Case report of long-term disease control of recurrent intraoral basal cell carcinoma with vismodegib at two-year follow-up

Introduction

Basal cell carcinoma (BCC) is the most common malignancy in humans, primarily occurring in the skin and accounting for approximately 75–80% of all malignant skin diseases (1). The incidence of cutaneous BCC (cBCC) has been increasing, with the age-adjusted incidence reported as 360.0 per 100,000 persons for men and 292.9 for women in the United States (2). Intraoral BCC (IOBCC), on the other hand, is a rare entity, and its diagnosis can sometimes be controversial due to its rarity, with only a few case reports published and histologic features that are similar to peripheral ameloblastoma (PA) (1,3).

The treatment of cBCC and IOBCC comprises a variety of surgical and non-surgical approaches, with the choice depending on factors such as tumour type, location, and extent. For localised cBCC, surgical excision remains the gold standard, offering high cure rates while preserving tissue. Mohs micrographic surgery is particularly effective for high-risk cBCC and those located in cosmetically sensitive areas (4). Non-surgical options like photodynamic therapy (PDT) are also available for low-risk cBCC, especially when surgery is contraindicated (4,5). Hedgehog pathway inhibitors (HHIs) such as vismodegib and sonidegib are effective treatment options for advanced cases, including locally advanced or metastatic cBCC (6-8).

On the other hand, treatment paradigm for IOBCC is less known due to the rarity of these tumours. Based on published case reports, the most common treatment is wide local excision in localised, resectable cases, followed by close clinical follow-up. Local recurrence has been reported in IOBCC, with a recurrence rate of up to 17% in a case series (1). The use of radiation and systemic therapy for IOBCC has not been documented in the literature. Management of recurrent IOBCC that is not amenable to resection remains unclear.

Despite the availability of various treatment options, managing cBCC and IOBCC presents several clinical challenges. These challenges include addressing recurrent tumours, ensuring complete excision, balancing effective treatment with cosmetic outcomes, and managing advanced or metastatic cases. The rarity of IOBCC can make accurate diagnosis difficult, potentially leading to misidentification or delayed treatment. Additionally, the lack of long-term efficacy data for some non-surgical treatments and the need for diligent follow-up care further complicate the management of these skin cancers. Ongoing research into immunotherapies and targeted molecular treatments offers promise for improving outcomes, particularly in challenging cases.

We report a case of effective treatment of unresectable recurrent IOBCC with vismodegib, which yielded a rapid and durable response. Treatment was additionally delivered via a gastrotomy feeding tube, with no unexpected side effects reported. We present this article in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-24-235/rc).

Case presentation

A 60-year-old female was first diagnosed in August 2016 with IOBCC when she presented with burning pain in the right buccal mucosa and right anterior hard palate. Prior to this presentation, she had a history of multiple cBCC since age 23 years [1979] on her limbs and torso, including a right upper lip and vermilion junction BCC. She has not been tested for Gorlin syndrome and has declined testing for this thus far. Her cBCCs were primarily treated with surgical excisions and superficial radiotherapy. In 2008, at age 52 she was treated with Mohs surgery for the recurrence of lip BCC. She had further recurrence in 2009 and was treated with wide local excision and Abbe flap. Her other relevant past medical history is ovarian cancer treated in 2012 with hysterectomy. In 2016, she was independent of her activities of daily living and had a good performance status of Eastern Cooperative Oncology Group (ECOG) score of 0. She is an ex-smoker and lives at home alone.

At her initial presentation in August 2016, clinical examination showed diffuse erythroplakic lesion at the maxillary gingivolabial sulcus and right anterior aspect of the hard palate. There were no discrete areas of thickening suspicious for invasive carcinoma, and no cervical lymphadenopathy found on examination. The oral cavity lesion was biopsied and showed an immunoprofile consistent with BCC. A computed tomography (CT) scan did not show any evidence of metastasis, and the lesion was not seen on CT. In particular, there was no maxillary bone destruction or cervical lymphadenopathy found in the CT scan. She subsequently underwent wide local excision with split skin graft for the intraoral lesion; however, it had involved margins in August 2016. The histology results from the surgery confirmed multifocal superficial BCC, and the diagnosis was discussed and confirmed in a head and neck multidisciplinary meeting as primary IOBCC. She later underwent re-excision with full maxillary dental clearance with close margins in January 2017 and received postoperative radiation 60 Gy in 30 fractions completed in May 2017. This was complicated by osteoradionecrosis treated with hyperbaric oxygen therapy. In February 2018, she underwent a revision of the scar and a full-thickness skin graft with a biopsy of a vallecula cyst, which was benign. In August 2019, she had reconstruction of the zygomaticomaxillary complex, where she received four anterior regular maxillary implants and placement of two zygomatic implants.

Her first IOBCC recurrence was in December 2020, 52 months after her initial presentation, when she presented with a new erythroplakic lesion in the left maxillary alveolar sulcus (Figure 1), noted incidentally by her prosthodontist, and the biopsy confirmed recurrent IOBCC. She later underwent removal of her left zygomatic implant and total inferior maxillectomy and left neck dissection, tracheostomy plus fibula free flap for the left maxilla and right buccal surface in February 2021. She then went on surveillance for a year but unfortunately had her second IOBCC recurrence in February 2022, 66 months after her first recurrence. This was during routine surveillance examination, when she was found to have a 1-cm area of erythroplakia at the left retromolar trigone region inferior to the flap, and a punch biopsy revealed superficial mucosal BCC (Figure 2). The biopsy showed strong positive immunohistochemical staining with BEREP4 while epithelial membrane antigen (EMA) and cytokeratin 19 were negative (1). CT chest and neck did not show any recurrence or evidence of metastatic disease. Her case was discussed in the head and neck multidisciplinary team meeting and surgery was thought to be too morbid. She was unable to have further radiotherapy as she had already received 60 Gy of treatment back in 2017, which resulted in osteoradionecrosis. She was then referred to medical oncology to try vismodegib, a hedgehog inhibitor used for locally advanced or metastatic cBCC (6). She commenced vismodegib 150 mg once daily via radiologically inserted gastrostomy (RIG) as she was unable to tolerate any oral intake due to post-treatment morbidities from her previous surgeries. The lesion at baseline was measured to be around 1 cm.

Figure 1 Leukoplakia lesion seen in left maxillary labial sulcus during her first IOBCC recurrence in 2020. This image is published with the patient’s consent. IOBCC, intraoral basal cell carcinoma.

Figure 2 Histological section of intraoral stratified squamous mucosa demonstrating a proliferation of malignant basaloid cells arising from the basal layer of the surface epithelium. The constituent cells contain enlarged, irregular, and hyperchromatic nuclei with peripheral palisading at the base. Haematoxylin and eosin slide at 20× magnification.

After 2 weeks of treatment, she had been tolerating vismodegib with mild side effects such as hair thinning, mild nausea, and fatigue. The lesion was reported to be much smaller on clinical examination after 2 weeks of treatment. On review after 4 weeks of treatment, the initial lesion has clinically resolved completely with only residual leukoplakia change. At her 3 months review, there was no resectable lesion seen and decision was made for further 6 months of vismodegib followed by close surveillance and a plan for resection if she had early recurrence. She completed further 6 months of vismodegib and remains clinically in complete response. She then had a staging CT scan after completion of treatment which did not show any recurrence, lymphadenopathy or distant metastasis.

She continued surveillance with the plan for at least annual whole-body imaging with either a positron emission tomography (PET) or CT scan, and she remains disease-free 2 years after stopping vismodegib. Since her disease was not visible on CT scans, she continues surveillance with regular clinical examination by the Ear, Nose and Throat (ENT) team. In March 2024, on clinical examination, there was an area of raised erythroleukoplakia between the left posterior and anterior implant, corresponding to the area of previous recurrences. This area was biopsied and showed hyperkeratotic squamous mucosa and granulation tissue containing mixed acute on chronic inflammatory cell infiltrate, including giant cell reaction to foreign material with no evidence of dysplasia or malignancy. Her last review was in February 2025, and her examination was unremarkable as she remains in complete remission to date, as supported by her negative clinical examination and previous CT imaging and pathology, which did not show disease recurrence. She remains on surveillance and continues to be followed up (Figure 3).

Figure 3 Summary timeline of case presentation. IOBCC, intraoral basal cell carcinoma.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

IOBCC shares similar histopathological features with cBCC; however, it can be challenging to diagnose due to its similarity to other mucosal oral lesions, such as PA and basaloid squamous cell carcinoma, which can mimic IOBCC by exhibiting basaloid cells with peripheral palisading and surface epithelial involvement. True oral mucosal BCC, either de novo or an extension from cBCC to oral mucosa, is extremely rare with only a few case reports published (1,9,10). Since IOBCC shares the same histopathological features with cBCC and has the same origins from pluripotent basal cells, we postulated that the hedgehog pathway is likely to be involved as well (1). Therefore, we extrapolated the results of the phase II vismodegib trial in cBCC, in choosing vismodegib to treat this patient.

BCC is generally associated with a good prognosis, but relapses may occur, particularly in certain high-risk situations. While the incidence of metastases is minimal, relapses are frequent, occurring in 40% to 50% of cBCC cases (11). IOBCC is a rare neoplasm with potential local recurrence and aggressive behaviour (1). Although specific recurrence rates for IOBCC are not well-documented due to its rarity, prognosis and relapse patterns can be inferred from general studies on cBCC. cBCC typically have an excellent prognosis, with a 100% survival rate for cases that have not metastasised to other sites. The recurrence rate after complete excision is less than 2%; however, it is influenced by risk factors such as size, clinical subtype, tumour depth, infiltrative and micronodular histological subtype, and recurrent lesions (4).

The optimal treatment strategy for unresectable recurrent IOBCC remains undetermined due to the rarity of this condition, which is primarily documented through isolated case reports (1,12). All 6 cases of histologically confirmed IOBCC in the case series done by Woods et al. were treated with surgical excision (1,3,10,13). A more recent case report of IOBCC was the first case IOBCC known to be treated with Mohs surgery. The IOBCC was incidentally found during the Mohs surgery extending to the buccal mucosa, which was done for treatment of a lip cBCC (9). Only one of the cases was reported to have recurrent disease after excision and was further treated with surgical excision (10). The standard treatment options for locally advanced or metastatic BCC are local therapies with surgery or radiotherapy. If local therapy has failed or is no longer feasible if it would be too morbid, then systemic therapy such as hedgehog inhibitor is recommended as the next line of treatment (14).

Notably, our case represents the first documented instance of IOBCC being treated with vismodegib, a HHI. The selection of vismodegib was informed by phase II clinical data with 104 patients demonstrating its efficacy in treating metastatic or unresectable cBCC, with an objective response rate (ORR) of 48.5%, and a median progression-free survival (PFS) of 9.3 months and median overall survival (OS) of 33.4 months (6). Several real-world studies of vismodegib on cBCC have reported better response rates than the phase II ERIVANCE, with response rates ranging from 78% to 100% (8,15,16).

Cemiplimab, a programmed cell death protein-1 (PD-1) inhibitor, is another systemic treatment option for locally advanced or metastatic cBCCs. Currently, cemiplimab is approved by the Food and Drug Administration (FDA) for the treatment of cBCC after the failure of hedgehog inhibitor treatment. This is based on the phase II trial with 84 patients, which showed a response rate of 31% with an estimated duration of response exceeding 1 year in 85% of the responders (14,17). Other checkpoint inhibitors such as nivolumab and pembrolizumab have also shown benefit in small early phase I studies and case series (18-21). The combination therapy of hedgehog inhibitors and immune checkpoint inhibitors is currently being investigated. However, running large phase III randomised controlled trials in this cohort of patients is extremely difficult due to the rarity of locally advanced and metastatic cBCC, especially patients refractory to first-line hedgehog inhibitors (14).

Prior to our study, the use of vismodegib for IOBCC had not been reported. Vismodegib is typically administered orally; however, in this case, the patient opened the capsule and delivered the contents through the RIG tube. Given that vismodegib is a highly permeable compound with low aqueous solubility, its administration via RIG presents challenges, including potential dissolution issues that could impair its efficacy (22). Our case study is the first to document the administration of vismodegib via RIG, highlighting an important consideration for treatment, particularly for patients with advanced BCC in the head and neck region, who frequently suffer from swallowing impairments and subsequently rely on RIG or percutaneous endoscopic gastrostomy (PEG) for para-enteral feeding. There is no data regarding its safety or efficacy to be administered via RIG or PEG. Another hedgehog inhibitor, sonidegib, is also a capsule similar to vismodegib and does not have data on administration via RIG or PEG (23). This highlights the area of need for more studies to be done on the safety and administration of hedgehog inhibitors through RIG or PEG.

This case merits reporting due to the positive outcome, emphasising the importance of exploring novel therapeutic approaches when addressing rare and aggressive forms of skin cancer. Vismodegib, a HHI, has demonstrated effectiveness as a treatment option for this patient, potentially paving the way for managing similar cases in the future. This report highlights the need for ongoing research and clinical trials to investigate further the efficacy of targeted therapies in treating recurrent and challenging forms of IOBCC.

The main limitation of this case report is that it is a single case, which restricts the generalisability of the findings. While the effective treatment of recurrent IOBCC with vismodegib is encouraging, further studies with larger patient cohorts and longer-term follow-up are necessary to validate its efficacy and safety for this rare condition. Additionally, the long-term effects and the potential for recurrence beyond the current follow-up period remain unknown. The administration of vismodegib through a gastrostomy tube, while innovative, requires further investigation to assess its broader applicability and potential impact on drug absorption and efficacy. Finally, since IOBCC is extremely rare, limited comparative data is available, making it challenging to contextualise this case within the broader landscape of IOBCC treatment approaches.

Conclusions

Our findings suggest that vismodegib can induce rapid, effective, and durable responses in IOBCC. Furthermore, the administration of vismodegib via RIG was found to be safe and did not compromise its efficacy. This case underscores the potential of vismodegib as a viable treatment option for IOBCC and provides a precedent for its administration via alternative routes in patients with advanced disease who are unable to swallow oral medications.

Acknowledgments

We thank the patient for her kindness in participation and support in writing this case report.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-24-235/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-24-235/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-24-235/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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