Inflammatory Myofibroblastic Tumor: Diagnosis & Treatment

Inflammatory myofibroblastic tumor, or IMT, is a rare soft tissue growth with low to intermediate malignant potential that most often appears in the lungs, abdomen, or pelvis of children and young adults. Diagnosing it reliably depends on a combination of imaging, tissue biopsy, and molecular testing for specific gene fusions, while treatment centers on complete surgical removal whenever possible. For tumors that cannot be fully removed or that recur, targeted drugs matched to the tumor’s genetic profile have transformed outcomes over the past decade.

Where IMTs Grow and How They Present

IMTs can develop almost anywhere in the body, but they have strong site preferences. The lungs are the single most common location, followed by the abdomen, pelvis, and retroperitoneum (the space behind the abdominal cavity). A study of 84 extrapulmonary cases found that the abdomen, retroperitoneum, or pelvis accounted for the large majority, with the head and neck region and trunk making up most of the rest. Tumors ranged from about 1 cm to 17 cm, with an average around 6 cm, and abdominal masses tended to be the largest.¹ In the abdomen, the mesentery and omentum are frequent sites, and patients there often show up with a painless mass or signs of bowel obstruction.²

Symptoms depend heavily on where the tumor sits, but there is also a systemic inflammatory signature that crops up in many patients. Fever, anemia, elevated platelet counts, and high levels of immunoglobulins in the blood are common. Research has shown that interleukin-6 (IL-6), a signaling molecule involved in inflammation, is often the cytokine behind these symptoms, with IL-6 levels climbing higher during afternoon fever spikes than during fever-free mornings.³ These laboratory abnormalities can be confusing because they mimic infection or autoimmune disease, and sometimes a patient undergoes weeks of workup for fever of unknown origin before the real diagnosis surfaces.

The Gene Fusions Driving IMT

For decades, pathologists debated whether IMT was truly a tumor or just an exaggerated healing response. That debate was largely settled when researchers discovered recurrent chromosomal rearrangements, especially involving the ALK gene. Roughly half of conventional IMTs carry an ALK gene rearrangement, a fusion where part of the ALK gene gets spliced to another gene, producing an abnormal protein that drives cell growth. A molecular study of 62 IMTs found ALK rearrangements in 56% of cases, with the EML4-ALK fusion particularly common in lung and soft tissue tumors of young children.⁴ The ALK gene can fuse with a remarkably long list of partner genes, including LMNA, TPM3, TPM4, SEC31A, TFG, RANBP2, and CLTC, each producing a slightly different fusion protein.⁵

But ALK is not the only game in town. That same 62-case study found that 68% of all IMTs harbored some kind of kinase fusion when the net was cast wider.⁴ Among ALK-negative tumors, ROS1 rearrangements are the next most common find. A study of thoracic IMTs identified ROS1 rearrangements in six ALK-negative cases and ETV6-NTRK3 fusions in three others.⁶ RET fusions have also been documented, though they remain rare. Identifying which fusion a particular tumor carries matters enormously because it determines which targeted drug can be used if surgery alone is not enough.

Getting the Diagnosis Right

Under the microscope, IMT is a mix of spindle-shaped myofibroblastic cells and a heavy inflammatory infiltrate of lymphocytes and plasma cells. Pathologists typically start by staining the tissue for ALK protein. A positive ALK stain is a strong hint that the tumor carries an ALK fusion, but the testing rarely stops there. Fluorescence in situ hybridization (FISH), a technique that looks for gene rearrangements directly, is the standard next step. However, FISH has real blind spots in IMT. One study of uncommon ALK-positive IMTs found that over 90% showed equivocal FISH signals, meaning the results fell in a gray zone that was hard to call positive or negative. When those same cases were examined using targeted RNA sequencing, all but one were confirmed to harbor ALK fusions. RNA sequencing also caught an ALK fusion in a case that appeared outright FISH-negative, revealing a false-negative result from the older test.⁷ RNA sequencing can also detect ROS1 and other non-ALK fusions simultaneously, making it a particularly valuable tool when the initial results are ambiguous.

The evidence is pushing the field toward broader molecular profiling at the time of diagnosis rather than relying on a single test. Because the specific fusion gene dictates which targeted therapy could work, getting this information upfront saves time if the tumor ever recurs or proves unresectable.

Telling IMT Apart From IgG4-Related Disease

One of the trickiest diagnostic challenges is distinguishing IMT from IgG4-related disease, a condition where the immune system causes inflammation and fibrosis in various organs. Both can produce dense masses packed with plasma cells and scarring tissue, and both can show storiform (whorling) fibrosis under the microscope. A study of 36 IMTs found that about 40% had an IgG4-to-IgG plasma cell ratio in the range normally considered supportive of IgG4-related disease, meaning that ratio alone cannot reliably separate the two.⁸

A next-generation sequencing study of seven IMTs that closely mimicked IgG4-related disease illustrates how misleading the microscopy can be. All seven had dense plasma cell infiltrates, all showed storiform fibrosis, and all exceeded the 40% IgG4-to-IgG threshold. Yet four of them were ALK-positive on molecular testing, confirming they were genuine IMTs.⁹ The practical takeaway is that molecular testing for ALK and other kinase fusions, combined with clinical context such as patient age and tumor behavior, remains the most reliable way to clinch the diagnosis. A combination of plasma cell counts, presence of cellular atypia, IgG4 staining, and ALK status together gives the best discriminating power.¹⁰

Surgery Remains the Cornerstone

Complete surgical removal with clear margins, referred to in surgical shorthand as R0 resection, is the single most important factor determining long-term outcome. A study of pulmonary IMTs found that complete resection was the only factor significantly linked to both overall survival and disease-free survival.¹¹ A systematic review of pediatric IMTs confirmed the same pattern: positive tumor margins at the initial operation were a significant risk factor for both recurrence and death.¹² A separate single-center adult series reinforced that R0 resection was the strongest predictor of favorable outcomes.¹³

The challenge is that not every IMT can be removed cleanly. Tumors growing around vital structures in the abdomen, pelvis, or mediastinum sometimes force surgeons to leave microscopic or even visible disease behind. And even after what appears to be a complete resection, local recurrence is not rare. In abdominal IMTs the reported recurrence rate runs roughly 14% to 35%, influenced by factors like margin status, tumor location, and size.¹⁴ These numbers underscore why long-term follow-up matters. A typical surveillance schedule involves clinic visits every three months during the first year after surgery, then every six months from the second year onward.¹⁴

Targeted Therapies Matched to Fusion Type

When surgery cannot achieve clear margins, or when an IMT recurs after an initially successful operation, the tumor’s molecular profile becomes the roadmap for treatment. The clearest success story is the use of ALK inhibitors in ALK-rearranged IMT. A landmark report in the New England Journal of Medicine described a sustained partial response to crizotinib in a patient with ALK-translocated IMT, while a patient without the ALK fusion showed no benefit.¹⁵ Since then, case reports have documented complete responses, including one woman with recurrent retroperitoneal IMT who achieved a complete response on crizotinib after the tumor came back following surgery.¹⁶

In children and adolescents, crizotinib has been used as a bridge to make surgery possible or to avoid disfiguring operations. A series of six pediatric and adolescent patients with ALK-positive IMT reported that all responded to crizotinib, and five were able to stop therapy without recurrence after a median treatment duration of about one year.¹⁷ That ability to discontinue treatment and stay in remission is notable because many cancers treated with targeted drugs relapse as soon as the drug is stopped.

Resistance to ALK inhibitors does eventually develop in some patients. Second- and third-generation ALK inhibitors such as ceritinib, alectinib, and lorlatinib have each shown some ability to hold disease progression in check, but resistance has eventually emerged with each successive generation of drug.¹⁸ The field is still learning the best sequence of inhibitors and when to add other approaches.

Beyond ALK

For the roughly one-third of IMTs that lack ALK fusions altogether, other molecular targets are increasingly relevant. Crizotinib also has activity against ROS1, and case reports have documented responses in ROS1-rearranged IMTs. For tumors with NTRK fusions, the drugs entrectinib and larotrectinib are approved under a tumor-agnostic indication, meaning they can be prescribed for any solid tumor carrying the fusion, IMT included. And for the uncommon RET-rearranged IMTs, selpercatinib received U.S. approval in 2022 for solid tumors with RET fusions.¹⁹ The expanding menu of approved drugs means that even patients whose tumors lack ALK fusions now have realistic pharmacologic options, as long as their tumor’s fusion gene has been identified.

Anti-Inflammatory Drugs and Chemotherapy

Not every IMT patient needs or responds to kinase inhibitors. In cases where no targetable fusion is found, or when disease is limited and a lighter-touch option is preferred, anti-inflammatory medications have occasionally produced surprising results. A case report described complete remission of an ALK-negative pulmonary IMT after treatment with celecoxib, a COX-2 inhibitor, after corticosteroids had provided only a transient six-month response. A literature review accompanying that report identified ten patients across various body sites who had been successfully treated with nonsteroidal anti-inflammatory drugs.²⁰

Traditional chemotherapy is reserved for the most aggressive or refractory tumors. Regimens using methotrexate and cisplatin have been tried in unresectable cases. One patient with an aggressive abdominal IMT was successfully treated with postoperative chemotherapy combined with the NSAID diclofenac, with imaging afterward showing complete resolution of the mass.²¹ These remain anecdotal reports rather than proven regimens, so they are typically considered when targeted therapy and surgery are not feasible.

ALK-Negative Tumors Behave Differently

Although IMT as a whole carries a favorable outlook, ALK status appears to separate tumors into clinically distinct groups. A comparison of 59 IMTs spanning ages from 3 weeks to 74 years found that ALK-negative tumors occurred in older patients (mean age around 20 versus younger for ALK-positive cases) and showed more pronounced nuclear irregularity and atypical cell divisions under the microscope. Strikingly, all six cases with metastatic disease in that series were ALK-negative.²² This does not mean every ALK-negative IMT is dangerous, but it does mean the pathologist and oncologist pay extra attention to those tumors for signs of more aggressive behavior.

Epithelioid Inflammatory Myofibroblastic Sarcoma

At the far end of the aggressiveness spectrum sits epithelioid inflammatory myofibroblastic sarcoma, or EIMS, a rare variant that behaves more like a frank malignancy. EIMS typically presents in the abdominal cavity of children and young adults and is characterized by plump, rounded cells instead of the elongated spindle cells typical of conventional IMT. A hallmark under the microscope is a distinctive nuclear or perinuclear ALK staining pattern, usually tied to a RANBP2-ALK fusion.²³ EIMS tends to relapse early even when treated with crizotinib, setting it apart from conventional ALK-positive IMT.²⁴ Emerging research is exploring combination strategies, including targeting CD30, a surface marker that EIMS cells express, alongside ALK inhibition.²⁴ Recognizing EIMS at diagnosis is critical because it changes both the treatment plan and the expected prognosis.

Pregnancy-Associated IMTs

A small but growing number of reports describe IMTs arising in the uterus during pregnancy, and these appear to be biologically distinct from IMTs at other sites. In a series of pregnancy-associated cases, all tumors occurred alongside pregnancy complications such as preeclampsia, gestational diabetes, or abnormal placental implantation. Every tumor was either attached to the placenta or expelled as a detached tissue fragment at delivery or immediately afterward, and none of the cases with available follow-up experienced recurrence.²⁵ These tumors carry unique ALK fusion partners, such as TIMP3-ALK and THBS1-ALK, which are thought to involve extracellular matrix proteins and may explain why the tumor separates so readily from the uterine wall at delivery.²⁶

One case followed a patient for nearly five years after a placental IMT was found at delivery. She received no further treatment, went on to have a normal subsequent pregnancy, and ultimately had a hysterectomy by choice, which revealed no residual tumor at 59 months.²⁷ For patients who may otherwise be told they need a hysterectomy after a pregnancy-associated IMT, this kind of longer-term data is reassuring, though the numbers are still small. The current thinking is that these tumors are transient growths that develop during pregnancy and shed at delivery, carrying an excellent prognosis. They should be discussed with a specialist rather than assumed to behave like IMTs arising at other body sites.

1
PubMed. Extrapulmonary inflammatory myofibroblastic tumor (inflammatory pseudotumor): A clinicopathologic and immunohistochemical study of 84 cases
2
PubMed Central. Mesenteric inflammatory myofibroblastic tumors
3
PubMed. Time lag between the increase of IL-6 with fever and NF-kappaB activation in the peripheral blood in inflammatory myofibroblastic tumor
4
PubMed Central. Molecular characterization of inflammatory myofibroblastic tumors with frequent ALK and ROS1 gene fusions and rare novel RET rearrangement
5
Journal of Clinical Oncology. Potentially actionable kinase fusions in inflammatory myofibroblastic tumors
6
Journal of Thoracic Oncology. Expanding the Molecular Characterization of Thoracic Inflammatory Myofibroblastic Tumors beyond ALK Gene Rearrangements
7
PubMed. Assessment of ALK Fusions in Uncommon Inflammatory Myofibroblastic Tumors With ALK IHC Positivity but FISH-Equivocal Findings by Targeted RNA Sequencing
8
PubMed. IgG4 plasma cells in inflammatory myofibroblastic tumor: inflammatory marker or pathogenic link?
9
PubMed Central. Morphologic overlap between inflammatory myofibroblastic tumor and IgG4-related disease: lessons from next-generation sequencing
10
PubMed Central. Pulmonary inflammatory myofibroblastic tumor versus IgG4-related inflammatory pseudotumor: differential diagnosis based on a case series
11
PubMed Central. Surgical treatment outcomes of pulmonary inflammatory myofibroblastic tumors
12
European Journal of Surgical Oncology. Treatment and outcomes in pediatric inflammatory myofibroblastic tumors – A systematic review of published studies
13
Scientific Reports. Clinical characteristics and survival outcomes of adult inflammatory myofibroblastic tumor: a retrospective single-center study
14
PubMed Central. Clinical diagnosis and treatment of abdominal inflammatory myofibroblastic tumors
15
PubMed Central. Crizotinib in ALK-rearranged inflammatory myofibroblastic tumor
16
PubMed Central. Effectiveness of Crizotinib for Inflammatory Myofibroblastic Tumor with ALK mutation
17
PubMed Central. Crizotinib and Surgery for Long-Term Disease Control in Children and Adolescents With ALK-Positive Inflammatory Myofibroblastic Tumors
18
Journal of Oncology Pharmacy Practice. A case report: Pharmacology and resistance patterns of three generations of ALK inhibitors in metastatic inflammatory myofibroblastic sarcoma
19
Japanese Journal of Clinical Oncology. Inflammatory myofibroblastic tumors: recent progress and future of targeted therapy – Section: Targeted IMT treatments other than ALK inhibitors
20
PubMed Central. Complete remission of ALK-negative plasma cell granuloma (inflammatory myofibroblastic tumor) of the lung induced by celecoxib: A case report and review of the literature
21
PubMed Central. Inflammatory myofibroblastic tumor successfully treated with chemotherapy and nonsteroidals: a case report
22
The American Journal of Surgical Pathology. Inflammatory Myofibroblastic Tumor: Comparison of Clinicopathologic, Histologic, and Immunohistochemical Features Including ALK Expression in Atypical and Aggressive Cases
23
PubMed Central. Epithelioid Inflammatory Myofibroblastic Sarcoma: Case Series With a First Report of CLTC::ALK Fusion in an Aggressive Disease
24
PubMed Central. CD30 and ALK combination therapy has high therapeutic potency in RANBP2-ALK-rearranged epithelioid inflammatory myofibroblastic sarcoma
25
The American Journal of Surgical Pathology. Pregnancy-associated Inflammatory Myofibroblastic Tumors of the Uterus Are Clinically Distinct and Highly Enriched for TIMP3-ALK and THBS1-ALK Fusions
26
Human Pathology Reports. Placenta-associated uterine inflammatory myofibroblastic tumor with a novel FBLN1-ALK1 fusion
27
International Journal of Gynecological Pathology. Inflammatory Myofibroblastic Tumor of the Placenta With Subsequent Successful Pregnancy and Benign Hysterectomy: A Case Report With 59-Month Follow-up