麻豆传媒

Three boys (ages 10, 13, and 15) with confirmed BRAF V600E mandibular presented separately to a hospital. The tumors were all deemed to be "marginally resectable," and histopathologic examination found unicystic ameloblastoma, mural type, in all three cases.

Clinicians planned standard-of-care treatment, which was radical surgery to completely excise the mandibular ramus and body, followed by planned reconstruction with vascularized free flap and reconstruction plates.

Prior to surgery, clinicians treated the three patients with BRAF-inhibiting agents, starting with targeted therapy with the oral kinase inhibitor dabrafenib (Tafinlar) at a pediatric dose of 4.5 mg/kg/day, administered in two doses daily. The patients were monitored throughout for cardiologic, ophthalmologic, dermatologic, and endocrinologic treatment-related effects.

All three patients developed mild nausea, which abated within a few days. Other grade I‐II adverse events included "abnormal hair texture" in the curly hair of one patient, and all three boys had some form of adverse dermatologic event, including acneform rash, erythema nodosum, and folliculitis, all of which resolved with treatment. Grade I-II fever was the only cause of short‐term treatment interruption.

This report will focus mainly on the treatment of the second patient, who was 13 years old at the time of presentation. On imaging, he presented with a large expansile conspicuous osteolytic lesion identified as a mural type unicystic ameloblastoma on the ramus and body of his right mandible. Mutation analysis showed BRAF V600E, with a variation allele frequency of 44.4%.

Based on his weight, the patient received dabrafenib 100 mg twice daily. The tumor mass was significantly reduced after 10 months of targeted therapy, which clinicians noted brought the mandible close to a pre‐disease state.

The earliest MRI scans from October 2018 showed the heterogeneous, mixed solid and cystic nature of the intramedullary lesion, with evidence of buccolingual expansion of the body and ramus of the right mandible. As the tumor mass decreased, repeated scans showed that the bony contour was improving.

Targeted therapy was continued for 16 months; time to nadir – reached in June 2019 – was 12 months. Tumor volume was 89 cc at diagnosis, decreasing to 23 cc at nadir. The anteroposterior, transversal, and craniocaudal tumor dimensions were 76, 31, and 76 mm, respectively, at diagnosis, decreasing to 52, 18, and 50 mm at nadir.

There was a radiological partial response followed by progressive disease, clinicians noted, and the patient was followed for 31 months. Postoperative variation allele frequency was 5%, and there was no evidence of disease.

In November 2019, a fourth follow‐up scan was performed, which revealed what clinicians suspected was a recurrent cystic lesion distal to the tooth bud; curettage and histological testing subsequently identified the growth as a "pseudo progression."

The medical team reported that none of the three patients had any serious toxicities or discontinued treatment due to adverse events. All three demonstrated a marked radiologic and clinical response to medical treatment, allowing for a conservative surgical approach with good success. Histologic assessment showed only "minimally residual tumor with extensive tumoral necrosis and fibrosis and generation of new bone," clinicians noted.

They assessed the patients' responses every 3 months through clinical examinations and MRI.

Partial response -- defined as at least 50% reduction in tumor size – returned the contour of the jaw to a near pre‐disease state and occurred at a median of 10 months. Rapid initial bone recontouring was followed by a stable/progressive radiological response, with minimal tumor regrowth foci observed in the second and third patients, clinicians reported

They timed surgical removal of the shrunken residual tumor within the remaining bone defect to occur after there was no MRI evidence of further bone deposition. The remaining tumor was completely resected, while preserving the temporomandibular joint, mandibular body, and ramus.

None of the three patients had any complications from surgery, and all were followed for a mean of 31 months, with no evidence of disease recurrence.

Pathology findings were comparable in all three patients, the team said. There was evidence of minimal residual tumor with extensive tumor necrosis and fibrosis, along with newly formed trabecular and cortical bone surrounding the residual tumor and in the previous core location of the original tumor. Bone samples taken along the original margin of the tumor were completely disease-free.

"Interestingly, pathological response revealed major architectural and cytological alterations in the neoplastic epithelium that were accompanied by extensive fibrosis and varying amounts of macrophage‐rich inflammatory reaction," the medical team observed. BRAF‐mutated alleles remained, but the variant allele frequency was significantly decreased, the team stated, noting that imaging evidence of an increase in focal tumor size during the treatment of the second and third patients was likely due to inflammatory and stromal changes, rather than to an actual increase in tumor burden.

Discussion

Ameloblastoma, a rare benign tumor that typically develops in the jaw near the molars, originates in the cells of the teeth's enamel lining.

Clinicians presenting this said they believe it to be the first report of this novel use of a BRAF inhibitor as neoadjuvant therapy for ameloblastoma in the pediatric population. Previous descriptions of the approach were single case reports of adult patients with recurrent or metastatic tumors.

Balancing the goals of acceptable disease‐free survival with the importance of unimpeded facial growth and minimal surgical defects in children and adolescents creates important clinical dilemmas for clinicians treating craniofacial tumors, given the absence of a proven regenerative therapy, the case authors noted. They cautioned that this may lead to a compromise of conservative surgical approach, with a potential for disease recurrence and an increased risk of malignant transformation.

"Although classified as a benign tumor, ameloblastoma is also the most common odontogenic tumor of epithelial origin with severe clinical implications," noted the authors of one . In addition, the growth pattern may be locally aggressive, with occurring in about 70% of cases, and up to 2% of cases metastasizing to other sites.

The standard treatment approach for recurrent ameloblastoma is radical surgery, which is usually associated with at least 10 years of disease-free survival, although ongoing clinical and radiographic monitoring is required throughout.

Ameloblastoma is insensitive to radiation therapy, and "should be avoided due to serious immediate and late sequelae," the case authors wrote.

"Current standard of care is radical surgery consisting of complete resection of affected bones with safety margins of 1.5 cm," one of the authors, Ariel Hirschhorn, MD, of Sheba Medical Center in Tel Hashomer, Israel, told 麻豆传媒. "Reconstruction of the ablative defect is carried out by vascularized free (usually bone harvested from the fibula) and reconstruction plates. In a growing child, placing substances and tissues which lack the ability to expand with the growing face, may lead to subsequent disfigurement."

Hirschhorn and co-author wrote: "Our findings in this small group of patients, may herald a paradigm change in the treatment of benign but locally aggressive tumors, in the mandible as well as other locations." Such targeted rational therapy might be used to debulk a large tumor and allow its safe excision while preserving normal appearance and function, the team added.

Somatic oncogenic mutations in the BRAF gene occur in more than 60% of mandibular ameloblastomas, driving the mitogen‐activated kinase (MAPK) pathway and thereby escalating cell proliferation activity in a ligand‐independent manner, the authors said.

They added that in their experience with these three patients, the presence of an activating BRAF mutation (mainly V600E), made it possible to use selective BRAF inhibitors in previously resected or unresectable advanced-stage ameloblastoma.

The authors cautioned, however, that although BRAF-targeted therapy is known to provide a rapid and significant clinical response, this benefit may be short-lived and ultimately followed by recurrence. When using such neoadjuvant bridging therapy for ameloblastoma, therefore, it is important to use serial MRI assessments to ensure maximal response and identify optimal timing for the surgical procedure, "either at the nadir or at the earliest detection of regrowth," the team said.

In these three patients, targeted neoadjuvant monotherapy with a selective BRAF inhibitor allowed the facial tissues to be restored to the pre‐disease state, the case authors explained. They added that replacement of the BRAF-mutated tumor by new, viable cortical and cancellous bone provided an "ideal natural reconstruction with inherent growth potential," with healing of bone occurring due to "carefully coordinated crosstalk between inflammatory and bone forming cells."

Conclusion

The case authors concluded that treatment of the human face needs needs to be carefully tailored, since it is the "personality determining organ." In the three cases reported, face-preservation therapy was achieved in pediatric patients presenting with BRAF V600E-mutated ameloblastoma. The use of BRAF inhibition in a neoadjuvant setting can spare the need to perform radical mutilating surgery, which allowed for unimpeded facial growth and development and afforded satisfactory disease‐free survival.

"Our study, though limited to a small number of patients, demonstrates the translational potential of targeted therapy as a neoadjuvant agent," the team wrote. "Patient‐specific organ preservation therapy should be considered as the new standard of care in ameloblastoma, mainly for children and adolescents."

Comment