scholarly journals Standard immunohistochemistry efficiently screens for anaplastic lymphoma kinase rearrangements in differentiated thyroid cancer

2015 ◽  
Vol 22 (1) ◽  
pp. 55-63 ◽  
Author(s):  
Gahee Park ◽  
Tae Hyuk Kim ◽  
Hae-Ock Lee ◽  
Jung Ah Lim ◽  
Jae-Kyung Won ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Anaplastic Lymphoma Kinase ◽  
Differentiated Thyroid Cancer ◽  
Ectopic Expression ◽  
Practical Method ◽  
Thyroid Tumor ◽  
Anaplastic Lymphoma ◽  
Formalin Fixed Paraffin ◽  
Wide Availability ◽  
Formalin Fixed Paraffin Embedded

The anaplastic lymphoma kinase (ALK) gene is frequently rearranged in various types of cancer and is highly responsive to targeted therapeutics. We developed a system to detect rearrangement of ALK in a large group of Korean thyroid cancer patients. We screened 474 malignant or benign thyroid tumor cases to identify ALK fusions. Expression and translocation of the ALK gene were analyzed by immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and digital multiplexed gene expression (DMGE) analysis in formalin-fixed paraffin-embedded tissues. Four cases of rearrangement of ALK were detected by IHC, and these cases were validated with FISH on 189 samples. On the other hand, DMGE analysis using Nanostring detected three out of four IHC-positive cases. Two rearrangements of ALK were striatin (STRN)–ALK fusions, which were identified by 5′ RACE analysis. Rearrangements of ALK were found exclusively in v-raf murine sarcoma viral oncogene homolog B (BRAF) WT papillary carcinomas. Given the wide availability and accuracy of IHC for detecting ectopic expression of ALK in the thyroid, we suggest that IHC-based screening can be a practical method for identifying patients with ALK rearrangements in differentiated thyroid cancer.

scholarly journals Anaplastic Lymphoma Kinase Immunocytochemistry on Cell-Transferred Cytologic Smears of Lung Adenocarcinoma

2015 ◽  
Vol 59 (2) ◽  
pp. 213-218 ◽  
Author(s):  
Chen Zhang ◽  
Melissa L. Randolph ◽  
Kelly J. Jones ◽  
Harvey M. Cramer ◽  
Liang Cheng ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Anaplastic Lymphoma Kinase ◽  
Needle Aspiration ◽  
Alk Rearrangement ◽  
Anaplastic Lymphoma ◽  
Ct Technique ◽  
Formalin Fixed Paraffin ◽  
Formalin Fixed Paraffin Embedded ◽  
Hybridization In Situ

Background: Anaplastic lymphoma kinase (ALK) immunohistochemical staining on formalin-fixed paraffin-embedded tissue or cell blocks (CB) has been reported as an effective alternative to fluorescence hybridization in situ (FISH) for the detection of ALK gene rearrangement. However, CB frequently lack adequate cellularity even when the direct smears are cellular. This study aims to assess the utility of ALK immunocytochemical (ICC) staining on direct smears using the cell transfer (CT) technique for the detection of ALK rearrangement. Methods: Fine-needle aspiration (FNA) cases of lung adenocarcinoma in which the ALK status had been determined by FISH on CB or a concurrent biopsy were identified. ICC staining for ALK was performed on alcohol-fixed Papanicolaou-stained direct smears using the CT technique. ALK immunoreactivity was evaluated using a modified semiquantitative scale. Results were compared with those of FISH. Results: A total of 47 FNA specimens were included. Five of 7 FISH-positive cases showed positive ALK ICC staining (71.4%), and 39 of 40 FISH-negative cases were negative on ALK ICC staining (97.5%). The overall correlation between ALK ICC and FISH was 93.6%. Conclusion: ICC performed on FNA smears using the CT technique is an alternative method for the assessment of ALK rearrangement, especially when CB lack adequate cellularity.

scholarly journals Expression of the Ring Ligase PRAJA2 in Thyroid Cancer

2012 ◽  
Vol 97 (11) ◽  
pp. 4253-4259 ◽  
Author(s):  
Silvia Cantara ◽  
Francesco D'Angeli ◽  
Paolo Toti ◽  
Luca Lignitto ◽  
Maria Grazia Castagna ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Differentiated Thyroid Cancer ◽  
Cultured Cells ◽  
Thyroid Tumor ◽  
Mrna Levels ◽  
Malignant Phenotype ◽  
Hormone Production ◽  
Thyroid Cells ◽  
Mutational Status ◽  
Benign Nodules

Introduction: In thyroid cells, binding of TSH to its receptor increases cAMP levels, sustaining thyrocytes growth and hormone production. The main cAMP effector enzyme is protein kinase A (PKA). Praja2 is a widely expressed RING (Really Interesting New Gene) ligase, which degrades the regulatory subunits of PKA, thus controlling the strength and duration of PKA signaling in response to cAMP. Differentiated thyroid cancer expresses a functional TSH receptor, and its growth and progression are positively regulated by TSH and cAMP signaling. Aim: We aimed to analyze the expression of praja2 in a group of 36 papillary thyroid cancer (PTC), 14 benign nodules, and six anaplastic thyroid cancers (ATC). Methods: We measured praja2 mRNA levels by quantitative RT-PCR and praja2 expression by Western blot and immunohistochemistry. Possible association between praja2 mRNA and the presence of known mutations was evaluated. Results: We found a statistical significant increase of mRNA levels in PTC tissue samples, compared with benign nodules and ATC. In particular, mRNA levels were maximal in differentiated thyroid cancer (PTC), progressively decreasing in more aggressive tumors, ATC having the lowest amount of praja2 mRNA. Accordingly, higher levels of praja2 protein were detected in lysates from PTC, compared with ATC. By immunohistochemistry, in PTC sections we observed a marked increase of cytoplasmic praja2 signal, which significantly decreased in less differentiated thyroid tumors, completely disappearing in ATC. Studies in cultured cells stably expressing RET/PTC1 oncogene or mutant BRAF revealed a direct correlation between praja2 mRNA levels and malignant phenotype of transformed cells. Similar results were obtained using thyroid cancer tissues carrying the same mutations. Conclusions: praja2 is markedly overexpressed in differentiated thyroid cancer, and its levels inversely correlate with the malignant phenotype of the tumor. Thus, praja2 is a novel cancer-related gene whose expression is linked to the histotype and mutational status of the thyroid tumor.

Immunoexpression of BAP1, ROS1, and ALK in Spitzoid Melanocytic Tumors

2018 ◽  
Vol 26 (6) ◽  
pp. 514-520
Author(s):  
Leonardo Cardili ◽  
Cristiano Ribeiro Viana ◽  
Andressa Germano ◽  
Mariana Fernandes ◽  
Denise Barcellos ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Low Grade ◽  
Tissue Samples ◽  
Anaplastic Lymphoma ◽  
Melanocytic Tumors ◽  
Formalin Fixed Paraffin ◽  
Formalin Fixed Paraffin Embedded ◽  
Diagnostic Difficulties ◽  
Related Proteins

Background. Spitzoid tumors are a heterogeneous group of melanocytic neoplasms that frequently imposes diagnostic difficulties. Lately, several advances in molecular biology afforded significant discoveries on the pathogenesis of these tumors. BAP1 (BRCA-1 associated protein-1) inactivation and anomalous expression of kinase translocation-related proteins are among the main criteria launched by new classification proposals. Our aim was to systematically assess the immunoexpression of BAP1, ROS1 (receptor tyrosine kinase c-Ros oncogene 1), and ALK (anaplastic lymphoma receptor tyrosine kinase) proteins in an unpublished series of spitzoid tumors. Methods. Retrospective study based on 47 formalin-fixed paraffin-embedded tissue samples from 3 different institutions. BAP1, ROS1, and ALK immunostains were performed in all cases. We included 27 Spitz tumors without significant abnormality, 15 atypical spitzoid tumors, and 5 spitzoid melanomas. Results. We observed loss of BAP1 nuclear immunolabeling in 4.3% of evaluable cases (2/46), both of them atypical spitzoid tumors. The proportional frequency of BAP1-inactivated cases among atypical spitzoid tumors was 14.2% (2/14). No immunoexpression of ROS1 or ALK was found. Conclusions. Our study revealed 2 additional BAP1-inactived cases and described its respective frequency. The absence of anomalous expression of translocation-related proteins ALK and ROS1 in this series, composed predominantly of low-grade/low-risk tumors, indicates that translocated spitzoid lesions may not be as prevalent as initially suggested, at least in some populations. Furthermore, our findings encourage additional investigation on unequal occurrence of such immunomarkers among different diagnostic categories of spitzoid neoplasms.

scholarly journals Anaplastic lymphoma kinase L1198F and G1201E mutations identified in anaplastic thyroid cancer patients are not ligand-independent

Oncotarget ◽  
2016 ◽  
Vol 8 (7) ◽  
pp. 11566-11578 ◽  
Author(s):  
Jikui Guan ◽  
Georg Wolfstetter ◽  
Joachim Siaw ◽  
Damini Chand ◽  
Fredrik Hugosson ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Cancer Patients ◽  
Anaplastic Lymphoma Kinase ◽  
Anaplastic Thyroid Cancer ◽  
Anaplastic Lymphoma

Rearranged anaplastic lymphoma kinase (ALK) gene in adult-onset papillary thyroid cancer among atomic-bomb survivors

Thyroid ◽  
2012 ◽  
pp. 120622084931008
Author(s):  
Kiyohiro Hamatani ◽  
Mayumi Mukai ◽  
Keiko Takahashi ◽  
Yuzo Hayashi ◽  
Kei Nakachi ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Papillary Thyroid Cancer ◽  
Anaplastic Lymphoma Kinase ◽  
Atomic Bomb ◽  
Adult Onset ◽  
Papillary Thyroid ◽  
Atomic Bomb Survivors ◽  
Anaplastic Lymphoma ◽  
I Gene

scholarly journals P53-regulated miR-320a targets PDL1 and is downregulated in malignant mesothelioma

2020 ◽  
Vol 11 (9) ◽  
Author(s):  
Caterina Costa ◽  
Paola Indovina ◽  
Eliseo Mattioli ◽  
Iris Maria Forte ◽  
Carmelina Antonella Iannuzzi ◽  
...  
Keyword(s):  
Asbestos Exposure ◽  
Ectopic Expression ◽  
High Specificity ◽  
Migration Ability ◽  
Dismal Prognosis ◽  
Specificity And Sensitivity ◽  
Formalin Fixed Paraffin ◽  
Intrinsic Roles ◽  
Formalin Fixed Paraffin Embedded ◽  
And Migration

Abstract Malignant pleural mesothelioma (MPM) is an aggressive cancer, related to asbestos exposure, which has a dismal prognosis. MPM diagnosis is late and often challenging, suggesting the need to identify more reliable molecular biomarkers. Here, we set out to identify differentially expressed miRNAs in epithelioid, biphasic, and sarcomatoid MPMs versus normal mesothelium and explored specific miRNA contribution to mesothelial tumorigenesis. We screened an LNA™-based miRNA-microrray with 14 formalin-fixed paraffin-embedded (FFPE) MPMs and 6 normal controls. Through real-time qRT-PCR we extended the analysis of a miRNA subset and further investigated miR-320a role through state-of-the-art techniques. We identified 16 upregulated and 32 downregulated miRNAs in MPMs versus normal tissue, including the previously identified potential biomarkers miR-21, miR-126, miR-143, miR-145. We showed in an extended series that miR-145, miR-10b, and miR-320a levels can discriminate tumor versus controls with high specificity and sensitivity. We focused on miR-320a because other family members were found downregulated in MPMs. However, stable miR-320a ectopic expression induced higher proliferation and migration ability, whereas miR-320a silencing reduced these processes, not supporting a classic tumor-suppressor role in MPM cell lines. Among putative targets, we found that miR-320a binds the 3′-UTR of the immune inhibitory receptor ligand PDL1 and, consistently, miR-320a modulation affects PDL1 levels in MPM cells. Finally, we showed that p53 over-expression induces the upregulation of miR-320a, along with miR-200a and miR-34a, both known to target PDL1, and reduces PDL1 levels in MPM cells. Our data suggest that PDL1 expression might be due to a defective p53-regulated miRNA response, which could contribute to MPM immune evasion or tumorigenesis through tumor-intrinsic roles.

scholarly journals Aggressive Differentiated Thyroid Cancer due to EML4e13-ALKe20 Fusion: A Case Presentation and Review of the Literature

2021 ◽  
Vol 2021 ◽  
pp. 1-7
Author(s):  
Rodhan Khthir ◽  
Zainab Shaheen ◽  
Prasanna Santhanam ◽  
Saroj Sigdel
Keyword(s):  
Thyroid Cancer ◽  
Lymph Node ◽  
Differentiated Thyroid Cancer ◽  
Residual Disease ◽  
Disease Patient ◽  
Clinical Signs ◽  
Cervical Lymphadenopathy ◽  
Rapid Progression ◽  
Anaplastic Lymphoma ◽  
Aggressive Form

Background. Differentiated thyroid cancer (DTC) is an indolent malignancy. It rarely presents with aggressive local invasion and/or distant metastatic disease. Patient findings. We describe a case of a 30-year-old man with a locally aggressive form of papillary thyroid cancer with EML4e13-ALKe20 fusion (EML4: echinoderm microtubule-associated protein-like 4; ALK: anaplastic lymphoma kinase). He presented with right-side cervical lymphadenopathy with a highly suspicious right-side thyroid nodule. Total thyroidectomy and level IV lymph node resection showed extensive bilateral disease, with extrathyroidal and extranodal extension. FDG-PET CT scan following surgery confirmed the presence of significant residual disease in the neck area. He underwent bilateral lateral lymph node dissection followed by radioactive iodine treatment. Somatic mutation testing showed EML4e13-ALKe20 fusion. Summary. This case represents an aggressive form of DTC with EML4e13-ALKe20 fusion. The rapid progression of clinical signs and symptoms and the local extension beyond the thyroid and lymph nodes with the persistence of high-volume local disease after thyroidectomy highlight the aggressive nature of this mutation and the importance of performing genetic analysis to guide future treatments and determine prognosis. Conclusion. This case highlights the importance of using molecular diagnostics in patient care, especially if the presentation is unusual for DTC. A thorough evaluation of the tumor pathology and the somatic mutational profile analysis are important for obtaining vital therapeutic and prognostic guidance.

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