Clinicopathologic and Genomic Characterization of Inflammatory Myofibroblastic Tumors of the Head and Neck

Inflammatory myofibroblastic tumor (IMT) is a distinctive fibroblastic and myofibroblastic spindle cell neoplasm with an accompanying inflammatory cell infiltrate and frequent receptor tyrosine kinase activation at the molecular level. The tumor may recur and rarely metastasizes. IMT is rare in the head and neck region, and limited information is available about its clinicopathologic and molecular characteristics in these subsites. Therefore, we analyzed a cohort of head and neck IMTs through a multi-institutional approach. Fourteen cases were included in the provisional cohort, but 1 was excluded after molecular analysis prompted reclassification. Patients in the final cohort included 7 males and 6 females, with a mean age of 26.5 years. Tumors were located in the larynx (n=7), oral cavity (n=3), pharynx (n=2), and mastoid (n=1). Histologically, all tumors showed neoplastic spindle cells in storiform to fascicular patterns with associated chronic inflammation, but the morphologic spectrum was wide, as is characteristic of IMT in other sites. An underlying fusion gene event was identified in 92% (n=11/12) of cases and an additional case was ALK-positive by IHC but could not be evaluated molecularly. ALK represented the driver in all but 1 case. Rearrangement of ALK, fused with the TIMP3 gene (n=6) was most commonly detected, followed by 1 case each of the following fusion gene partnerships: TPM3-ALK, KIF5B-ALK, CARS-ALK, THBS1-ALK, and a novel alteration, SLC12A2-ROS1. The excluded case was reclassified as spindle cell rhabdomyosarcoma after detection of a FUS-TFCP2 rearrangement and retrospective immunohistochemical confirmation of rhabdomyoblastic differentiation, illustrating an important diagnostic pitfall. Two IMT patients received targeted therapy with crizotinib, with a demonstrated radiographic response. One tumor recurred but none metastasized. These results add to the growing body of evidence that kinase fusions can be identified in the majority of IMTs and that molecular analysis can lead to increased diagnostic accuracy and broadened therapeutic options for patients.

[1]  Carmen Rodríguez-Jiménez,et al.  Novel SLC12A2‐ROS1 Fusion in Non‐Small Cell Lung Cancer with a Significant Response to Crizotinib: The Importance of Choosing the Appropriate Next‐Generation Sequencing Assay , 2021, The oncologist.

[2]  B. Wenig,et al.  The Most Common Mistake in Laryngeal Pathology and How to Avoid it , 2021, Head and Neck Pathology.

[3]  K. Perry,et al.  “Inflammatory Leiomyosarcoma” and “Histiocyte-rich Rhabdomyoblastic Tumor”: a clinicopathological, immunohistochemical and genetic study of 13 cases, with a proposal for reclassification as “Inflammatory Rhabdomyoblastic Tumor” , 2020, Modern Pathology.

[4]  D. Roberts,et al.  Inflammatory Myofibroblastic Tumors associated with the placenta, a series of 9 cases. , 2020, Human pathology.

[5]  L. Vaickus,et al.  Fine needle aspiration of an intranodal follicular dendritic cell sarcoma: A case report with molecular analysis and review of the literature , 2020, Diagnostic cytopathology.

[6]  Masayuki Yoshida,et al.  ALK-positive Histiocytosis of the Breast: A Clinicopathologic Study Highlighting Spindle Cell Histology. , 2020, The American journal of surgical pathology.

[7]  A. Folpe,et al.  Well-Differentiated/Dedifferentiated Liposarcoma Arising in the Upper Aerodigestive Tract: 8 Cases Mimicking Non-adipocytic Lesions , 2020, Head and Neck Pathology.

[8]  C. Kunder,et al.  Pregnancy-associated Inflammatory Myofibroblastic Tumors of the Uterus Are Clinically Distinct and Highly Enriched for TIMP3-ALK and THBS1-ALK Fusions , 2020, The American journal of surgical pathology.

[9]  B. Rubin,et al.  Inflammatory leiomyosarcoma shows frequent co-expression of smooth and skeletal muscle markers supporting a primitive myogenic phenotype: a report of 9 cases with a proposal for reclassification as low-grade inflammatory myogenic tumor , 2020, Virchows Archiv.

[10]  E. Imyanitov,et al.  Gene rearrangements in consecutive series of pediatric inflammatory myofibroblastic tumors , 2020, Pediatric blood & cancer.

[11]  A. Clayton,et al.  Uterine inflammatory Myofibroblastic tumors in pregnant women with and without involvement of the placenta: a study of six cases with identification of a novel TIMP3-RET fusion. , 2020, Human pathology.

[12]  S. Salas,et al.  A subset of epithelioid and spindle cell rhabdomyosarcomas is associated with TFCP2 fusions and common ALK upregulation , 2019, Modern Pathology.

[13]  Y. Oda,et al.  Vocal cord inflammatory myofibroblastic tumor with mucoid deposits harboring TIMP3–ALK fusion: A potential diagnostic pitfall , 2019, Pathology international.

[14]  F. Mertens,et al.  Gene fusion involving the insulin‐like growth factor 1 receptor in an ALK‐negative inflammatory myofibroblastic tumour , 2019, Histopathology.

[15]  S. Yuen,et al.  ALK-positive histiocytosis: an expanded clinicopathologic spectrum and frequent presence of KIF5B-ALK fusion , 2018, Modern Pathology.

[16]  L. Le,et al.  Morphologic Overlap Between Inflammatory Myofibroblastic Tumor and IgG4-related Disease: Lessons From Next-generation Sequencing , 2018, The American journal of surgical pathology.

[17]  M. Levy,et al.  A novel KIF5B-ALK fusion in a child with an atypical central nervous system inflammatory myofibroblastic tumour , 2018, BMJ Case Reports.

[18]  Asha A. Nair,et al.  Spindle cell rhabdomyosarcoma of bone with FUS–TFCP2 fusion: confirmation of a very recently described rhabdomyosarcoma subtype , 2018, Histopathology.

[19]  O. Delattre,et al.  Transcriptomic definition of molecular subgroups of small round cell sarcomas , 2018, The Journal of pathology.

[20]  H. Qin,et al.  ALK‐rearrangement in non‐small‐cell lung cancer (NSCLC) , 2018, Thoracic cancer.

[21]  E. Oliva,et al.  Inflammatory myofibroblastic tumor of the uterus: a clinicopathological, immunohistochemical, and molecular analysis of 13 cases highlighting their broad morphologic spectrum , 2017, Modern Pathology.

[22]  Y. Oda,et al.  ALK, ROS1 and NTRK3 gene rearrangements in inflammatory myofibroblastic tumours , 2016, Histopathology.

[23]  Gary K. Schwartz,et al.  Alternative transcription initiation leads to expression of a novel ALK isoform in cancer , 2015, Nature.

[24]  C. Antonescu,et al.  Molecular Characterization of Inflammatory Myofibroblastic Tumors With Frequent ALK and ROS1 Gene Fusions and Rare Novel RET Rearrangement , 2015, The American journal of surgical pathology.

[25]  Shuihong Zhou,et al.  Inflammatory myofibroblastic tumors of the head and nec. , 2015, International journal of clinical and experimental medicine.

[26]  P. Cin,et al.  Expression of ROS1 predicts ROS1 gene rearrangement in inflammatory myofibroblastic tumors , 2015, Modern Pathology.

[27]  Jeffrey W. Clark,et al.  Crizotinib in ROS1-rearranged non-small-cell lung cancer. , 2014, The New England journal of medicine.

[28]  P. Stephens,et al.  Inflammatory myofibroblastic tumors harbor multiple potentially actionable kinase fusions. , 2014, Cancer discovery.

[29]  R. Doebele,et al.  Molecular Pathways Molecular Pathways : ROS 1 Fusion Proteins in Cancer , 2013 .

[30]  F. Cappuzzo,et al.  Identifying and Targeting ROS1 Gene Fusions in Non–Small Cell Lung Cancer , 2012, Clinical Cancer Research.

[31]  Z. Tothova,et al.  Anaplastic lymphoma kinase-directed therapy in inflammatory myofibroblastic tumors , 2012, Current opinion in oncology.

[32]  Yuki Togashi,et al.  RET, ROS1 and ALK fusions in lung cancer , 2012, Nature Medicine.

[33]  Y. Ishikawa,et al.  Pulmonary Inflammatory Myofibroblastic Tumor Expressing a Novel Fusion, PPFIBP1–ALK: Reappraisal of Anti-ALK Immunohistochemistry as a Tool for Novel ALK Fusion Identification , 2011, Clinical Cancer Research.

[34]  Wei-Lien Wang,et al.  Epithelioid Inflammatory Myofibroblastic Sarcoma: An Aggressive Intra-abdominal Variant of Inflammatory Myofibroblastic Tumor With Nuclear Membrane or Perinuclear ALK , 2011, The American journal of surgical pathology.

[35]  Marc Ladanyi,et al.  Crizotinib in ALK-rearranged inflammatory myofibroblastic tumor. , 2010, The New England journal of medicine.

[36]  R. Kumar,et al.  Inflammatory myofibroblastic tumour , 2010, European Respiratory Journal.

[37]  Y. Ishikawa,et al.  KIF5B-ALK, a Novel Fusion Oncokinase Identified by an Immunohistochemistry-based Diagnostic System for ALK-positive Lung Cancer , 2009, Clinical Cancer Research.

[38]  J. Hornick,et al.  Inflammatory myofibroblastic tumours: where are we now? , 2007, Journal of Clinical Pathology.

[39]  C. Fletcher,et al.  Inflammatory Myofibroblastic Tumor: Comparison of Clinicopathologic, Histologic, and Immunohistochemical Features Including ALK Expression in Atypical and Aggressive Cases , 2007, The American journal of surgical pathology.

[40]  Y. Oda,et al.  Absence of human herpesvirus‐8 and Epstein–Barr virus in inflammatory myofibroblastic tumor with anaplastic large cell lymphoma kinase fusion gene , 2006, Pathology international.

[41]  W. Sanger,et al.  Expression of ALK1 and p80 in Inflammatory Myofibroblastic Tumor and Its Mesenchymal Mimics: A Study of 135 Cases , 2002, Modern Pathology.

[42]  P. Marynen,et al.  Identification of novel fusion partners of ALK, the anaplastic lymphoma kinase, in anaplastic large‐cell lymphoma and inflammatory myofibroblastic tumor , 2002, Genes, chromosomes & cancer.

[43]  S. Morris,et al.  Anaplastic Lymphoma Kinase (ALK) Expression in the Inflammatory Myofibroblastic Tumor: A Comparative Immunohistochemical Study , 2001, The American journal of surgical pathology.

[44]  S. Tripp,et al.  Are Myogenin and MyoD1 Expression Specific for Rhabdomyosarcoma?: A Study of 150 Cases, With Emphasis on Spindle Cell Mimics , 2001, The American journal of surgical pathology.

[45]  P. D. Dal Cin,et al.  TPM3-ALK and TPM4-ALK oncogenes in inflammatory myofibroblastic tumors. , 2000, The American journal of pathology.

[46]  Louis P. Dehner,et al.  Extrapulmonary Inflammatory Myofibroblastic Tumor (Inflammatory Pseudotumor) A Clinicopathologic and Immunohistochemical Study of 84 Cases , 1995, The American journal of surgical pathology.

[47]  F. Mertens,et al.  Inflammatory leiomyosarcoma is a distinct tumor characterized by near-haploidization, few somatic mutations, and a primitive myogenic gene expression signature , 2018, Modern Pathology.

[48]  Thomas R. Gingeras,et al.  STAR: ultrafast universal RNA-seq aligner , 2013, Bioinform..

[49]  I. Kazantseva,et al.  [Extrapulmonary inflammatory myofibroblastic tumor]. , 2001, Arkhiv patologii.