We describe two poorly differentiated, non-myofibroblastic (SMA−, S100+, CD34±), spindle cell neoplasms with immunohistochemical positivity for ALK and with ALK gene rearrangements leading to PLEKHH2::ALK and CLTC::ALK fusions, respectively. ALK protein overexpression and/or gene fusions should be evaluated in poorly differentiated spindle cell neoplasms, even when there is an absence of a myofibroblastic phenotype. A positive ALK evaluation has therapeutic implications as both tumors responded to single-agent treatment with the tyrosine kinase inhibitor crizotinib.
GabbianiG. The myofibroblast in wound healing and fibrocontractive diseases. J Pathol. 2003;200(4):500‐503. doi:10.1002/path.1427
2.
MartinJMidgleyAMeranS, et al.Tumor necrosis factor-stimulated gene 6 (TSG-6)-mediated interactions with the inter-alpha-inhibitor heavy chain 5 facilitate tumor growth factor beta1 (TGFbeta1)-dependent fibroblast to myofibroblast differentiation. J Biol Chem. 2016;291(26):13789‐13801. doi:10.1074/jbc.M115.670521
3.
MidgleyACRogersMHallettMB, et al.Transforming growth factor-beta1 (TGF-beta1)-stimulated fibroblast to myofibroblast differentiation is mediated by hyaluronan (HA)-facilitated epidermal growth factor receptor (EGFR) and CD44 co-localization in lipid rafts. J Biol Chem. 2013;288(21):14824‐14838. doi:10.1074/jbc.M113.451336
4.
TomasekJJGabbianiGHinzBChaponnierCBrownRA. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol. 2002;3(5):349‐363. doi:10.1038/nrm809
5.
BaranovEHornickJL. Soft tissue special issue: fibroblastic and myofibroblastic neoplasms of the head and neck. Head Neck Pathol. 2020;14(1):43‐58. doi:10.1007/s12105-019-01104-3
6.
CoffinCMHornickJLFletcherCD. Inflammatory myofibroblastic tumor: comparison of clinicopathologic, histologic, and immunohistochemical features including ALK expression in atypical and aggressive cases. Am J Surg Pathol. 2007;31(4):509‐520. doi:10.1097/01.pas.0000213393.57322.c7
7.
CoffinCMHumphreyPADehnerLP. Extrapulmonary inflammatory myofibroblastic tumor: a clinical and pathological survey. Semin Diagn Pathol. 1998;15(2):85‐101.
8.
CoffinCMWattersonJPriestJRDehnerLP. Extrapulmonary inflammatory myofibroblastic tumor (inflammatory pseudotumor). A clinicopathologic and immunohistochemical study of 84 cases. Am J Surg Pathol. 1995;19(8):859‐872. doi:10.1097/00000478-199508000-00001
9.
DavisJLRudzinskiER. Pediatric and infantile fibroblastic/myofibroblastic tumors in the molecular era. Surg Pathol Clin. 2020;13(4):739‐762. doi:10.1016/j.path.2020.08.009
10.
GleasonBCHornickJL. Inflammatory myofibroblastic tumours: where are we now?J Clin Pathol. 2008;61(4):428‐437. doi:10.1136/jcp.2007.049387
11.
HornickJL. Myofibroblastic tumors in children. Surg Pathol Clin. 2010;3(3):653‐688. doi:10.1016/j.path.2010.06.004
12.
YamamotoHYoshidaATaguchiK, et al.ALK, ROS1 and NTRK3 gene rearrangements in inflammatory myofibroblastic tumours. Histopathology. 2016;69(1):72‐83. doi:10.1111/his.12910
13.
AntonescuCRSuurmeijerAJZhangL, et al.Molecular characterization of inflammatory myofibroblastic tumors with frequent ALK and ROS1 gene fusions and rare novel RET rearrangement. Am J Surg Pathol. 2015;39(7):957‐967. doi:10.1097/PAS.0000000000000404
14.
LovlyCMGuptaALipsonD, et al.Inflammatory myofibroblastic tumors harbor multiple potentially actionable kinase fusions. Cancer Discov. 2014;4(8):889‐895. doi:10.1158/2159-8290.CD-14-0377
15.
TheilenTMSoerensenJBochennekK, et al.Crizotinib in ALK(+) inflammatory myofibroblastic tumors-current experience and future perspectives. Pediatr Blood Cancer. 2018;65(4):e26920. doi:10.1002/pbc.26920
16.
PearsonADJBarryEMosseYP, et al.Second paediatric strategy forum for anaplastic lymphoma kinase (ALK) inhibition in paediatric malignancies: ACCELERATE in collaboration with the European medicines agency with the participation of the food and drug administration. Eur J Cancer. 2021;157:198‐213. doi:10.1016/j.ejca.2021.08.022
17.
WuJHuYAbdihamidOHuangGXiaoSLiB. Crizotinib in sarcomatous malignancies harboring ALK fusion with a definitive partner(s): response and efficacy. Front Oncol. 2021;11:684865. doi:10.3389/fonc.2021.684865
18.
RyserCODieboldJGautschiO. Treatment of anaplastic lymphoma kinase-positive non-small cell lung cancer: update and perspectives. Curr Opin Oncol. 2019;31(1):8‐12. doi:10.1097/CCO.0000000000000494
19.
KempsPGPicarsicJDurhamBH, et al.ALK+ histiocytosis: a new clinicopathologic spectrum highlighting neurologic involvement and responses to ALK inhibition. Blood. 2022;139(2):256‐280. doi:10.1182/blood.2021013338
20.
ArganiP. Translocation carcinomas of the kidney. Genes Chromosomes Cancer. 2021. Epub ahead of print. doi:10.1002/gcc.23007
21.
KazlouskayaVHoJJedrychJKarunamurthyA. Spindle cell variant of epithelioid cell histiocytoma (spindle cell histiocytoma) with ALK gene fusions: cases series and review of the literature. J Cutan Pathol. 2021;48(7):837‐841. doi:10.1111/cup.13923
22.
FeltyCCLinosK. Epithelioid fibrous histiocytoma: a concise review. Am J Dermatopathol. 2019;41(12):879‐883. doi:10.1097/DAD.0000000000001272
23.
NagasakaMFisherAChowdhuryTGeYSukariA. PLEKHH2-ALK: a novel in-frame fusion with durable response to alectinib: utilizing RNA sequencing in search for hidden gene fusions susceptible to targeted therapy. Clin Lung Cancer. 2021;22(1):e51‐e53. doi:10.1016/j.cllc.2020.07.017
24.
GarciaRPatelNUddinNParkJY. Development and clinical validation of a multiplex gene fusion assay. Lab Med. 2020;51(5):512‐518. doi:10.1093/labmed/lmz102
25.
HisaokaMShimajiriSMatsukiY, et al.Inflammatory myofibroblastic tumor with predominant anaplastic lymphoma kinase-positive cells lacking a myofibroblastic phenotype. Pathol Int. 2003;53(6):376‐381. doi:10.1046/j.1440-1827.2003.01484.x
26.
SuurmeijerAJDicksonBCSwansonD, et al.The histologic spectrum of soft tissue spindle cell tumors with NTRK3 gene rearrangements. Genes Chromosomes Cancer. 2019;58(11):739‐746. doi:10.1002/gcc.22767
27.
SuurmeijerAJHDicksonBCSwansonD, et al.A novel group of spindle cell tumors defined by S100 and CD34 co-expression shows recurrent fusions involving RAF1, BRAF, and NTRK1/2 genes. Genes Chromosomes Cancer. 2018;57(12):611‐621. doi:10.1002/gcc.22671
28.
AntonescuCR. Emerging soft tissue tumors with kinase fusions: an overview of the recent literature with an emphasis on diagnostic criteria. Genes Chromosomes Cancer. 2020;59(8):437‐444. doi:10.1002/gcc.22846
29.
AntonescuCRDicksonBCSwansonD, et al.Spindle cell tumors with RET gene fusions exhibit a morphologic spectrum akin to tumors with NTRK gene fusions. Am J Surg Pathol. 2019;43(10):1384‐1391. doi:10.1097/PAS.0000000000001297
30.
DrilonALaetschTWKummarS, et al.Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med. 2018;378(8):731‐739. doi:10.1056/NEJMoa1714448
31.
OrtizMVGerdemannURajuSG, et al.Activity of the highly specific RET inhibitor selpercatinib (LOXO-292) in pediatric patients with tumors harboring RET gene alterations. JCO Precis Oncol. 2020;4:341‐347. doi:10.1200/PO.19.00401
32.
MosseYPVossSDLimMS, et al.Targeting ALK with crizotinib in pediatric anaplastic large cell lymphoma and inflammatory myofibroblastic tumor: a children’s oncology group study. J Clin Oncol. 2017;35(28):3215‐3221. doi:10.1200/JCO.2017.73.4830
33.
HongDSDuBoisSGKummarS, et al.Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials. Lancet Oncol. 2020;21(4):531‐540. doi:10.1016/S1470-2045(19)30856-3
34.
PreobrazhenskayaEVIyevlevaAGSuleymanovaAM, et al.Gene rearrangements in consecutive series of pediatric inflammatory myofibroblastic tumors. Pediatr Blood Cancer. 2020;67(5):e28220. doi:10.1002/pbc.28220
35.
TokudaKEguchi-IshimaeMYagiC, et al.CLTC-ALK fusion as a primary event in congenital blastic plasmacytoid dendritic cell neoplasm. Genes Chromosomes Cancer. 2014;53(1):78‐89. doi:10.1002/gcc.22119
36.
WangWYGuLLiuWPLiGDLiuHJMaZG. ALK-positive extramedullary plasmacytoma with expression of the CLTC-ALK fusion transcript. Pathol Res Pract. 2011;207(9):587‐591. doi:10.1016/j.prp.2011.07.001
37.
PatelASMurphyKMHawkinsAL, et al.RANBP2 And CLTC are involved in ALK rearrangements in inflammatory myofibroblastic tumors. Cancer Genet Cytogenet. 2007;176(2):107‐114. doi:10.1016/j.cancergencyto.2007.04.004
38.
GascoyneRDLamantLMartin-SuberoJI, et al.ALK-positive diffuse large B-cell lymphoma is associated with clathrin-ALK rearrangements: report of 6 cases. Blood. 2003;102(7):2568‐2573. doi:10.1182/blood-2003-03-0786
39.
De PaepePBaensMvan KriekenH, et al.ALK Activation by the CLTC-ALK fusion is a recurrent event in large B-cell lymphoma. Blood. 2003;102(7):2638‐2641. doi:10.1182/blood-2003-04-1050
40.
CoolsJWlodarskaISomersR, et al.Identification of novel fusion partners of ALK, the anaplastic lymphoma kinase, in anaplastic large-cell lymphoma and inflammatory myofibroblastic tumor. Genes Chromosomes Cancer. 2002;34(4):354‐362. doi:10.1002/gcc.10033
41.
BridgeJAKanamoriMMaZ, et al.Fusion of the ALK gene to the clathrin heavy chain gene, CLTC, in inflammatory myofibroblastic tumor. Am J Pathol. 2001;159(2):411‐415. doi:10.1016/S0002-9440(10)61711-7
42.
LorenziLCigognettiMMedicinaD, et al.ALK-positive inflammatory myofibroblastic tumor of the abdomen with widespread microscopic multifocality. Int J Surg Pathol. 2014;22(7):640‐644. doi:10.1177/1066896914525232
43.
DodgeGRKovalszkyIMcBrideOW, et al.Human clathrin heavy chain (CLTC): partial molecular cloning, expression, and mapping of the gene to human chromosome 17q11-qter. Genomics. 1991;11(1):174‐178. doi:10.1016/0888-7543(91)90115-u
44.
PatrakkaJXiaoZNukuiM, et al.Expression and subcellular distribution of novel glomerulus-associated proteins dendrin, ehd3, sh2d4a, plekhh2, and 2310066E14Rik. J Am Soc Nephrol. 2007;18(3):689‐697. doi:10.1681/ASN.2006060675
45.
PalmirottaRQuaresminiDLoveroDSilvestrisF. ALK Gene alterations in cancer: biological aspects and therapeutic implications. Pharmacogenomics. 2017;18(3):277‐292. doi:10.2217/pgs-2016-0166
46.
CaoZGaoQFuMNiNPeiYOuWB. Anaplastic lymphoma kinase fusions: roles in cancer and therapeutic perspectives. Oncol Lett. 2019;17(2):2020‐2030. doi:10.3892/ol.2018.9856
47.
HeyerEEDevesonIWWooiD, et al.Diagnosis of fusion genes using targeted RNA sequencing. Nat Commun. 2019;10(1):1388. doi:10.1038/s41467-019-09374-9
48.
StichelDSchrimpfDCasaliniB, et al.Routine RNA sequencing of formalin-fixed paraffin-embedded specimens in neuropathology diagnostics identifies diagnostically and therapeutically relevant gene fusions. Acta Neuropathol. 2019;138(5):827‐835. doi:10.1007/s00401-019-02039-3
49.
KhaterFVairySLangloisS, et al.Molecular profiling of hard-to-treat childhood and adolescent cancers. JAMA Netw Open. 2019;2(4):e192906. doi:10.1001/jamanetworkopen.2019.2906
50.
ForrestSJGeoergerBJanewayKA. Precision medicine in pediatric oncology. Curr Opin Pediatr. 2018;30(1):17‐24. doi:10.1097/MOP.0000000000000570
51.
SeibelNLJanewayKAllenCE, et al.Pediatric oncology enters an era of precision medicine. Curr Probl Cancer. 2017;41(3):194‐200. doi:10.1016/j.currproblcancer.2017.01.002
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
