A novel ALK rearrangement in an inflammatory myofibroblastic tumor (IMT) in a neonate

2013-10-11 11:55:52

Cancer Genetics; 2013 Oct 11; DOI:

Nicci Owusu-Brackett, Romaine Johnson, David T. Schindel, Prasad Koduru, Sandy Cope-Yokoyama


Inflammatory myofibroblastic tumor (IMT) is a lesion primarily affecting children and young adults. Although there are many case reports of IMTs arising in the region of the larynx, none has been associated with the hyoid bone. In addition, the development of this tumor in a neonate is extremely rare, with only three reported cases in the literature. In this lesion, myofibroblastic cells expand in a background of mixed inflammation including lymphocytes, plasma cells, and eosinophils. The neoplastic nature of this previously controversial entity was established by the presence of clonal cytogenetic abnormalities, and the presence of structural rearrangements in the anaplastic large cell lymphoma kinase (ALK) gene. In these rearrangements, the C-terminal kinase domain of ALK is fused with different partners leading to constitutive kinase activity. Here we report a case of IMT arising from the central portion of the hyoid bone. In addition to this rare clinical presentation, the tumor showed a novel rearrangement of the ALK gene that has not been reported previously.

Materials and Methods

Ultrasound examination of the fetus of a 25 year old gravida 3 para 1 aborta 1 woman at 21 weeks gestation revealed a solid, anterior neck mass measuring 4.1 x 3.3 x 3.0 cm, extending from chin to mid-thorax, and causing neck hyperextension. No other fetal anomalies were seen. At 23 weeks gestation, magnetic resonance imaging (MRI) of the fetus demonstrated an enlarging, solid, homogenous neck mass extending superiorly to compress the base of the tongue and the larynx. The lesion extended beyond the mandible laterally to the level of the ears bilaterally.

At 36 weeks gestation, an ex-utero intrapartum treatment (EXIT) procedure was performed, and the infant’s airway was successfully managed by flexible bronchoscopic-directed intubation. A computed tomography (CT) scan of the neck confirmed the prenatal findings of a large, solid, heterogeneously-enhancing anterior neck mass measuring in excess of 8 x7 cm. On day one of life, the infant underwent resection of the mass, which arose from the central portion of the hyoid bone. The central portion of the hyoid bone was excised en bloc with the tumor. The infant was extubated on the third postoperative day.

Gross examination of the tumor showed a firm, lobulated mass with a thin, transparent capsule and tan, whorled cut surface without hemorrhage or necrosis. Microscopic examination showed spindled to plump cells arranged in short fascicles, with focal concentricity around blood vessels. The nuclei demonstrated vesicular chromatin with occasional small nucleoli, and rare mitoses. There were occasional inflammatory cells, primarily lymphocytes with rare plasma cells. The cells were positive for epithelial membrane antigen and smooth muscle actin, and focally positive for calponin and CD34, indicating the tumor cells had some characteristics of both smooth muscle and epithelial lineages. The cells were negative for Collagen IV, Claudin, and Glut-1 (ruling out perineurioma) and negative for S-100 (ruling out other peripheral nerve sheath tumors). They were negative for the epithelial marker pankeratin (AE1/AE3) and the muscle marker desmin. Beta-catenin was membranous and cytoplasmic- the normal pattern for this stain- making desmoid-type fibromatosis unlikely.

Conventional cytogenetics that was performed on short term (7 days) cultured tumor cells revealed a normal karyotype (46,XX). Fluorescence in situ hybridization (FISH) was performed with ALK dual colored break-apart probe (Abbott Molecular, Downers Grove, IL) on sections of paraffin embedded tumor tissue. In addition, FISH for a possible fusion partner (ATIC) was attempted using a FISH probe, RP11-804M4 (Empire Genomics, Buffalo NY) that covered the ATIC gene.


In the 200 nuclei examined, 49% had one fusion signal and one red signal (loss of 5’-green signal), 32.5% had one fusion signal, and 18.5% had normal signal pattern – nuc ish (5’ALKx1,3’ALKx2)(5’ALK con 3’ALKx1)[98/200]/ (5’ALK,3’ALK)x1(5’ALK con3’ALKx1)[65/200]/(5’ALK,3’ALK)x2(5’ALK con 3’ALKx2)[37/200]. To further characterize the genomic alteration seen in FISH analysis, metaphase FISH was performed on previously Gbanded slides. This study showed a novel rearrangement in one copy of the ALK gene. The ALK signal at 2p23 was missing, while a red signal appeared at 2q33-q35. This pattern suggests a cryptic rearrangement in which the 5’-region of ALK was deleted and 3’-region translocated from 2p23 to 2q33-q35. In several successive hybridizations, the probe for ATIC did
not yield analyzable signals, whereas the control probe CEP-2 showed signals.

Because of the morphologic and immunophenotypic pattern, as well as a clonal rearrangement of the ALK gene, a diagnosis of inflammatory myofibroblastic tumor was rendered. The patient has been followed by the oncology service at our institution, with no residual or recurrent tumor on multiple imaging studies for greater than 32 months.


IMTs are commonly reported in children and young adults, but are only rarely reported in infants and newborns. Previous cases of prenatally diagnosed IMT include tumors in the paravertebral space, at the skull base, and in the thoracic cavity/chest wall. As in our case, the latter two cases also presented with airway obstruction and respiratory compromise.

This lesion can display a variety of morphologies: from haphazardly arranged spindle cells in a loose myxoid background, to compact fascicles with a dense collagenized background, to a morphology evoking desmoid-type fibromatosis with uniform cellularity and sparse inflammation. The spindle cells in IMTs have a variable immunophenotypic pattern usually positive for vimentin, smooth muscle actin, and desmin. They are usually negative for myogenin, myoglobin, and S100 protein. Immunohistochemical positivity for ALK-1 is present in 50% of IMTs and correlates with the presence of ALK gene rearrangements.

The tumors that commonly present in utero or early neonatal period are a small group. Based on the location and prenatal presentation of tumor in the current patient, the primary clinical and radiologic differential diagnosis included germ cell tumor, neuroblastoma, and myofibroma of infancy, but these were ruled out based on the histologic appearance of the tumor. The morphologic differential diagnosis included a perineurioma (because of a focal concentric fascicular arrangement around vessels), which was ruled out by immunohistochemistry. There were also focal areas resembling desmoid-type fibromatosis, prompting staining with betacatenin, which showed the normal membranous pattern. Although the morphology was consistent with IMT, the relative absence of inflammatory cells was puzzling, but may be explained by the immature inflammatory milieu of the newborn infant. In a previous report of prenatally diagnosed IMT, the tumor also showed a lack of a prominent inflammatory infiltrate.

Clonal chromosome changes, simple to complex, have been reported in multiple IMTs. In five of these cases, chromosome region 2p23 was visibly involved. In another tumor with abnormal karyotype, FISH analysis detected rearrangement of ALK. Originally identified as a consistent genetic change associated with t(2;5)(p23;q35) in anaplastic large cell lymphoma, rearrangements in the ALK gene have been implicated in the pathogenecity of tumors of diverse histology such as non-small cell lung cancer, neuroblastoma, tumors of the bladder, tumors of the head and neck region, and IMT. Chromosome rearrangements involving 2p23 with different other partners or pericentric inversion in 2 (p23q25) are frequent genetic alterations of ALK, both in lymphoid and non-lymphoid tumors. Other types of genomic alterations such as intrachromosomal deletion, gene truncation, and copy number changes have also been identified as other mechanisms leading to deregulated ALK expression. There is a report of a case in a post-transplant patient that showed loss of the 5' ALK and translocation of the 3' ALK in an Epstein-Barr virus associated myogenic liver tumor with a complex karyotype that had del(2)(p23),der(3)t(2;3)(p23;q29),der(21)t(Y;21)(q12;p13). However, cryptic deletion and intrachromosomal-insertional translocation have not been reported previously. In this tumor ALK is inserted at 2q35 region. Previously, two cases of ALCL with inv(2)(p23q25) and one case of urinary bladder IMT with complex karyotype involving chromosome 2 and a rearrangement of the ALK gene were reported. In these tumors the rearranged ALK fused with ATIC at 2q35. Therefore, it is conceivable that the rearranged ALK in the present case may have fused with ATIC. The presence of ALK gene abnormalities in tumors of diverse origin suggests that these tumors may respond to ALK inhibitors, a concept strongly in synchrony with the current strategies to treat tumors based on pathogenetic molecular signature rather than histologic signature.

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