Morphologic Overlap Between Inflammatory Myofibroblastic Tumor and IgG4-related Disease

Abstract

Introduction: Inflammatory myofibroblastic tumor (IMT), a locally aggressive neoplasm capable of metastasis, may show an IgG4-rich lymphoplasmacytic infiltrate. Prior reports suggest that storiform-fibrosis and obliterative phlebitis aid in the distinction of IMT from IgG4-related diseases. Herein, we highlight the morphologic overlap between the two diseases, and emphasize the importance of a multiplex fusion assay in the distinction of IgG4-RD from IMT. Methods: We identified 7 IMTs with morphologic and immunohistochemical features of IgG4-RD; 3 patients were originally diagnosed with IgG4-RD. Demographic, clinical and morphologic data was recorded. We also re-evaluated 56 patients with IgG4-RD. We performed immunohistochemistry for IgG4, IgG, ALK and ROS1. In situ hybridization for IgG4 and IgG was performed in selected cases. A multiplex next-generation sequencing (NGS) based RNA assay for gene fusions was performed to detect all known IMT-related gene fusions. Results: All 7 IMTs showed a dense lymphoplasmacytic infiltrate and storiform-type fibrosis, with obliterative phlebitis noted in 3 cases. The neoplastic stromal cells constituted <5% of overall cellularity and stromal atypia was either absent or focal and mild. Elevated numbers of IgG4 positive cells and increased IgG4 to IgG ratio was identified in all cases. Four cases showed ALK related abnormalities; while two patients showed ROS1 and NTRK3 fusions. One tumor was negative for known IMT-related gene fusions. All 56 IgG4-RD cases were negative for ALK and ROS1 on immunohistochemistry; 6 cases were negative on the fusion assay. Conclusion: Highly-inflamed IMTs are indistinguishable from IgG4-RD both histologically and on immunohistochemistry for IgG4. We advocate scrutinizing patients with presumptive single organ IgG4-RD for IMT and the diagnostic algorithm should include ALK and ROS1 immunohistochemistry and, in selected cases, a NGS-based fusion assay that covers known IMTassociated gene fusions.

Needle Biopsy Compared With Surgical Biopsy: Pitfalls of Small Biopsy in Histologial Diagnosis of IgG4-related Disease

“…Even cases classi ed in the pathological category of insu cient IgG4-RD do not exclude the diagnosis thoroughly. For highly suggestive cases, the pathology criteria might not be infallible, either [19,20] . Potential reasons might include sampling artifact, the effects of previous therapy, and progression to a brotic stage, etc [3] .…”

The histological diagnosis of IgG4‐related disease on small biopsies: challenges and pitfalls

“…Inflammatory myofibroblastic tumour and multicentric Castleman disease are other conditions that show overlapping features with IgG4‐RD . Granulomatosis and polyangiitis and inflammatory myofibroblastic tumour may show storiform‐type fibrosis, and obliterative phlebitis has been observed in the latter neoplasm . Almost all of the aforementioned diseases can show elevated numbers of IgG4‐positive cells, although, with the exception of inflammatory myofibroblastic tumour and multicentric Castleman disease, an elevated IgG4/total IgG ratio is distinctly uncommon.…”

Malignant transformation of inflammatory myofibroblastic tumor of urinary bladder: A rare case scenario

“…In addition, several ALK fusion partners have been identified where ALK fusions arise from fusion of the 3' end of the ALK gene (exons 20-29) with the 5' region of a different gene such as TPM3, TPM4, CLTC, RANBP2, CARS, SEC1L1 and ATIC [7,8]. The ALK rearrangement by FISH can substantiate IHC findings although in rare case other none-ALK translocations such as TFG-ROS1 and ETV6-NTRK have also been identified [9]. Usually, ALK reactivity rules out other entities in the differential diagnosis for IMT.…”

“…One study found that a higher percentage of patients with localized disease were ALK-positive (about 60%) as compared to those without ALK-expression. Taylor et al (2019) demonstrated the utility of next generation sequencing especially for ALK negative IMT cases in patients where ROS1 and NTRK3 fusions especially for cases displaying morphological similarity to IgG4 related diseases [9].…”

“…Taylor et al . (2019) demonstrated the utility of next generation sequencing especially for ALK negative IMT cases in patients where ROS1 and NTRK3 fusions especially for cases displaying morphological similarity to IgG4 related diseases [ 9 ].…”