ALK Rearrangement Research Articles

Environment-Sensitive Fluorescent Probe Enables Assessment of Anaplastic Lymphoma Kinase Activity in Nonsmall Cell Lung Cancer.

Anaplastic lymphoma kinase (ALK) rearrangements have been identified as key oncogenic drivers of a subset of nonsmall cell lung cancer (NSCLC). The final chimeric protein of the fusion gene can be constitutively activated, which accounts for the growth and proliferation of ALK-rearranged tumors and thus strongly associates with cancer invasion and metastasis. Diagnostic tools enabling the visualization of ALK activity in a structure-function-based approach are highly desirable to determine ALK status and guide ALK tyrosine kinase inhibitor (ALK-TKI) treatment making. Here, we describe the design, synthesis, and application of a new environment-sensitive fluorescent probe HX16 by introducing an environment-sensitive fluorophore 4-sulfonamidebenzoxadiazole to visualize ALK activity in living cancer cells and tumor tissue slices (mouse model and human biopsy sample). HX16 is a multifunctional chemical tool based on the pharmacophore of ALK-TKI (ceritinib) and can specifically target the kinase domain of ALK with a high sensitivity. Using flow cytometry and confocal microscopy, HX16 enables visualization of ALK activity in various cancer cells with distinct ALK fusion genes, as well as xenograft mouse models. Importantly, HX16 was also applied to visualize ALK activity in a tumor biopsy from a NSCLC patient with ALK-echinoderm microtubule-associated protein-like-4 fusion gene for prediction of ALK-TKI sensitivity. These results demonstrate that strategically designed ALK-TKI-based probe allows the assessment of ALK activity in tumor tissues and hold promise as a useful diagnostic tool in predicting ALK-TKI therapy response.

Ciliated Muconodular Papillary Tumors of the Lung Harboring STRN::ALK Fusion: Case Report and Review of the Literature.

Ciliated muconodular papillary tumor (CMPT) is a rare pulmonary tumor, typically occurring in middle-aged and elderly individuals. The molecular mutation spectrum of CMPT remains insufficiently explored. Commonly known driver gene alterations include KRAS, BRAF, EGFR, and ALK rearrangement. This report details the clinicopathological features of 2 patients presenting with CMPT as pulmonary nodules during clinical examinations. Microscopic analysis revealed tumors with glandular or papillary structures, consisting of mucinous cells, ciliated columnar cells, and basal cells. Notably, both patients exhibited STRN::ALK fusion, a finding not previously associated with CMPT. STRN::ALK fusion serves as a target for therapy in various tumors, including non-small cell lung cancer, thyroid cancer, and colon cancer. Consequently, we conducted a review of relevant literature, summarizing the clinicopathological and molecular characteristics of CMPT to facilitate further research. Our insights enhance the understanding of this uncommon tumor and contribute to the expansion of its molecular alteration spectrum.

Genetic Profiling of Non-Small Cell Lung Cancer in Moroccan Patients by Targeted Next-Generation Sequencing.

We retrospectively analyzed the next-generation sequencing (NGS) results from diagnosed NSCLC patients to identify and compare genomic alterations of NSCLC between Moroccan patients and the Cancer Genome Atlas (TCGA). We also aimed to investigate the distribution and frequency of concurrent genomic alterations. From December 2022 to December 2023, a retrospective study of 76 formalin-fixed paraffin-embedded (FFPE) samples have been profiled using the Oncomine™ Precision Assay on the Ion Torrent™ Genexus™ Integrated Sequencer across the panel of 50 key genes that are applicable for the selection of targeted therapy. Seventy of the 76 FFPE sequenced samples carried at least one genetic alteration in the tested genes. The study identified 234 genetic alterations in 18 genes. Targetable genetic alterations in EGFR, KRAS, MET, BRAF, ALK, RET and ROS1 were identified in 84.3% of tumors. EGFR and KRAS mutations were frequently reported, occurring in 24.3% and 22.9% of cases, respectively. The untargetable genetic alterations were found in 74.3% of the specimens in FGFR3, TP53, ERBB2, PIK3CA, CDKN2A, PDL1, FGFR1, PTEN, CHEK2 and ERBB3. There were additional uncommon/rare mutations in EGFR, BRAF, RET and ROS1. Comparing the prevalence of selected mutated genes in the NSCLC patients from the TCGA database identified substantial differences in EGFR (24.3%, vs14.97%), KRAS (22.9%, vs 25.99%), and TP53 (34.3%, vs 50.94%). ALK, ROS1, and RET gene rearrangements were detected in 4.3% of the 70 tumors tested. The ALK/RET/MET/ROS1/EML4 fusions were detected in 11.4% of samples. Co-alterations occurred in 67.1% of specimens. Co-occurring driver gene mutations were observed in 44.3%. TP53 mutations co-occurred driver gene mutations in 30% of tumors. Three cases (4.3%) harbored concurrent FGFR3, TP53, and PIK3CA alterations. Our results regarding the proportion of samples with actionable mutations demonstrate the value of NGS testing for NSCLC patients in a real-world clinical diagnostic setting.

EML4-ALK fusions drive lung adeno-to-squamous transition through JAK-STAT activation.

Human lung adenosquamous cell carcinoma (LUAS), containing both adenomatous and squamous pathologies, exhibits strong cancer plasticity. We find that ALK rearrangement is detectable in 5.1-7.5% of human LUAS, and transgenic expression of EML4-ALK drives lung adenocarcinoma (LUAD) formation initially and squamous transition at late stage. We identify club cells as the main cell-of-origin for squamous transition. Through recapitulating lineage transition in organoid system, we identify JAK-STAT signaling, activated by EML4-ALK phase separation, significantly promotes squamous transition. Integrative study with scRNA-seq and immunostaining identify a plastic cell subpopulation in ALK-rearranged human LUAD showing squamous biomarker expression. Moreover, those relapsed ALK-rearranged LUAD show notable upregulation of squamous biomarkers. Consistently, mouse squamous tumors or LUAD with squamous signature display certain resistance to ALK inhibitor, which can be overcome by combined JAK1/2 inhibitor treatment. This study uncovers strong plasticity of ALK-rearranged tumors in orchestrating phenotypic transition and drug resistance and proposes a potentially effective therapeutic strategy.

Anaplastic and poorly differentiated thyroid carcinomas: genetic evidence of high-grade transformation from differentiated thyroid carcinoma.

Anaplastic thyroid carcinoma (ATC) is the most advanced and aggressive thyroid cancer, and poorly differentiated thyroid carcinoma (PDTC) lacks anaplastic histology but has lost architectural and cytologic differentiation. Only a few studies have focused on the genetic relationship between the two advanced carcinomas and coexisting differentiated thyroid carcinomas (DTCs). In the present study, we investigated clinicopathologic features and genetic profiles in 57 ATC and PDTC samples, among which 33 cases had concomitant DTC components or DTC history. We performed immunohistochemistry for BRAF V600E, p53, and PD-L1 expression, Sanger sequencing for TERT promoter and RAS mutations, and fluorescence in situ hybridization for ALK and RET rearrangements. We found that ATCs and PDTCs shared similar gene alterations to their coexisting DTCs, and most DTCs were aggressive subtypes harboring frequent TERT promoter mutations. A significantly higher proportion of ATCs expressed p53 and PD-L1, and a lower proportion expressed PAX-8 and TTF-1, than the coexisting DTCs. Our findings provide more reliable evidence that ATCs and PDTCs are derived from DTCs.

Molecular and Immunohistochemical Testing in Mesothelioma and Other Mesothelial Lesions.

Molecular testing has increasingly been utilized in the evaluation of mesothelioma. Diffuse mesothelioma comprises multiple distinct genetic subgroups. While most diffuse mesotheliomas lack oncogenic kinase mutations and instead harbor alterations involving tumor suppressors and chromatin regulators, a minor subset of tumors is characterized by uncommon alterations such as germline mutations, genomic near-haploidization, ALK rearrangement, ATF1 rearrangement, or EWSR1::YY1 fusion. To provide updates on the salient molecular features of diffuse mesothelioma, mesothelioma in situ, and other mesothelial lesions: well-differentiated papillary mesothelial tumor, adenomatoid tumor, peritoneal inclusion cyst, and others. We consider the diagnostic, prognostic, and predictive utility of molecular testing in mesothelial lesions. We performed a literature review of recently described genetic features, molecular approaches, and immunohistochemical tools, including BAP1, MTAP, and merlin in mesothelioma and other mesothelial lesions. Our evolving understanding of the molecular diversity of diffuse mesothelioma and other mesothelial lesions has led to considerable changes in pathology diagnostic practice, including the application of immunohistochemical markers such as BAP1, MTAP, and merlin (NF2), which are surrogates of mutation status. In young patients and/or those without significant asbestos exposure, unusual mesothelioma genetics such as germline mutations, ALK rearrangement, and ATF1 rearrangement should be considered.

Concordance of ALK fusion gene-rearrangement between immunohistochemistry and next-generation sequencing.

Although various companion diagnostic tests of ALK fusion gene-rearrangement are approved, few reports have assessed the concordance of ALK fusion gene-rearrangement in two companion diagnostic tests: next-generation sequencing (NGS) testing and immunohistochemistry (IHC). The samples evaluated for gene alterations using NGS testing between May 2019 and November 2021 were included in this study. The inclusion criteria were as follows: samples were diagnosed with non-small cell lung cancer; the results of the NGS analysis were informative; and samples had residual specimens for IHC. We performed IHC on the residual specimens and retrospectively collected sample characteristics from medical records. A total of 185 samples were analyzed using NGS. Twenty-six samples were excluded because of failure to analyze gene alterations using NGS, no residual samples, and inadequate IHC. We analyzed 159 samples. The major histological type was adenocarcinoma (115 samples). The number of surgical and transbronchial lung biopsy specimens was 59 and 56, respectively. ALK fusion gene-rearrangement was detected in four samples using NGS, and five were detected using IHC. The sensitivity and specificity of IHC referred to by NGS were 75.0% and 98.7%, respectively. The concordance rate between IHC and NGS was 98.1%. ALK rearrangement was detected in two patients using IHC but not using NGS. In addition, ALK rearrangement was detected in one patient using NGS but not using IHC. Our results suggest that IHC and NGS might be complementary tests. In patients suspected of harboring ALK fusion gene-rearrangement, it should be analyzed using another diagnostic method.

Lorlatinib for the Treatment of Inflammatory Myofibroblastic Tumor after Allogeneic Hematopoietic Stem Cell Transplantation: A Case Report.

Inflammatory myofibroblastic tumors (IMTs) are rare sarcomas composed of myofibroblastic and fibroblastic cells, accompanied by inflammatory cell infiltration. Many IMTs exhibit clonal rearrangement of anaplastic lymphoma kinase (ALK). We herein report a 56-year-old woman with uterine IMT harboring a thrombospondin-1::ALK fusion that developed after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Laboratory data before systemic therapy indicated increased interleukin-6 and severe leukocytosis. The patient was treated with lorlatinib; however, the response duration was approximately two months. Similar case reports need to be compiled and evaluated to elucidate the efficacy of lorlatinib in post-allo-HSCT IMT with ALK rearrangement.

Associations Among Optimal Lung Cancer Treatment, Clinical Outcomes, and Health Care Utilization in Patients Who Underwent Comprehensive Genomic Profiling.

Although immune checkpoint inhibitor immunotherapies are contraindicated as first-line treatment of advanced non-small cell lung cancer (NSCLC) in patients with ALK rearrangement and EGFR mutation, many receive them. The purpose of this study was to examine the association between optimal first-line treatment in this population and clinical outcomes. Claims and genomic data from patients with advanced or metastatic NSCLC were extracted from a nationally representative GuardantINFORM dataset. Patients who had their first claim mentioning advanced or metastatic NSCLC between March 2019 and February 2020 and had ALK rearrangement or EGFR mutation detected by comprehensive genomic profiling were included in this study. Patients were classified as having received optimal or suboptimal first-line treatment. Claims were reviewed to determine real-world time to next treatment, real-world time to discontinuation, and health services utilization (emergency department, inpatient, and outpatient) in the 12 months following first-line treatment initiation. Survival analyses were conducted using Kaplan-Meier plots and Cox proportional hazard models. Health services utilization was compared between the groups using t tests and negative binomial models. Of the 359 patients included, 280 (78.0%) received optimal first-line treatment. Optimally treated patients had longer median real-world time to next treatment (11.2 vs 4.4 months; P<.01) and real-world time to discontinuation (10.4 vs 1.9 months; P<.01). The optimal group had significantly fewer emergency department presentations (0.76 vs 1.27; P<.01) and outpatient visits (22.9 vs 42.7; P<.01) than the suboptimal group but did not significantly differ in inpatient utilization. Adjusted utilization analysis yielded similar findings. Patients with NSCLC who received optimal treatment, as determined by comprehensive genomic profiling using next-generation sequencing-based circulating tumor DNA testing (Guardant360), had significantly superior clinical and utilization outcomes, reinforcing existing guidelines recommending profiling at the onset of treatment.

Inflammatory myofibroblastic tumor from molecular diagnostics to current treatment.

Inflammatory myofibroblastic tumor (IMT) is a rare neoplasm with intermediate malignancy characterized by a propensity for recurrence but a low metastatic rate. Diagnostic challenges arise from the diverse pathological presentation, variable symptomatology, and lack of different imaging features. However, IMT is identified by the fusion of the anaplastic lymphoma kinase (ALK) gene, which is present in approximately 70% of cases, with various fusion partners, including ran-binding protein 2 (RANBP2), which allows confirmation of the diagnosis. While surgery is the preferred approach for localized tumors, the optimal long-term treatment for advanced or metastatic disease is difficult to define. Targeted therapies are crucial for achieving sustained response to treatment within the context of genetic alteration in IMT. Crizotinib, an ALK tyrosine kinase inhibitor (TKI), was officially approved by the US Food and Drug Administration (FDA) in 2020 to treat IMT with ALK rearrangement. However, most patients face resistance and disease progression, requiring consideration of sequential treatments. Combining radiotherapy with targeted therapy appears to be beneficial in this indication. Early promising results have also been achieved with immunotherapy, indicating potential for combined therapy approaches. However, defined recommendations are still lacking. This review analyzes the available research on IMT, including genetic disorders and their impact on the course of the disease, data on the latest targeted therapy regimens and the possibility of developing immunotherapy in this indication, as well as summarizing general knowledge about prognostic and predictive factors, also in terms of resistance to systemic therapy.

Uterine inflammatory myofibroblastic tumor: a retrospective analysis.

Uterine inflammatory myofibroblastic tumor (UIMT) is a rare tumor of the female reproductive tract with uncertain malignant potential. Previous case series reports have limited our understanding of its diagnosis and treatment. Therefore, we conducted a retrospective analysis of patient files at West China Second University Hospital, Sichuan University to contribute valuable clinical insights to future treatment strategies for this disease. We comprehensively reviewed patient files of individuals diagnosed with UIMT from January 1st, 2013 to May 1st, 2023. We included twenty-seven cases of uterine inflammatory myofibroblastic tumor in our study. Of these, 51.85% (14 cases) were diagnosed with abnormal uterine bleeding, 2 cases had dysmenorrhea, and 12 were unexpectedly diagnosed with suspected uterine fibroids. Ten cases performed total hysterectomy, and 17 cases underwent lesion resection. The positive rate of anaplastic lymphoma kinase (ALK) immunohistochemistry reached 96.3%. After a median of 8 months follow-up time, all patients were disease-free and had survived. Uterine inflammatory myofibroblastic tumor is easily misdiagnosed, making its diagnosis challenging. Histological features, immunohistochemical results, and molecular confirmation using fluorescence in situ hybridization (FISH) or Next-generation sequencing should be used to confirm the diagnosis. Positive ALK immunohistochemistry, ALK rearrangement, ALK fusion are helpful in diagnosis and ALK inhibitor therapy. Total hysterectomy is often performed for women who do not require fertility, while lesion resection and close follow-up may be considered for those who require fertility preservation.

Front-line liquid biopsy for early molecular assessment and treatment of hospitalized lung cancer patients

BackgroundMolecular characterization is pivotal for managing non-small cell lung cancer (NSCLC), although this process is often time-consuming and patients’ conditions might worsen while molecular analyses are processed.Our primary aim was to evaluate the performance of “up-front” next-generation sequencing (NGS) through liquid biopsy (LB) of hospitalized patients with newly detected lung neoplasm in parallel with conventional diagnosis. The secondary aim included longitudinal monitoring through LB of patients with oncogenic alterations at baseline. MethodsWe enrolled 47 consecutive patients immediately after hospitalization and radiological detection of symptomatic lung neoplasm. LB from peripheral blood was performed at baseline, in parallel with conventional biopsy (CB), when feasible. Additionally, LBs were repeated during treatment in patients with actionable gene alterations at baseline. Oncomine™ Lung cfTNA Research Assay panel was employed for processing plasma samples in NGS. Results47 hospitalized patients were enrolled. LB identified 28 patients with gene alterations, including mutations of EGFR (n = 7), KRAS (n = 12), ERBB2 (n = 1), TP53 (n = 2), BRAF (n = 1), one ALK rearrangement, and 4 patients with combined mutations involving EGFR, KRAS and PIK3CA.LB and CB were consistent, except for two patients. Three patients with positive LB for oncogenic drivers did not undergo CB due to contraindications.Median time to molecular results after LB was significantly lower compared to time to molecular report after CB (11 versus 22 days, p < 0.001). ConclusionsDespite limited numbers, our study supports the role of front-line LB for improving management of symptomatic patients with lung cancer, potentially leading to early targeted therapy initiation.

A Paradigm Shift in Non-Small-Cell Lung Cancer (NSCLC) Diagnostics: From Single Gene Tests to Comprehensive Genomic Profiling.

Lung cancer imposes a burden on the health care system worldwide affecting 2 million people and causing 1.8 million deaths in 2021.More than 85% of all lung cancer cases are reported under Non-small-cell lung cancer (NSCLC). It is critical to discover gene alterations to treat non-small cell lung cancer successfully. The CAP/IASLC/AMP recommendations supported use of polymerase chain reaction (PCR) and fluorescent in situ hybridization (FISH) EGFR (epidermal growth factor receptor) mutations and ALK (Anaplastic lymphoma kinase) rearrangements, respectively. A study presented in the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago emphasized the need for comprehensive genomic profiling (CGP) before single gene tests (SGTs) since it demonstrated that SGT can result in the depletion of precious biopsy samples. As a result, the efficacy of thorough genetic Profiling (CGP) is reduced, preventing patients from receiving valuable genetic information about their tumors.

Real-World Data Presenting the Descriptive Analysis of the Use of Tyrosine Kinase Inhibitors (TKIs) Among Metastatic Non-Small-Cell Lung Cancer (mNSCLC) Patients in Qatar: A Nationwide Retrospective Cohort Study.

There has been significant improvement in treating metastatic non-small-cell lung cancer (mNSCLC) over the past 2 decades. The aim of this study is to describe the use of tyrosine kinase inhibitors (TKIs) in Qatar. This study focuses on the objective response rate (ORR) and reported adverse drug events (ADEs) of TKIs used for the management of patients with mNSCLC. This is a descriptive retrospective cohort study. All non-small-cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations who received TKIs between 2015 and 2019 in Qatar were included. The TKIs used during this period include EGFR inhibitors such as afatinib, erlotinib, gefitinib, and osimertinib and ALK inhibitors such as alectinib and crizotinib. The response on each TKI was identified by reporting the ORR (as the sum of the complete response [CR] and the partial response [PR]), in addition stable disease (SD) and disease progression (DP) were reported. While ADEs were reported using the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE). A total of 63 patients were included, of which 36 cases (57.1%) expressed EGFR mutation, and 27 patients (42.9%) expressed ALK rearrangement. The ORR in EGFR inhibitors was as follows: osimertinib 40%, gefitinib 33%, afatinib 22%, and erlotinib 18%. However, the response to the ALK-targeted therapy was 43% with alectinib and 40% with crizotinib. A total of 112 ADEs were reported. They were distributed as 63.4% (71 of 112) with the anti-EGFR and 36.6% (41 of 112) ADEs with the ALK inhibitors. In the anti-EGFR group, the most common types of ADEs were dermatological toxicity 30%, whereas, in the anti-ALK group, gastrointestinal toxicity was the most common (29%). The EGFR-targeted and ALK-targeted therapies appear to have acceptable clinical response rate and safety profile in our population. Close and frequent monitoring of adverse events is advised to ensure a good quality of life and prevent serious complications.

Next-Generation Sequencing (NGS) in lung cancer care: Advantages, applications, and challenges

Lung cancer, a prevalent and lethal malignancy, has witnessed significant therapeutic strides driven by the identification and application of predictive biomarkers. These biomarkers, such as EGFR mutations and ALK rearrangements, guide treatment decisions and improve patient outcomes. The advent of Next-Generation Sequencing (NGS) has revolutionized lung cancer diagnostics and treatment by enabling comprehensive genomic profiling. NGS, a high- -throughput sequencing technology, stands out by simultaneously analyzing multiple genes and addressing the genetic diversity inherent in lung tumors. This article explores the transformative role of NGS in lung cancer, emphasizing its applications in personalized treatment strategies, early detection, immunotherapy selection, and disease monitoring through liquid biopsies. Despite challenges, NGS emerges as a beacon of hope, propelling precision oncology and promising improved patient outcomes. This article underscores the impact of NGS in reshaping the landscape of lung cancer care, guiding therapeutic decisions, and advancing scientific understanding.

Clinical Outcomes of Crizotinib Readministration in Patients with Nonsmall Cell Lung Cancer with Anaplastic Lymphoma Kinase Rearrangement: Case Report and Review of Literature

AbstractRecent studies have demonstrated promising outcomes of the first-line anaplastic lymphoma kinase-tyrosine kinase inhibitor (ALK-TKI) “crizotinib” in patients with locally advanced and metastatic lung cancers with high expression of the fusion protein “EML4-ALK.” High drug resistance, however, restricts the therapeutic advantages of ALK-TKIs in patients with nonsmall cell lung cancer (NSCLC). The contemporary literature documents limited treatment approaches for patients with NSCLC relapse or nonresponsiveness to second-/third-generation ALK-TKIs. We hereby provide a descriptive analysis of five NSCLC cases treated with crizotinib, ceritinib, and alectinib for a median duration of 54 months. The outcomes indicate a profound therapeutic response in patients receiving 4th and subsequent line of treatment with crizotinib. The crizotinib retreatment actively reduced patient resistance to the ALK-TKIs by reversing the mesenchymal epithelial transition amplification. The results from this case series also emphasize the possible role of next-generation sequencing in determining therapeutic resistance and transforming the treatment paradigm for NSCLC. Partial response was observed in the patients after 6 months of crizotinib readministration. This is possibly the first case series reporting crizotinib rechallenge in patients of ALK positive NSCLC who failed on subsequent ALK-TKIs and multiple lines of chemotherapies.

A case study on severe psychiatric symptoms induced by lorlatinib.

Key points Due to its macrocyclic properties, lorlatinib has increased penetrance of the blood brain barrier compared to most other tyrosine kinase inhibitors. Lorlatinib is a promising therapy in patients with non‐small cell lung cancer with ALK or ROS1 rearrangements, particularly in patients with evidence of intracranial disease. However, behavioral and central nervous system side effects are common with lorlatinib. Lorlatinib can rarely result in severe psychosis, as with the presented case. In patients with lung cancer on lorlatinib, medication‐induced psychosis must be considered among the common differentials, including: the psychological response of patients to the cancer itself, somatic symptoms from brain metastases, and unmasking of underlying psychiatric disorders.

Molecular and Genetic Advances in Small Cell Lung Cancer Landscape: From Homogeneity to Diversity.

Small cell lung cancer (SCLC) has been historically considered a homogeneous disease and thus approached as a single entity when it comes to clinical studies design and new treatments developments. However, increasing knowledge in the genetic and molecular landscape of this disease challenges this concept, opening the possibility that different subtypes might show differential vulnerability to treatments. In this narrative review, we gather the most relevant advances in genetic and molecular characterization of SCLC, focusing on how these discoveries may be used to design the path for a personalized treatment approach. Indeed, we discuss the new classification based on differential protein expression, the prevalence and significance of oncogenic drivers (e.g., EGFR mutations and ALK rearrangements) in SCLC, the genetic characteristics of SCLC in patients with no smoking history, and the existing evidence supporting the use of liquid biopsy for capturing the heterogeneity of the disease. We use the keywords "small cell lung cancer", "SCLC", "EGFR", "ALK", "histological transformation", and "transcriptional factors" to identify original research manuscripts, clinical trials, case reports, and case series from PubMed.

Primary mucinous adenocarcinoma of the urethra: Aclinicopathological analysis of 35 cases.

Primary mucinous adenocarcinoma of the urethra represents an extremely rare entity. We sought to characterise further these tumours' clinicopathological, immunohistochemical and molecular features. Thirty-five cases were identified, occurring in 18 males and 17 females. The mean age at diagnosis was 65 years (28-89 years). The main presentation symptoms were haematuria and urinary outlet obstruction. Microscopic analysis revealed that all 35 tumours have stromal dissection by mucin. Ten tumours showed villoglandular dysplasia, nine showed mucinous metaplasia, two showed adenocarcinoma in situ and four showed signet ring cell features. All tumours were immunopositive for CEA, while immunonegative for nuclear β-catenin; 19 of 23 (83%) expressed high molecular weight cytokeratin; 19 of 33 (58%) CK7; 28 of 34 (82%) CK20; 32 of 35 (91%) CDX2; 22 of 27 (81%) cadherin-17 (CDH-17); 26 of 29 (90%) SATB2; and one of 31 (3%) GATA3. Mismatch repair gene products, including MLH1, PMS2, MSH2 and MSH6, were immunopositive, suggesting the MSI-low genotype of mucinous adenocarcinoma of the urethra. BRAF V600E and ALK rearrangements were not detected. During the mean follow-up of 20 months, nine patients either developed distant metastasis or succumbed to the illness. Our study, encompassing the most extensive series of 35 cases of primary mucinous adenocarcinoma of the urethra, provides crucial insights into its precise diagnosis, management and potential targeted treatments. We found a greater CDX2, SATB2 and CDH17 sensitivity in these urethral tumours for the first time, to our knowledge. We identified characteristics such as an MSI-low profile, non-V600E BRAF mutations and an absence of ALK rearrangements.

Clinicopathological significances of cribriform pattern in lung adenocarcinoma

The present study aimed to investigate the clinicopathological and prognostic implications of the cribriform pattern in lung adenocarcinoma through a meta-analysis. The estimated rates of cribriform pattern in lung adenocarcinomas were investigated. The correlations between cribriform pattern and clinicopathological characteristics, including genetic alterations and prognosis were evaluated. The estimated rate of cribriform pattern was 0.150 (95% confidence interval [CI], 0.101–0.218) in lung adenocarcinoma. The estimated rates of cribriform pattern in the 5% and 10% criteria were 0.230 (95% CI 0.125–0.386) and 0.130 (95% CI 0.062–0.252), respectively. The presence of cribriform pattern was significantly correlated with larger tumor size (> 30 mm), spread through air spaces, and lymph node metastasis (P < 0.001, P < 0.001, and P = 0.007, respectively, in the meta-regression test). There were no significant differences between cribriform pattern, smoking history, and vascular and lymphatic invasion. In lung adenocarcinoma with cribriform pattern, the estimated rates of ALK rearrangement, KRAS, and EGFR mutations were 0.407 (95% CI 0.165–0.704), 0.330 (95% CI 0.117–0.646), and 0.249 (95% CI 0.125–0.437), respectively. ALK rearrangement was significantly more frequent in lung adenocarcinomas with cribriform pattern than in those without. The overall survival rate was significantly worse in lung adenocarcinomas with a cribriform pattern than in those without (hazard ratio 2.051, 95% CI 1.369–3.075). In conclusion, the presence of a cribriform pattern can be a useful predictor of the clinicopathological characteristics and prognosis of patients with lung adenocarcinoma.