. Epub 2017 Jul 3.

Department of Pathology, North Hospital, University Hospital of Saint Etienne, Saint Etienne, France.

Lung sarcomatoid carcinoma of the lung is a rare tumor with a poor prognosis. More than 90% of them are pleomorphic, spindle cell and giant cell carcinoma (PSCGCC). This rare subtype of lung cancer is thought to be more resistant to chemotherapy, and a small subset of them seems to exhibit targetable mutations. Immunotherapy against PD1/PDL-1 is a new emerging treatment, and might be of interest in PSGSCC because they frequently express PD-L1. The aim of our work is to evaluate PD1 and PDL-1 expression in a surgical series of lung PSCGCC and their relationship with morphological and immunohistochemical parameters and prognosis. Thirty-six patients who underwent surgical resection of a PSGSCC were included. PD-L1 (E1L3N) expression on tumor cells and PD1 (NAT105) expression by tumor infiltrating lymphocytes (TILs) were performed by immunohistochemistry. Results were compared to immunohistochemistry tests of TTF1, Napsin A, p40 and to molecular study of EGFR, KRAS, BRAF and HER2. Seventy-five % of PSCGCC were considered as positive for PD-L1.PD-L1 expression in PSGSCC is associated with TTF-1 and/or Napsin A expression (47.2%, p = 0.039). Few p40 positive PSCGCC expressed PD-L1 (8.3%, p = 0.013). PD1 expression was not related to TTF-1 and/or Napsin A expression (p = 0.47), p40 expression (p = 0.68) or survival (p = 0.14). PD-L1 or PD1 expression were not related to the age, gender, pT, pN, stage, visceral pleura invasion, histopathological subtype, the presence of giant cell component, the predominance of sarcomatoid component, and the presence of EGFR or BRAF or HER2 or PIK3CA mutation (p>0.05). PD-L1 expression was correlated with a worse overall survival in PSCGCC (p = 0.045). PD-L1 expression is frequent in PSCGCC and might be associated with the expression of adenocarcinoma markers (TTF-1, Napsin A) or the lack of expression of squamous cell carcinoma marker (p40).
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0180346PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5495439PMC
October 2017

Histopathologic features predict survival in diffuse pleural malignant mesothelioma on pleural biopsies.

Virchows Arch 2017 Jun 27;470(6):639-646. Epub 2017 Mar 27.

Department of Pathology, North Hospital, University Hospital of Saint Etienne, Avenue Albert Raimond, Cedex 2, 42055, Saint Etienne, France.

Malignant pleural mesothelioma is a rare tumor with a poor prognosis. The only universally recognized pathological prognostic factor is histopathological subtype with a shorter survival in non-epithelioid subtypes. Recently, a grading of epithelioid mesothelioma on surgical resection has been proposed. The aim of our work is to assess the prognostic role of several histopathological factors on a retrospective cohort of 116 patients diagnosed as a pleural mesothelioma for more than 95% of patients on pleural biopsy. Our work shows that mitotic count <3/10 HPF (p < 0.0001), the lack of necrosis (p = 0.0379), mild nuclear atypia (p = 0.0054), the lack of atypical mitoses (p = 0.0265), a nucleoli size <3 μm (p = 0.0139), and a nucleoli absent or visible at 200× or higher magnification (p = 0.0170) are significantly associated with a better median overall survival in epithelioid mesothelioma. The presence of atypical mitoses was found to be related to a worse median survival in non-epithelioid mesothelioma. Mitotic count, necrosis, nuclear atypia, and nucleoli size are not associated with overall survival in non-epithelioid mesothelioma. Our work highlights that histopathological prognostic factors can be assessed on pleural biopsies and can predict reliably median overall survival. This is of interest in order to define subgroups of patients who could benefit of different therapies and select patients who could benefit of surgical excision.
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http://dx.doi.org/10.1007/s00428-017-2109-zDOI Listing
June 2017

FOXA1 in HPV associated carcinomas: Its expression in carcinomas of the head and neck and of the uterine cervix.

Exp Mol Pathol 2017 04 14;102(2):230-236. Epub 2017 Feb 14.

Department of Pathology, North Hospital, University Hospital of St-Etienne, France.

Background: FOXA1 is a major transcription factor involved in the action of human papilloma virus (HPV). However, it has been never studied in HPV-associated tumors.

Aim Of The Study: To investigate its expression in cervical and head and neck tumors.

Material And Methods: 63 cervical carcinomas/dysplasias and 152 head and neck squamous cell carcinomas (HNSCC) were immunohistochemically studied for the expression of FOXA1.

Results: 63.1% of cervical SCC and 40.7% of endocervical adenocarcinomas strongly expressed FOXA1. Most (90%) pre-invasive lesions (CIN3 and in situ adenocarcinomas) strongly expressed FOXA1 and this difference from invasive lesions was statistically significant (p=0.005). No association with clinicopathological factors was found. 51.3% of HNSCC expressed FOXA1. In these tumors, FOXA1 expression was associated with the non-keratinizing morphology but not with the HPV/p16 status neither other clinicopathological features. Of normal structures, salivary glands, endocervical glands and basal/parabasal cell layer of squamous epithelium of both uterine cervix and head and neck mucosa, all strongly expressed FOXA1.

Conclusion: FOXA1 is expressed by basal cells of squamous epithelium, pre-invasion lesions of the uterine cervix and the head/neck and almost half invasive cervical and head/neck carcinomas, supporting its possible implication in HPV pathogenesis.
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http://dx.doi.org/10.1016/j.yexmp.2017.02.010DOI Listing
April 2017

Prognostic impact of immune microenvironment in laryngeal and pharyngeal squamous cell carcinoma: Immune cell subtypes, immuno-suppressive pathways and clinicopathologic characteristics.

Oncotarget 2017 Mar;8(12):19310-19322

Department of Pathology, North Hospital, University Hospital of St-Etienne, St-Etienne, France.

Background: Immune system affects prognosis of various malignancies. Anti-immune pathways like PD-L1 and CTLA4 are used by the tumor to overcome immune system and they serve as immunotherapy targets. The immune microenvironment of head-and-neck squamous cell carcinoma (SCCHN) has not been sufficiently studied.

Patients And Methods: 152 SCCHN were immunohistochemically studied for the expression of CD3, CD8, CD57, CD4, granzyme b, CD20, CD163, S100, PD-L1, CTLA4 and CXCR4.

Results: CD3, CD8, CD57 and stromal S100 higher density is a good prognostic factor (p=0.02, 0.01, 0.02, 0.03 respectively). CTLA4 tumor expression is a poor prognostic factor (p=0.05). The rest immune cells do not affect prognosis. CD3 and CD8 density does not correlate with clinicopathological factors or p16/p53 expression, while CD57 and CD4 higher density is associated with the absence of distant metastases (p=0.03 and 0.07, respectively). Higher CD20 and S100 density is associated with lower T stage (p=0.04 and 0.03, respectively). PD-L1 expression is higher in CD3, CD8, and CD163 infiltrated tumors and in histologically more aggressive tumors. Response to neoadjuvant chemotherapy is better in highly CD3 infiltrated tumors and in tumors with less intraepithelial macrophages.

Conclusion: Rich T-lympocytic and dendritic cell response is a good prognostic factor in SCCHN, whereas tumors expressing CTLA4 show poor prognosis. PDL1 expression does not affect prognosis, but it is expressed in histologically more aggressive tumors and in T-cells rich tumors. Response to induction chemotherapy is better in tumors less infiltrated by macrophages and mostly infiltrated by T cells.
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http://dx.doi.org/10.18632/oncotarget.14242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386686PMC
March 2017

p16 and p53 expression status in head and neck squamous cell carcinoma: a correlation with histological, histoprognostic and clinical parameters.

Pathology 2016 Jun 23;48(4):341-8. Epub 2016 Apr 23.

Department of Pathology, North Hospital, University Hospital of St-Etienne, France.

Different histopathology and prognosis characterise the human papillomavirus (HPV)-related oropharyngeal tumours, but squamous cell carcinomas (SCC) of other localisations have not been exhaustively studied. Tissues from 120 patients with a head and neck SCC were studied for the expression of p16 and p53, and the Brandwein-Gensler (BG) histological risk assessment model. p16 positivity and p53 normal expression were significantly correlated with non-smoking, an earlier T stage and a non-keratinising morphology. The BG risk score was not associated with p16 or p53 expression; p16 expression was associated with a lymphocytic T-cytotoxic response. BG risk score was significantly correlated with overall survival and progression-free survival, while neither p16 nor p53 expression were associated with prognosis. p16 and p53 expression are associated with the histological subtype and the T stage even in non-oropharyngeal-restricted tumours. The BG risk score is not correlated with p16 or p53 and retains its power in non-site-specific SCCs.
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http://dx.doi.org/10.1016/j.pathol.2016.01.005DOI Listing
June 2016

A 48-YEar-Old Male with a Pituitary Tumor.

Brain Pathol 2016 Jan;26(1):130-1

Department of Pathology, Hôpital Nord, Saint Etienne, CEDEX2, France.

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http://dx.doi.org/10.1111/bpa.12339DOI Listing
January 2016

[Carcinosarcomas in female genital tracts: general review].

Bull Cancer 2014 Jul-Aug;101(7-8):760-4

Institut de cancérologie de la Loire Lucien Neuwirth, Département de radiothérapie, 108 bis, avenue Albert-Raimond, BP 60008, 42271 Saint-Priest-en-Jarez, France.

Carcinosarcoma, also known as mixed mesodermal tumor or malignant mixed Mullerian tumor (MMMT) is a pathological entity combining a sarcomatous and a carcinomatous component. Found in thoracic, digestive, genitourinary, liver or skin locations, the most common location is the female genital tract. In gynecological tumors, carcinosarcoma accounts for about 2-5% of endometrial cancers, and 1% of ovarian cancers. To date, there is no consensus on the therapeutic strategy. It relies mostly on maximum cytoreductive surgery. Adjuvant therapy remains controversial, and few prospective studies investigating its interest. Retrospective studies show the benefits of adjuvant chemotherapy based on platinum in most cases. Radiation therapy has a place in the adjuvant situations of endometrial and cervical carcinosarcoma. A more detailed pathological knowledge, and the use of targeted therapies may be promising in this histological subtype whose prognosis remains very poor. The objective of this study is to present the main principles of carcinosarcoma management in female genital tracts, describing pathological and prognostic features at the same time.
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http://dx.doi.org/10.1684/bdc.2014.1937DOI Listing
September 2014