WHO grading system for invasive pulmonary lung adenocarcinoma reveals distinct molecular signature: An analysis from the cancer genome atlas database.

Lung adenocarcinoma grading has gained interest in the past years. Recently a three-tier tumor grading was proposed showing that it is related to patients' prognosis. Nevertheless, the underlying molecular basis of this morphological grading remains partly unknown. The aim of our work is to take advantage of The Cancer Genome Atlas lung adenocarcinoma (TCGA_LUAD) cohort to describe the molecular data associated to tumor grading. We performed a study on publicly available data of the TCGA database first by assessing a tumor grade on downloadable tumor slides. Secondly we analyzed the molecular features of each tumor grade group. Our work was performed on a study group of 449 patients. We show that aneuploidy score was significantly different between grade 2 and grade 3 groups with different chromosomal imbalance (p < 0.001). SCGB1A1 mRNA expression was higher in grade 2 (p = 0.0179) whereas NUP155, CHFR, POLQ and CDC7 have a higher expression in grade 3 (p = 0.0189, 0.0427, 0.0427 and 0.427 respectively). GZMB and KRT80 have a higher methylation of DNA in grade 2 (p = 0.0201 and 0.0359 respectively). MT1G, CLEC12B and NDUFA7 have a higher methylation of DNA in grade 3 (p < 0.001, 0.0246 and 0.0359 respectively). We showed that the number of activated pathways is different between grade 2 and grade 3 patients (p = 0.004). We showed that differentially expressed genes by mRNA analysis and DNA methylation analysis involve several genes implied in chemoresistance. This could suggest that grade 3 lung adenocarcinoma might be more resistant to chemotherapy.

Histopathological and molecular profiling of lung adenocarcinoma skin metastases reveals specific features.

AIMS: Little is known regarding the histopathological and molecular features of lung adenocarcinoma skin metastases. Our study is the largest, to our knowledge, to comprehensively explore these to date. METHODS AND RESULTS: We performed a retrospective cohort study analysing 42 lung adenocarcinoma skin metastasis samples obtained from a database of 2659 lung adenocarcinomas collected between 2010 and 2020. EGFR exon 19 deletion was detected in one patient and KRAS mutations were detected in 12 (33.3%) patients. The programmed cell death ligand 1 (PD-L1) tumour proportion score was <1% in 27 patients, ≥1% and <50% in eight patients, ≥50% in six patients and not assessable in one patient. We showed that the predominant histopathological subtype is different from that at other metastatic sites (P = 0.024). Thyroid transcription factor I (TTF-1) was more often negative in skin metastases compared to other sites (P < 0.001). The EGFR mutation rate tended to be lower for skin metastases compared to other sites (P = 0.079). Skin metastases were associated with a high rate of PD-L1-negative cases (P = 0.022). CONCLUSION: Our work shows that the skin metastases of lung adenocarcinoma have a specific histopathological profile.

Comparative eye and liver differentially expressed genes reveal monochromatic vision and cancer resistance in the shortfin mako shark (Isurus oxyrinchus).

The shortfin mako, Isurus oxyrinchus is an oceanic pelagic shark found worldwide in tropical and subtropical waters. However, the understanding of its biology at molecular level is still incipient. We sequenced the messenger RNA isolated from eye and liver tissues. De novo transcriptome yielded a total of 705,940 transcripts. A total of 3774 genes were differentially expressed (DEGs), with 1612 in the eye and 2162 in the liver. Most DEGs in the eye were related to structural and signaling functions, including nonocular and ocular opsin genes, whereas nine out of ten most overexpressed genes in the liver were related to tumor suppression, wound healing, and human diseases. Furthermore, DEGs findings provide insights on the monochromatic shark vision and a repertory of cancer-related genes, which may be insightful to elucidate shark resistance to cancer. Therefore, our results provide valuable sequence resources for future functional and population studies.

[Hobnail variant of papillary thyroid carcinoma]. / Carcinome papillaire de la thyroïde à cellules en clous de tapissier.

We report the case of a hobnail variant of papillary thyroid carcinoma revealed by a cervical mass in a 67 years-old patient. This new entity in the 2017 WHO classification is rare. Histopathological diagnosis is based on four main criteria, present in≥30% of tumor cells: a discohesive tumor, micropapillary structures and loss of cell polarity and hobnail cells. This tumor expresses markers of thyroid differentiation. The most widely described molecular alteration is BRAF V600E mutation associated with other alterations, especially p53 mutations. This reflects the agressivness of this variant. It is important to recognize the hobnail variant of papillary thyroid carcinoma and to specify it in the pathological report because of its more pejorative prognosis, with local invasion, lymph node and distant metastasis, and deacreased survival. No specific management is recommended, but a close follow up seems necessary.

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

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.

Vascular lesions of the female genital tract: Clinicopathologic findings and application of the ISSVA classification.

INTRODUCTION: Vascular lesions of the female genital tract are extremely rare and their nomenclature does not widely follow the International Society for the Study of Vascular Anomalies (ISSVA) classification. AIM OF THE STUDY: To describe the clinicopathologic characteristics of vascular lesions of the female genital tract and to apply the ISSVA classification. MATERIAL AND METHODS: 19 vascular lesions were diagnosed during a 20 year period. Their histological features including size, localization, type of vessels, endothelial atypia, mitotic activity, relation with surrounding tissues are described. Immunohistochemical analysis using CD31, CD34, D2-40, WT1, MiB1 and GLUT1 is performed. RESULTS: 8 ovarian lesions were found including small cortical lymphatic malformations and medullary lesions resembling pyogenic granulomas, as well as two tubal lesions resembling true hemangiomas. They were all incidental findings. Cervical lesions (n=7) included endocervical polypoid venous malformations and paracervical combined malformations presenting clinically as leiomyomas; they probably represent static vessels. Vulvar lesions (n=4) consist of lymphatic and venous malformations and by angiokeratomas. No malignant lesions were found. WT1 is expressed by most of these lesions with the exception of the lymphatic malformations and the paracervical combined malformations. GLUT1 was consistently negative. MiB1 was only rarely positive. CONCLUSION: Vascular lesions of the female genital tract consist of lesions with different morphology by organ and of probably different pathogenesis. The ISSVA classification can be adopted for most of these lesions. WT1 should be best considered as a marker of endothelia with proliferative capacity rather than a marker of neoplastic endothelia.

Distribution and New Records of the Bluntnose Sixgill Shark, Hexanchus griseus (Hexanchiformes: Hexanchidae), from the Tropical Southwestern Atlantic.

The bluntnose sixgill shark, Hexanchus griseus, is a widely distributed demersal species found in tropical and temperate waters of the Pacific, Atlantic, and Indian Oceans, inhabiting continental shelves and slopes, islands, and mid-ocean ridges at depths ranging from 200 to 1100 m. In the Southwestern Atlantic, this species has been recorded from northeastern to southern Brazil, Argentina, and Uruguay. Despite this, the known distribution of this species in the Southwestern Atlantic is very patchy and, in some cases, still mostly ignored in the literature, such as in northeastern Brazil. This study, therefore, aimed to report 23 new records of Hexanchus griseus in the Tropical Southwestern Atlantic and highlight the presence of this species off the northeastern Brazilian coast. So far, Hexanchus griseus was officially reported from the Fernando de Noronha Archipelago, Saint Peter and Saint Paul Archipelago, and the state of Ceará along the northeast coast of Brazil. Herein, the known distribution is extended to the continental shelf breaks and upper slopes of other Brazilian states, reinforcing the previously reported occurrence of the species near the Saint Peter and Saint Paul Archipelago.

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

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.

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

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.

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

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.

Phenotypic and genetic spectrum of alveolar capillary dysplasia: a retrospective cohort study.

OBJECTIVE: Alveolar capillary dysplasia (ACD) is one of the causes of pulmonary hypertension. Its diagnosis is histological but new pathogenetic data have emerged. The aim of this study was to describe a French cohort of patients with ACD to improve the comprehension and the diagnosis of this pathology which is probably underdiagnosed. METHODS: A retrospective observational study was conducted in French hospitals. Patients born between 2005 and 2017, whose biological samples were sent to the French genetic reference centres, were included. Clinical, histological and genetic data were retrospectively collected. RESULTS: We presented a series of 21 patients. The mean of postmenstrual age at birth was 37.6 weeks. The first symptoms appeared on the median of 2.5 hours. Pulmonary hypertension was diagnosed in 20 patients out of 21. Two cases had prolonged survival (3.3 and 14 months). Histological analysis was done on lung tissue from autopsy (57.1% of cases) or from percutaneous biopsy (28.6%). FOXF1 was found abnormal in 15 patients (71.4%): 8 deletions and 7 point mutations. Two deletions were found by chromosomal microarray. CONCLUSION: This study is one of the largest clinically described series in literature. It seems crucial to integrate genetics early into diagnostic support. We propose a diagnostic algorithm for helping medical teams to improve diagnosis of this pathology.

Lepidic, Papillary Components and EGFR Mutations are Frequent in Patients With Lung Adenocarcinoma Who are Over 75 Years Old.

Treatment for lung adenocarcinoma frequently diverges from standard treatment in older patients. Clinical, pathologic, and molecular characteristics of lung cancer in patients over 75 years old have not been fully described. The aim of our work was to describe the rate of EGFR, KRAS, BRAF, and HER2 mutations, and ALK rearrangement and pathologic characteristics in patients with lung adenocarcinoma over 75, compared with patients below 75 years old. This is a retrospective study from 2 cohorts: a histopathologic cohort of all consecutively resected lung adenocarcinoma in our institution for patients over 75 (n=54, from 2006 to 2017) compared with patients below 75 years old (n=148, from 2014 to 2017) and a molecular cohort of all stage IIIb or IV lung adenocarcinoma from 2009 to 2017 (n=1611). Papillary and lepidic components were more frequently found in patients over 75 years old (P=0.046 and 0.0078, respectively). The rate of current smokers was lower in older patients (P<0.0001). EGFR mutations were more frequent in patients over 75 than in younger patients: 17% versus 8.1% (P<0.0001). The mutually exclusive KRAS mutation was more frequent in patients below 75 years old than in older patients: 25.8% versus 12.8% (P<0.0001). There was no difference for the proportion of the 2 most frequent EGFR mutations (exon 19 deletion and L858R mutation) (P=0.85) or KRAS-mutated codon (P=0.22) between tumors in younger or older patients. There was no statistically significant difference for the presence of BRAF, HER2 mutations, and ALK rearrangement (P=0.44, 0.71, and 1, respectively). Our work highlights the fact that EGFR mutations are more frequent in patients over 75 years old in our population. We can hypothesize that this difference might be mainly caused by the less frequent occurrence of tobacco-smoking-related lung cancers in the elderly and the presence of a lepidic or papillary component in this age group.

Impact of delayed fixation and decalcification on PD-L1 expression: a comparison of two clones.

The bone is a frequent localization for lung non-small cell cancer metastasis; decalcification is required to permit tissue section. Pre-analytical conditions can influence the detection of immunohistochemical markers. The aim of our work is to evaluate PD-L1 expression in samples with delayed fixation and in decalcified tissue with chelating agent or acid at different time. Tumor-expressing PD-L1 and placental tissue were fixed at different times or decalcified with an acid decalcifier or EDTA for different durations. For 22C3 antibody, when tissues were decalcified with DC3, there was a significant decrease in the percentage of tumor cells or placental villi stained which after 4 h (p = 0.035 at 4 h). When EDTA is used for 22C3 antibody, there was a slight decrease in the percentage of stained tumor cells or villi but although there was a trend (p = 0.058 at 20 h), this was never statistically significant. For E1L3N antibody, when tissues were decalcified either with DC3 or EDTA, there was no significant decrease for the proportion of stained tumor cells or placental villi, neither for staining intensity for the first 24 h. The proportion of placental villi and tumor stained or intensity of staining was not significantly lower for any sample after delayed fixation also at 24 h for both PD-L1 clones. Delayed fixation does not affect the proportion of stained cell and intensity with PD-L1 immunohistochemistry. Decalcification also performed with EDTA lower the proportion and intensity of stained cells with PD-L1 immunohistochemistry.

Endobronchial melanoma metastasis 40 years after the excision of the primary cutaneous tumor: A case report.

RATIONALE: Endobronchial melanoma metastases are rare, comprising 4.5% of all endobronchial metastases. They are diagnosed at a median time of 48 months from primary tumor presentation, and survival of these patients is poorer when accompanied by other metastatic sites or malignant pleural effusion. We present a case of endobronchial melanoma metastasis happening 40 years after the initial diagnosis. The need of adjuvant techniques in the diagnosis of this tumor is highlighted and a short review on this rare phenomenon is provided. PATIENTS CONCERNS: An 83-year old nonsmoking woman, presented with dyspnea. DIAGNOSES: Left lung atelectasis was found. INTERVENTIONS: Endobronchial resection of a tumor of the left main stem bronchus was achieved by rigid bronchoscopy under general anesthesia with complete reventilation of the left lung. OUTCOMES: Histopathological, immunohistochemical and molecular diagnostics of the resected tumor led to a diagnosis of an endobronchial melanoma metastasis. LESSONS: Melanoma is a type of tumor that cannot be regarded as cured even after long disease-free periods, and thus, any new symptomatology in these patients warrants stringent work up.