A Paradigm Shift in the Management of Cherubism? A Preliminary Report Using Imatinib
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Article InfoArticle Outline
Cherubism is an autosomal-dominant inherited mutation in the SH3BP2 gene on chromosome 4p16.3. It is characterized by bilateral symmetric fibro-osseous lesions that are limited to the maxilla and mandible. The lesions present in early childhood and typically spontaneously involute after puberty. Current standard practice is to reserve surgery for symptomatic or severely disfiguring cases. This report presents 3 patients with cherubism who exhibited marked reduction in tumor size with imatinib, a tyrosine kinase inhibitor. Treatment was well tolerated, with few side effects.
Cherubism is a skeletal dysplasia caused by mutation of the SH3BP2 gene. This leads to bilateral symmetric fibro-osseous lesions of the maxilla and mandible. Initial jaw expansion typically begins during the toddler years, with progression through puberty. After puberty, the lesions usually involute and disappear by adulthood. Therefore, surgery is typically reserved for the most symptomatic or disfiguring cases. Reported symptoms include pain, difficulty with mastication, and airway compromise. Once symptoms present, definitive management options are few and can carry great risks.1 There are many case reports of surgical management of cherubism lesions using resection and reconstruction. There also are reports of attempts at management with tumor necrosis factor-α inhibitors, calcitonin, steroids, tacrolimus, imatinib, and denosumab, with varied success.2, 3, 4This report presents 3 patients with cherubism who were managed with imatinib. All patients exhibited marked involution of their jaw lesions and improvement of dental eruption.
Report of Cases
Case 1
A 6-year-old boy with cherubism presented with left mandibular swelling that had become more prominent during the previous 2 years. The patient's mother reported that when he was actively playing, the jaw became “bigger and red.” On examination the patient had severe bilateral jaw expansion and tender cervical lymphadenopathy. Computed tomography (CT) visualized bilateral multilocular lesions involving the mandibular body, angle, ramus, and condyles.
Biopsy examination of the lesions disclosed loose cellular fibrous connective tissue containing numerous multinucleated giant cells, fibroblasts, and vesicular nuclei. The histopathology was consistent with central giant cell granuloma of cherubism. His symptoms were managed with occasional use of acetaminophen or ibuprofen. Two years later he returned with substantial enlargement of the lesions, increased pain, and difficulty with oral intake. At this point he had been diagnosed with attention-deficit and hyperactivity disorder and had been started on methylphenidate hydrochloride and melatonin. His family no longer wished to continue expectant observation. Baseline imaging studies and laboratory values were obtained, and the patient started imatinib therapy at 300 mg/m2 rounded to nearest tablet, which was 200 mg, by mouth daily. The patient was treated for 6 months consistently and then sporadically for another 6 months because of family social issues. Then, he was lost to follow-up for 1 year.
He presented to the authors' clinic 1 year after self-discontinuation of treatment and 2 years after the initial decision to begin imatinib therapy. His family reported, “he is back to normal.” He ate well, had no pain, and could play without restrictions. Their only concern was a palpable bony protrusion along the left mandibular border. Examination disclosed near complete resolution of jaw lesions. His asymmetric facial dysmorphology and intraoral alveolar expansion had normalized. There was an area near the left body of the mandible with a small bony prominence that was believed to be residual bone remodeling. His lymphadenopathy was much improved, with only a few small palpable submental nodes (Fig 1A, B). Repeat imaging studies showed near complete involution of lesions with remodeling of his mandible and improvement in dental eruption. Two lesions remained, 1 at each ascending ramus, and were visible on panoramic radiograph (Fig 2A, B). Volumetric analysis of his imaging studies before and 2 years after initiation of treatment showed an approximate reduction of tumor size by 75%. He was always a small child, less than the fifth percentile for height and weight, with a petite mother and father. His mother's height measured 4 feet 10 inches and his father's height measured 5 feet 6 inches. His growth curves were carefully monitored and remained stable throughout the 2 years. At this time, 2 years after initiation of treatment, he returned to the operating room to reshape the remodeled bone, and tissue samples were obtained from the jaw lesions. Histopathology disclosed lesions similar to those at the original biopsy examination. The lesion did not display decreased vascularity or fewer giant cells. Fluorescent in situ hybridization testing was negative for the BCR-Abl gene.
Figure 1
Case 1. A, Start of treatment. B, Two years later. The patient took medication for 1 year and then discontinued.
Figure 2
Case 1. A, Panorex view at start of treatment. B, Panorex view 2 years later.
Case 2
A 6-year-old boy with cherubism presented to the authors' clinic with jaw swelling since 3 years of age. He had bilateral maxillary and mandibular lesions. At 5 years, he underwent 2 surgical debulking procedures by another surgeon. Pathology showed giant cell fibro-osseous lesions consistent with cherubism. His family history showed multiple affected family members. On presentation he also had obstructive sleep apnea (OSA) and slept with bilevel positive airway pressure (BiPap), which he tolerated well. His family elected no treatment, and he was lost to follow-up for 2 years. At 8 years of age, he returned with worsening OSA and was no longer tolerating his BiPap. He also developed occasional epistaxis and iron deficiency anemia. Baseline laboratory values were obtained, and he began iron supplementation and imatinib 300 mg (300 mg/m2) by mouth daily. Within 3 months his epistaxis and anemia resolved, and by 5 months of treatment, the patient reported being able to breathe through his nose. Side effects included occasional nausea, which was controlled by ondansetron. At 10 months into treatment, the patient's growth curves thus far have been unaffected during therapy (Fig 3A-G). Volumetric analysis of his imaging studies before and 10 months into treatment showed an approximate reduction of tumor size by 22%.
Figure 3
Case 2. A, Initial presentation. B, Facial view depicting progression of disease over 2 years. C, Worm's eye view showing progression of disease over 2 years. D, Facial view 10 months into treatment. E, Worm's eye view 10 months into treatment. F, Three-dimensional computed tomogram before treatment. G, Three-dimensional computed tomogram 10 months into treatment showing ossification of the lesions.
Case 3
A 4-year-old relative of case 2 presented for evaluation of cherubism. She was 2 years old when her jaw lesions were identified and underwent debulking with bone grafting by another surgeon. The lesions had since regrown. Her legal guardian did not want to consider expectant observation because of the aggressive nature of her cousin's lesions. On examination she was noted to have bilateral alveolar expansion and jaw enlargement with bilateral cervical lymphadenopathy and an anterior open bite. She was otherwise asymptomatic. Her CT displayed multilocular lesions in the maxilla and mandible. Her pathology was reviewed and was consistent with fibro-osseous lesions of cherubism. Baseline laboratory values were obtained, and she was started on imatinib at 200 mg (300 mg/m2) orally once daily. She had occasional nausea when taking the medication on an empty stomach, which resolved when taking it with food. Ten months into treatment her jaw lesions have considerably involuted, facial dysmorphology has resolved, and her open bite has mostly corrected (Fig 4A, B). Her growth curve has been unaffected thus far. Volumetric analysis of her imaging studies before and 10 months into treatment showed an approximate reduction of her tumor size by 65%.
Figure 4
Case 3. A, Facial view before treatment. B, Facial view 10 months into treatment.
Discussion
Cherubism is a skeletal dysplasia caused by mutation of the SH3BP2 gene. This leads to bilateral symmetric fibro-osseous lesions of the maxilla and mandible. Initial jaw expansion typically begins during the toddler years, with progression through puberty. After puberty the lesions usually involute and disappear by adulthood. Therefore, surgery is typically reserved for the most symptomatic or disfiguring cases. Medications have been largely ineffective in the management of this condition.2
This report presents 3 cases in which imatinib, a tyrosine kinase inhibitor (TKI), was used to manage aggressive fibro-osseous jaw lesions in cherubism. Patients were treated off study and off label as compassionate use based on the proposed mechanism of action and efficacy. Parents and physicians were aware of the potential complications and unknown degree of efficacy. Interestingly, the lesions not only stopped growing but also involuted, allowing for regression of symptoms, improvement and normalization of facial dysmorphology, and correction of dental malocclusion and dental eruption issues.
Imatinib is a TKI most commonly used to target the BCR-Abl tyrosine kinase in pediatric patients with Philadelphia chromosome positive chronic myelogenous leukemia (Ph+ CML) or acute lymphoblastic lymphoma (Ph+ ALL). It is generally well tolerated, but side effects can include bone marrow suppression (with initiation of therapy), nausea, edema, muscle cramps, diarrhea, hepatotoxicity, or skin allergic reactions. Pediatric patients with Ph+ ALL are treated with continuous TKIs in combination with standard chemotherapy regimens. The average length of treatment for Ph+ ALL with a TKI is 27 months; the average treatment for CML can be up to 60 months, and it is mostly used for adult patients. There are advantages for the pediatric population, including a low side effect profile and ease of use, and it allows for outpatient monitoring. Blood cell counts, liver function, and kidney function were monitored closely with the initiation of imatinib. The pediatric-specific side effects can include growth suppression in prepubertal populations that returns to baseline with puberty.5 Monthly monitoring of weight and height showed no changes in growth curves in any of the patients. The present patients did experience intermittent nausea, which was easily controlled. One patient had lymphopenia 2 months after initiation but this quickly resolved and was likely related to a concurrent infection. Although pain scales were not charted, the parents of case 1 reported improved oral intake and normalization of childhood behavior within a few months of taking the medication.
The mechanism of action of imatinib in cherubism is completely speculative and requires further research. The pathogenesis of cherubism is under investigation, but the lesions appear to be potentiated by inflammation and bony resorption. This is secondary to a mutation in the SH3BP2 gene, which encodes for the adapter protein 3BP2.6, 7 Although the full extent of this protein's actions are still being discovered, mouse models have shown that this protein attaches to the tyrosine kinase c-abl, leading to an upregulation of inflammation and osteoclastogenesis.8, 9, 10 Imatinib is an active inhibitor of the c-abl, c-kit, and platelet-derived growth factor tyrosine kinases.4 Inhibiting c-abl could directly mitigate the effects of the aberrant 3BP2 protein. In addition, imatinib has been shown to promote osteoblast differentiation by inhibiting platelet-derived growth factor.11
There are several unanswered questions in this case series that will require further investigation. First, it is uncertain for how long patients need to be treated. Because most jaw lesions begin involution at the time of puberty, should the medication be used only until that time? Second, if the medication is discontinued and the lesions regrow, then can they mutate and become resistant to imatinib? Third, is the appropriate dose being used? The dose used was extrapolated from leukemia data, and it is not certain whether that is, in fact, the most appropriate dose in pediatric prepubescent children with cherubism. It also is unclear in this population whether there could be long-term growth-related consequences. In the present patients, the length of treatment will be reassessed every 6 months based on medication tolerability, patient growth curves, and size of lesions. The authors hope to obtain complete eradication of lesions but might discontinue therapy if a plateau is reached or if the medication becomes poorly tolerated.
This investigation brings to light another important question that must be considered. Can cherubism be cured? If imatinib, or one of its sister medications, can be used to block the phosphorylation of a binding protein that can somehow prevent jaw lesions from forming, then at what age should the medication be started? Perhaps it should begin before jaw lesions are identified?
Because most extant literature regarding the management of cherubism is focused on decreasing inflammation, decreasing osteoclasts, or surgically debulking lesions, the use of imatinib for cherubism is a paradigm shift in addressing this disease. Specifically, one must consider whether the aggressive central giant cell granulomatous lesions can be prevented or cured with medication. In the current era of molecular medicine, clinicians should have more options than expectant management to offer these patients. The authors hope this report will inspire others to continue research on this very important topic.
References
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- Chihara, K., Kato, Y., Yoshiki, H. et al. Syk-dependent tyrosine phosphorylation of 3BP2 is required for optimal FcRγ-mediated phagocytosis and chemokine expression in U937 cells. Sci Rep. 2017; 7: 11480
- Kadlub, N., Sessiecq, Q., Dainese, L. et al. Defining a new aggressiveness classification and using NFATc1 localization as a prognostic factor in cherubism. Hum Pathol. 2016; 58: 62
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