BRAF inhibitors in BRAF V600E-mutated ameloblastoma: systematic review of rare cases in the literature

Abstract

Background: Ameloblastoma in 66% of the cases harbor a somatic mutation of the "mitogen-activated protein kinase" signaling pathway (BRAF V600E). In V600E mutations, BRAF is in the permanent "on" state and relays the growth-promoting signals independently of the EGFR pathway. Therefore, mutant BRAF represents a target for handful of new drugs.

Methods: We conducted a literature search, with the search terms "Vemurafenib, Dabrafenib, Ameloblastoma, and BRAF." These included seven case reports with nine patients who underwent monotherapy with Dabrafenib or Vemurafenib or combination therapy with Dabrafenib and Trametinib.

Results: The patients age ranges from 10 years up to 86 years. The distribution of women and men is 4:5. Patients with an initial diagnosis of ameloblastoma, as well as recurrences or metastasized ameloblastoma were treated. Indications cover neoadjuvant therapy up to the use in metastasized patients in an irresectable state. Results ranging from "only" tumor size reduction to restitutio ad integrum.

Conclusion: We see the use of BRAF Inhibitors to reduce tumor size with consecutive surgical treatment as a reasonable option for therapy. However, we are aware that at present the data are based only on case reports with the longest follow-up of just 38 months. We encourage further clinical trials in the use of BRAF Inhibitors for selecting ameloblastoma patients in a multi-center setting.

Keywords: Ameloblastoma; BRAF; Chemotherapy; Dabrafenib; Facial reconstruction; Vemurafenib.

Fig. 1

BRAF pathway: from the outer membrane to the nucleus

Fig. 2

Top row shows the reconstructed 3-dimensional computerized tomography demonstrating on the left an osteolytic lesion involving the right mandibular body and ramus. On the right the partial radiologic response is demonstrated, observed after 10 months of targeted therapy which brought the mandible to a near pre-disease state. Middle and bottom rows—a consecutive series of MR images at different time points along the treatment course, from left to right, including Coronal T2 Fat saturated images (middle row) and corresponding Coronal T1 post-contrast Fat-suppressed images (bottom row). The Earliest scan from Oct 2018 (Image 1) shows the heterogeneous, mixed solid, and cystic nature of the intramedullary lesion, with resultant Bucco–lingual expansion of the body and ramus of the right mandible. One can notice the noticeable gradual reduction of the tumor mass with accompanying improvement of the bony contour, till the Nadir at June 2019 (Image 3). A 4th follow-up scan performed on Nov 2019 showed a suspected recurrent cystic lesion distal to the tooth bud, which upon curettage, eventually represented histologically proven pseudo-progression

Fig. 3

Top row: (A, B) Tumor at initial diagnosis. A Photomicrograph of one of the initial lesions of unicystic ameloblastoma—mural type, showing typical basal cells with a palisading pattern (arrows) and stellate reticulum-like appearance of the more superficial layers (asterisk) of the cystic epithelium (HE, original magnification X200). B BRAF immunostain of the initial lesion showing diffuse and strong reaction (BRAF, original magnification ×200). Tumor after anti-BRAF therapy. C BRAF immunostain shows only weak reaction of the ameloblastic lining epithelium (BRAF, original magnification ×200); Novel bone. D The bone at the periphery of the residual lesion was viable, of woven type and free of disease (HE, original magnification ×100). E The same field as in D seen with polarized light. The arrows point to small fragments of lamellar bone, while the main bone mass is of woven type (HE and polarized light, original magnification ×100); bottom row: Targeted therapy-mediated immune response (F). The persistent cystic lesion lined by ameloblastic epithelium. The lumen contains sheets of lining epithelium admixed with an inflammatory reaction predominated by multinucleated giant cells (asterisks) shown at a higher magnification in (H). In addition, the connective tissue wall contains many aggregates of multinucleated giant cells (arrow) (HE, original magnification ×40). G Major architectural alterations of tumor—The lining ameloblastic epithelium is devoid of the characteristic basal cell palisading pattern, and the other layers show dis-cohesion and/or changes indicative of apoptosis, which consist of an eosinophilic cytoplasm and small and pyknotic, almost absent, nucleus (HE, original magnification ×200). H–J Inflammatory reaction (H). The solid aggregate in the lumen from (F) at a higher magnification is composed of disintegrating ameloblastic epithelium admixed with numerous inflammatory cells, multinucleated giant cells, and hemorrhagic areas (HE, original magnification ×200); I CD68 (marker of macrophages) showing remarkable infiltration into the ameloblastic lining epithelium; numerous positively stained cells are also seen within the connective tissue wall (CD68, original magnification ×200). J CK19 immunostain (marker of odontogenic epithelium) highlights residual ameloblastic epithelium. One of the multinucleated giant cells contains remnants of CK19-stained fragments (arrow) (CK19, original magnification ×400)