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.


| INTRODUCTION
Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal neoplasm predominantly found in children and young adults; in 75% of cases, the condition occurs in the abdominal cavity, such as the mesentery, omentum, and retroperitoneal space. 1 A variety of other sites may be affected, including head/neck, lungs, bladder, central nervous system, and ovaries/uterus. While patients may present with symptoms associated with mass effects from the primary tumor, IMT may also have a variety of vague and non-specific signs and symptoms, reflecting its "inflammatory" behavior, such as fevers, fatigue and weight loss. 1,2 Laboratory assessments may demonstrate an elevated erythrocyte sedimentation rate (ESR) or C-reactive protein, thrombocytosis, anemia, leukocytosis, and hypergammaglobulinemia, phenomena potentially related to paraneoplastic expression of interleukin-6. 2,3 First-line treatment for IMT is complete surgical resection, if possible, with the possibility of re-resection for local recurrence. No formal clinical trials of conventional cytotoxic therapies have been conducted in IMT; retrospective analyses demonstrate some responses, although no clear pattern of benefit. 4 Despite recognition of the condition decades ago, IMT was conflated with a benign, reactive process now known as inflammatory pseudotumor, which has no malignant potential. 1,5 Observation of recurrent translocations at 2p23 with identification of the anaplastic lymphoma kinase (ALK) gene in fusion proteins led to the recognition that IMT cases with these alterations have intermediate malignant potential. [6][7][8] Translocations involving ALK may be present in 50%-60% of IMT cases, although there is heterogeneity. 1,4,9 In cases with absent ALK protein expression or translocation, additional target genes, such as ROS1, NTRK, RET, and PDGFR-beta, have been identified. 9 In its native state, ALK is a transmembrane receptor tyrosine kinase that peaks in expression during the first 3 weeks of life. Its baseline physiologic role is poorly understood, with some animal models suggesting a role in fetal nervous system development. 10,11 A specific ligand for the receptor has not been identified. ALK activation leads to activity in several downstream pathways, including Janus kinase-signal transducer and activator of transcription, RAS-mitogen activated protein kinase, and the phosphoinositide-3-kinase-Aktmammalian target of rapamycin pathways.    Several observations suggested that this patient might be affected by a variant of epithelioid inflammatory myofibroblastic sarcoma (EIMS). [16][17][18] These findings included its mesenteric site of origin, rapid multi-focal recurrence after initial surgical treatment, and the focal epithelioid cytology with severe cytologic atypia and occasional atypical mitotic figures. EIMS is reported to have more aggressive clinical behavior, and has been associated, although not exclusively, with the RANBP2-ALK fusion protein. 16 A nuclear or peri-nuclear ALK IHC staining pattern, reported in association with the RNABP2 partner, was not present in our patient; its lack does not exclude the clinical diagnosis of EIMS.   Instead, an ALK fusion protein with an N-terminal derived from SQSTM1 was identified. This has been reported in two other cases of IMT. 9,15 In one patient, the primary tumor originated in the right subclavian region and progressed slowly over the course of 5 years until margin-negative resection. Multi-focal recurrent disease was identified 12 months later. This patient, similar to ours, received alectinib treatment with partial response and controlled disease after 12 months. This behavior was similar to that seen in our patient and suggests that the SQSTM1::ALK fusion is associated with a more aggressive clinical course. A second patient was reported to have this fusion and was treated for 4.2 months with crizotinib, achieving stable disease. 9 At present, crizotinib is the only drug approved by the US Food and Drug Administration for treatment of ALK-positive IMT. 19 Use of other ALK inhibitors for IMT is consistent with treatment recommendations from the National Comprehensive Cancer Network. 20 Alectinib has been compared directly to crizotinib in NSCLC. 21,22 In NSCLC, alectinib is associated with improved progression-free survival and better safety/tolerability than crizotinib. Alectinib has additional theoretical advantages, including activity against ALK mutants selected during crizotinib therapy. 14  SQSTM1 encodes a highly conserved 62 kDa protein (also known as p62) which exerts effects as a main regulator of multiple signaling pathways, including Nrf2, mTORC1, and NF-κB. 30 It has been associated with a variety of malignancies, and non-malignant conditions, including Paget's disease of bone, amyotrophic lateral sclerosis, and steatohepatitis and alcoholic hepatitis. Studies of the SQSTM1::ALK fusion protein in B-cell lymphoma have suggested that the STAT3 pathway may be a viable therapeutic target. 24 As early as 2002, it was suggested that therapeutic strategies targeting ALK and its downstream effectors, including STAT3, might represent effective approaches in ALK-driven malignancies. 31 A recent pre-clinical report identified synergistic activity against ALK-fusion-dependent H2228 cells when the orally bioavailable STAT3 inhibitor YHO-1701 was used in combination with alectinib. 32 STAT3 also has a complex relationship with endogenous SQSTM1. The addition of quercetin, a STAT3-inhibiting flavonoid, leads to decreased accumulation and activity of SQSTM1 and decreased Epstein Barr virusmediated B cell immortalization. 33 It would be worth exploring whether such a combination ALK/STAT3-inhibitor strategy may be applicable in IMT.

| CASE
In conclusion, we report a patient with IMT associated with an SQSTM1::ALK fusion protein, which has been reported in only two other cases. As in one of the prior patients, the disease has responded to treatment with alectinib, and continues to do so 3 years after diagnosis of recurrent disease. This provides evidence of the utility of this therapy in this clinical setting, and potentially in other malignancies in which this rare, but recurrent fusion protein target is found.

CONFLICT OF INTEREST STATEMENT
The authors have stated explicitly that there are no conflicts of interest in connection with this article.

DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no new data were created or analyzed in this study.

ETHICS STATEMENT
The reporting of this case does not meet the definition of "research" according to 45 CFR 46.102d. Approval by Human Subjects Protection is not required. Written informed consent was obtained directly from the patient for the publication of case details and use of images.
All activities were consistent with the Declaration of Helsinki. Work submitted has been performed according to Wiley's Publication Ethics Guidelines with no data fabrication or misconduct.