Inflammatory myofibroblastic tumour of the central airways: treatment and molecular analysis

Discussion

IMT is a soft tissue neoplasm of mesenchymal origin composed of spindle cell myofibroblasts accompanied by an inflammatory reaction. Nomenclature of IMT was ambiguous in the past. Terms such as inflammatory pseudotumour (IPT), plasma cell granuloma, pseudoxanthomatous tumours, were used interchangeably and it was considered to be benign. Subsequently, it was noted that a subset of these pseudotumours had clonal proliferation, harboured genetic mutations and showed potential for local recurrence and distant metastases. These tumours were recognised as IMTs and classified as an intermediate grade bone and soft tissue neoplasm by WHO [1–3]. Approximately 50–70% of IMTs harbour rearrangements of ALK-4, ROS1, PDGFRβ, RET and ETV6 genes, most of them members of the mitogen-activated protein kinase pathway [4, 5]. These insights into the molecular genetics of IMT denote a malignant potential and delineate it from benign mimickers like immunoglobulin (Ig)G4-related plasma cell granulomas, inflammatory pseudotumour of the lymph node and spleen or mycobacterial pseudotumour. These genetic alterations result in activation of the tyrosine kinase receptor and may offer novel possibilities for treatment with receptor kinase inhibitors in unresectable and metastatic cases [6, 7].

IMTs can involve many organs including abdomen, mesentery, lung, head, neck, extremities, genito-urinary tract and orbit. Local recurrence rates of 15–37% and metastases rates of 5–11% have been reported [2, 3, 8].

Incidence of pulmonary IMT in adults is around 0.04–1% of all lung tumours. Most tumours are found in patients less than 40 years of age with a reported mean range of 27–50 years. No gender predilection has been noted. Endobronchial growth of IMT is rare, with a prevalence of 0–12%, although one study reported 22% [9].

Tracheobronchial IMTs may present with airway obstruction, respiratory distress or collapse of the distal lung. Rare presentations include pneumothorax [10] and pneumomediastinum as noted in one of our patients.

Surgery is often the first treatment choice but may result in significant loss of lung function especially if the location of the tumour renders it unsuitable for parenchyma sparing surgeries such as sleeve resection. Bronchoscopic removal is a minimally invasive technique and a valuable tool for preserving lung function especially if the tumour is purely endoluminal [11, 12]. Bronchoscopic removal of IMTs has been well documented in the paediatric age group and recurrence was mainly noted following partial resection. In adults, data are largely restricted to case reports.

We conducted a review from PubMed, Embase and Medline database for case reports and series wherein bronchoscopic methods were used as an intervention for management of inflammatory myofibroblastic tumours. Studies with full text available in English were included in the analysis.

We reviewed 27 articles that included 22 case reports and five case series [10–36].

Including the three patients from our series, 37 patients underwent resection of endobronchial IMT with the help of bronchoscopic techniques. 22 (69%) patients were over 16 years of age. The most common site of tumour involvement was the left main bronchus (17) followed by the trachea (14). 24 (65%) out of 37 patients were successfully treated with bronchoscopic interventions. Modalities of therapy included use of the rigid bronchoscope with mechanical or forceps debulking (17), laser resection (10), use of diathermy (9), argon plasma coagulation, cryotherapy and electrocautery snare. Flexible bronchoscopic resection was undertaken in one patient.

Five patients had to undergo repeat bronchoscopic procedures, following which the tumour was completely removed [12, 26, 29, 30].

Surgery was done after primary bronchoscopic treatment in 12 patients. Indications for surgery were elective (3) [10, 14, 29], incomplete bronchoscopic resection (2) [15, 21] extraluminal component (1) [25] and recurrence (6) [18, 23, 27, 28, 32]. One patient was deemed too old and unfit for surgery due to severe COPD and hence endobronchial treatment was palliative [19]. Thus, only eight (21%) of the 37 patients who underwent bronchoscopic resection as the primary treatment modality needed surgery for tumour recurrences or incomplete removal. Mean follow-up period after successful resection was 22 months and mean time to recurrence, when noted, was 14 months.

Considering the rare occurrence of this tumour, it is unlikely that a prospective study comparing success rates of surgery versus endoscopic removal will be conducted.

Endoscopic resection can also be a useful approach in conditions such as pregnancy, for which the risk of definitive surgery may be higher [37] or in patients who are unfit or unwilling for surgical resection [19, 36]. Even with large tumours having extra-luminal components, it is useful in managing respiratory distress as a bridge until the patient is fit to undergo surgery [14, 21, 25]. This approach was used for 10 out of the 11 paediatric patients with IMTs who subsequently underwent definitive surgery for submucosal components [38].

When single step resection is not possible, a repeat procedure may also be successfully performed [12, 26, 29, 30] as was the scenario in five cases including one from our series. Regular follow-up with computed tomography scans and repeat bronchoscopy with biopsies when required is mandatory to assess response and recurrences.

Endoluminal location of the tumour may be confirmed with imaging with thin slice computed tomography scan and endoscopic evaluation. Radial endobronchial ultrasound (EBUS) can be used to determine if the tumour is extending beyond the cartilage or is limited to submucosal layers and is superior to computed tomography scan in this respect. For better approximation in proximal airways the central probes with balloon sheath may be used for airway assessment. The normal central airways have seven layers visualised on radial EBUS: the innermost two are the mucosa and submucosa, the third, fourth and fifth correspond to the cartilage, and the external two are loose and dense fibroelastic tissue surrounding the airway. One of the first indications for use of EBUS was for identifying extent of tumour extension prior to endobronchial treatment of tumours. In differentiating tumour compression and infiltration, EBUS has an accuracy of 94% [39]. Linear EBUS may be used to detect nodal involvement. IMTs may be FDG avid and positron emission tomography computed tomography may be a sensitive tool in determining pulmonary and mediastinal involvement, distant metastases, recurrences and residual disease [40]. Advances such as confocal laser endomicroscopy and biopsy may be an added asset in assessing adequate resection and possible recurrences in the future [41].

An important aspect to be considered is the vascularity of the tumour and the potential for bleeding. Significant bleeding was noted in two of our cases requiring use of haemostatic measures including the use of a bronchial blocker. It is imperative that resections be undertaken at centres with the required expertise and facilities for haemorrhage control.

On histology, IMTs show the presence of spindle cells of myofibroblast origin with low mitotic activity, an inflammatory component of plasma cells, lymphocytes and histiocytes, and fibromyxoid stroma. The ratio of different components may vary. Some cases show a prominent number of inflammatory cells, while others may have a mild inflammatory component. The cytoplasm of the spindle cells may be homogeneously stained or sometimes appear granular. Histological spectrum is quite broad and three patterns have been described, as follows [42]. 1) Myxoid/vascular which resembles nodular fasciitis with loosely arranged plump spindle cells in a myxoid stroma and prominent vasculature. This variant may have more eosinophils or neutrophils and fewer plasma cells than the other types. 2) The compact spindle cell pattern with a cellular proliferation of spindle cells and a fascicular architecture in a collagenous stroma. These foci show numerous plasma cells and lymphocytes. 3) Fibromatosis type which is relatively hypocellular with elongated spindle cells in a densely collagenous background with lymphocytes, plasma cells and eosinophils.

The differential diagnosis includes reactive lesions like granulation tissue and plasma cell granulomas [1–3]. Differentiation from reactive lesions can be difficult on morphology alone. High cellularity, and the fascicular, relatively monomorphic growth pattern of the IMT can be helpful in this matter. Standard immunohistochemistry is mostly of no specific help, SMA is positive as it is in the reactive myofibroblasts. However, molecular abnormalities, such as ALK, ROS1, RET and NTRK1 fusions are definite in the differentiation from reactive pseudotumours. If immunohistochemistry is used for fusion screening, a positive ALK/ROS1 should always be confirmed by an orthogonal technique, FISH or next generation sequencing as we presented in our cases.

In the second case of our series, a granular cell tumour was considered in the differential diagnosis due to prominent granular cytoplasm. The absence of S100 immunohistochemistry staining renders a granular cell tumour unlikely.

Nuclear pleomorphism and atypia are rare in the myofibroblasts of IMT, and when present should warrant that a differential of sarcoma should be ruled out.

Clonal cytogenetic rearrangements that activate the ALK receptor kinase gene in the chromosome band 2p23 emerged in recent years as genetic drivers in IMTs harbouring different fusion partners. Immuno-histochemistry for ALK1 may be positive in 45–50% of IMTs and shows a granular or perinuclear staining pattern. In ALK-negative cases other rearrangements may be found. Its genetic profile closely resembles that of lung adenocarcinoma even when it arises in soft tissue and other organs. In 10% of IMTs, ROS1 rearrangement was found. Occasionally tumours harboured RET, PDGFRβ and ETV6 gene rearrangements [5, 6]. These new findings imply that IMT is a kinase fusion-driven neoplasm [4]. Interestingly, around 90% of paediatric IMTs are ALK fusion positive whereas only 10% of adult IMTs are ALK fusion positive tumours [5]. Roughly 30% of IMTs do not harbour any known mutations or genetic rearrangements, mostly in adults. Novel genes might still emerge as drivers of this neoplasm. The presence of ALK- RANBNP2 fusion has been associated with a distinct variant of IMT with round or epithelioid cells on morphology, a perinuclear staining pattern and an aggressive clinical course. The term epithelioid inflammatory myofibroblastic sarcoma (EIMS) has been suggested to distinguish this aggressive variant [43].

In a previous study of 59 IMTs, analysis of a subset of tumours with histological atypia and aggressive clinical course had revealed that ALK negative tumours were associated with older age of presentation, greater nuclear pleomorphism, nuclear atypia and atypical mitosis with a tendency for distant metastasis [44]. In our series, two patients were adult males in the 40–50 age group, while the third was a 16-year-old female. All three had IMTs with IHC positive for ALK protein and FISH detected EML4-ALK1 re-arrangement. While the two older males could be treated with endobronchial resection, the female had a local recurrence. This series is too small to draw firm conclusions about tumour site, molecular profile, histological profile and prognosis.

The molecular genetics of IMT has opened up a potentially new therapeutic possibility in unresectable and refractory tumours. The ALK inhibitor crizotinib has been evaluated in patients with advanced or metastatic IMTs deemed incurable by surgery, radiotherapy or systemic therapy with response rates of 50% by RECIST criteria in ALK-positive and 14% in ALK-negative tumours, concluding that crizotinib should be considered standard of care in the subset of patients with ALK-positive IMTs who do not qualify for curative surgery [7]. However, amongst ALK-negative tumours, the presence of other oncogenic drivers such as ROS1 gene rearrangements may render them amenable to treatment with crizotinib [6]. Ceritinib has been used with a significant and sustained partial response in an IMT that had progressed despite crizotinib [45]. A future perspective may be to study the efficacy of combined modalities including bronchoscopic resection and ALK1 inhibitors, especially in refractory or recurrent tumours.

In conclusion, interventional bronchoscopic techniques are minimally invasive lung function preserving modalities for resection of endobronchial IMTs in adults. They are particularly useful when the tumour has essentially endoluminal localisation and complete resection of the tumour can be performed during the bronchoscopic procedure. Regular follow-up is essential to detect residual tumour or recurrence. It may also prove useful for airway recanalisation in patients who are unfit for surgery or in emergency respiratory distress as a bridge to surgical resection. In unresectable and metastatic cases, targeted treatment with ALK inhibitors may be considered standard of care as guided by the molecular profile of the tumour.