Inflammatory Myofibroblastic Tumor

Inflammatory myofibroblastic tumor is a rare neoplasm characterized by the growth of specialized cells interspersed with inflammatory cells, occurring most commonly in children and young adults, particularly in the lungs, abdomen, and retroperitoneum.

Table of contents

• What Is Inflammatory Myofibroblastic Tumor?
• How Common Is This Tumor?
• Who Gets Inflammatory Myofibroblastic Tumor?
• Where Does This Tumor Occur?
• Signs and Symptoms
• How Is It Diagnosed?
• Molecular and Genetic Features
• Treatment Options
• Prognosis and Outlook
• Alternative Names

What Is Inflammatory Myofibroblastic Tumor?

Inflammatory myofibroblastic tumor (IMT) is a distinctive neoplasm with limited metastatic potential, meaning it rarely spreads to distant parts of the body. The tumor is characterized by the proliferation of myofibroblastic and fibroblastic spindle cells, which are specialized cells that are longer than wide and help maintain the structure of organs and heal wounds. These cells are accompanied by a dense inflammatory infiltrate primarily composed of plasma cells, lymphocytes, and eosinophils, which are types of white blood cells^[1][2].

IMT is named for two types of cells in the tumor. It forms from cells called myofibroblasts and also contains many immune cells, making the tumor look “inflamed” like an infection^[12]. This is why the word “inflammatory” is part of its name.

The World Health Organization, in 2020, reclassified IMT as a specific tumor form in the category of intermediate (rarely metastasizing) fibroblastic and myofibroblastic tumors^[2]. This means that while IMT is usually benign (not cancer), it can invade nearby tissue and cause problems. In very rare cases, IMT can spread to distant organs^[12].

How Common Is This Tumor?

Inflammatory myofibroblastic tumor is very rare. An estimated 150 to 200 people are diagnosed with IMT annually in the United States^[2][12]. It occurs in less than one in one million people^[12]. IMT accounts for between 16% and 38% of lung tumors in children in various studies, making it one of the most frequent lung tumors in pediatric patients^[10].

Who Gets Inflammatory Myofibroblastic Tumor?

IMT predominantly occurs in children and young adults^[1][3]. It was initially regarded as a tumor that most often developed in young populations^[2]. However, IMT can arise at any age^[11][12]. There is no sex-specific difference in incidence, meaning it affects males and females equally^[9].

Where Does This Tumor Occur?

IMT can arise in various anatomical locations but most commonly occurs in the abdominal cavity, retroperitoneum, and lung^[1]. The lungs are the most commonly involved organs^[10]. When occurring in the lungs, IMT typically presents with a large, peripherally located lobulated mass with a lower lobe predominance^[10].

IMT may also begin in many other sites throughout the body, including the bladder, uterus, larynx, stomach, liver, intestine, mesentery, greater omentum, heart, spleen, pancreas, colon, small intestine, spermatic cord, prostate, eye orbit, peripheral or central nervous system nerves, brain meninges, spinal cord, or other locations^[2][12]. IMT forms in tissues called mucosal surfaces and mesentery, which are found in the eyes, nose, mouth, digestive tract, lungs, and genital and urinary tracts^[12].

• Lung
• Abdominal cavity
• Retroperitoneum
• Bladder
• Uterus
• Liver
• Stomach
• Intestine
• Heart
• Spleen
• Pancreas

Signs and Symptoms

Although IMT can cause specific symptoms, some people with IMT do not have any symptoms at all. IMT is often discovered during routine health checkups because patients can be entirely asymptomatic until the tumor has grown to a size that can cause complications^[1].

The type and severity of symptoms presented by patients with IMT mainly depend on where the tumor is located and its size^[1][12]. Common presenting symptoms include:

• Fever, night sweats, and general malaise (not feeling well)^[3][12]
• Weight loss and fatigue^[1]
• Pain at the site of the tumor^[12]
• Respiratory symptoms such as cough, dyspnea (difficulty breathing), or chest pain when the tumor affects the lungs^[15]
• Abdominal pain when the tumor is located in the abdomen^[7]

In some cases, the presentation may be similar to a respiratory tract infection, asthma, or may appear like malignancy-associated constitutional symptoms^[15]. When IMT develops within the airways, it can cause blockage leading to atelectasis or obstructive pneumonia^[15].

How Is It Diagnosed?

Diagnosing IMT requires several steps because it can look like other tumors or infections and can be hard to identify^[12].

Imaging studies: If you have symptoms of IMT, your doctor will use imaging scans to determine where the tumor is in the body and its size. These may include computed tomography (CT), ultrasound, or magnetic resonance imaging (MRI)^[12]. On CT scans, IMT typically shows a solitary, sharply circumscribed and lobulated mass^[15]. The appearance of IMTs on imaging studies is variable and non-specific. Enhancement is heterogeneous on contrast-enhanced CT^[10].

Positron emission tomography (PET): IMTs demonstrate variably intense uptake on 18-FDG PET scans depending on their pathological properties such as cellularity, proliferative index, and the amount of plasma cell infiltrates^[15]. This can make the picture perplexing, as surgeons can neither propose nor oppose the possibility of malignancy based on radiological features alone^[15].

Biopsy: To check if the tumor is IMT, your doctor will perform a biopsy, taking a small sample from the tumor with a needle^[12]. This can be done through bronchoscopy for lung lesions or through CT-guided percutaneous biopsy^[9]. A pathologist will study the cells from the sample under the microscope to see what kind of tumor it is^[12]. However, there is no strong evidence to suggest that bronchoscopic or percutaneous needle biopsy can confidently diagnose or exclude malignancy, as the appearance of spindle cells in tiny specimens usually does not point towards IMTs unless a representative sampling and analysis can be performed^[15].

Molecular diagnostics: Molecular diagnostics are techniques used to identify a disease by studying molecules, such as proteins, DNA, and RNA, in a tissue or fluid. Your doctor will test your biopsy sample for markers that show whether it is IMT. This helps them decide which treatment is best for you^[12]. Testing for specific genetic abnormalities such as ALK gene rearrangement is particularly important^[3].

Molecular and Genetic Features

Recent molecular diagnostic techniques have led to the identification of genetic abnormalities in tumor tissue. The ALK locus (anaplastic lymphoma kinase), located on chromosome 2p23, is rearranged in approximately 50% of IMT cases^[10]. Some studies report ALK gene rearrangement and ROS1 gene fusions in more than 90% of children with IMT^[3]. ALK rearrangements can involve various different genes^[10].

Other potentially targetable fusions have been reported in a smaller fraction of IMTs, including ROS1, NTRK3, RET, and PDGFRB fusions^[10][11]. In some cases of IMT, chromosomes (the structures in cells that contain all genes) break apart and get put back together in the wrong way. This can cause cells to not function properly^[12].

It is not clear whether inflammation, genetic abnormalities, or both contribute to the development of IMT, but drugs blocking the activities of the fusion proteins made by these genetic abnormalities may be useful in treating the disease^[2].

Treatment Options

Treatment of IMT depends on where the tumor is located, which proteins it makes, and whether it has spread to other parts of the body^[12].

Surgery: Complete surgical excision is the treatment of choice for IMT^[3][10]. If possible, surgical resection is the preferred approach. Patients with completely resected tumors have an excellent prognosis^[10]. However, IMTs are hard to completely remove by surgery and often come back. It is important to follow up with your doctor to check if the tumor has returned^[12].

Chemotherapy: If the IMT is faster growing or has returned after surgery, your doctor may use chemotherapy to treat it^[12]. In patients with unresectable or metastatic tumors, chemotherapy has been used in the past^[3]. Chemotherapy regimens result in an overall response rate of approximately 50% based on retrospective data^[5]. The use of methotrexate and cisplatin for aggressive myofibroblastic tumors has been reported^[7].

Non-steroidal anti-inflammatory drugs (NSAIDs): Non-steroidal anti-inflammatory drugs have been used in the past for some patients^[3]. There have been case reports of successful treatment with postoperative chemotherapy and oral diclofenac sodium^[7]. In rare cases, short-term oral steroid treatment has shown efficacy, with tumors shrinking in size after administration^[9].

Targeted therapy: Some IMTs make proteins that can be targeted by new drugs. Depending on how well your IMT is removed by surgery, your doctor may try one of these targeted therapies^[12]. Novel therapeutic agents targeting genetic abnormalities such as crizotinib have shown promising activity against IMTs^[3].

Crizotinib, a first-generation ALK tyrosine kinase inhibitor (TKI), was officially approved by the U.S. Food and Drug Administration in 2020 to treat unresectable ALK-positive IMT^[8]. Patients with unresectable or recurrent tumors may respond to crizotinib if the ALK variant is present^[10]. Treatment with ceritinib and entrectinib have also produced objective responses^[10]. Other ALK-TKIs, such as alectinib, brigatinib, and lorlatinib, have proven their efficacy on ALK-positive IMT with sporadic case reports^[8]. Ceritinib has been administered to patients with YWHAE-ROS fusion, resulting in more than 90% reduction in tumor volume^[11].

Prognosis and Outlook

The prognosis for IMT is generally favorable but is affected by the anatomical location of tumors and the feasibility of complete surgical resection^[1]. IMT typically demonstrates local invasion or recurrence, whereas metastasis is rare^[1].

IMT has a recurrence rate of approximately 25%, but this is highly dependent on the IMT location^[8]. Studies have reported higher recurrence rates in lesions located in the abdominal space when the tumor size is greater than 8 cm^[8]. Younger age, larger tumors, and detection at abdominopelvic and pulmonary sites were indicative of higher metastatic potential^[8].

Distant metastasis has occurred in approximately 5% of cases^[8]. In one study evaluating metastatic potential, among 59 documented cases, metastasis was restricted to six ALK-negative IMT cases (10.2%), whereas none of the ALK-positive IMT cases exhibited metastasis^[8].

In one pediatric study, the five-year overall survival and event-free survival rates for the cohort were 85.7% and 72.9%, respectively^[11]. Tumor size and patient age are considered prognostic factors; in younger patients or in patients with tumor sizes less than 6.5 cm, survival rates tend to be better^[8].

Alternative Names

inflammatory pseudotumor, plasma cell granuloma, plasma cell pseudotumor, inflammatory myofibrohistiocytic proliferation, omental mesenteric myxoid hamartoma, inflammatory fibrosarcoma, inflammatory myofibroblastic sarcoma, epithelioid inflammatory myofibroblastic sarcoma

IMT is the generally accepted term encompassing lesions that were previously classified under various reactive and neoplastic entities^[1]. Inflammatory pseudotumor was a former designation for IMT^[2]. However, inflammatory pseudotumor currently designates a large and heterogeneous group of soft tissue tumors that includes inflammatory myofibroblastic tumor along with other entities^[2].

In some IMT cases, the lesions are dominated by sheets of epithelioid cells with only a minor component of spindle cells. Tumors with these characteristics are regarded as a subtype of IMT termed epithelioid inflammatory myofibroblastic sarcoma (EIMS)^[2].