Inflammatory Myofibroblastic Tumour

Not clinically relevant

IMTs are genetically heterogeneous. In 50–60% of cases of IMT in children and young adults, the tumors harbor clonal cytogenetic rearrangements, involving chromosome band 2p23, that fuse the 3′ kinase region of the ALK gene with various partner genes, including TPM3, TPM4, CLTC, CARS, ATIC, SEC31L1, PPFIBP1, DCTN1, EML4, PRKAR1A, LMNA, TFG, FN1, HNRNPA1, and others in a growing list. EIMS is often associated with RANBP2-ALK or RRBP1-ALK gene rearrangements. IMT with ALK genomic rearrangement features activation and overexpression of the ALK C-terminal kinase region, which is restricted to the neoplastic myofibroblastic component. ROS1 and NTRK3 gene rearrangements are each found in 5–10% of IMTs; TFG-ROS1, YWHAE-ROS1, and ETV6-NTRK3 gene fusions have been reported. Very rare cases have RET or PDGFRB gene rearrangements. In contrast, such rearrangements are uncommon in IMTs diagnosed in adults aged > 40 years.

IMT is a nodular, circumscribed, or multinodular mass with a tan, whorled, fleshy, or myxoid cut surface and variable hemorrhage, necrosis, and calcification. The diameter of the lesion ranges from 1 to 20 cm or more, with a median size of 5–6 cm.

The spindled fibroblastic-myofibroblastic cells and inflammatory cells form three basic histological patterns. The first is a myxoid pattern, which consists of loosely arranged plump or spindled myofibroblasts in an edematous myxoid background with abundant blood vessels and an infiltrate of plasma cells, lymphocytes, and eosinophils, mimicking granulation tissue or a reactive process. The second is a hypercellular pattern, which is characterized by a compact fascicular spindle cell proliferation with variable myxoid and collagenous stroma and inflammatory infiltrate. The third is a hypocellular fibrous pattern, which features hyalinized collagenous stroma with lower cellularity of spindle cells and a relatively sparse inflammatory infiltrate, mimicking desmoid fibromatosis. Dystrophic calcifications and osseous metaplasia are occasionally seen. One or more patterns are often seen within a single tumor. Myofibroblasts with vesicular nuclei, 1–3 small nucleoli, and eosinophilic cytoplasm are typical and sometimes show a ganglion-like appearance. Necrosis is uncommon. Mitotic activity varies but is generally low. EIMS is an aggressive IMT subtype with plump epithelioid or histiocytoid tumor cells with vesicular chromatin, prominent nucleoli, and amphophilic or eosinophilic cytoplasm, often admixed with neutrophils in an abundant myxoid stroma. By immunohistochemistry, IMT displays variable staining for SMA, MSA, calponin, and desmin. Focal keratin immunoreactivity can be seen in as many as 30% of cases. Immunoreactivity for ALK is detectable in 50–60% of cases and correlates well with the presence of ALK gene rearrangement. Of note, the ALK immunostaining pattern varies depending on the ALK fusion partner; for example, RANBP2-ALK is associated with a nuclear membranous pattern, RRBP1-ALK with a perinuclear accentuated cytoplasmic pattern, and CLTC-ALK with a granular cytoplasmic pattern; many other ALK fusion variants show a diffuse cytoplasmic pattern (most commonly seen in IMT). Highly sensitive ALK antibody clones (5A4, D5F3) may improve detection of the ALK protein in IMT. ROS1-rearranged IMT typically shows cytoplasmic expression of ROS1.

The cytology of IMT consists of bland spindle cells with oval nuclei and small distinct nucleoli in a background of lymphocytes and plasma cells. Atypical ganglion-like polygonal cells can be seen.

Approximately 25% of extrapulmonary IMTs recur, in part depending on anatomical site and resectability. ALK-negative IMTs may have a higher likelihood of metastasis, but ALK immunoreactivity does not appear to correlate with recurrence. Distant metastases are rare (< 5%) and involve the lungs, brain, liver, and bone. However, reliable prognostic indicators have not been developed for conventional IMT. Intra-abdominal EIMS behaves much more aggressively.

In addition to immunohistochemical detection of ALK protein, molecular assays for ALK may be used to confirm the diagnosis but are generally not required. Exceptional situations such as inversion of ALK on the same chromosome arm may lead to a false-negative FISH result. In ALK-negative cases, immunohistochemistry for ROS1 and/or molecular tests for non-ALK gene fusions (e.g. NTRK3) may be useful.

Essential: loose or compact fascicles of spindle cells with a prominent inflammatory infiltrate and a variable fibrous or myxoid stroma; expression of ALK (seen in as many as 60% of cases).

Desirable: ALK or other gene rearrangements (in selected cases).