Case 3 -
Inflammatory Myofibroblastic Tumor
PathWest Laboratory Medicine and Princess Margaret Hospital
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- 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.
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.
Case 3 - Slide 1
Case 3 - Figure 1 - The biopsy sections show a cellular neoplasm with compact fascicles of spindle cells. Figure 2.
Case 3 - Figure 2 - In some foci the cells are arranged a storiform pattern.
Case 3 - Figure 3 - In one or two areas the tumor cells are more polygonal, or ganglion-like. There were no epithelioid cells.
Case 3 - Figure 4 - The spindled cells have uniform, elongated, vesicular nuclei and indistinct cytoplasm. There are no anaplastic cells.
Case 3 - Figure 5 - There is a background inflammatory infiltrate composed of lymphocytes and plasma cells.
Case 3 - Figure 6 - The spindle cells are mitotically active (3 per high power field).
Case 3 - Figure 7 - Focally beneath the respiratory epithelium the cells had an edematous background. There was no compact cambian layer.
Case 3 - Figure 8 - The spindle cells have diffuse cytoplasmic vimentin staining.
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.
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
- Bridge JA, Kanamori M, Ma Z, Pickering D, Hill DA, Lydiatt W, Lui MY, Colleoni GW, Antonescu CR, Ladanyi M, Morris SW. Fusion of the ALK gene to the clathrin heavy chain gene, CLTC, in inflammatory myofibroblastic tumor. Am J Pathol. 2001;159(2):411-5.
- Browne M, Abramson LP, Chou PM, Acton R, Holinger LD, Reynolds M. Inflammatory myofibroblastic tumor (inflammatory pseudotumor) of the neck infiltrating the trachea. J Pediatr Surg. 2004;39(10):e1-4.
- Cessna MH, Zhou H, Sanger WG, Perkins SL, Tripp S, Pickering D, Daines C, Coffin CM. Expression of ALK1 and p80 in inflammatory myofibroblastic tumor and its mesenchymal mimics: a study of 135 cases. Mod Pathol. 2002 Sep;15(9):931-8.
- Coffin CM, Watterson J, Priest JR, Dehner LP. Extrapulmonary inflammatory myofibroblastic tumor (inflammatory pseudotumor). A clinicopathologic and immunohistochemical study of 84 cases. Am J Surg Pathol. 1995;19(8):859-72.
- Coffin CM, Patel A, Perkins S, Elenitoba-Johnson KS, Perlman E, Griffin CA. ALK1 and p80 expression and chromosomal rearrangements involving 2p23 in inflammatory myofibroblastic tumor. Mod Pathol. 2001;14(6):569-76.
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