The diagnosis of inflammatory myofibroblastic tumour, is often overlooked and missed because it is very rare. Symptoms are often non-specific though they could be related to the anatomical location of IMT and mass effect [6]. Recurrent bleeding manifestations by way of epistaxis, haematuria and rectal bleeding [1,6,7] have been observed and attributed to the vascular nature of the neoplasm [1]. However this manifestation alone has little diagnostic value. In the absence of definite histology a variety of differential diagnoses could have been entertained in the case subject including Wegner’s granulamatosis, lymphoma, opportunistic infections such as rhinocerebral mucormycosis and tuberculosis. Imaging was helpful to identify a neoplastic process as a result of prominent local infiltration. The value of histology in the diagnosis of this condition is quite apparent.

Follicular dendritic cell (FDC) tumour is an equally rare differential diagnosis that should be entertained as a result of stark similarity in histology. Nonetheless the clinical picture of FDC tumour is significant for lymphadenopathy with involvement of the head, neck, mediastinum and axilla in the context of a painless mass lesion most importantly in the absence of significant constitutional symptoms. However involvement of extra-nodal reticulo-endothelial sites have been reported including tonsils, spleen and gastrointestinal mucosa associated lymphoid tissue [4]. Immuno-histochemistry is useful to separate FDC from IMT, as CD 21,23 and 35 are positive only in FDC. Other useful bio markers include R4/23, Ki-FDC1p, KiM4 and clusterin which are seen in FDC [8]. These markers are currently not available in Sri Lanka and hence could not be performed in the case subject. Anaplastic lymphoma kinase reactivity, which was negative in our patient, is known to be seen in approximately 56% of cases of IMT, and when present has prognostic value by way of lower likelihood of metastases however a greater probability of recurrence [9] and favors a diagnosis of IMT over FDC. Spindle cells in IMT also show positivity for vimentin and smooth muscle actin, both of which were seen in the case subject. However vimentin may also stain positive in FDC. SMA positivity which was noted in the case subject is common in IMT though not common in FDC, its presence does not exclude it completely [4,10-13]. Though the absence of comprehensive immunohistochemistry panel studies was an impediment in establishing an irrefutable diagnosis of IMT, the absence of involvement of structures typical for FDC including nodal and extranodal sites both clinically and on computed tomography imaging and the presence of prominent constitutional symptoms and typical histology (presence of spindle cells associated with infiltrates of mononuclear inflammatory cells such as plasma cells, lymphocytes, histiocytes) and available immunohistochemistry findings favoured and supported the diagnosis of IMT and excluded FDC [4].

Medical literature shows confusing, overlapping and interchangeable use of the terminologies IMT and IPT (inflammatory pseudo tumour) and this is an area of debate as both terms describe pathologies with very similar clinical and histological presentations. IMT is defined by World Health Organization as a distinct borderline lesion composed of myofibroblastic cells with a variable admixture of inflammatory cells, and the terms IPT and IMT are considered synonymous [14]. However some authorities in the subject consider IPT as an overall broader category, and IMT as a subset of IPT that can show prominent neoplastic features [15], though considered histologically benign [16]. Despite numerous similarities in histology, subtle differences such as marked spindle cell proliferation in IMT and prominent lymphoplasmacytic infiltrates in IPT help to histologically differentiate them. Immunohistochemical markers such as IgG4-positive plasma cells and an increased ratio of IgG4+/IgG+ are invaluable in differentiating IPT from IMT, where these are not significantly present. ALK exclusivity to IMT is invaluable in differentiation from IPT [17]. In the index patient, cellular atypia, atypical mitosis and pleomorphism favoring malignant transformation were not seen [9]. However, radiological evidence of sino-nasal destruction exemplifies the malignant tendencies of the lesion despite benign histology [3]. Similarly tumour recurrence also is a feature of malignant neoplastic tendencies. The mixed benign and malignant features of the neoplasm and the observed remission to initial chemotherapy and relapse of on withdrawal is keeping in line with the poorly understood characteristics of the lesion [7]. Furthermore, IMT originating from extra-pulmonary regions is known to show a more aggressive behaviour [4].

Management of IMT can be challenging as there are no established treatment protocols [1]. Surgery is considered first line for resectable lesions and may be combined with alternate regimens such as corticosteroids, radiotherapy or chemotherapy [3]. Radical surgical excision has shown to be curative in 90% of the cases [18]. However the anatomical location and proximity to vital structures may preclude surgical excision [19]. Mortality is well documented despite optimal multimodal therapy [2,20]. Glucocorticoids are considered more effective in children than in adults [16] however literature evidence in adults shows good response to high dose glucocorticoid mono-therapy with rapid induction of remission [21,22]. Multi agent combination therapy regimens have been suggested for unresectable tumors’ [23], however their value in the treatment of IMT is controversial [24]. There is little literature guidance on treatment duration with glucocorticoids and success has been reported with treatment durations spanning from anywhere between 6 months to years [4,8,3]. Variable response to long term use of steroids as well as complete remission following weaning of steroids have been noted [8]. Steroid dependence to maintain remission is a therapeutic problem often encountered in the treatment of IMT [12]. Steroid refractory IMT requiring alternate agents is well documented [13]. Paradoxically emergence of IMT whilst on immunosuppression following kidney transplant has been reported putting into perspective the basis of immunosuppressive treatment in the management of IMT [11]. The definitive role of glucocorticoid therapy in IMT is not clearly understood but a therapeutic trial should be considered in appropriate cases and continued into remission if clinical and radiological response is apparent.

Chemotherapy is recommended when IMT is multifocal, invasive or shows local recurrence [16]. It is often a combination of agents including methotrexate, cisplatin, vinorelbine, Adriamycin®, carboplatin and paclitaxel given with a view of achieving complete remission [13,15,17,23,25]. These agents have also been used as an adjunct with non-steroidal anti-inflammatory drugs and glucocorticoids and combination therapy has shown good response in instances where mono-therapy had failed [13]. A change in the combination of chemotherapeutic agents has been shown to be beneficial when the initial choice of combination agents have failed to yield good response [17]. Chemotherapy can also be utilized as neo-adjuvant treatment prior to definitive surgical intervention [14]. Non-steroidal anti-inflammatory drugs used alone has also demonstrated success [26]. Immunomodulation with intravenous immunoglobulin therapy has been tried with success for post-surgical residual tumour with successful long term remission [27]. Another novel therapy under evaluation is the ALK inhibitor crizotinib, which showed long term partial response in those who were ALK positive [28]. Radiotherapy is usually considered ineffective at standard doses. Response with high doses is purported, however the side effects and complications may be a limiting factor [29].

The variable response to glucocorticoids and other forms of chemotherapy, with non-uniformity in response to similar regimens and the use of agents as individualized therapeutic trials have their foundation in the lack of clinical evidence to guide management. The anatomical sites of involvement and the involvement of critical structures and the side effects of classical chemo-radiotherapy fuelled by the favourable response to glucocorticoid mono-therapy, guided us to opt for combination chemotherapy with steroids and methotrexate. Clinical, radiological (Figure 3) and inflammatory marker response were helpful in adjusting dosage of treatment.

The prognosis in IMT is generally good [10]. Precise prognostic predictors are yet to be established. However surgical resectability with complete resection, tumour size and ALK expression [16,20,30] are variables that have been known to alter prognosis and disease evolution. Recurrence is known to be associated to site, size, age and incomplete resection [31,32]. Tumour recurrence after surgery was found to be as much as 25-37% in extra-pulmonary IMT [3,18] and up to 85% in abdomino-pelvic IMT [9]. IMT recurrence in nasal sinuses is common with usually an aggressive course, and may be influenced by histology [3] though it is a subject of much debate [31]. Long term follow up is important as the condition has been reported to recur many years after apparent cure [10].