Version May 2024
INTRODUCTION — Inflammatory myofibroblastic tumor (IMT) of the lung (also known as plasma cell granuloma, inflammatory pseudotumor, fibrous histiocytoma, fibroxanthoma, and xanthogranuloma) includes a spectrum of pulmonary lesions. Such lesions most commonly present as solitary pulmonary nodules but can also be locally invasive [1-5]. The pathologic hallmark of these lesions is a proliferation of spindle cells with accompanying and admixed inflammatory cells [6]. It is unclear whether these lesions represent a primary inflammatory process versus a low-grade malignancy with a prominent inflammatory response.
Similar lesions, referred to variably in the literature as plasma cell granulomas or inflammatory pseudotumors, can also develop in the orbit, skull base, thyroid, liver, spine, spleen, lymph nodes, and other tissues [1-3,7-12]. (See "Evaluation of peripheral lymphadenopathy in adults" and "Uncommon sarcoma subtypes".)
EPIDEMIOLOGY — IMTs can occur in any age group, but over one-half of the patients are less than 40 years of age [13,14]. Although IMTs are rare in adults, comprising less than 1 percent of all surgically resected lung lesions, they do represent one of the most common primary lung tumors in the pediatric age group [4,15-20]. Both males and females and all ethnic groups appear to be equally affected.
PATHOLOGY — There is significant controversy and confusion regarding the pathogenesis and histogenesis of these uncommon tumors or tumor-like masses (picture 1). Much of the confusion has been caused by the varying degrees of inflammatory cell infiltration noted on pathologic examination and the observation that the disease process, although usually following a benign course, is sometimes invasive. As a result, a variety of terms have been used to describe lesions falling under the category of IMT.
The early terminology "pulmonary plasma cell/histiocytoma complex" emphasized the histologic heterogeneity and a belief in the benign nature of the lesions [21]. Subsequently, plasma cell granuloma was the common terminology for lung lesions, acknowledging the circumscribed appearance, presence of plasma cells and histiocytes, and generally benign course. The term inflammatory pseudotumor was typically used to describe extrapulmonary lesions with similar pathology [22-24]. More malignant variants were felt to be analogous to undifferentiated "pleomorphic" sarcomas (previously termed malignant fibrous histiocytoma) arising in soft tissues. (See "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma", section on 'Histopathology'.)
The most consistent pathologic feature of these lesions is a background proliferation of spindle cells associated with a variably dense polymorphic infiltrate of mononuclear inflammatory cells (picture 2 and picture 3) [14]. The spindle cells tend to be arranged in short fascicles with a focal storiform (whorled or cartwheel-like) architecture. Immunohistochemical and ultrastructural studies of the spindle cells show features of fibroblasts and myofibroblasts in various proportions [24]. Focal invasion, vascular invasion, and nuclear pleomorphism are all suggestive of more malignant behavior and a worse prognosis.
The inflammatory infiltrate is composed of a mixed population of lymphocytes, plasma cells, histiocytes, and occasional eosinophils and may be dense enough to obscure the underlying spindle cells [24]. Any individual cell type can predominate, although plasma cells and histiocytes tend to be the most conspicuous. Histiocytes may include multinucleated forms and frequently contain finely vacuolated cytoplasmic lipid droplets. Plasma cells may contain cytoplasmic Russell bodies (globular cytoplasmic inclusions of immunoglobulin) and demonstrate a polyclonal pattern of light chain expression. A nonspecific pattern of organizing pneumonia is frequently seen at the periphery of fibrous histiocytomas. Small vessel invasion can be demonstrated in some cases, and is of uncertain significance [25].
ETIOLOGY — The etiology of IMT is unknown; theories include an inflammatory reaction to an infection or to an underlying low grade malignancy. Immunohistochemical staining of IMT reveals the presence of IgG-predominant, polyclonal plasma cells. This finding lends support to the theory that IMT is a reactive inflammatory process. Consistent with the reactive hypothesis is the observation that as many as one-third of these lesions have developed after a respiratory infection [26,27].
Several infectious agents have been linked to the development of IMT of the lung in specific patients, but these findings have not been noted universally. As examples, multiorgan disease has been noted in association with chronic persistent Eikenella corrodens infection, and some investigators have identified clonal DNA expression of Epstein Barr virus in extrapulmonary IMT [2,9,10].
Similarly, human herpes virus (HHV)-8 infection, which is linked to Kaposi's sarcoma and multicentric Castleman's disease, has also been proposed as a precipitant of IMT in the lung, based on identification of HHV-8 DNA within these lesions [28,29]. However, a number of cases have been negative for HHV-8 [30]. (See "Human herpesvirus-8 infection".)
How an initial infection might lead to IMT is not well understood. Increased serum levels and increased local production of the cytokines interleukin-1 and interleukin-6 were demonstrated in one symptomatic patient, raising the possibility that the disease is initiated by dysregulation of cytokine production [31].
Another hypothesis, based upon detailed histopathological studies, is that some plasma cell granulomas are low-grade mesenchymal neoplasms with a secondary inflammatory component [32]. This is supported by the observation of a chromosomal rearrangement at band 2p23 in one-half to two-thirds of cases; this is the site of the anaplastic lymphoma kinase (ALK) gene in the tyrosine kinase locus [14,23,33-36]. Cytoplasmic expression of ALK has been noted in some IMT using immunohistochemistry. ALK mutations are found less commonly in pulmonary IMT than in extrapulmonary IMT [30]. ALK expression is abnormal outside the central nervous system. (See "Clinical manifestations, pathologic features, and diagnosis of systemic anaplastic large cell lymphoma (sALCL)", section on 'ALK expression'.)
A molecular mechanism for inflammatory myofibroblastic tumors has been suggested by a study reporting disruption of an RNA degradation pathway. In 13 of 15 samples of involved tissue from patients with these tumors, mutations were demonstrated in the UPF1 gene, which encodes an RNA helicase essential for nonsense-mediated RNA decay [37].
CLINICAL MANIFESTATIONS — The clinical features, including evidence of a preceding or concurrent respiratory infection, are variable. Approximately 70 percent of patients are asymptomatic [26]. Symptomatic patients may complain of cough, dyspnea, chest pain, or hemoptysis. Approximately 50 percent of patients have an elevated sedimentation rate, and mild anemia and thrombocytosis can also occur.
IMAGING — IMT of the lung is detected by chest radiography, which generally shows a solitary, well-circumscribed mass or ill-defined, pneumonia-like density [38]. Focal calcifications, multiple nodules, and locally invasive disease have also been reported [14,39]. Usually, a chest computed tomography (CT) scan is obtained to clarify the extent of disease; however, there are no radiographic features that reliably differentiate IMT from other causes of pulmonary nodules. (18)F-2-deoxy-2-fluoro-D-glucose-positron emission tomography (FDG-PET) scans may show increased uptake [40-42].
EVALUATION AND DIAGNOSIS — The diagnosis of IMT and differentiation from other malignant, infectious, and congenital lesions require histologic examination of tissue. The diagnosis is usually obtained with surgical resection, which is preferred since complete resection is almost always curative [16].
The diagnosis requires the presence of characteristic findings on histologic examination. The most consistent pathologic feature of these lesions is a background proliferation of spindle cells associated with a variably dense polymorphic infiltrate of mononuclear inflammatory cells [14]. (See 'Pathology' above.)
Attempts at fine needle aspiration have had some success, but have also yielded false positive and false negative results for the presence of carcinoma [16,43]. Bronchoscopy is rarely successful, because endobronchial IMT account for less than 5 percent of cases [26,44,45]. The diagnosis has rarely been made by transbronchial biopsy [46].
DIFFERENTIAL DIAGNOSIS — The pathologic differential diagnosis of IMT is lengthy and includes nonspecific inflammatory reactions secondary to various other conditions (eg, proximal airway obstruction, infection), cryptogenic organizing pneumonia (idiopathic bronchiolitis obliterans with organizing pneumonia), immunoglobulin G (IgG)-4-related disease, pseudolymphoma, small lymphocytic lymphomas, inflammatory sarcomatoid carcinomas, so-called inflammatory fibrosarcoma, and undifferentiated/unclassified or "pleomorphic" soft tissue sarcomas (previously termed malignant fibrous histiocytoma). Most of these diagnostic dilemmas can be resolved by careful attention to the bland cytologic features of IMT as well as by application of appropriate panels of immunostains to difficult cases [14,24,47].
TREATMENT — Complete surgical resection is the treatment of choice for IMT [13,22,23,27,39,45,48-52]. Depending on local expertise, this may be accomplished by video-assisted thoracoscopy or open thoracotomy; larger lesions and those with evidence of local invasion of adjacent tissues will likely require a thoracotomy. Frozen section examination is helpful in guiding the extent of excision, which is generally minimized to preserve lung function [53]. The thrombocytosis associated with IMT has been reported to regress after surgical resection [54].
For patients who are unable to have complete surgical resection (eg, poor surgical candidates, multiple nodules, or unresectable disease), nonsurgical modalities may be used. There are anecdotal reports of both success and failure with glucocorticoids, radiotherapy, and chemotherapy [16,33,46].
A potential form of therapy for IMT has been described that uses a competitive inhibitor of the anaplastic lymphoma kinase (ALK) tyrosine kinase, called crizotinib (see 'Etiology' above) [35,55-59]. In an initial case report, crizotinib appeared to be beneficial in a patient with rearrangements in the ALK gene, but not in a patient without such rearrangement [35]. A subsequent review of 32 patients with IMT (including its subtype epithelioid inflammatory myofibroblastic sarcoma) found that 12 patients had complete or partial remission with crizotinib; however, there was incomplete information about ALK status and duration of follow-up in some of the reported patients [60]. (See "Uncommon sarcoma subtypes", section on 'Inflammatory myofibroblastic tumor'.)
PROGNOSIS — The natural history of IMT is somewhat variable. The lesions typically remain stable in size or grow slowly, and some have regressed spontaneously after open biopsy [13,32,53]. Most patients are cured with complete surgical resection [51,61]. However, some lesions become locally invasive and involve the mediastinum, diaphragm, chest wall, vertebral bodies, heart, and major vessels [16,62,63]. Complete tumor excision and tumor size ≤3 cm are factors associated with a decreased risk of recurrence [22].
Long-term follow-up is recommended for patients who have undergone surgery, as recurrent tumors have been reported as long as 11 years after resection [64,65].
SUMMARY AND RECOMMENDATIONS
●Overview – Inflammatory myofibroblastic tumor (IMT) of the lung (also known as plasma cell granuloma, inflammatory pseudotumor, fibrous histiocytoma, fibroxanthoma, and xanthogranuloma) includes lesions with a spectrum of pulmonary manifestations, from the more common solitary pulmonary nodules to the rare locally invasive tumors or multiple nodules. (See 'Introduction' above.)
●Pathology – The consistent pathologic feature of IMT is a background proliferation of spindle cells associated with a variably dense polymorphic infiltrate of mononuclear inflammatory cells (eg, lymphocytes, plasma cells, histiocytes, and occasional eosinophils). (See 'Pathology' above.)
●Clinical features – The clinical features are variable. Patients may be asymptomatic or may have cough, dyspnea, chest pain, or hemoptysis. Some may report a preceding or concurrent respiratory infection. (See 'Clinical manifestations' above.)
●Imaging – IMT in the lung is detected by chest radiograph, which generally shows a solitary, well-circumscribed mass or ill-defined, pneumonia-like density. Less commonly, more than one nodule or evidence of locally invasive disease may be noted. (See 'Imaging' above.)
●Diagnosis – Histologic examination of tissue is needed to make the diagnosis of IMT of the lung. Usually, this is obtained during surgical resection by open thoracotomy or video-assisted thoracoscopic surgery. The choice between these options depends on the size and location of the nodule, and whether there is local invasion of adjacent tissues. (See 'Evaluation and diagnosis' above.)
●Treatment – We recommend complete surgical resection of IMT of the lung in the majority of patients (Grade 1B). (See 'Treatment' above.)
For patients who are unable to have complete surgical resection (eg, poor surgical candidates, multiple nodules, or unresectable disease) glucocorticoids, radiotherapy, and chemotherapy have been used with variable success. For patients with IMT who have anaplastic lymphoma kinase (ALK) rearrangements and multifocal disease or are otherwise not surgical candidates, preliminary data suggest that crizotinib may be beneficial. (See 'Etiology' above and 'Treatment' above.)
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