Inflammatory myofibroblastic tumor of the mesentery with a SQSTM1::ALK fusion responding to alectinib

Abstract

Background: Inflammatory myofibroblastic tumor (IMT) is an ultra-rare soft tissue neoplasm associated with fusion proteins encompassing the anaplastic lymphoma kinase (ALK) protein fused to a variety of partner proteins. Data regarding response to ALK-targeting agents based on fusion partner is limited.

Case: A 30-year-old female sought emergency care after onset of abdominal and lower back pain in 2019. Computed tomography (CT) demonstrated a cystic, mesenteric mass within the pelvis measuring up to 8.9 cm. Complete laparoscopic excision of the mass from the mesentery of the right colon and terminal ileum was performed. Pathologic assessment revealed IMT with a fusion between sequestosome 1 and ALK (SQSTM1::ALK), described in only two other cases of IMT. Four months after surgery, CT revealed multi-focal, unresectable disease recurrence. She was referred to the University of Washington/Fred Hutchinson Cancer Center and placed on therapy with alectinib, after which she experienced a partial response. Three years after IMT recurrence, disease remains under control.

Conclusion: This is the third reported case of IMT associated with the novel SQSTM1::ALK fusion protein, and the second treated with alectinib. Treatment with the ALK inhibitor alectinib appears to be active in this setting.

Keywords: alectinib; anaplastic lymphoma kinase; inflammatory myofibroblastic tumor; sequestosome 1.

FIGURE 1

Computed tomography of the abdomen and pelvis. (A) Coronal images at time of diagnosis, demonstrating an 8.9 cm mesenteric mass. (B) Coronal images obtained 4 months after resection, with circles indicating sites of disease recurrence. (C) Axial image obtained 3 months after initiation of alectinib treatment. A 2 cm tumor mass is circled. (D) Axial image at similar level as that in image (C), obtained 14 months after initiation of alectinib treatment. The previously noted mass is now less than 1 cm maximal dimension.

FIGURE 2

Images obtained during complete laparoscopic resection. (A) Mesenteric mass in situ. (B) Mesentery after tumor and small bowel resection.

FIGURE 3

Histopathology of mesenteric mass obtained after resection. (A) Histologic appearance of the neoplasm demonstrating eosinophilic spindle cells with background mixed inflammatory infiltrate typical of inflammatory myofibroblastic tumor (H&E, 400×). (B) An area of the neoplasm demonstrating more epithelioid cells with greater nuclear pleomorphism within a somewhat myxocollagenous matrix. Mitotic figures, including an atypical tripolar mitosis, are present (H&E, 400×). (C) Immunohistochemical staining for ALK expression using a D5F3 antibody clone shows diffuse cytoplasmic expression (400×).

FIGURE 4

SQSTM1::ALK fusion identified by RNA‐seq. (A) The structures of SQSTM1 (blue boxes), ALK (gray boxes), and SQSTM1::ALK fusion transcript with their functional protein domains. SQSTM1::ALK fusion transcript has 3′ end of exon 5 of SQSTM1 fused (::) with 5′ end of exon 19 of ALK. Untranslated regions (5′ UTR and 3′ UTR) are shown as narrow bars. Exons are shown as boxes with numbers. The keys of protein domains are shown in the wider boxes behind exons with letters: for the domain structure of SQSTM1/p62 protein, KIR, Keap1‐interacting region; LB, LIM protein‐binding; LDL, low‐density lipoprotein receptor domain class A; LIR, LC3‐interacting region; MAM, meprin, A5 protein, and Mu domain; PB1, Phox and Bem1p; SP, signal peptide; TB, TRAF6‐binding domain; TM, transmembrane region; Tyr Kinase, tyrosine kinase domain; UBA, ubiquitin‐associated; for the domain structure of ALK protein; ZZ, Zinc finger. The blue lines and arrows indicate the breakpoints and fusion points. (B) Representative sequence reads over the breakpoints of the SQSTM1::ALK fusions by paired‐end RNA sequencing, including exon mapping of chimeric transcripts to the reference sequence at base resolution with amino acid translation in frame. Total BAM coverages of the breakpoints (~200 reads) were shown as gray bar scale. Examples of next‐generation sequencing reads over the breakpoints were shown in red bars (R1 reads) and blue bars (R2 reads).