Prognostic impact of the IASLC grading system of lung adenocarcinoma: a systematic review and meta-analysis.

AIMS: Tumour grading is an essential part of the pathologic assessment that promotes patient management. The International Association for the Study of Lung Cancer (IASLC) proposed a grading system for non-mucinous lung adenocarcinoma in 2020. We aimed to validate the prognostic impact of this novel grading system on overall survival (OS) and recurrence-free survival (RFS) based on literature data. METHODS AND RESULTS: The review protocol was registered in PROSPERO (CRD42023396059). We aimed to identify randomized or non-randomized controlled trials published after 2020 comparing different IASLC grade categories in Medline, Embase, and CENTRAL. Hazard ratios (HRs) with 95% confidence intervals (CIs) of OS and RFS were pooled and the Quality In Prognosis Studies (QUIPS) tool was used to assess the risk of bias in the included studies. Ten articles were eligible for this review. Regarding OS estimates, grade 1 lung adenocarcinomas were better than grade 3 both in univariate and multivariate analyses (HROSuni = 0.19, 95% CI: 0.05-0.66, p = 0.009; HROSmulti = 0.21, 95% CI: 0.12-0.38, p < 0.001). Regarding RFS estimates, grade 3 adenocarcinomas had a worse prognosis than grade 1 in multivariate analysis (HRRFSmulti: 0.22, 95% CI: 0.14-0.35, p < 0.001). CONCLUSION: The literature data and the result of our meta-analysis demonstrate the prognostic relevance of the IASLC grading system. This supports the inclusion of this prognostic parameter in daily routine worldwide.

Pulmonary Adenocarcinoma with Enteric Differentiation without TTF-1 Expression Is a Very Rare Subtype with Limited Treatment Options and Poor Prognosis.

INTRODUCTION: Pulmonary adenocarcinoma with enteric differentiation (PAED) without thyroid transcription factor-1 (TTF-1) expression is an extremely rare variant of lung cancer. Due to its rarity, few clinicopathological and molecular studies have been performed on PAED, particularly in Caucasian patients. Therefore, it is necessary to obtain clinicopathological data of Caucasian PAED patients without TTF-1 expression, their systemic therapy options, and the efficacy of their systemic treatment. METHODS: We examined the clinicopathological features of 121 cases of TTF-1-negative pulmonary adenocarcinoma at a certified German lung cancer center including 79 cases without a PAED and 42 cases with a PAED, compared these subgroups, and investigated patients' response to chemotherapy and immunotherapy as first-line treatment. By using endoscopy and/or a PET-CT, a primary adenocarcinoma of the digestive tract was excluded in all PAED patients. RESULTS: A comparison of clinicopathological data of TTF-1-negative PAED and non-PAED patients revealed a significantly lower frequency of high programmed death receptor ligand 1 (PD-L1) expression in PAED resulting in the lack of single-agent immunotherapy (p = 0.032) in this subgroup. Frequencies of an activating Kirsten rat sarcoma viral oncogene homolog (KRAS) gene mutation were high in both groups (46.7% and 50.0%), but G12C gene mutations were seldomly noted (in 6.7% and 18.5% of patients with evaluable data). Median overall survival (OS) was poor in both groups (10 and 12 months). The majority of PAED patients received platinum-based and taxane-containing chemotherapy or chemo-/immunotherapy with an objective response rate (ORR) of 31.6% and a disease control rate of 57.9%. Median progression-free survival (PFS) and OS of PAED patients with systemic therapy were very poor (3.9 months and 5.9 months). CONCLUSIONS: Caucasian patients with TTF-1 negative PAED have a poor prognosis with a reduced ORR to standard first-line systemic therapy and short survival times (PFS and OS).

Clinicopathological features of cytokeratin 5-positive pulmonary adenocarcinoma.

Cytokeratin 5 (CK5) is a marker for pulmonary squamous cell carcinoma; however, CK5 is sometimes present in pulmonary adenocarcinoma (ADC), and there is insufficient information regarding the clinicopathological features of CK5-positive ADC. We aimed to explore the clinicopathological characteristics of CK5-positive ADC using immunohistochemistry. We prepared the following two cohorts: a resected cohort containing 220 resected tumours for primarily studying the detailed morphological characteristics, and a tissue microarray (TMA) cohort containing 337 samples for investigating the associations of CK5 expression with other protein expressions, genetic and prognostic findings. CK5-positive ADC was defined to have ≥ 10% tumour cells and presence of CK5-positive tumour cells in the resected and TMA cohorts, respectively. CK5-positive ADCs were identified in 91 (16.3%) patients in the combined cohort. CK5-positive ADCs had male predominance (P = 0.012), smoking history (P = 0.001), higher stage (P < 0.001), histological high-grade components (P < 0.001), vascular invasion (P < 0.001), mucinous differentiation (P < 0.001), spread through airspaces (P < 0.001), EGFR wild-type (P < 0.001), KRAS mutations (P < 0.001), ALK rearrangement (P < 0.001) and ROS1 rearrangement (P = 0.002). In the resected cohort, more than half the CK5-positive ADCs (19 cases, 65.5%) showed mucinous differentiation; the remaining cases harboured high-grade components. In the TMA cohort, CK5-positive ADCs correlated with TTF-1 negativity (P = 0.002) and MUC5B, MUC5AC and HNF4alpha positivity (P < 0.001, 0.048, < 0.001). Further, CK5-positive ADCs had significantly lower disease-free and overall survival rates than CK5-negative ADCs (P < 0.001 for each). Additionally, multivariate analysis revealed that CK5 expression was an independent poor prognostic factor. CK5-positive ADCs showed aggressive clinical behaviour, with high-grade morphology and mucinous differentiation.

Immunohistochemical Analysis of Lung Adenocarcinoma in Russian Mayak Nuclear Workers.

Specimens of lung adenocarcinoma (AdCa) from Russian nuclear workers (n = 54) exposed to alpha particles and gamma rays and from individuals non-exposed to radiation (n = 21) were examined using immunohistochemistry. Estimated significant associations with alpha dose were negative for Ki-67 and collagen IV in AdCa. Associations with gamma-ray dose were negative for tissue inhibitor of matrix metalloproteinase 2 and caspase 3 and positive for matrix metalloproteinase 2 and leukemia inhibiting factor in AdCa. The findings provide some evidence supporting alterations in apoptosis, cell proliferation and extracellular matrix in lung tissues affected by chronic radiation exposure that can contribute to radiogenic cancerogenesis.

The More Extensive the Spread through Air Spaces, the Worse the Prognosis Is: Semi-Quantitative Evaluation of Spread through Air Spaces in Pulmonary Adenocarcinomas.

INTRODUCTION: The extent of spread through air spaces (STAS) is less investigated among patients with lung adenocarcinoma who underwent sublobar resection. Therefore, we aimed to evaluate the extent of STAS semi-quantitatively, to assess its prognostic impact on overall survival (OS) and recurrence-free survival (RFS), and to investigate the reproducibility of this assessment. METHODS: The number of tumour cell clusters and single tumour cells within air spaces was recorded in three different most prominent areas (200x field of view). The extent of STAS was categorized into three groups, and the presence of free tumour cluster (FTC) was recorded. RESULTS: Sixty-one patients were included. Recurrence was more frequent with higher grade (p = 0.003), presence of lymphovascular invasion (p = 0.027), and presence of STAS of any extent (p = 0.007). In multivariate analysis, presence of FTC (HR: 5.89; 95% CI: 1.63-21.26; p = 0.005) and more pronounced STAS (HR: 7.46; 95% CI: 1.60-34.6; p = 0.01) had adverse impact on OS and RFS, respectively. Concerning reproducibility, excellent agreement was found among STAS parameters (ICC range: 0.92-0.94). DISCUSSION: More extensive STAS is an unfavourable prognostic factor in adenocarcinomas treated with sublobar resection. As the evaluation of extent of STAS is reproducible, further investigation is required to gather more evidence.

Feline pulmonary carcinoma: Gross, histological, metastatic, and immunohistochemical aspects.

Feline pulmonary carcinoma (FPC) is an uncommon neoplasm with unique morphological features. We describe the gross, histological, metastatic, and immunohistochemical aspects of FPC, based on postmortem examinations from an 11-year retrospective study. Thirty-nine cases were selected. Predispositions were observed in senior (P < .001) and Persian (P = .039) cats. There were three gross patterns of the pulmonary tumors: (a) a large nodule and additional smaller nodules, (b) a solitary nodule, and (c) small, multifocal to coalescent nodules. Extrapulmonary metastases were present in 22/39 cases (56.4%), mainly in the regional lymph nodes (17/39, 43.5%), skeletal muscles (9/39, 23%), kidneys (6/39, 15.3%), and parietal pleura (4/39, 10.2%). The primary tumor size was correlated with the occurrence of extrapulmonary metastases (P = .002). Histologically, the tumors were classified as papillary adenocarcinoma (19/39, 48.7%), adenosquamous carcinoma (ADS) (8/39, 20.5%), acinar adenocarcinoma (6/39, 15.3%), solid adenocarcinoma (3/39, 7.6%), lepidic adenocarcinoma (2/39, 5.1%), and micropapillary adenocarcinoma (1/39, 2.5%). By immunohistochemistry, 39/39 cases (100%) were positive for pancytokeratin, 34/39 (87.1%) for thyroid transcription factor-1, and 8/39 (20.5%) for vimentin. Immunoreactivity for p40 was detected in the squamous component of all ADSs (8/8, 100%) and occasionally in the glandular component of adenocarcinomas (10/31, 32.2%). Napsin A expression was absent in all feline tissue tested. The results indicate that a modified and simplified histological classification based on current human and domestic animal systems is appropriate for cats. Additionally, this study highlights the utility of p40 as an immunohistochemical marker for the diagnosis of FPC with squamous differentiation.

Chemical Compositions and Experimental and Computational Modeling of the Anticancer Effects of Cnidocyte Venoms of Jellyfish Cassiopea andromeda and Catostylus mosaicus on Human Adenocarcinoma A549 Cells.

Nowadays, major attention is being paid to curing different types of cancers and is focused on natural resources, including oceans and marine environments. Jellyfish are marine animals with the ability to utilize their venom in order to both feed and defend. Prior studies have displayed the anticancer capabilities of various jellyfish. Hence, we examined the anticancer features of the venom of Cassiopea andromeda and Catostylus mosaicus in an in vitro situation against the human pulmonary adenocarcinoma (A549) cancer cell line. The MTT assay demonstrated that both mentioned venoms have anti-tumoral ability in a dose-dependent manner. Western blot analysis proved that both venoms can increase some pro-apoptotic factors and reduce some anti-apoptotic molecules that lead to the inducing of apoptosis in A549 cells. GC/MS analysis demonstrated some compounds with biological effects, including anti-inflammatory, antioxidant and anti-cancer activities. Molecular docking and molecular dynamic showed the best position of each biologically active component on the different death receptors, which are involved in the process of apoptosis in A549 cells. Ultimately, this study has proven that both venoms of C. andromeda and C. mosaicus have the capability to suppress A549 cells in an in vitro condition and they might be utilized in order to design and develop brand new anticancer agents in the near future.

Spatially Resolved Proteomic and Transcriptomic Profiling of Anaplastic Lymphoma Kinase-Rearranged Pulmonary Adenocarcinomas Reveals Key Players in Inter- and Intratumoral Heterogeneity.

Pulmonary adenocarcinomas (pADCs) with an ALK rearrangement are a rare cancer subtype, necessitating comprehensive molecular investigations to unravel their heterogeneity and improve therapeutic strategies. In this pilot study, we employed spatial transcriptomic (NanoString GeoMx) and proteomic profiling to investigate seven treatment-naïve pADCs with an ALK rearrangement. On each FFPE tumor slide, 12 smaller and 2-6 larger histopathologically annotated regions were selected for transcriptomic and proteomic analysis, respectively. The correlation between proteomics and transcriptomics was modest (average Pearson's r = 0.43 at the gene level). Intertumoral heterogeneity was more pronounced than intratumoral heterogeneity, and normal adjacent tissue exhibited distinct molecular characteristics. We identified potential markers and dysregulated pathways associated with tumors, with a varying extent of immune infiltration, as well as with mucin and stroma content. Notably, some markers appeared to be specific to the ALK-driven subset of pADCs. Our data showed that within tumors, elements of the extracellular matrix, including FN1, exhibited substantial variability. Additionally, we mapped the co-localization patterns of tumor microenvironment elements. This study represents the first spatially resolved profiling of ALK-driven pADCs at both the gene and protein expression levels. Our findings may contribute to a better understanding of this cancer type prior to treatment with ALK inhibitors.

Afatinib-Induced Tumor Lysis Syndrome in Pulmonary Adenocarcinoma: A Case Report and Literature Review.

Tumor lysis syndrome (TLS) is a potentially fatal oncological emergency that typically develops during the treatment of rapidly proliferating malignancies. It is infrequently reported in solid tumors, such as pulmonary adenocarcinoma. A 59-year-old male patient with shortness of breath presented with a 3.3 cm × 3.0 cm mass in the right upper lobe, along with massive right-sided pleural effusion. A percutaneous needle biopsy was performed, and a diagnosis of pulmonary adenocarcinoma with an epidermal growth factor receptor (EGFR) mutation was made. The patient was treated with afatinib because of the malignant pleural effusion and multiple metastases to the intrathoracic lymph nodes, left scapula, and brain. After 4 days of afatinib treatment, he developed oliguric acute kidney injury and progressively worsening dyspnea. Based on the clinical and laboratory findings, the patient was diagnosed with afatinib-induced TLS. To the best of our knowledge, this is the first reported case of afatinib-induced TLS in pulmonary adenocarcinoma.

Intratumoural metastasis of primary lung adenocarcinoma to non-invasive follicular thyroid neoplasm with papillary-like nuclear features.

Metastasis to the thyroid gland is very uncommon with an incidence of 2-3% of all thyroid malignancies. A higher incidence is noted in autopsy studies indicating incidental detection. However, tumour-to-tumour metastasis is extremely uncommon with a handful of cases published in the literature to date. Also, non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFT-P) is a rare neoplasm; diagnosis requires meticulous sampling of the entire capsule and fulfilment of other diagnostic criteria. We report a case of primary adenocarcinoma of lung in a 57-year-old female who additionally had a left thyroid nodule which appeared suspicious on ultrasonography. Histology of lung tumour was conventional papillary adenocarcinoma while aspiration cytology from the thyroid raised suspicion of metastatic adenocarcinoma. On hemithyroidectomy, the thyroid nodule showed metastatic adenocarcinoma in the centre of the nodule, while the peripheral portion showed non-invasive follicular thyroid neoplasm with papillary-like nuclear features; the diagnosis of which was confirmed with complete sampling of the thyroid capsule. The immunoprofile also supported the above dual histology. This is an extremely uncommon occurrence and metastasis within a NIFT-P has not been reported to the best of our knowledge.

Accuracy of 18F-FDG in Detecting Stage I Lung Adenocarcinomas According to IASLC/ATS/ERS Classification.

BACKGROUND: Only a small number of studies have explored the clinicopathological features of pulmonary adenocarcinoma (PA) associated with 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) false-negative (FN) results. Herein, we investigated the FDG-PET diagnostic performance by stratifying PAs according to International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) classification. METHODS: From January 2002 to December 2016, all consecutive patients who underwent pulmonary resection for stage I PA at six thoracic surgery institutions were retrospectively reviewed. The diagnostic performance of FDG-PET was analysed according to IASLC/ATS/ERS classification and two validated subclassifications. Univariable and multivariable logistic analysis were used to identify predictors of FDG-PET FN results. RESULTS: Five hundred and fifty (550) patients with stage I PA were included in the analyses. Most of the patients were male (n=354 [64.4%]) and smokers (n=369 [67.1%]). Ninety-seven (n=97 [17.6%]) FN cases were observed at FDG-PET imaging. On multivariable analysis, a lepidic pattern was found to be independently associated with FDG-PET FN results (odds ratio [OR], 3.20; p<0.001), while a solid pattern more commonly presented with a positive finding (OR, 0.40; p=0.066). According to Nakamura's classification, we observed an independent association between lepidic pattern and FDG-PET FN results (OR, 3.17; p<0.001), while solid/micropapillary patterns were independently related with increased FDG uptake (OR, 0.35; p=0.021). According to Yoshizawa's classification, Intermediate-grade tumours were independently correlated with FN FDG-PET results (OR, 2.78; p=0.005). CONCLUSIONS: In our cohort, histopathological features were significantly associated with FDG uptake. In particular, some adenocarcinoma subtypes (mostly Lepidic pattern) have a tendency towards FN FDG-PET findings. The correlation between computed tomography findings, clinical characteristics, and FDG uptake is mandatory, in order to tailor the precise diagnostic and therapeutic pathway for each patient.

Diagnosis and Molecular Profiling of Lung Cancer by Percutaneous Ultrasound-Guided Biopsy of Superficial Metastatic Sites Is Safe and Highly Effective.

BACKGROUND: Diagnosis, staging, and molecular profiling of lung cancer are mostly carried out with bronchoscopy or CT-guided aspiration/biopsy. However, patients with locally advanced or advanced disease often harbor "superficial" metastases for which a percutaneous, ultrasound-assisted needle aspiration/biopsy (US-NAB) might represent an equally effective yet less invasive and costly alternative. PATIENTS AND METHODS: We reviewed a prospectively collected database of consecutive patients with known/suspected lung cancer who underwent a US-NAB of a suspected "superficial" metastasis. Cancer genotyping was carried out with next-generation sequencing using the Oncomine™ Focus DNA and RNA fusion panels. PD-L1 immunohistochemistry was performed with the SP263 antibody. Feasibility, diagnostic yield for tissue diagnosis, sensitivity for malignancy, diagnostic yield for the molecular profiling, and complications were the study endpoints. RESULTS: A total of 98 lesions were evaluated, and 93 were biopsied (95% feasibility). The spectrum of sampled sites included lymph nodes (63 patients), bone (11), subcutaneous tissue (8), muscle (7), and the pleura (4). The diagnostic yield for a tissue diagnosis was 93% (91/98). US-NAB correctly identified 85 of the 87 patients finally diagnosed with malignancy (98% sensitivity). Cancer genotyping and PDL1 testing were successfully completed in 41/42 patients (98%) and in 40/50 patients (80%) for whom these tests were requested, respectively. No complications were observed. CONCLUSION: US-NAB of "superficial" metastasis of lung cancer is safe and is associated with high success for diagnosis and molecular profiling. In this clinical setting, using US-NAB as a first-step technique would significantly limit the use of more invasive and costly diagnostic procedures.

Exogenous Small Ruminant Betaretrovirus Envelope Protein Is Detected in Draining Lymph Nodes in Contagious Respiratory Tumors of Sheep and Goats.

Contagious respiratory tumors of sheep and goats are epithelial neoplasms of the lung and nasal cavities. They are associated with oncogenic betaretroviruses known as jaagsiekte sheep retrovirus and enzootic nasal tumor retrovirus of sheep and goats. We investigated the presence of the envelope protein (ENV) of these retroviruses in retropharyngeal and mediastinal lymph nodes using a specific monoclonal antibody by immunohistochemistry methods, single-labeled or combined with ovine B or T lymphocytes or macrophage cell markers. Samples of lymph nodes, fixed in formalin and zinc fixative, were obtained from paraffin-embedded material. Four groups of samples were used: 24 natural cases of ovine pulmonary adenocarcinoma (OPA), 13 of enzootic nasal adenocarcinoma of sheep (ENAS), 19 of enzootic nasal adenocarcinoma of goats (ENAG), and 14 control samples. ENV was detected by single labeling in cortical lymphoid follicles. Six of 24 OPA samples were positive and only in those from sheep with extensive neoplasia. Immunolabeling was detected in 5/13 ENAS and 10/19 ENAG samples. Positive labeling was found either in the intercellular spaces, membranes, or cytoplasm of cells in follicles. Control samples were not correspondingly labeled. Double immunohistochemistry demonstrated co-labeling of ENV and CD21 (B cells and follicular dendritic cells) in all samples, CD14 (macrophage) in OPA samples, and Pax-5 (B cells) in ENAG samples, but not with CD8 or CD4 (T lymphocytes). These results demonstrate the presence of betaretrovirus ENV proteins in nontumor cells in regional lymph nodes in sheep and goats with contagious respiratory tumors.

Pulmonary Enteric Adenocarcinoma Harboring a BRAF G469V Mutation.

Pulmonary enteric adenocarcinoma (PEAC) is a rare subtype of lung cancer that should be differentiated from colorectal cancer metastasis. Little is known about its genetic background. An 84-year-old male with adenocarcinoma of the lung underwent left upper lobectomy. The histology of the surgical specimen was suggestive of PEAC. Gastrointestinal and colorectal fiberscopy revealed no evidence of colorectal cancer. Next-generation sequencing of the tumor identified a G469V substitution in serine/threonine-protein kinase B-raf (BRAF). Based on the higher prevalence of the G469 substitution in BRAF-mutant lung adenocarcinoma than in BRAFmutant colorectal cancer, the tumor likely originated from the lung. Identification of mutational genotype may be of some help in distinguishing PEAC from the lung metastasis of colorectal cancer.

[Acrometastasis revealing a pulmonary adenocarcinoma: Report of a case with unusual histopathological findings]. / Acrométastase révélatrice d'un adénocarcinome pulmonaire : à propos d'un cas de présentation histopathologique inhabituelle.

Acrometastasis are rare and can be exceptionally indicative of an occult carcinoma. The prognosis is generally poor. The radiological and immunohistochemical findings can be of great value to determine the primary and to guide treatment. We report a case of a 56-years-old man with acrometastasis at the fourth finger of the left hand revealing a pulmonary adenocarcinoma. Histopathological analysis showed a cribriform adenocarcinoma with an unusual cytoplasmic co-expression of TTF1 and Hepar-1 upon immunohistochemical analysis. There was no nuclear TTF1 immunostaining. Imaging explorations showed a 6-cm mass of the left superior pulmonary lobe. The patient received immunochemotherapy. Upon follow-up, there was evidence of disease progression on chest computed tomography scan.

[A rare synchronous occurrence of multiple myeloma and pulmonary adenocarcinoma with multiple solitary extramedullary plasmacytomas of the liver].

We report the case of a 62-year-old woman with multiple liver tumors. She was diagnosed with synchronous occurrence of multiple myeloma (MM) and primary pulmonary adenocarcinoma 4 years ago. She was treated with bortezomib and dexamethasone for MM, and then she underwent thoracoscopic lobectomy. After the surgery, she received autologous peripheral blood stem cell transplantation. However, recurrence of MM was observed 9 months later. She received multiple chemotherapies for MM, but the effect was limited. Meanwhile, brain metastasis of pulmonary adenocarcinoma was observed; therefore, she underwent surgical resection and received radiation therapy. Furthermore, she had elevated levels of liver enzymes, and ultrasonography revealed multiple liver tumors. Because of thrombocytopenia, liver biopsy could not be performed, and chemotherapies for MM did not improve the tumors. Therefore, we clinically determined that the liver tumors were metastatic pulmonary adenocarcinomas. The epidermal growth factor receptor mutation was present in the pulmonary adenocarcinoma, so gefitinib was administered. However, the tumors were uncontrollable and the patient died within 1 month. From autopsy, the liver lesion was confirmed to be MM. Synchronous occurrence of MM and other primary cancers is very rare, and no standard treatment has yet been established. Thus, it is crucial to accumulate synchronous cases and develop treatment methods in the future.

[Radial endobronchial ultrasound combined with transbronchial lung cryobiopsy in differential diagnosis of pulmonary infiltrate]. / Radial'naya endobronkhial'naya ul'trasonografiya v kombinatsii s endoskopicheskoi transbronkhial'noi kriobiopsiei v differentsial'noi diagnostike infil'trata v legkom.

Differential diagnosis of pulmonary infiltrates is difficult due to the absence of specific clinical and radiological manifestations. Differential diagnosis of pulmonary infiltrates usually includes the following «triad¼: pneumonia, tuberculosis, lung cancer. Diagnosis of pulmonary tuberculosis is based on microbiological examination of sputum and bronchoscopic respiratory samples - bronchial washing and bronchoalveolar lavage. Efficiency of molecular genetic methods (including express tests) in detecting M. tuberculosis DNA can reach 91-98%. Therefore, treatment may be started without data of microbiological examination. Nevertheless, there are rare cases of false-positive results of PCR in patients with non-tuberculous lung lesions. This aspect often results false diagnosis and delayed verification of true cause of lung lesion. Another adverse effect is associated with anti-tuberculosis therapy. Endoscopic transbronchial lung biopsy and its modern version (transbronchial cryobiopsy) as a minimally invasive diagnostic procedure are performed in such patients. These methods require a sufficiently high experience and qualification of specialist and following such aspects as navigation techniques and balloon bronchial blocking. We present this clinical case as a demonstration of modern possibilities of multimodal navigational bronchoscopic diagnosis with transbronchial cryobiopsy for local pulmonary infiltrate.

Pulmonary enteric adenocarcinoma: an overview.

Most commonly described as sporadic, pulmonary adenocarcinoma with enteric differentiation (PAED) is a rare variant of invasive lung cancer recently established and recognised by the World Health Organization. This tumour is highly heterogeneous and shares several morphological features with pulmonary and colorectal adenocarcinomas. Our objective is to summarise current research on PAED, focusing on its immunohistochemical and molecular features as potential tools for differential diagnosis from colorectal cancer, as well as prognosis definition and therapeutic choice. PAED exhibits an 'entero-like' pathological morphology in more than half cases, expressing at least one of the typical immunohistochemical markers of enteric differentiation, namely CDX2, CK20 or MUC2. For this reason, this malignancy appears often indistinguishable from a colorectal cancer metastasis, making the differential diagnosis laborious. Although standard diagnostic criteria have not been established yet, in the past few years, a number of approaches have been addressed, aimed at defining specific immunohistochemical and molecular signatures. Based on previously published literature, we have collected and analysed molecular and immunohistochemical data on this rare neoplasm, and have described the state of the art on diagnostic criteria as well as major clinical and therapeutic implications.The analysis of data from 295 patients from 58 published articles allowed us to identify the most represented immunohistochemical and molecular markers, as well as major differences between Asian PAEDs and those diagnosed in European/North American countries. The innovative molecular approaches, exploring driver mutations or new gene alterations, could help to identify rare prognostic factors and guide future tailored therapeutic approaches to this rare neoplasm.

Transcriptional Response of Ovine Lung to Infection with Jaagsiekte Sheep Retrovirus.

Jaagsiekte sheep retrovirus (JSRV) is the etiologic agent of ovine pulmonary adenocarcinoma (OPA), a neoplastic lung disease of sheep. OPA is an important economic and welfare issue for sheep farmers and a valuable naturally occurring animal model for human lung adenocarcinoma. Here, we used RNA sequencing to study the transcriptional response of ovine lung tissue to infection by JSRV. We identified 1,971 ovine genes differentially expressed in JSRV-infected lung compared to noninfected lung, including many genes with roles in carcinogenesis and immunomodulation. The differential expression of selected genes was confirmed using immunohistochemistry and reverse transcription-quantitative PCR. A key finding was the activation of anterior gradient 2, yes-associated protein 1, and amphiregulin in OPA tumor cells, indicating a role for this oncogenic pathway in OPA. In addition, there was differential expression of genes related to innate immunity, including genes encoding cytokines, chemokines, and complement system proteins. In contrast, there was little evidence for the upregulation of genes involved in T-cell immunity. Many genes related to macrophage function were also differentially expressed, reflecting the increased abundance of these cells in OPA-affected lung tissue. Comparison of the genes differentially regulated in OPA with the transcriptional changes occurring in human lung cancer revealed important similarities and differences between OPA and human lung adenocarcinoma. This study provides valuable new information on the pathogenesis of OPA and strengthens the use of this naturally occurring animal model for human lung adenocarcinoma.IMPORTANCE Ovine pulmonary adenocarcinoma is a chronic respiratory disease of sheep caused by jaagsiekte sheep retrovirus (JSRV). OPA is a significant economic problem for sheep farmers in many countries and is a valuable animal model for some forms of human lung cancer. Here, we examined the changes in host gene expression that occur in the lung in response to JSRV infection. We identified a large number of genes with altered expression in infected lung, including factors with roles in cancer and immune system function. We also compared the data from OPA to previously published data from human lung adenocarcinoma and found a large degree of overlap in the genes that were dysregulated. The results of this study provide exciting new avenues for future studies of OPA and may have comparative relevance for understanding human lung cancer.

Exogenous Jaagsiekte Sheep Retrovirus type 2 (exJSRV2) related to ovine pulmonary adenocarcinoma (OPA) in Romania: prevalence, anatomical forms, pathological description, immunophenotyping and virus identification.

BACKGROUND: Ovine pulmonary adenocarcinoma (OPA) is a neoplastic disease caused by exogenous Jaagsiekte Sheep Retrovirus (exJSRV). The prevalence of JSRV-related OPA in Eastern European countries, including Romania is unknown. We aimed to investigate: the prevalence and morphological features of OPA (classical and atypical forms) in the Transylvania region (Romania), the immunophenotype of the pulmonary tumors and their relationships with exJSRV infection. A total of 2693 adult ewes slaughtered between 2017 and 2019 in two private slaughterhouses from Transylvania region (Romania) was evaluated. Lung tumors were subsequently assessed by cytology, histology, immunocytochemistry, immunohistochemistry, electron microscopy and DNA testing. RESULTS: Out of 2693 examined sheep, 34 had OPA (1.26% prevalence). The diaphragmatic lobes were the most affected. Grossly, the classical OPA was identified in 88.24% of investigated cases and the atypical OPA in 11.76% that included solitary myxomatous nodules. Histopathology results confirmed the presence of OPA in all suspected cases, which were classified into acinar and papillary types. Myxoid growths (MGs) were diagnosed in 6 classical OPA cases and in 2 cases of atypical form. Lung adenocarcinoma was positive for MCK and TTF-1, and MGs showed immunoreaction for Vimentin, Desmin and SMA; Ki67 expression of classical OPA was higher than atypical OPA and MGs. JSRV-MA was identified by IHC (94.11%) in both epithelial and mesenchymal cells of OPA. Immunocytochemistry and electron microscopy also confirmed the JSRV within the neoplastic cells. ExJSRV was identified by PCR in 97.05% of analyzed samples. Phylogenetic analysis revealed the presence of the exJSRV type 2 (MT809678.1) in Romanian sheep affected by lung cancer and showed a high similarity with the UK strain (AF105220.1). CONCLUSIONS: In this study, we confirmed for the first time in Romania the presence of exJSRV in naturally occurring OPA in sheep. Additionally, we described the first report of atypical OPA in Romania, and to the best of our knowledge, in Eastern Europe. Finally, we showed that MGs have a myofibroblastic origin.