Recurrent Inflammatory Myofibroblastic Tumor of Larynx Harboring a Novel THBS1::ALK Fusion

Abstract

Inflammatory myofibroblastic tumor (IMT) is a rare soft tissue tumor primarily occurring in the abdominopelvic region of young patients, and it is characterized by spindle-shaped myofibroblasts, or fibroblasts surrounded by inflammatory infiltrate. Herein, we report a case of a 24-year-old male with a firm submucosal mass in the anterior right vocal fold diagnosed as an IMT that recurred 14 months later. The tumor demonstrated a novel THBS1::ALK fusion containing Exons 1-7 of the thrombospondin 1 (THBS1) gene fused to Exon 19 of the anaplastic lymphoma kinase (ALK) gene via next-generation sequencing with the NextSeq sequencer. The fusion of THBS1 to ALK potentially results in increased expression and constitutive activation of the ALK kinase domain. These findings not only broaden the repertoire of known ALK fusion partners implicated in tumorigenesis but also provide a novel avenue for investigating the etiology of recurrent IMT by considering this fusion event as a causal factor. To our knowledge, this is the second case of IMT of the larynx with this novel mutation reported in the literature and the first such case with a detailed description of this specific fusion and clinical recurrence.

Keywords: ALK fusion; IMT; Inflammatory myofibroblastic tumor; THBS1; larynx.

Figure 1

Timeline of events from initial presentation to present.

Figure 2

(a) Section showing benign squamous mucosa with rare inflammatory cells. Beneath squamous mucosa, fascicles of spindle cells are present (haematoxylin and eosin stain, magnification ×200). (b) Microscopic sections show a dense spindle cell proliferation associated with acute inflammatory (arrow) and lymphoplasmacytic infiltrate (haematoxylin and eosin stain ×400). (c) The spindle cells show diffuse cytoplasmic granular staining for anaplastic lymphoma kinase-1 (ALK1), (immunohistochemistry staining ×400). (d) The spindle cells show focal staining for alpha-smooth muscle actin (SMA) (immunohistochemistry staining ×400).

Figure 3

(a) G-banding ideograms of Chromosomes 2 and 15. The location of the THBS1 and ALK genes on respective chromosomes. Molecular characterization of FFPE sample from the larynx, right vocal fold mass. (b) NGS revealed an in-frame novel THBS1-ALK fusion with 5′ partner (Exons 1–7) of THBS1 and 3′ (Exons 19–29) of ALK. VWC, von Willebrand factor type C domain (318-372); TSP_1, thrombospondin Type 1 domain (383-428); EGF, calcium-binding EGF domain (588-625); TSP_3, thrombospondin Type 3 repeat (727-762); TSP_C, thrombospondin C-terminal region (972-1169); MAM-MAM domain, meprin/A5/mu (285-426); Gly_rich, glycine rich protein (733-960); Pkinase_Tyr, protein tyrosine kinase (1117-1382).