ALK + Inflammatory Myofibroblastic Tumor of the Tongue in a Neonate Treated With Crizotinib

Inflammatory myofibroblastic tumor (IMT) is a rare, mesenchymal neoplasm primarily occurring in the lung and abdominopelvic regions in children and young adults with a prevalence ranging from 0.04-0.7% [1-3]. IMT presents as a painless, enlarging mass and may show invasiveness and local recurrence but is rarely metastatic [4]. Histologic characteristics include a mixture of inflammatory and myofibroblastic spindle cells with hypocellular fibrous patterns that can be well-circumscribed to ill-defined on imaging [1,3]. Surgical intervention have been mostly noted as the mainstay treatment for IMTs, though chemotherapy agents and anti-inflammatory therapies such as steroidal and non-steroidal anti-inflammatory drugs have been reported, as well [5]. To date, there are published cases of IMT involving the head and neck, including the oral cavity, but to our knowledge, there are no reported studies of inflammatory myofibroblastic tumor with anaplastic lymphoma kinase (ALK) positivity of the tongue in a neonate [2,4,6-16].


INTRODUCTION
Inflammatory myofibroblastic tumor (IMT) is a rare, mesenchymal neoplasm primarily occurring in the lung and abdominopelvic regions in children and young adults with a prevalence ranging from 0.04-0.7% [1][2][3]. IMT presents as a painless, enlarging mass and may show invasiveness and local recurrence but is rarely metastatic [4].
Histologic characteristics include a mixture of inflammatory and myofibroblastic spindle cells with hypocellular fibrous patterns that can be well-circumscribed to ill-defined on imaging [1,3]. Surgical intervention have been mostly noted as the mainstay treatment for IMTs, though chemotherapy agents and anti-inflammatory therapies such as steroidal and non-steroidal anti-inflammatory drugs have been reported, as well [5].

CASE REPORT
A 0-day-old neonate, born without complication at 41 weeks, presented as a transfer from an outside facility to Children's Mercy Hospital (CMH) in Kansas City, Missouri for further evaluation and management of a large, bleeding tongue mass. Of note, there was reported comprehensive antenatal care without complication or detection of the tongue mass on three prenatal ultrasounds. At birth, the tongue mass was noted. The patient did not have significant airway obstruction with APGARs 8 and 9 at one and five minutes of life, respectively. On physical exam, there was a large, firm, oozing tongue mass with transition from normal appearing tongue mucosa to necrotic and atypical tongue mucosa roughly halfway posterior on the lingual surface ( Figure 1). The patient's airway was widely patent on flexible laryngoscopic exam, and she was saturating well on room air.
The patient then underwent transnasal intubation in the operating room and magnetic resonance imaging (MRI). MRI face with and without contrast showed a large mass that filled and distorted the normal anatomy of the oral cavity and floor of mouth with extent inferiorly and laterally to the level of the mandible without bony extension and superiorly to the level of the hard   palate and posteroinferiorly to the vallecula, measuring 3.4 x 5.5 x 3.1 cm. The mass was isointense to soft tissue on T1 and heterogeneously hyperintense on T2 with absence of vascular flow voids ( Figure 2). MRI brain was noted to be normal. Biopsy of the tongue mass, tracheotomy, and gastrostomy tube placement occurred. Pathology, which was analyzed by CMH and an outside facility, was consistent with a congenital inflammatory myofibroblastic tumor with ALK, S100-protein, smooth muscle actin (SMA), desmin, and p53 positivity.
Traditional therapy would be complete resection, but in this patient would require subtotal glossectomy. Due to the high morbidity with this procedure, we received compassionate approval for targeted therapy with an ALK inhibitor, crizotinib. Prior to initiation of therapy, due to the necrotic nature of the tumor, dubulking was performed. Despite initial growth of the tumor, after twelve months of receiving crizotinib, there was good response with noticeable shrinkage of the tumor ( Figure 3A). The patient did have prolongation of her QTc interval, though a normal baseline echocardiogram, which can be a side effect of crizotinib. She underwent serial electrocardiograms (EKGs) during treatment to monitor her QTc interval, which normalized after cessation of crizotinib. The patient was last seen at 18 months old , off of therapy for eight months without signs or symptoms of recurrence with no detectable tumor by MRI imaging ( Figure 2B). She has been decannulated with removal of her gastrostomy tube without difficulties talking, swallowing, or breathing ( Figure 3B).

DISCUSSION Overview
Inflammatory myofibroblastic tumor is an overall rare, mesenchymal neoplasm that occurs primarily in the lung and abdominopelvic regions, with only 14-18% of the extrapulmonary IMTs occurring in the head and neck region [5]. Of that small subset of head and neck occurrences, the orbits and upper airways are most common [5]. Our study adds to the literature in that it is a tongue IMT, positive for ALK, in a neonate.

Pathological, Histological, and Imaging Features
Extrapulmonary cases of inflammatory myofibroblastic tumor show a combination of spindled fibroblastic and myofibroblastic cells with inflammatory infiltrate of lymphocytes, eosinophils and plasma cells [17]. The pathology in our patient showed relatively monotonous sheets of cells with ovoid to spindle-shaped nuclei, indistinct pale-gray cytoplasm with a delicate slightly vacuolated chromatin pattern (Figure 4). Mitotic figures and foci of necrosis visible. Other features are prominent hemangiopericytomatous vasculature with lymphocytic infiltrate and focal collections of osteoclastic giant cells. Fluorescence in situ hybridization (FISH) was positive for ALK in our patient. Positivity for the ALK gene has been reported in approximately 50% of IMTs [1,18]. The diagnosis of IMT requires histo-

CASE REPORT
logical and immunohistochemical staining to confirm diagnosis [8]. In this case, ALK, S-100 protein, SMA, desmin and p53 was positive. In a study observing immunohistochemical aspects of IMT, it showed vimentin was present in 100% of the cases (30/30) then in descending order SMA at 70% (21/30), desmin and ALK at 27% (8/30), and cytokeratin (CK) at 13% (4/30) [17]. Another study confirmed that most commonly SMA and vimentin are found to be positive to diagnose IMT [19]. Imaging features are variable depending where they are found in the body. Commonly, one will see an ill-defined soft tissue mass with heterogenous enhancement with or without invasive features on computed tomographic (CT) or MRI [19].

Treatment
Traditionally, since IMT is noted to be an aggressive and localized disease, treatment options for head and neck IMT have been reported to be managed with complete surgical resction [1,20]. Though, there are cases in which ALK gene positivity can be treated successfully with medical management, such as crizotinib. Crizotinib, a first-generation ALK inhibitor, has been shown to have good response rates in IMT with ALK positivity. Other therapies such as chemotherapy agents and radiotherapy have been described for unresectable tumors [21]. Adjuvant therapies such as steroidal and non-steroidal anti-inflammatory agents have been shown to be beneficial in metastatic disease [1]. In our case, a subtotal to complete glossectomy would have been the surgical treatment. This option would have been extremely morbid in a neonate, so further options were explored including a combination of a surgical debulking of the tongue mass with medical management administration of crizotinib. Crizotinib has possible side effects including visual disorders, gastrointestinal effects, hepatoxicity, pneumonitis, and cardiac effects such as QTc interval prolongation and bradycardia [22].

Outcomes
Outcomes seem to be substantial in surgical interventions, whether complete or partial resections, for treatment of IMTs [5]. Further, when observing the use of an ALK inhibitor agent in ALK positive IMTs, Thielen et al. reported achievement of partial to complete remission in 40% (12/30) patients with use of crizotinib [23]. Another study observed metastatic or inoperable ALK+ IMT reported the overall response rate for patients with IMT was 86% (N=14) with a partial response seen in 36% (5/14) [24]. The recurrence rate has been reported to be low with a 10-year survival rate at approximately 80% [1]. Our unique case showed complete clinical and radiological remission without recurrence at 8 months post-treatment with use of crizotinib.

CONCLUSION
Inflammatory myofibroblastic tumor is a low-grade malignancy that rarely occurs in the head and neck. To date, there are no reportable cases of IMT with ALK positivity occurring in the tongue in a neonate. Though, surgical resection has been the mainstay of treatment for IMTs, if positive for ALK, crizotinib may be considered. This study shows complete remission in an enlarging tongue mass in a neonate treated with crizotinib with no signs of recurrence at eight months follow-up. Therefore, it is important for clinicians to consider other treatment options for IMT in select patient populations.