Targeting ALK in Neuroendocrine Tumors of the Lung
BackgroundAnaplastic lymphoma kinase (ALK) rearrangements are known oncogenic drivers in non-small cell lung cancer (NSCLC). Few case reports described the occurrence of such rearrangements in large cell neuroendocrine carcinomas (LCNECs) of the lung without information on clinical responses to ALK...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-06-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.911294/full |
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| author | Dilara Akhoundova Dilara Akhoundova Dilara Akhoundova Martina Haberecker Ralph Fritsch Sylvia Höller Michael K. Kiessling Michael K. Kiessling Markus Rechsteiner Jan H. Rüschoff Alessandra Curioni-Fontecedro |
| author_facet | Dilara Akhoundova Dilara Akhoundova Dilara Akhoundova Martina Haberecker Ralph Fritsch Sylvia Höller Michael K. Kiessling Michael K. Kiessling Markus Rechsteiner Jan H. Rüschoff Alessandra Curioni-Fontecedro |
| author_sort | Dilara Akhoundova |
| collection | DOAJ |
| description | BackgroundAnaplastic lymphoma kinase (ALK) rearrangements are known oncogenic drivers in non-small cell lung cancer (NSCLC). Few case reports described the occurrence of such rearrangements in large cell neuroendocrine carcinomas (LCNECs) of the lung without information on clinical responses to ALK tyrosine kinase inhibitors (TKIs) in these cases. Currently, neuroendocrine tumors of the lungs are not screened for ALK rearrangements.MethodsTo illustrate the clinical impact of molecular characterization in LCNECs, we report the disease course in three patients with ALK-rearranged metastatic LCNEC from our clinical routine, as well as their treatment response to ALK TKIs (index cases). To gain insight into the prevalence of ALK rearrangements in neuroendocrine tumors of the lung, we analyzed a retrospective cohort of 436 tumor biopsies including LCNEC (n = 61), small cell lung cancer (SCLC) (n = 206), typical (n = 91) and atypical (n = 69) carcinoids, and mixed histology (n = 9) for the presence of ALK rearrangements using a sequential diagnostic algorithm. ALK immunohistochemistry (IHC) was evaluable in 362 cases; fluorescence in situ hybridization (FISH) was evaluable in 28 out of the 35 IHC-positive cases, followed by next-generation sequencing (NGS) that was available in 12 cases.ResultsWithin the retrospective cohort, ALK IHC was positive in 35 out of 362 (9.7%) evaluable samples. FISH was positive in 3 out of the 28 (10.7%) evaluable cases: 2 with atypical carcinoids and 1 with LCNEC. Additionally, the 3 index cases showed positive ALK IHC, which was confirmed by NGS. Within the retrospective cohort, NGS confirmed the presence of an ALK genomic rearrangement in one FISH-positive atypical carcinoid where material was sufficient for sequencing. Two out of three patients with metastatic ALK-rearranged LCNEC received up-front treatment with the ALK TKI alectinib and showed rapid tumor response at all metastatic sites, including multiple brain metastases.ConclusionsALK rearrangements represent rare but targetable oncogenic driver alterations in LCNEC. Contrarily to NSCLC, the detection of ALK rearrangements in neuroendocrine tumors of the lung is challenging, since ALK IHC can lead to false-positive results and therefore needs confirmation by FISH or NGS. Up-front comprehensive molecular profiling with NGS should be performed in metastatic LCNEC in order not to miss actionable genomic alterations. |
| first_indexed | 2024-04-13T21:32:53Z |
| format | Article |
| id | doaj.art-e591e9021ef5464abbf98b549a36cd75 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-13T21:32:53Z |
| publishDate | 2022-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-e591e9021ef5464abbf98b549a36cd752022-12-22T02:29:07ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-06-011210.3389/fonc.2022.911294911294Targeting ALK in Neuroendocrine Tumors of the LungDilara Akhoundova0Dilara Akhoundova1Dilara Akhoundova2Martina Haberecker3Ralph Fritsch4Sylvia Höller5Michael K. Kiessling6Michael K. Kiessling7Markus Rechsteiner8Jan H. Rüschoff9Alessandra Curioni-Fontecedro10Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, SwitzerlandDepartment of Medical Oncology, Inselspital, University Hospital of Bern, Bern, SwitzerlandDepartment for BioMedical Research, University of Bern, Bern, SwitzerlandDepartment of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, SwitzerlandDepartment of Medical Oncology and Hematology, University Hospital Zurich, Zurich, SwitzerlandInstitute of Pathology, Stadtspital Zurich Triemli, Zurich, SwitzerlandDepartment of Medical Oncology and Hematology, University Hospital Zurich, Zurich, SwitzerlandDepartment of Internal Medicine–Oncology, See Spital Horgen, Horgen, SwitzerlandDepartment of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, SwitzerlandDepartment of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, SwitzerlandDepartment of Medical Oncology and Hematology, University Hospital Zurich, Zurich, SwitzerlandBackgroundAnaplastic lymphoma kinase (ALK) rearrangements are known oncogenic drivers in non-small cell lung cancer (NSCLC). Few case reports described the occurrence of such rearrangements in large cell neuroendocrine carcinomas (LCNECs) of the lung without information on clinical responses to ALK tyrosine kinase inhibitors (TKIs) in these cases. Currently, neuroendocrine tumors of the lungs are not screened for ALK rearrangements.MethodsTo illustrate the clinical impact of molecular characterization in LCNECs, we report the disease course in three patients with ALK-rearranged metastatic LCNEC from our clinical routine, as well as their treatment response to ALK TKIs (index cases). To gain insight into the prevalence of ALK rearrangements in neuroendocrine tumors of the lung, we analyzed a retrospective cohort of 436 tumor biopsies including LCNEC (n = 61), small cell lung cancer (SCLC) (n = 206), typical (n = 91) and atypical (n = 69) carcinoids, and mixed histology (n = 9) for the presence of ALK rearrangements using a sequential diagnostic algorithm. ALK immunohistochemistry (IHC) was evaluable in 362 cases; fluorescence in situ hybridization (FISH) was evaluable in 28 out of the 35 IHC-positive cases, followed by next-generation sequencing (NGS) that was available in 12 cases.ResultsWithin the retrospective cohort, ALK IHC was positive in 35 out of 362 (9.7%) evaluable samples. FISH was positive in 3 out of the 28 (10.7%) evaluable cases: 2 with atypical carcinoids and 1 with LCNEC. Additionally, the 3 index cases showed positive ALK IHC, which was confirmed by NGS. Within the retrospective cohort, NGS confirmed the presence of an ALK genomic rearrangement in one FISH-positive atypical carcinoid where material was sufficient for sequencing. Two out of three patients with metastatic ALK-rearranged LCNEC received up-front treatment with the ALK TKI alectinib and showed rapid tumor response at all metastatic sites, including multiple brain metastases.ConclusionsALK rearrangements represent rare but targetable oncogenic driver alterations in LCNEC. Contrarily to NSCLC, the detection of ALK rearrangements in neuroendocrine tumors of the lung is challenging, since ALK IHC can lead to false-positive results and therefore needs confirmation by FISH or NGS. Up-front comprehensive molecular profiling with NGS should be performed in metastatic LCNEC in order not to miss actionable genomic alterations.https://www.frontiersin.org/articles/10.3389/fonc.2022.911294/fullALK rearrangementsneuroendocrine tumors of the lunglarge cell neuroendocrine carcinomaALK inhibitorstargeted treatment |
| spellingShingle | Dilara Akhoundova Dilara Akhoundova Dilara Akhoundova Martina Haberecker Ralph Fritsch Sylvia Höller Michael K. Kiessling Michael K. Kiessling Markus Rechsteiner Jan H. Rüschoff Alessandra Curioni-Fontecedro Targeting ALK in Neuroendocrine Tumors of the Lung Frontiers in Oncology ALK rearrangements neuroendocrine tumors of the lung large cell neuroendocrine carcinoma ALK inhibitors targeted treatment |
| title | Targeting ALK in Neuroendocrine Tumors of the Lung |
| title_full | Targeting ALK in Neuroendocrine Tumors of the Lung |
| title_fullStr | Targeting ALK in Neuroendocrine Tumors of the Lung |
| title_full_unstemmed | Targeting ALK in Neuroendocrine Tumors of the Lung |
| title_short | Targeting ALK in Neuroendocrine Tumors of the Lung |
| title_sort | targeting alk in neuroendocrine tumors of the lung |
| topic | ALK rearrangements neuroendocrine tumors of the lung large cell neuroendocrine carcinoma ALK inhibitors targeted treatment |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.911294/full |
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