Verrucous carcinoma (VC) is an uncommon type of well-differentiated squamous cell carcinoma (SCC) that most commonly affects men in the fifth to sixth decades of life. 1 The tumor grows slowly over a decade or more and does not frequently metastasize but has a high propensity for recurrence and local invasion. 2 There are 3 main subtypes of VC classified by anatomic site: oral florid papillomatosis (oral cavity), Buschke-Lowenstein tumor (anogenital region), and epithelioma cuniculatum (EC)(feet). 3 Epithelioma cuniculatum, also known as carcinoma cuniculatum or papillomatosis cutis carcinoides, most commonly presents as a solitary, warty or cauliflowerlike, exophytic mass with keratin-filled sinus tracts and malodorous discharge. 4 Diabetic foot ulcers and chronic inflammatory conditions are predisposing risk factors for EC, and it can result in difficulty walking/immobility, pain, and bleeding depending on anatomic involvement. 5-9
The differential diagnosis for VC includes refractory verruca vulgaris, clavus, SCC, keratoacanthoma, deep fungal or mycobacterial infection, eccrine poroma or porocarcinoma, amelanotic melanoma, and sarcoma.10-13 The slow-growing nature of VC, sampling error of superficial biopsies, and minimal cytological atypia on histologic examination can contribute to delayed diagnosis and appropriate treatment.14 Characteristic histologic features include hyperkeratosis, papillomatosis, marked acanthosis, broad blunt-ended rete ridges with a “bulldozing” architecture, and minimal cytologic atypia and mitoses.5,6 In some cases, pleomorphism and glassy eosinophilic cytoplasmic changes may be more pronounced than that of a common wart though less dramatic than that of conventional SCCs.15 Antigen Ki-67 and tumor protein p53 have been proposed to help differentiate between common plantar verruca, VC, and SCC, but the histologic diagnosis remains challenging, and repeat histopathologic examination often is required.16-19 Following diagnosis, computed tomography or magnetic resonance imaging may be necessary to determine tumor extension and assess for deep tissue and bony involvement.20-22
Treatment of EC is particularly challenging because of the anatomic location and need for margin control while maintaining adequate function, preserving healthy tissue, and providing coverage of defects. Surgical excision of EC is the first-line treatment, most commonly by wide local excision (WLE) or amputation. Mohs micrographic surgery (MMS) also has been utilized. One review found no recurrences in 5 cases of EC treated with MMS.23 As MMS is a tissue-sparing technique, this is a valuable modality for sites of functional importance such as the feet. Herein, we review various reported EC treatment modalities and outcomes, with an emphasis on recurrence rates for WLE and MMS.
METHODS
A systematic literature review of PubMed articles indexed for MEDLINE, as well as databases including the Cochrane Library, Web of Science, and Cumulative Index to Nursing and Allied Health Literature (CINAHL), was performed on January 14, 2020. Two authors (S.S.D. and S.V.C.) independently screened results using the search terms (plantar OR foot) AND (verrucous carcinoma OR epithelioma cuniculatum OR carcinoma cuniculatum). The search terms were chosen according to MeSH subject headings. All articles from the start date of the databases through the search date were screened, and articles pertaining to VC, EC, or carcinoma cuniculatum located on the foot were included. Of these, non–English-language articles were translated and included. Articles reporting VC on a site other than the foot (eg, the oral cavity) or benign verrucous skin lesions were excluded. The reference lists for all articles also were reviewed for additional reports that were absent from the initial search using both included and excluded articles. A full-text review was performed on 221 articles published between 1954 and 2019 per the PRISMA guidelines (Figure).
PRISMA flow diagram of the screening process for a systematic review of the literature using the search terms (plantar OR foot) AND (verrucous carcinoma OR epithelioma cuniculatum OR carcinoma cuniculatum). Reasons for exclusion of articles included unavailable full text, errata or responses, not verrucous carcinoma, not plantar, or not malignant. CINAHL indicates Cumulative Index to Nursing and Allied Health Literature.
A total of 101 articles were included in the study for qualitative analysis. Nearly all articles identified were case reports, giving an evidence level of 5 by the Centre for Evidence-Based Medicine rating scale. Five articles reported data on multiple patients without individual demographic or clinical details and were excluded from analysis. Of the remaining 96 articles, information about patient characteristics, tumor size, treatment modality, and recurrence were extracted for 115 cases.
RESULTS
Of the 115 cases that were reviewed, 81 (70%) were male and 33 (29%) were female with a male-to-female ratio of 2.4:1. Ages of the patients ranged from 18 to 88 years; the mean and median age was 56 years. Nearly all reported cases of EC affected the plantar surface of one foot, with 4 reports of tumors affecting both feet.24-27 One case affecting both feet reported known exposure to lead arsenate pesticides27; all others were associated with a clinical history of chronic ulcers or warts persisting for several years to decades. Other less common sites of EC included the dorsal foot, interdigital web space, and subungual digit.28-30 The most common location reported was the anterior ball of the foot. Tumors were reported to arise within pre-existing lesions, such as hypertrophic lichen planus or chronic foot wounds associated with diabetes mellitus or leprosy.31-35 Tumor size ranged from 1 to 22 cm with a median of 4.5 cm.
Eight cases were reported to be associated with human papillomavirus; low-risk types 6 and 11 and high-risk types 16 and 18 were found in 6 cases.36-41 Two cases reported association with human papillomavirus type 2.7,42