Anaplastic Lymphoma Kinase Positivity Research Articles

Challenges in utilizing ALK expression to distinguish primary cutaneous from systemic anaplastic large cell lymphoma.

Anaplastic large cell lymphoma (ALCL) is a CD30+ peripheral T-cell lymphoma with a clinical spectrum including cutaneous and systemic presentations. While primary cutaneous ALCL (pcALCL) has a favorable prognosis, systemic ALCL (sALCL) has poorer survival outcomes. Expression of anaplastic lymphoma kinase (ALK) by malignant cells has been suggested to distinguish sALCL from pcALCL. However, there have been documented cases of ALK-positive ALCL confined to the skin. The present study reviewed characteristics of published cutaneous ALK-positive ALCL cases to distinguish between these two entities. In 23 identified adults with ALK-positive pcALCL, 26% developed systemic involvement and 74% had skin-limited disease. In 14 pediatric patients, 36% had both cutaneous and systemic involvement and 64% had cutaneous disease only. This analysis revealed that pcALCL and sALCL could not reliably be distinguished by ALK expression or nuclear vs. cytoplasmic localization. Localized treatment with frequent monitoring may be sufficient in ALK-positive pcALCL until there is evidence of progression. Physicians should be aware of the overall spectrum of ALCL, including cutaneous limited disease, systemic disease, disease with NPM-ALK translocation, disease with ALK positivity and disease with skin recurrence.

Immunohistochemical expression of anaplastic lymphoma kinase in neuroblastoma and its relations with some clinical and histopathological features.

Anaplastic lymphoma kinase (ALK) mutations have been identified as a prominent cause of some familial and sporadic neuroblastoma (NB). ALK expression in NB and its relationship with clinical and histopathological features remains controversial. This study investigated ALK expression and its potential relations with these features in NB. Ninety cases of NB at the Department of Pathology, University of Medicine and Pharmacy at Ho Chi Minh City, Viet Nam from 01/01/2018 to 12/31/2021, were immunohistochemically stained with ALK (D5F3) antibody. The ALK expression and its relations with some clinical and histopathological features were investigated. The rate of ALK expression in NB was 91.1%. High ALK expression (over 50% of tumor cells were positive with moderate-strong intensity) accounted for 65.6%, and low ALK expression accounted for 34.4%. All the MYCN-amplified NB patients had ALK immunohistochemistry positivity, most cases had high ALK protein expression. The undifferentiated subtype of NB had a lower ALK-positive rate than the poorly differentiated and differentiated subtype. The percentages of ALK positivity were significantly higher in more differentiated histological types of NB (p = .024). There was no relation between ALK expression and: age group, sex, primary tumor location, tumor stage, MYCN status, clinical risk, Mitotic-Karyorrhectic Index, prognostic group, necrosis, and calcification. ALK was highly expressed in NB. ALK expression was not related to several clinical and histopathological features. More studies are needed to elucidate the association between ALK expression and ALK gene status and to investigate disease progression, especially the oncogenesis of ALK-positive NB.

Molecular analysis for EGFR, ALK, and ROS1 alterations in over 3000 Indian patients with non-small-cell lung cancer: A retrospective observational study

Background: Accurate molecular testing in non-small-cell lung cancer (NSCLC) is of paramount importance for treatment, prediction, and prognostication. Objectives: We aimed to comprehensively describe the clinicopathological and molecular profile of Indian patients with NSCLC with regard to alterations in the epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and c-ros oncogene 1 (ROS1). Materials and Methods: We conducted a retrospective analysis of lung tissue samples tested between January 2015 and December 2021 at the Metropolis Healthcare Limited global referral laboratory facility in Mumbai, Maharashtra, India. Testing was conducted for EGFR by real time reverse transcriptase polymerase chain reaction (RT-PCR) and Sanger sequencing, ALK by immunohistochemistry (IHC), ALK by fluorescence in situ hybridization (FISH), and c-ros oncogene 1 (ROS1) by FISH. We analyzed the positivity status and determined the trends in the results of the molecular targets in NSCLC cases. Results: Out of 3220 samples with malignancy, 1750 (54.3%) were tested for EGFR, out of which 510 (29.1%) were positive. The most common mutation detected was in exon 19 of EGFR (334/510, 65.5%), followed by exon 21 (164/510, 32.2%). A total of 1548 (48.1%) cases were tested for ALK by IHC, of which 125/1548 (8.1%) showed positivity, while among the 372/3220 (11.6%) cases tested for ALK by FISH, 29/372 (7.8%) were positive. In patients with squamous cell carcinoma, the ALK positivity rate by IHC was 5.3%. Of the 372 cases tested for ALK by FISH, 353 (94.9%) cases were tested for ALK by IHC as well; 98.9% concordance was observed for the positive cases. ROS1 testing was conducted in 370/3220 (11.5%) samples and showed a low positivity rate of 13/370 (3.5%). Conclusions: Indian patients with NSCLC have 29% EGFR positivity, 8.1% ALK positivity, and 3.5% ROS1 positivity, when tested with RT-PCR, IHC, and FISH, respectively. A detailed molecular analysis using next-generation sequencing (NGS) may help detect a higher number of molecular targets amenable to therapy.

ALK-rearranged Renal Cell Carcinoma (ALK-RCC): Evaluation of Histomorphological and Immunohistochemical Features by Analysis of 276 Renal Cell Carcinoma Cases in Turkey

Anaplastic lymphoma kinase (ALK) rearrangement-associated renal cell carcinoma (ALK-RCC) is characterized by ALK fusion at chromosome 2p23. It has recently been included as a recognized entity with the 5th edition of the WHO classification urinary and male genital tumor. However, our knowledge about ALK-RCC is limited due to the small number of reported cases. In our study, we aimed to contribute the histomorphological and immunohistochemical features of ALK-rearranged renal cell carcinoma cases. We reviewed 276 cases diagnosed as RCC in order to detect ALKRCCs.We used immunohistochemistry to screen ALK rearrangement and then confirmed the ALK rearrangement by fluorescence in situ hybridization (FISH) method.ALK was immunohistochemically positive in 8 of 276 cases. ALK rearrangement was detected by FISH in 3 of 8 cases. These cases were previously diagnosed as clear cell renal cell carcinoma (CRCC), papillary renal cell carcinoma (PRCC), and chromophobe renal cell carcinoma (ChRCC). Their histomorphological findings were diverse, and all three cases exhibited different immunohistochemical findings. Survival of these patients ranged between 6 to 24 months. ALK immunohistochemical findings were also different in each case as perinuclear, weak cytoplasmic, and membranous.ALK RCCs appear to be very rare tumors with heterogeneous histomorphological and immunohistochemical features. Although immunohistochemistry may be useful to detect ALK positivity, genetic evaluation is required to confirm the diagnosis. With identifying ALK-RCCs, ALK inhibitors, which are currently used in the treatment of lung adenocarcinomas, can be used as a targeted therapy option in ALK-RCCs.

A novel TPD52L2-ROS1 gene fusion expanding the molecular alterations in inflammatory myofibroblastic tumor: case report and literature review

BackgroundInflammatory myofibroblastic tumor (IMT) is a distinctive tumor composed of spindle cells accompanied by mixed inflammatory cells, and immunohistochemical positivity for ALK (anaplastic lymphoma kinase protein) can be detected in half of IMTs. The diagnosis of ALK-negative IMT could be a challenge. Recently, the fusions of some kinase genes, such as RET, NTRK1, ROS1, etc., are revealed in ALK-negative IMT.Case presentationA 19-year-old woman presented with swelling of the left upper arm. Magnetic resonance imaging (MRI) scan revealed a tumor in the left postbrachium extended to the left axillary, serratus anterior muscle, and latissimus dorsi muscle. Histopathologically, the irregular-circumscribed tumor was composed of dense spindle-shaped cells with eosinophilic abundant cytoplasm and hyalinized mesenchyme in an inflammatory background. Immunohistochemically (IHC), tumor cells were positive for SMA, MDM2, and p16; the cells were negative for desmin, MyoD1, Myogenin, pan-cytokeratin, S100, SOX10, HMB45, Malen-A, CD34, CD31, CD99, and ALK. By RNA-based NGS, a novel fusion between TPD52L2 3’ end of exon 1–4 and ROS1 5’ end of exon 36–43 was revealed. ROS1 IHC staining was negative. The final diagnosis of IMT with TPD52L2-ROS1 fusion was made. Subsequently, the patient experienced a good clinical response to Crizotinib, and clinical follow-up showed stable disease after 9 months.ConclusionThis report expands the spectrum of ROS1 gene rearrangements in the IMT and highlights the importance of molecular analysis of IMT for getting a diagnostic clue and determining potential therapeutic strategies.

Mutation status analysis of 58 patients with advanced ALK fusion gene positive non small cell lung cancer

PurposeTo analyze the characteristics and prognostic values of Anaplastic Lymphoma Kinase (ALK) fusion gene partner, gene subtype and abundance in tumor tissues of advanced Non Small Cell Lung Cancer (NSCLC) patients with positive ALK fusion gene and to explore the best treatment mode of ALK-Tyrosine Kinase Inhibitors(TKIs).MethodsCases of advanced NSCLC patients with ALK positive confirmed by both Next Generation Sequencing (NGS) and immunohistochemistry were retrospectively collected. The relationships of Overall Survival (OS)/Progression Free Survival (PFS) between different mutation subtypes, mutation abundance, clinicopathological features were analyzed. OS/PFS between different treatment mode of ALK inhibitors were compared.ResultsFifty-eight patients were enrolled. There were diverse fusion partners. Five subtypes of Echinoderm Microtubule-associated protein-Like 4 gene (EML4)-ALK fusion mutation were detected: V1,V2,V3,V5 and V7. The mutation abundance ranged from 0.13 to 27.77%, with a median of 5.34%. The abundance of V2 and V5 was higher than V1 and V3 respectively. There was no difference in OS between the low abundance group(≤ 5.34%) and the high abundance group(>5.34%) (P = 0.434). PFS of second-generation ALK inhibitors as first-line treatment was longer than that of Crizotinib as first-line (P<0.001). Never smokers had longer OS than current smokers(P = 0.001).ConclusionsThere are differences in abundance between different fusion partners and subtypes in advanced NSCLC with positive ALK. OS is not associated with subtypes, mutation abundance and first line treatment option of either generation of ALK inhibitors. Smoking is a poor prognostic factor.

Deep learning based automated epidermal growth factor receptor and anaplastic lymphoma kinase status prediction of brain metastasis in non-small cell lung cancer.

The aim of this study was to investigate the feasibility of developing a deep learning (DL) algorithm for classifying brain metastases from non-small cell lung cancer (NSCLC) into epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangement groups and to compare the accuracy with classification based on semantic features on imaging. Data set of 117 patients was analysed from 2014 to 2018 out of which 33 patients were EGFR positive, 43 patients were ALK positive and 41 patients were negative for either mutation. Convolutional neural network (CNN) architecture efficient net was used to study the accuracy of classification using T1 weighted (T1W) magnetic resonance imaging (MRI) sequence, T2 weighted (T2W) MRI sequence, T1W post contrast (T1post) MRI sequence, fluid attenuated inversion recovery (FLAIR) MRI sequences. The dataset was divided into 80% training and 20% testing. The associations between mutation status and semantic features, specifically sex, smoking history, EGFR mutation and ALK rearrangement status, extracranial metastasis, performance status and imaging variables of brain metastasis were analysed using descriptive analysis [chi-square test (χ2)], univariate and multivariate logistic regression analysis assuming 95% confidence interval (CI). In this study of 117 patients, the analysis by semantic method showed 79.2% of the patients belonged to ALK positive were non-smokers as compared to double negative groups (P = 0.03). There was a 10-fold increase in ALK positivity as compared to EGFR positivity in ring enhancing lesions patients (P = 0.015) and there was also a 6.4-fold increase in ALK positivity as compared to double negative groups in meningeal involvement patients (P = 0.004). Using CNN Efficient Net DL model, the study achieved 76% accuracy in classifying ALK rearrangement and EGFR mutations without manual segmentation of metastatic lesions. Analysis of the manually segmented dataset resulted in improved accuracy of 89% through this model. Both semantic features and DL model showed comparable accuracy in classifying EGFR mutation and ALK rearrangement. Both methods can be clinically used to predict mutation status while biopsy or genetic testing is undertaken.

Anaplastic lymphoma kinase (ALK) and ROS 1– positive advanced NSCLC: A real-world institutional experience.

e21074 Background: A novel fusion gene of EML4-ALK and ROS 1 has been identified in a subset of non-small-cell lung cancers (NSCLCs). Patients with the ALK-EML4 and ROS1 fusion gene demonstrate unique clinicopathological characteristics and treatment with targeted therapy led to improved survivals. Various clinical trials had shown the efficacy of ALK inhibitors, and they had become the standard of care. The real-world data of ALK inhibitors from a developing country like India is sparse and the present study was designed to analyze the incidence and outcomes of ALK positive NSCLC. Methods: Data of advanced NSCLC patients diagnosed between 2016 and 2022 with ALK and ROS1 positivity was analyzed. Detection of ALK was done by IHC or fluorescent in situ hybridization (FISH) and ROS1 was done by FISH. Results: A total of 776 advanced NSCLC patients between 2016 and 2022 were tested for ALK of which 63(8.1%) were positive. The median age at presentation was 50 years (range, 19-80 years). Of 63 patients, 34(54%) and 29(46%) were males and females. Cough (83%) was the most common symptom at presentation followed by breathlessness (73%), anorexia (59%) weight loss (59%) and chest pain (43%). The median duration of symptoms was 3 months (range, 1-18). 44(86%) patients were never smokers and 9(14%) patients had history of smoking or tobacco usage. The most common site of metastases was opposite lung (59%) followed by bone (50%), pleural effusion (41%) and brain metastasis were seen in 13(21%) patients. Adenocarcinoma was the most common histology (95%). Detection of ALK positivity was done by IHC and FISH in 45(72%) and 18(28%) patients. Of 63 patients, 52 patients received at least 4 months of treatment and were assessed for survival. First line therapy was crizotinib, chemotherapy followed by maintenance crizotinib, ceritinib, Alectinib in 40(77%), 4(7.7%), 6(11.5%) and 2(3.8%) patients respectively. At a median follow up of 14 months, the one-year progression free and overall survival was 71% and 75% respectively. The 2 year and 3-year OS were 54% and 30% respectively. Of 322 patients tested for ROS1, 9(2.8%) were positive for ROS1 translocation and received first line therapy with crizotinib. The one-year PFS and OS of ROS 1 positive patients were 75% and 89% respectively. Conclusions: ALK and ROS1 positivity was seen in 8.1% and 2.8% of advanced NSCLC patients. Majority of patients were never smokers. Opposite lung and bone were the most common site of metastases. Approximately more than half of the patients had two-year survival rate and survivals are almost similar to clinical trials. Crizotinib is well tolerated in majority of patients.

Arterial and Venous Thromboembolism in ALK-Rearrangement-Positive Non-small Cell Lung Cancer: A Population-Based Cohort Study.

There is scarce data regarding the incidence of venous thromboembolism (VTE) and arterial thromboembolism (ATE) in the molecular subtypes of non-small cell lung cancer (NSCLC). We aimed to investigate the association between Anaplastic Lymphoma Kinase (ALK)-positive NSCLC and thromboembolic events. A retrospective population-based cohort study of the Clalit Health Services database, included patients with NSCLC diagnosed between 2012 and 2019. Patients exposed to ALK-tyrosine-kinase inhibitors (TKIs) were defined as ALK-positive. The outcome was VTE (at any site) or ATE (stroke or myocardial infarction) 6 months prior to the diagnosis of cancer, until 5 years post-diagnosis. The cumulative incidence of VTE and ATE and hazard-ratios (HR) with 95% CIs were calculated (at 6- 12- 24 and 60-months), using death as a competing risk. Cox proportional hazards multivariate regression was performed, with the Fine and Gray correction for competing risks. The study included 4762 patients, of which 155 (3.2%) were ALK-positive. The overall 5-year VTE incidence was 15.7% (95% CI, 14.7-16.6%). ALK-positive patients had a higher VTE risk compared to ALK-negative patients (HR 1.87 [95% CI, 1.31-2.68]) and a 12-month VTE incidence of 17.7% (13.9-22.7%) compared to 9.9% (9.1-10.9%) in ALK-negative patients. The overall 5-year ATE incidence was 7.6% [6.8-8.6%]. ALK positivity was not associated with ATE incidence (HR 1.24 [0.62-2.47]). In this study, we observed a higher VTE risk, but not ATE risk, in patients with ALK-rearranged NSCLC relative to those without ALK rearrangement. Prospective studies are warranted to evaluate thromboprophylaxis in ALK-positive NSCLC.

ALK-positive Large B-cell Lymphoma: A Clinicopathologic Retrospective Descriptive Study from a Tertiary Care Cancer Centre in India

Introduction: Anaplastic Lymphoma Kinase (ALK) positive Large B-Cell Lymphoma (ALK+ LBCL) is a very rare aggressive B-cell lymphoma presenting significant diagnostic challenges due to their rarity and unique immunophenotypic features. ALK is a tyrosine kinase receptor and is expressed by ALK+ LBCL due to ALK rearrangement. Aim: To analyse the histopathological features including morphology and immunophenotype, clinical details, pattern of care, progression-free survival (PFS) and overall survival of cases diagnosed as ALK+ LBCL. Materials and Methods: This clinicopathological retrospective descriptive study was conducted in the Department of Pathology at a Tertiary Care Cancer Centre, Thiruvananthapuram, Kerala, India. The duration of the study was six months, from January 2022 to June 2022. All the cases of ALK+ LBCL were diagnosed over a period of 10 years, from January 1st 2010 to December 31st 2020. The cases of LBCL diagnosed during the 10 year period were reviewed. Clinical details were obtained from the case sheets of the cases diagnosed as ALK+ LBCL and summarised. Data collection variables included age, sex, stage, nodal and extranodal status, bone marrow, Central Nervous System (CNS) involvement, haemoglobin, Total Leukocyte Count (TLC) and platelet count, Lactate Dehydrogenase (LDH) value, performance status, date of diagnosis, date of treatment started, date of progression, date of last follow-up, date of death (if dead). Review of Haematoxylin &amp; Eosin (H&amp;E) sections and immunohistochemical slides were done and observations were recorded. Descriptive statistics was used to summarise the basic features of the dataset and Kaplan-Meier method was used for calculation of survival. Results: The age of study participants was ranged from 16- 56 years. During the 10 year period, LBCL accounted for 2415 cases. Among these, ALK+ LBCL constituted 6 (0.25%) cases. There was a male predilection (n=5). Blood counts were normal except for anaemia in three patients. LDH was raised in all the patients. Advanced stage disease was present in two patients. Histopathologically, tumour cells in all the cases showed plasmablastic morphology. Immunohistochemistry (IHC) revealed plasma cell immunophenotype and positivity for ALK in all the cases. Cytokeratin (CK) and Epithelial Membrane Antigen (EMA) were positive in three cases simulating carcinomas. Six year overall survival and progression free survival in the present study was 50% and 33.3%, respectively. Conclusion: Careful interpretation of the morphology and immunophenotype is essential for diagnosis of ALK+ LBCL, as it can be easily misdiagnosed as a non haematological malignancy thus, affecting the treatment and prognosis in these patients.

Evaluation of clinicopathological features determining treatment response in patients with ALK mutant NSCLC.

ALK (anaplastic lymphoma kinase) inhibitors may be used to treat patients with ALK mutant metastatic nonsmall cell cancer (NSCLC). This study aimed to investigate the factors affecting the patients response to treatment with ALK-positive metastatic NSCLC. Data of the patients were investigated retrospectively. Binary regression analysis was performed to evaluate response predictors of treatment. Furthermore, we determined the cut-off value of the ALK-positivity for objective response to the therapy using ROC analysis. A total of 68 patients were included in the research. The median overall survival was observed 39.2 months. The overall response rate was 66.2%. The ratio of ALK positivity (P = .02), gender (P = .04), and the total number of metastatic sites (P = .02) all were detected as predictors of the response to ALK inhibitor in binary regression analysis. ALK inhibitor type (P = .56), primary tumor location (P = .35), pathological subtype (P = .68), de-novo metastatic disease (P = .28), and age (P = .94) were not predictive indicators for response. The cut-off level of ALK positivity was found to be 33% in patients with an objective response. The real-life effectiveness of ALK inhibitors in NSCLC patients with ALK mutations was shown in this research. We determined that having less than 3 metastatic sites, having a high ALK positivity ratio, and being female were all good predictors of ALK inhibitor response.

Chinese Expert Consensus on Management of Special Adverse Effects Associated with Lorlatinib

间变性淋巴瘤激酶（anaplastic lymphoma kinase, ALK）融合基因是非小细胞肺癌（non-small cell lung cancer, NSCLC）中第二常见的肿瘤驱动基因。作为新型的第三代ALK酪氨酸激酶抑制剂（tyrosine kinase inhibitor, TKI），洛拉替尼对多种ALK激酶域突变具有广谱且高效的临床活性，并具有强大的穿透血脑屏障效力。洛拉替尼的总体耐受性良好，其独特的不良反应或不良事件包括高脂血症与中枢神经系统反应等，多为轻至中度，通常经剂量调整和/或标准医疗干预即可管理。对于ALK阳性晚期NSCLC，开始洛拉替尼治疗前应充分评估患者基线特征与既往用药状况，预先告知患者可能经历的用药相关不良反应，并定期监测以实现药物临床获益的最大化。同时，多学科专家团队对于建立全面的诊断和治疗策略是至关重要的。

Detecting anaplastic lymphoma kinase (ALK) gene rearrangements with next-generation sequencing remains a reliable approach in patients with non-small-cell lung cancer.

Next-generation sequencing (NGS) is rapidly becoming routine in clinical oncology practice to identify therapeutic biomarkers, including gene rearrangements in anaplastic lymphoma kinase (ALK). Our study investigated the concordance of ALK positivity evaluated by DNA-based NGS with orthogonal ALK testing methods such as fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), and RNA-based NGS (RNA-NGS). Thirty-eight patients with lung adenocarcinoma who were detected with ALK rearrangements using DNA-NGS and also had adequate tissue samples submitted for FISH, IHC, and RNA-NGS, were included in this study. Of the 38 patients, RNA samples from 3 patients failed quality control for RNA-NGS. The concordance of ALK positivity was calculated relative to DNA-NGS results. The concordance rates were 97.1% (34/35) for RNA-NGS, 94.7% (36/38) for IHC, and 97.4% (37/38) for FISH. DNA-NGS detected single ALK rearrangements in 14 (35.0%) patients and complex ALK rearrangements in 26 (65.0%). RNA-NGS detected only single transcripts of the primary ALK fusions. A novel LANCL1-ALK (L7:A20) detected using DNA-NGS was detected as EML4-ALK (E13:A20) transcripts using RNA-NGS. Interestingly, patients with single ALK rearrangements were more likely to be detected with atypical isolated red signals (p < 0.001), while patients with complex ALK rearrangements were more likely to be detected with atypical split red and green signals less than 2 signal diameters apart (p < 0.001). Our study highlights the reliability of NGS in the accurate detection of specific ALK fusion variants and concomitant mutations that are crucial for individualized treatment decisions in patients with lung cancer.

Multiplex fluorescence in situ hybridization testing for anaplastic lymphoma kinase and c-ros oncogene 1 gene rearrangements on cytology smears in lung adenocarcinomas: comparative study with formalin-fixed paraffin-embedded sections.

Multiplex anaplastic lymphoma kinase (ALK)/c-ros oncogene 1 (ROS1) fluorescence in situ hybridization (FISH) probes conserve tissue by analyzing both ALK and ROS1 gene rearrangements (ALK-R/ROS1-R) in a single test. The positivity cutoffs have been validated on formalin-fixed, paraffin-embedded (FFPE) tissue sections and not tested on non-cell block (CB) cytology preparations. We sought to validate non-CB cytology preparations for the detection of ALK-R/ROS1-R using multiplex ALK/ROS1 FISH probes by comparing the results with matched FFPE results. During the 3.5-year study period, FISH using the FlexISH ALK/ROS1 DistinguISH Probe (ZytoVision) was performed in non-CB cytology preparations of patients for whom FISH on FFPE sections was performed. A total of 20 patients had one or more non-CB cytology preparations (n = 27) suitable for FISH analysis. These comprised direct smears (n = 17), smears from centrifuged effusion pellets (n = 8), cytospin smears (n = 1), and biopsy imprint smears (n = 1). These had been fixed in 95% ethanol (n = 18) or air dried (n= 9), and stained with Papanicolaou (n = 14), May-Grünwald-Giemsa (n = 9), immunocytochemistry (n= 3), or hematoxylin and eosin (n = 1). The median archival time was 1 year. Successful FISH results were achieved in 14 samples (6 with ALK-R, 2 with ROS1-R, 6 negative) and were concordant with the FFPE FISH results for 13 of 14 cases. The single case with discordant results between cytology and FFPE FISH showed ALK-R on cytology concordant with positive ALK D5F3 companion diagnostics assay results and was considered a false-negative FFPE FISH result. FISH failure occurred mainly in the older archived slidesbecause of overdigestion (n = 5), hybridization failure (n = 5), or excessive background fluorescence (n = 3). Non-CB cytology smears are highly suitable for multiplex FISH analysis with 100% concordance with FFPE FISH and/or ALK D5F3 companion diagnostics assay results.

Erythematous, telangiectatic nodule within the melomental fold

Erythematous, telangiectatic nodule within the melomental fold

Histopathologic and Molecular Characterization of Uterine Leiomyoma-like Inflammatory Myofibroblastic Tumor: Comparison to Molecular Subtypes of Uterine Leiomyoma.

Uterine leiomyoma (UL) is a common benign neoplasm which can sometimes be difficult to differentiate from the uterine inflammatory myofibroblastic tumor (IMT) based on morphology alone. IMT is a myofibroblastic/fibroblastic neoplasm which has typically been considered to be rare in the uterus. Its clinical behavior is usually indolent although aggressive variants exist. The majority of IMTs harbor genomic rearrangement of anaplastic lymphoma kinase ( ALK ), while ALK fusion has not been thus far detected in ULs. We analyzed 2263 ULs of which 9 (0.4%) had tyrosine-kinase activation. Seven of the samples were ALK immunopositive: 6 had an ALK fusion gene and 1 overexpressed an ALK transcript skipping exons 2 to 3, Moreover, 1 sample had a RET , and 1 a PDGFRB fusion gene. While no recurrent somatic mutations were found, 1 patient had an ALK germline mutation. Seven tumors showed leiomyoma-like morphology, 1 tumor had slightly loose, and 1 fibrous growth pattern. Six tumors had mild to moderate lymphocyte infiltration, while no immune cell infiltration was detected in 3 cases. None of the tumors showed aggressive behavior. Except for strong ALK positivity (7/9 tumors) the protein expression profile of the tumors was identical to ULs and distinct from other mesenchymal uterine tumors. In gene expression level, these tumors and the known UL subclasses did not separate perfectly. However, vitamin C metabolism and epithelial-mesenchymal transition pathways were uniquely enriched in these lesions. The overall similarity of the analyzed tumors to UL raises the question whether an UL diagnosis would be more proper for a subset of uterine IMTs.

Resected stage I anaplastic lymphoma kinase-positive lung adenocarcinoma has a negative impact on recurrence-free survival.

BackgroundThe clinical and prognostic implications of anaplastic lymphoma kinase (ALK) status in resected lung cancers remain unclear. In this study we analyzed the prognostic and predictive significance of ALK‐positive among patients with completely resected lung adenocarcinoma.MethodsWe retrospectively reviewed 197 patients with lung adenocarcinoma who underwent complete surgical resection and had been tested for their ALK status. We investigated the impact of an ALK‐positive status on the recurrence‐free survival (RFS) and overall survival (OS) and examined the predictive factors for an ALK‐positive status.ResultsALK positivity was noted in 36 (18%) out of 197 patients, and when limited to stage I patients, in 24 (19%) out of 124. In the pathological‐stage I population, while the OS exhibited no significant difference between ALK‐positive and ALK‐negative patients (5‐year OS rate, 81.2% vs. 89.8%, p = 0.226), the RFS of ALK‐positive patients was significantly worse than that of ALK‐negative patients (5‐year RFS rate, 55.9% vs. 78.8%, p = 0.018). A multivariate analysis showed that ALK‐positive status (hazard ratio [HR] 3.431, p = 0.009) was an independent prognostic factor for the RFS. Regarding the relationship between clinicopathological factors and an ALK‐positive status, a high‐grade histological subtype, including solid and micropapillary subtypes (odds ratio [OR] 5.464, p < 0.001), and never‐smokers (OR 4.292, p = 0.018) were associated with ALK‐positive.ConclusionA high‐grade histological subtype and never‐smokers were associated with ALK positivity, and the RFS of ALK‐positive patients was worse than that of ALK‐negative patients among patients with completely resected stage I lung adenocarcinoma.

Short-Time Development of Esophageal Inflammatory Myofibroblastic Tumor Which Resected by Endoscopic Submucosal Dissection

A 53-year-old man was pointed out an elevated lesion in the esophagus by screening upper gastrointestinal series. A esophagogastroduodenoscopy showed a submucosal tumor 10 mm in diameter in the lower thoracic esophagus (Figure A). A biopsy specimen taken from the tumor showed no malignancy. One year later, the tumor had more than doubled in size (Figure B). So, we decided to perform endoscopic ultrasonography–guided fine-needle aspiration for this tumor. Endoscopic ultrasonography showed a hypoechoic mass 21 mm in size which come from the second layer. The biopsy specimen showed spindle cell proliferation and actin and anaplastic lymphoma kinase positivity (Figure C), which lead to the diagnosis of inflammatory myofibroblastic tumor (IMT). Because of the strong accumulation on positron emission tomography/computed tomography and the growing trend of submucosal tumor, we decided to perform endoscopic submucosal dissection (ESD). The pathological results were consistent with IMT which complete resected by ESD (Figure D). No recurrence has been observed for a year. Although IMT is a tumor of mesenchymal origin which occurs systemically, there are few reports of its occurrence in the esophagus. This is the first case in which short-time growth can be observed and resected by ESD.

Predictive role of neutropenia under crizotinib treatment in ALK-rearranged nonsmall cell lung cancer patients: A single-institution retrospective analysis.

Anaplastic lymphoma kinase (ALK)-rearranged nonsmall cell lung cancer (NSCLC) represents a molecular subgroup with high sensitivity to ALK inhibitors. Tyrosine kinase inhibitor crizotinib, an anticancer drug acting as an ALK inhibitor, has shown remarkable response in ALK-positive NSCLC. The aim of our study is to explore the adverse events (AEs) of patients on crizotinib therapy and analyze the predictability of AEs for better survival or response on NSCLC patients. The medical records of our ALK-positive metastatic NSCLC patients who applied between years 2013 and 2018 had been reviewed retrospectively. ALK positivity of all patients had been detected by fluorescence in situ hybridization and no other driver mutations were present. Patient demographics, performance status, smoking history, previous treatments, metastatic sites, and AEs were recorded for further analyses. Thirty-six ALK-positive metastatic NSCLC patients were included in the study. Median follow-up was 30.1 months. Median progression-free survival (PFS) for patients who developed hepatic, cardiac, or endocrine toxicities was similar when compared to patients who did not develop. Although there was a numeric median PFS difference between patients who did develop visual disorders (18.4 months) and did not develop visual disorders (15.5 month), this was not regarded as statistically significant. However, median PFS of the patients who developed neutropenia upon crizotinib treatment (31.9 months) was found to be more favorable than the patients with normal neutrophil counts (12.8 months) (P = 0.026). Neutropenia under crizotinib treatment was found to be associated with improved PFS suggesting that neutropenia might be an important determinant in treatment and survival strategies.

Clinical value of serum albumin level in patients with non-small cell lung cancer and anaplastic lymphoma kinase (ALK) rearrangement.

There are few data on the clinical value of serum albumin (Alb) level as a prognostic indicator in advanced non-small cell lung cancer (NSCLC) patients with positive anaplastic lymphoma kinase (ALK) rearrangement. Thus, we retrospectively analyzed the clinicopathological features of advanced, ALK-positive NSCLC patients diagnosed and treated at our institution to investigate the effects of pretreatment serum Alb on outcome in this patient setting. We selected 261 consecutive patients with newly diagnosed pathologically or cytologically confirmed NSCLC harboring ALK rearrangement between May 2016 and February 2018. The target-independent and dependent variables were Serum albumin level measured in patients before anticancer treatment and progression-free survival (PFS). Pre-treatment serum Alb levels and demographic, clinical, and histological characteristics, as well as outcome variables were recorded and analyzed. Serum albumin level was estimated before treatment and at every visit. The pretreatment and the lowest serum albumin level during treatment were recorded. The mean pretreatment Alb level was 42.185 g/L. Before the treatment initiation, low Alb level (<40 g/L) was measured in 74 (28.4%) patients and normal Alb (≥40 g/L) was measured in 187 (71.6%) participants. Low pretreatment Alb (<40 g/L) was more highly prevalent in those with pleural effusion (P=0.013). Pretreatment hypoalbuminemia was significantly associated with shorter progression-free survival (PFS) [8.0 months, 95% confidence interval (CI): 4.56-11.44 vs. 12.0 months, 95% CI: 9.85-14.15; P=0.046]. Crizotinib-treated participants had a significantly prolonged PFS compared to those treated with chemotherapy, regardless of Alb level [normal Alb level: 19.0 (95% CI: 12.72-25.28) vs. 8.0 (95% CI: 6.22-9.78), P<0.001; low Alb level: 12.0 months (95% CI: 10.13-13.87) vs. 6.0 months (95% CI: 2.95-9.05), P=0.006]. Multivariate analyses indicated that poor Eastern Cooperative Oncology Group performance status (ECOG PS) [hazard ratio (HR) =1.66; 95% CI: 1.16-2.38; P=0.005] and presence of pleural effusion (HR =2.43; 95% CI: 1.55-3.82; P<0.001) were significantly independent predictive factors for PFS in ALK-positive NSCLC. Pretreatment hypoalbuminemia is associated with poor outcome of NSCLC patients harboring ALK rearrangement. However, the role of the pretreatment serum Alb level as predictive biomarker requires further investigation.