Bone and Soft Tissue Pathology
Pediatric Pathology

Inflammatory Myofibroblastic Tumor

Gareth Jevon
PathWest Laboratory Medicine and Princess Margaret Hospital
Perth, WA


Bullet Points
  • The differential diagnosis of childhood tumors differs from adult tumors with the same histologic pattern.

  • The diagnosis of pediatric neoplasms requires immunohistochemical and molecular genetic studies.

  • Tumors in the pediatric population are unusual and require super-regional expertise.

Clinical History
A 5 year old girl was referred to Princess Margaret Hospital for Children, Perth WA , for evaluation of her respiratory distress. She had inspiratory and expiratory stridor, a tracheal tug, subcostal recession, and good bilateral air entry, without crepitations. There was no fever or clubbing. Examination of the ears, nose and throat was normal. Clinically she was thought to have a large airway obstruction and arrangements were made for an urgent flexible bronchoscopy.

A diagnosis of asthma had been made 6 months prior to her presentation. She had since been admitted to hospital 4 times. Following a streptococcal pneumonia of the right lower lobe 3 months earlier, she developed noisy breathing, with prolonged periods of wheezing and stridor, and little response to bronchodilators. Two weeks before her evaluation she was admitted to a peripheral hospital with asthma. She was afebrile, and chest X-ray showed patchy bilateral perihilar consolidations. Neck X rays did not show features of epiglottitis. Abnormal laboratory results included an arterial blood oxygen saturation of 80%, a white cell count 2.9 x 10 9 (5.0-17.0), neutrophils 18.9 x 10 9 (1.5-8.5), and C reactive protein 150 mg/L (<10). She responded poorly to nebulized adrenalin, intravenous dexamethazone, and azithromycin, but while her condition was stable, she was still wheezing when she was discharged.

At bronchoscopy there was a polypoid mass attached to the postero-lateral wall of the trachea above the carina, almost filling the lumen. The mass was resected leaving minor residual disease of the wall.


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Figure 1 - The biopsy sections show a cellular neoplasm with compact fascicles of spindle cells. Figure 2.
Figure 2 - In some foci the cells are arranged a storiform pattern.
Figure 3 - In one or two areas the tumor cells are more polygonal, or ganglion-like. There were no epithelioid cells.

Figure 4 - The spindled cells have uniform, elongated, vesicular nuclei and indistinct cytoplasm. There are no anaplastic cells.
Figure 5 - There is a background inflammatory infiltrate composed of lymphocytes and plasma cells.
Figure 6 - The spindle cells are mitotically active (3 per high power field).

Figure 7 - Focally beneath the respiratory epithelium the cells had an edematous background. There was no compact cambian layer.
Figure 8 - The spindle cells have diffuse cytoplasmic vimentin staining.

Figure 9 - Many of the tumor cells stain with smooth muscle actin.
Figure 10 -Leukocyte common antigen highlights the inflammatory infiltrate.


Differential Diagnosis
The sections show a cellular neoplasm with compact fascicles of spindle cells, and focal storiform areas lined by respiratory epithelium. There are moderate numbers of lymphocytes and plasma cells in the background. The cell nuclei are relatively uniform, elongated, and vesicular with small numbers of mitoses (3 per 10 high power fields). The cytoplasm is indistinct without rhabdomyoblastic differentiation. Giant cells or anaplastic cells are not seen.

The histologic differential diagnosis includes inflammatory myofibroblastic tumor, embryonal rhabdomyosarcoma, leiomyosarcoma, malignant peripheral nerve sheath tumor, and fibrosarcoma.

The cells are reactive to vimentin diffusely, and many stain with smooth muscle actin. There is no positivity for cytokeratin, desmin, myogenin, Myo-D, or CD99. None of the cells stain for AE1-AE3, S100 protein, or PGP 9.5. ALK1 immunohistochemistry is negative, but when repeated in a reference laboratory there is diffuse cytoplasmic staining.

Final Diagnosis
Inflammatory myofibroblastic tumor.

Inflammatory myofibroblastic tumor (IMT) is a distinctive neoplasm composed of myofibroblastic spindle cells accompanied by an inflammatory infiltrate of plasma cells, lymphocytes, and eosinophils (Coffin CM, 2002). It occurs primarily in the soft tissue and viscera of children and young adults. The lesion has also been referred to as inflammatory pseudotumor, plasma cell granuloma, and inflammatory fibrosarcoma.

IMTs are small to large, circumscribed, single or multinodular, firm, white or tan lesions, with a whorled, fleshy, or myxoid cut surface. Three histologic patterns are recognised; a spindle cell pattern resembling smooth muscle, myofibroblastic, and other spindle cell neoplasms lesions, with a compact fascicular spindle cell arrangement, variable myxoid and collagenized areas, and a lymphoplasmacytic infiltrate; a myxoid vascular pattern resembling nodular fasciitis with plump or spindled myofibroblasts in an edematous or myxoid stroma, abundant vessels and an infiltrate of lymphocytes, plasma cells and eosinophils; and a third scar-like pattern with dense, hypocellular collagen and scant inflammatory cells resembling a desmoid fibromatosis (Coffin CM, 1998). Most commonly IMT involves the lung, mesentery and omentum, but also the head and neck, retroperitoneum, liver and bladder. It has uncommonly been described in the upper airways and CNS (Browne M, 2004; Wenig BM, 1995, Hausler M, 2003). Extrapulmonary presentations usually occur in children. In up to a third of this group the tumor is associated with a clinical syndrome consisting of fever, malaise, weight loss, anemia, thrombocytosis, polyclonal hyperglobulinemia and an elevated ESR. IMTs mostly occur in the first two decades and the median age at diagnosis is 9 years, but they are not restricted to this age group.

The cells in IMT show the ultrastructural details and immunophenotypic features of myofibrolastic or fibroblastic differentiation. There is diffuse cytoplasmic staining for vimentin and smooth muscle actin staining is seen focally to diffusely in the spindle cells cytoplasm in nearly all cases. Reactivity for desmin is less common, and focal cytokeratin staining is also reported. Myogenin, myoglobin, S100, CD117 and epithelial membrane antigens are negative (Coffin CM, 2001).

Recurrent translocations involving 2p23, the anaplastic lymphoma kinase (ALK) gene site, and ALK gene fusions with two tropomyosin genes, TPM3 and TPM4, or the clathrin heavy chain gene, CLTC, in most cases indicate a neoplastic pathogenesis (Lawrence B, 2000; Bridge JA, 2001; Chan JK, 2001). ALK is a member of the insulin receptor family of receptor tyrosine kinases normally expressed in the central nervous system. ALK gene fusions were first identified in anaplastic large cell lymphomas (ALCL) where a t(2;5) chromosomal translocation results in a NPM-ALK gene fusion and an activated chimeric protein (Morris SW, 1994). TPM3-ALK and CLTC-ALK fusions have also been found in ALCL, implicating identical fusion proteins in the pathogenesis of both mesenchymal and lymphoid neoplasms. For diagnostic purposes the most effective method to demonstrate the fusion protein is immunohistochemistry. In one study 44/73 IMTs stained with ALK-11 (Ventana) showing diffuse cytoplasmic staining (corresponding to TPM3/4-ALK by RT-PCR), granular cytoplasmic staining (CLTC-ALK by RT-PCR), and nuclear membrane staining (RanBP2-ALK) (Cook JR, 2001). ALK detection does not correlate with any particular histologic pattern (Coffin CM, 2001). Although cytogenetic arrangements which activate the ALK receptor tyrosine kinase gene are found in children, they are uncommon in older patients. Epstein-Barr virus is not associated with IMT, but has a strong association with the with IMT-like follicular dendritic cell tumors of the liver and spleen in older patients, which in turn are ALK negative (Cheuk W, 2001). Fibroblasts in desmoid tumors and nodular fasciitis do not express ALK, nor do leiomyosarcoma or fibrosarcoma. Rhadomyosarcoma and malignant peripheral nerve sheath tumor stain in 20% and 40% of cases, respectively (Cessna MH, 2002).

Surgical resection is the appropriate treatment for IMT. The tumor does not usually recur when excision is complete, but some may be locally aggressive (depending on site and proximity to vital structures) or metastatic, uncommonly to lung and bone (Morotti RA, 2005). Radical surgery and adjuvant therapy are not indicated. Metastatic disease is most often reported in children with intraabdominal tumors. There are no criteria to distinguish metastases from multicentric disease and the tumor is sometimes found at more than one site. Sarcomatoid transformation has also been reported in retroperitoneal tumors. There are no histologic predictors of aggressive behaviour, and recurrence usually occurs within a year of diagnosis.

IMT is most easily confused with reactive processes or spindle cell neoplasms. Indeed, in the past it was thought that IMT represented an inflammatory reaction to trauma, infection, or autoimmune disorders. Given the histologic pattern in this case we considered embryonal rhabdomyosarcoma, malignant peripheral nerve sheath tumor and leiomyosarcoma in the differential diagnosis. However the immunophenotype was not supportive of any of these entities. Leiomyosarcoma is uncommon in childhood, when it involves visceral, rather than soft tissue sites. Both smooth muscle actin and desmin stain more uniformly, and the cells show ultrastructural features of smooth muscle differentiation. Embryonal rhabdomyosarcomas show myoblastic differentiation histologically, ultrastructurally and immunophenotypically. Adult fibrosarcoma does occur in the first two decades, but it does not have the characteristic inflammatory infiltrate seen in IMT. Other IMTs may mimic infantile myofibromatosis, or myofibroblastic and fibrohistiocytic proliferations such as desmoid fibromatosis, sclerosing mesenteritis, or sclerosing mediastinitis.

References
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