J Korean Assoc Oral Maxillofac Surg 2024; 50(1): 35~40
Management and treatment of four cases of oral carcinoma cuniculatum
Constantinos Mourouzis1, Iordanis Toursounidis1, Christos Eftychiadis2, Georgios Rallis1
1Department of Oral and Maxillofacial Surgery, 2Department of Pathology, KAT General Hospital of Attica, Athens, Greece
Iordanis Toursounidis
Department of Oral and Maxillofacial Surgery, KAT General Hospital of Attica, Nikis 2, Kifisia, Athens 145 61, Greece
TEL: +30-2132086613
E-mail: i.toursounidis@gmail.com
ORCID: https://orcid.org/0000-0001-8082-0540
Received July 9, 2023; Revised September 11, 2023; Accepted October 6, 2023.; Published online February 29, 2024.
© Korean Association of Oral and Maxillofacial Surgeons. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
 Abstract
Objectives: Oral carcinoma cuniculatum (OCC) is a rare variant of squamous cell carcinoma (SCC). It has similar clinicopathological characteristics to SCC and verrucous carcinoma (VC). We present a case series of OCC and analyse its unique features, diagnosis, and management. Patients and
Methods: We retrospectively reviewed the medical records of oral cancer patients treated by Oral and Maxillofacial Surgery department from 2009 to 2020 with OCC biopsy findings. The clinicopathological characteristics and management of the OCC cases were analysed.
Results: Four patients were identified with histologic findings of OCC, including three on the alveolar ridge mucosa and one on the tongue. Imaging revealed that two of the lesions located in the maxilla had osseous lysis. All four patients were all treated with radical excision, and the histopathology showed findings of SCC cuniculatum. It was decided that no further treatment was necessary. None of the patients has experienced recurrence during follow-up.
Conclusion: OCC is a distinct entity that is more locally aggressive than VC but is associated with good prognosis. Radical surgical removal is considered appropriate for OCC. Emphasis should be given on an early diagnosis, as it remains challenging.
Keywords: Carcinoma cuniculatum, Oral cancer, Head and neck cancer, Oral squamous cell carcinoma
I. Introduction

Oral carcinoma cuniculatum (OCC) is a rare variant of squamous cell carcinoma (SCC). It has similar characteristics to verrucous carcinoma (VC), although it is more locally aggressive and carries a rare risk of metastasis1.

Carcinoma cuniculatum (CC) usually affects the plantar aspect of the foot, but it has been reported at other sites as well, including the oesophagus, abdomen, palm, leg, penis, and cervix2-9. Flieger and Owiński10, who first described CC in the oral cavity in 1977, highlighted its aggressive behaviour and unique features. The incidence of OCC is very rare, with fewer than 60 cases ever reported11, and it accounts for 2.7% of all oral squamous carcinomas12. Its etiology remains unclear, although trauma, tobacco use, alcohol consumption, chronic inflammation, and human papilloma virus (HPV) have been implicated as potential risk factors11,13,14. The most common location of OCC is the alveolar mucosa and gingiva, followed by the tongue, hard palate, mandible, and buccal mucosa11. It can present with a variety of clinical manifestations such as exophytic induration, verrucous or cauliflower mass, erythroleukoplakia, or as a non-healing ulcer with or without bone exposure11. Histologically, OCC is characterized by well-differentiated epithelial cells that are organized into ramified sinuses and keratin-filled crypts that resemble rabbit burrows (cuniculatum in Latin) with a notable lack of cytological atypia, unlike SCC. This may be the reason it is often not identified as a malignancy, resulting in treatment delays15. Most clinicians are unaware of its distinct existence, which makes its diagnosis challenging and potentially missed16. In this article we present a series of four OCC cases that was referred to our department. Our goal was to demonstrate its unique features and discuss its diagnosis and management.

II. Patients and Methods

A retrospective review of oral cancer patients treated by Department of Oral and Maxillofacial Surgery between 2009 and 2020 was performed. The inclusion criterion was an OCC diagnosis based on biopsy findings. Four cases were identified, and their characteristics were analysed. This study was approved in accordance with the Institutional Review Board standards of KAT General Hospital of Attica (IRB No. 11/05-01-2021), and the written informed consent was obtained from all patients.

III. Results

1. Case 1

A 56-year-old man was referred to our department due to an ulcerated lesion located at his right maxillary gingivae. The lesion had been present for almost three months and had been examined by a dentist. The man’s medical history included arterial hypertension and type 2 diabetes. He reported a history of smoking but denied alcohol consumption. Clinical examination revealed a painful, non-healing erythematous ulceration on his upper right alveolar ridge mucosa with profuse bleeding. Extraoral inspection was unremarkable, and neck examination did not reveal palpable lymphadenopathy. Computed tomography (CT) imaging of the head and neck revealed a tumour at his right maxilla extending up to the pterygoid process with evident bone erosion at the floor of the maxillary sinus. A CT scan of the neck did not detect any enlarged cervical lymph nodes. An incisional biopsy was planned, as both clinical and imaging features raised suspicion for malignancy. The biopsy, which revealed a highly differentiated stratified squamous epithelium with keratin-filled crypts resembling rabbit burrows and no remarkable atypia, was characteristic of carcinoma cuniculatum. The patient underwent subsequent en bloc resection with clear margins, and the defect was covered with a full-thickness skin graft from his neck and an obturator. No neck dissection was performed. Histopathology confirmed the initial biopsy. Three years later, the patient remains disease free.(Fig. 1. A)

2. Case 2

A 58-year-old woman presented to our outpatient clinic with a progressively enlarging lesion on the posterior dorsal surface of her tongue, which was first noted 14 months prior. Incisional biopsy had been performed elsewhere and revealed pseudoepitheliomatosis hyperplasia. Intraoral examination revealed an ill-defined pebbly induration on the dorsal surface of her tongue that was mildly tender on palpation. Tongue mobility was normal without restriction. An additional 1-cm superficial ulceration located at the midline of the hard palate was also identified.(Fig. 2. A) Neck examination did not reveal any palpable lymph nodes. The patient had no history of smoking or alcohol consumption. Magnetic resonance imaging of the head and neck showed a 1.8-cm contract-enhanced lesion on the dorsal surface of the tongue and no cervical lymphadenopathy. The patient underwent wide local excision for both lesions under general anaesthesia. The histopathology revealed carcinoma cuniculatum for the tongue lesion and focal infiltration of well-differentiated SCC for the palatal lesion.(Fig. 1. B) Two and one-half years post-operatively, the patient shows no signs of recurrence.(Fig. 2. B)

3. Case 3

A 66-year-old man presented for evaluation of a 1.5-cm papillary lesion located on his left maxillary alveolar mucosa.(Fig. 3. A) The patient reported lesion presence for approximately two months. Clinically, the lesion presented as a papillary growth with an ulcerative broad base that was fixed to the underlying alveolar mucosa. On palpation, there was mild tenderness extending over the left cheek. The patient reported a history of smoking but denied alcohol consumption. Initial biopsy performed elsewhere was not diagnostic, so another tissue sample was obtained. In the meantime, CT imaging of the head and neck revealed a solitary irregularly shaped, space-occupying lesion of his left maxillary sinus with alveolar osteolysis. No enlarged lymph nodes were detected either clinically or radiographically. The second biopsy was also non-diagnostic. Therefore, the patient underwent wide local excision of the lesion en bloc with the underlying alveolar bone under general anaesthesia. The histopathology showed findings of carcinoma cuniculatum with clear margins.(Fig. 1. C) Five years after the surgery, the patient remains disease free.(Fig. 3. B)

4. Case 4

A 74-year-old man was referred to our department due to diffuse exophytic papillary oral lesions affecting his left buccal mucosa and extending to the mandibular gingivae.(Fig. 4) His medical history included arterial hypertension, coronary disease, and atopic dermatitis with concomitant exfoliating cheilitis. Clinical examination revealed an exophytic verrucous white patch on the left buccal mucosa extending to the mandibular gingivae. Extra-orally, no palpable cervical lymphadenopathy was present. Tissue samples were obtained under local anaesthesia, which showed findings of VC. CT of the head and neck did not reveal any enlarged cervical lymph nodes. Furthermore, cone beam tomography of the mandible showed no bone invasion. Due to the extent of the lesion, wide local excision was performed under general anaesthesia with simultaneous extraction of the involved teeth and marginal mandibulectomy. The defect was covered with a buccal fat pad and a fascia lata allograft. The histopathology of this lesion revealed carcinoma cuniculatum.(Fig. 1. D) The patient is followed on a regular basis. Twelve months post-operatively, the patient demonstrates satisfactory healing with no signs of recurrence.

IV. Discussion

OCC is a well-differentiated locally aggressive tumour that is characterized by minimal atypia but with evident ability to invade bony structures and rarely to metastasize15. Its incidence is quite rare, with fewer than 60 cases reported in the English literature11,17. Usually, OCC affects patients older than 60 years and has a slight female predominance, although it has been reported in children as well10,11,18. The mean age in our series was 63.5 years, and 3 of 4 patients were men. The aetiology of OCC remains unclear. Smoking and alcohol have been implicated to play a significant role, and trauma, chronic inflammation, and HPV have also been reported as potential etiologic factors11,13,14. However, unlike oral squamous carcinoma and VC, no clear association between these risk factors and OCC has been established. Two patients in our series (Case 1 and Case 3) had a history of smoking but none reported alcohol consumption. Immunohistochemically, HPV results were negative for all our cases.

Clinically, OCC typically presents as a slow growing, painful mass with an ulcerated/cobblestone surface that most commonly affects the alveolar mucosa/gingiva, followed by the tongue11,13. Imaging may reveal erosion and destruction of the underlying bone, indicating the aggressive behaviour of the tumor14,15,19. Two cases in our series (Case 1 and Case 3) involved lesions at the maxillary gingivae with bone involvement. Due to its rarity, OCC is unfamiliar to many clinicians, resulting in misdiagnosis. Diagnosis is based on histopathologic examination of the lesion for characteristic features of a branching network of keratin-filled crypts resembling rabbit burrows, well-differentiated squamous epithelium lining, and little or no atypia12,17. However, these keratin-filled burrows may not be identified in cases when the tissue sample is small or superficial, which can lead the pathologist to underdiagnose the lesion as pseudoepithelial hyperplasia20. For instance, the patient in Case 2 of our series was misdiagnosed with pseudoepithelial hyperplasia based on a biopsy of her tongue lesion at another institution.

In the past, OCC was thought to be a variant of VC and has been described as an inverted VC2,5. The World Health Organization classification of 2005 included OCC as a distinct new variant of oral squamous carcinoma19,21. To differentiate it from OCC, VC is defined by a verrucous growth pattern with vertical fronds mimicking church spires and an intact basal membrane. VC does not usually penetrate the lamina propria, while OCC may invade bony structures. Differential diagnosis also includes papillary squamous cell carcinoma (PSCC); however, PSCC has a characteristic papillary finger-like pattern of growth with a narrow stroma and carries a high risk of regional metastasis12.

Radical surgical excision is the treatment of choice for OCC. This may include subtotal maxillectomy or mandibulectomy because of the invasive nature of the tumour. To date, due to the low risk of metastasis of OCC, there is no clear evidence that neck dissection is required unless there is clear involvement11,20. Farag et al.11 in their systematic review found that 6.9% (3 out of 43 OCC cases) had lymph node metastasis, 2% distant metastasis, and 9.3% demonstrated local recurrence. Sun et al.12 performed the most comprehensive retrospective case series of OCC to date, with 15 cases and a mean follow-up of 45 months; they reported 13.3% nodal involvement in the initial diagnosis. A 20% local recurrence rate was recorded, with no neck involvement12. Nevertheless, despite its low risk of metastasis, OCC should not be disregarded as an early diagnosis because appropriate treatments can impede tumour spread. None of the cases in our series had initial cervical lymphadenopathy, and the follow-up ranged from 12 to 60 months. The role of other treatments, such as radiotherapy and/or chemotherapy, is controversial as radiotherapy may cause anaplastic transformation12,22.

OCC has a better prognosis than SCC, as it is associated with a low local recurrence rate and rare metastasis. In cases of recurrence, the tumour appears to have a more aggressive and resistant behaviour than does SCC, and chemo/radiotherapy do not seem to be effective12,22.

V. Conclusion

OCC is a rare entity. Although it shares some clinicopathological features with SCC, the two are distinct. Despite its locally invasive nature, OCC is associated with good prognosis after radical surgical treatment. Both clinicians and pathologists should be aware of its existence, as clinicopathologic correlation is essential to avoid misdiagnosis. It is recommended to perform multiple deep biopsies with adequate tissue sampling and to provide the pathologist with a thorough clinical description to achieve an accurate diagnosis. Long-term follow-up is mandatory to rule out recurrence.

Funding

No funding to declare.

Authors’ Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by C.M., I.T., and C.E. G.R. encouraged and supervised the project providing critical feedback. The first draft of the manuscript was written by C.M. and I.T. and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Ethics Approval and Consent to Participate

This study was approved in accordance with the Institutional Review Board standards of KAT General Hospital of Attica (IRB No. 11/05-01-2021), and the written informed consent was obtained from all patients.

Consent for Publishing Photographs

Written informed consent was obtained from all patients for publication of this article and accompanying images.

Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Figures
Fig. 1. A-D. Endophytic development of a well-differentiated squamous epithelium with minimal cytological atypia and multiple keratin-filled crypts resembling cuniculus (H&E staining, A-D: ×10).
Fig. 2. Clinical appearance of Case 2. A. Preoperatively. B. Postoperatively.
Fig. 3. Intraoral papillary lesion on the left maxillary alveolar mucosa in Case 3. A. Preoperatively. B. Three years postoperatively.
Fig. 4. Exophytic papillary lesion on the left buccal mucosa in Case 4.
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