July 2011

Resolution of Odontogenic Keratocysts of the Jaw in Basal Cell Nevus Syndrome With GDC-0449

Author Affiliations

Author Affiliations: DermSurgery Associates, Houston, Texas (Drs Goldberg, Moody, and Holzer and Ms Landau); Department of Dermatology, Weill Cornell Medical College, Methodist Hospital, Houston (Drs Goldberg, Kazakevich, and Holzer); Department of Dermatology, University of Texas, Houston (Dr Goldberg); and Department of Radiology, Baylor College of Medicine, Houston (Dr Myers).

Arch Dermatol. 2011;147(7):839-841. doi:10.1001/archdermatol.2011.50

Background Odontogenic keratocysts of the jaw are a central feature of basal cell nevus syndrome (BCNS) and arise from the basal cell layer of the surface epithelium. Although they are benign, they tend to be aggressive, with local invasion of bony structures, extensive growth, and potential for substantial disfigurement and speech dysfunction. Complete surgical resection is the current standard of care; however, the procedures are often technically challenging and are followed by high recurrence rates.

Observations We report the case of a 55-year-old man with a long-standing history of BCNS. Over a 25-year period, this patient had been treated for many basal cell carcinomas (BCCs). He also had multiple large odontogenic keratocysts in the mandible that had previously been treated using surgical, chemotherapeutic, and radiation treatment techniques. He had also undergone a right inguinal lymph node dissection after BCC metastasis was diagnosed within a lymph node. Owing to the recalcitrant nature of his condition and his history of BCC metastasis, the patient was started on a daily regimen of a new oral drug, GDC-0449, which inhibits the hedgehog signaling pathway, a key genetic contributor in the oncogenesis of BCCs. In addition to complete resolution of all his BCCs at 12-week follow-up, nearly complete resolution of 3 odontogenic keratocysts was documented by serial dental radiographs after 2 years of therapy.

Conclusions We report the nearly complete regression of multiple BCNS-associated odontogenic keratocysts following nonsurgical treatment with GDC-0449. This novel drug, useful for the treatment of BCC, also appears to be effective for treatment of odontogenic keratocysts.


A 55-year-old man with a strong family history of basal cell nevus syndrome (BCNS) had numerous basal cell carcinomas (BCCs) and multiple associated odontogenic keratocysts. The patient was first diagnosed as having BCCs in his early 20s and subsequently underwent treatment for over 750 BCCs. He had other features of BCNS, including odontogenic keratocysts, palmar pits, partial cleft lip, bifid ribs, frontal bossing, and pectus deformity. After numerous surgical procedures for BCCs, including a lymph node dissection, the patient refused to undergo any further surgery. Following a detailed discussion about his treatment options, he began treatment with a cyclopamine derivative1 experimental drug, GDC-0449, at a dose of 270 mg/d, which had recently been shown in phase 1 clinical trials to resolve or substantially reduce the tumor burden of advanced BCCs.

Most of his existing BCCs resolved after approximately 12 weeks of continuous treatment,2 and he continued the treatment to prevent development of new BCCs. After 2 years of this regimen, repeated radiographs obtained at a dental visit illustrated nearly complete resolution of existing odontogenic keratocysts without interval development of any new ones. Figures 1, 2, and 3, serial dental radiographs acquired from 2007 to 2010, show progressive involution and regression of 3 odontogenic keratocysts. In this case, it appears that GDC-0449 was effective in the treatment of odontogenic keratocysts associated with BCNS.

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Figure 1. Baseline panorex radiograph of our patient taken February 21, 2007. Three expansile, geographic, well-circumscribed, partially lobulated, radiolucent lesions with a narrow zone of transition are seen within the right mandible, spanning from the parasymphyseal region to the midbody of the mandible, underlying remaining teeth 25 through 32. There may be communication between the cavity spaces of these 3 adjacent lesions. An additional cystic lesion is seen medial to tooth 31. Tooth 27 is angled toward the midline, likely as a result of the underlying lucent lesion. An additional, smaller lesion is seen within the left midbody of the mandible, along the apex of tooth 18, underlying teeth 18 and 19.

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Figure 2. Interval panorex radiograph of our patient taken November 8, 2009. The 3 expansile, cystic lesions within the right mandible have markedly decreased in size since baseline. A single larger cystic lesion persists, mildly smaller than on comparison examination, underlying teeth 31 and 32. Two small, subtle, cystic-appearing, lucent lesions remain within the mandible underlying teeth 27 and 28. There has been a marked increase in sclerosis within the parasymphyseal and proximal body of the right mandible at the site of prior right mandibular cystic lesions. The additional, smaller lesion within the left midbody of the mandible, at the site of prior location of tooth 18, is suspected to have also minimally decreased in size.

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Figure 3. Most recent panorex radiograph of our patient taken December 2, 2010. Mildly limited examination owing to underexposure. The cystic lesions within the right mandible are unchanged over the interval, remaining markedly smaller than on February 21, 2007, with persistent increased sclerosis at the site of prior lesions. Continued interval decrease in size, with associated increase in sclerosis, involving the cystic lesion within the left mandibular body at the prior site of tooth 18. No new cystic lesions are identified.


The most common complications of BCNS are BCCs and odontogenic keratocysts; these cysts have the potential to be severely disfiguring. Until now, surgery has been the only effective treatment option for these cysts. The observed resolution of multiple odontogenic keratocysts in our patient with BCNS during his course of treatment with GDC-0449 was an unexpected benefit. Currently in stage 2 trials, GDC-0449 is not yet widely available to the general public. If and when it is made available, physicians can prescribe this medication for the treatment of odontogenic keratocysts.

Although the exact molecular mechanisms underlying the pathogenesis of BCC have yet to be fully elucidated, it appears that most cases, whether sporadic or hereditary, are related genetically and show aberrations in the hedgehog signaling pathway. The hedgehog signaling pathway involves a dynamic relationship between a series of tumor suppressor genes (patched homologue 1 [PTCH1 ]) and oncogenes (smoothened homologue [SMO ]). This pathway is especially active during embryogenesis, when it functions to regulate cellular proliferation during normal growth and development; it is generally quiescent in adult tissues.3 As an oncogene, activated SMO leads to cellular division and proliferation. Conversely, PTCH1 is a tumor suppressor gene; when activated, it exerts an inhibitory effect on SMO signaling to keep cell division under control. When the intricate dynamic relationship between these 2 opposing genes is disrupted, oncogenesis is the result; this most commonly occurs as a result of PTCH1 inactivation, or more rarely from SMO activation. The interactions of these particular pathways have been implicated in the growth and development of advanced BCCs. Specifically, a loss-of-function mutation in PTCH1 is the most common molecular aberration found in BCC.3

A selective inhibitor of SMO, GDC-0449 is currently being evaluated in clinical trials for the treatment of BCC and shows extremely promising results. Phase 1 trials have shown clinically significant responses, defined as disappearance of tumors or reduction in tumor size of greater than 50% in patients with advanced and metastatic BCC refractory to conventional therapies.3 The adverse effects of the drug consist of hair loss, fatigue, muscle spasms, and cardiac conduction abnormalities.2,3 To attest to the clinical effectiveness of the drug in treating advanced BCC, our research group2 has previously reported a case of resolution of all but 1 BCC in the same patient described herein after 12 weeks of oral therapy with this drug.

The present case suggests that GDC-0449 is also effective in treating the odontogenic keratocysts of BCNS. This finding may be further supported by the case report of a patient with BCNS who developed 2 jaw cysts that were genetically analyzed and found to possess distinct PTCH1 loss-of-function mutations similar to those previously implicated in the pathogenesis of BCC.4 Therefore, it is not surprising that GDC-0449 can cause resolution of these cysts, just as it eliminates BCCs through inhibition of the hedgehog signaling pathway.

The odontogenic keratocysts of BCNS have the potential to cause disfigurement and loss of function. Our patient had undergone multiple procedures to remove his cysts and was left with a noticeable speech impediment. The main treatment options include enucleation, with or without curettage, peripheral ostectomy, chemical curettage (Carnoy solution), and resection.5 Recurrences are fairly common and may be attributed to incomplete removal of the original cysts, microscopic satellite cysts, and the development of new cysts within the adjacent area.5 We treated our patient with oral GDC-0449 for BCCs in BCNS and incidentally noted nearly complete resolution of the odontogenic keratocysts without aggressive treatment.

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Article Information

Correspondence: Leonard H. Goldberg, MD, DermSurgery Associates, 7515 Main St, Ste 240, Houston, TX 77030 (goldb1@dermsurgery.org).

Accepted for Publication: January 26, 2011.

Published Online: March 21, 2011. doi:10.1001/archdermatol.2011.50

Author Contributions: Drs Goldberg, Landau, Moody, Kazakevich, and Holzer had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Goldberg, Landau, Moody, and Kazakevich. Acquisition of data: Landau, Moody, Kazakevich, and Holzer. Analysis and interpretation of data: Goldberg, Landau, Moody, Kazakevich, and Myers. Drafting of the manuscript: Landau, Moody, and Kazakevich. Critical revision of the manuscript for important intellectual content: Goldberg, Moody, Holzer, and Myers. Administrative, technical, and material support: Landau, Moody, Kazakevich, Holzer, and Myers. Study supervision: Goldberg.

Financial Disclosure: None reported.

Additional Information: Dr Goldberg is currently a principal investigator for this drug.

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