Verrucous carcinoma is a relatively uncommon, locally aggressive, clinically exophytic, low-grade, slow-growing, well-differentiated squamous cell carcinoma with minimal metastatic potential.
Verrucous carcinoma may involve the oral cavity, larynx, anogenital region, plantar surface of the foot, and, less commonly, other cutaneous sites. See the image below.
Verrucous carcinoma; an exophytic and hyperkeratotic mass that discharged malodorous debris through several sinus tracts. Courtesy of J García-Gavín, ....
In 1948, Ackerman first described verrucous carcinoma in the oral cavity as a low-grade tumor that generally is considered a clinicopathologic variant of squamous cell carcinoma. Aird et al first described cutaneous verrucous carcinoma (carcinoma cuniculatum) in 1954, and it was named as such because of its characteristic cryptlike spaces on histology.
The pathogenesis of verrucous carcinoma is not yet fully elucidated. Leading theories include human papillomavirus (HPV) infection (oral cavity, anogenital region, plantar foot, and a small subset of cutaneous verrucous carcinoma), chemical carcinogenesis induced by smoking and chewing tobacco, alcohol consumption and betel nut chewing (oral lesions), and chronic inflammation. Schistosomiasis is associated with verrucous carcinoma of the bladder.
The incidence of verrucous carcinoma in the United States and worldwide is unknown.
Verrucous carcinoma is reported predominantly in whites.
Verrucous carcinoma primarily affects men.
Verrucous carcinoma generally occurs in middle-aged (50s) patients ; however, the anogenital type of verrucous carcinoma has been reported to develop in men aged 18-86 years.
Overall, patients with verrucous carcinoma have a favorable prognosis, although the course of verrucous carcinoma lesions is characterized by slow, continuous, local growth. Morbidity results from local skin and soft-tissue destruction and, occasionally, from perineural, muscle, and even bone invasion. The development of distant metastases is rare. Verrucous carcinoma mortality usually is due to local invasion rather than metastatic spread.
In most cases of verrucous carcinomas, regardless of the variant, the clinical outcome is rarely an aggressive course. Local verrucous carcinoma recurrence following definitive treatment is not uncommon. Regarding oral verrucous carcinoma, the reported recurrence rate ranges from 6-40%. If metastasis does occur, it is mainly at the regional lymph nodes. There have been reports of metastases in distant sites, but this is considered rare. In long-standing lesions, occasional destruction of adjustment structures such as cartilage, tendons, and bones can occur. Patients with oral verrucous carcinoma may be at an increased risk of a second primary oral squamous cell carcinoma, which carries a poor prognosis.
Advise patients about the importance of receiving effective treatment for areas of chronic skin inflammation or trauma (eg, leg or decubitus ulcers) to prevent these problems from developing malignancies within them. Improved oral, genital, and perianal hygiene may help to prevent inflammatory conditions that predispose patients to verrucous carcinoma. Cessation of chewing tobacco use may help to prevent oral verrucous carcinoma.
For patient education resources, see the Cancer and Tumors Center and Warts Center, as well as Skin Cancer, Warts, and Skin Biopsy.
Verrucous carcinoma manifests as a cauliflowerlike, exophytic mass that typically develops at sites of chronic irritation and inflammation. Verrucous carcinoma is slow growing, but may display locally aggressive behavior. Penetration into the skin, fascia, and even bone has been reported; however, verrucous carcinoma has low metastatic potential.
Verrucous carcinoma may affect any part of the skin or mucosa, but it most commonly involves the oral cavity, anogenital region, or sole of the foot. Thus, it has been grouped into four clinicopathologic types based on the affected anatomic site: oroaerodigestive, anogenital, feet, and other cutaneous sites. However, this classification and the associated naming scheme is not used consistently across the literature, leading to confusing and, often, overlapping, nomenclature. Based on the anatomic site of involvement, verrucous carcinoma may be classified as described below.
Oroaerodigestive verrucous carcinoma (Ackerman tumor, oral florid papillomatosis )
The oral cavity is the most common site of occurrence of verrucous carcinoma and represents 2-12% of all oral carcinomas.[9, 12]
Early lesions appear as white, translucent patches on an erythematous base. They may develop in previous areas of leukoplakia, lichen planus,[13, 14] chronic lupus erythematosus, cheilitis, candidiasis, or submucous fibrosis.
The more fully developed lesions are white, soft, cauliflowerlike papillomas with a pebbly surface that may extend and coalesce over large areas of the oral mucosa.
Ulceration, fistulation, and local invasion into soft tissues and bone (eg, mandible) may occur.
Oroaerodigestive verrucous carcinoma most commonly occurs on the buccal mucosa. Other sites of oral involvement are the alveolar ridge, upper and lower gingiva, floor of the mouth, tongue, tonsils, and vermilion border of the lip. Verrucous carcinoma involving the hard palate and upper alveolus is considered more aggressive.
The larynx may also be affected; it usually presents as a bulky exophytic lesion with a papillomatous appearance that projects from the larynx.[15, 16] Furthermore, sinonasal tract involvement has also rarely been reported.
Painful nonmalignant lymphadenopathy can be seen with concurrent infection or inflammation.
Tumors most often grow around the lymph nodes rather than metastasizing to them. If metastases do occur, they usually remain limited to the regional lymph nodes.
Anogenital verrucous carcinoma (Buschke-Löwenstein tumor)
The Buschke-Löwenstein tumor usually manifests as an exophytic tumor of the genital or perianal area, with ulceration and sometimes fistulae and sinuses. The tumor accounts for 5-16% of all penile carcinomas.
They typically manifest as large, exophytic, nonhealing, cauliflowerlike lesions with a verrucous or ulcerated surface. The Buschke-Löwenstein tumor usually can only be differentiated from ordinary condylomata based on histologic findings. These tumors tend to infiltrate deeply, and recurrence is common.[18, 20]
The Buschke-Löwenstein tumor is preferentially seen in men and immunocompromised patients. It commonly occurs on the glans penis, mainly in uncircumcised men. In females, this tumor is most often found on the vulva.
Less commonly, the Buschke-Löwenstein tumor occurs in the bladder[6, 22] or on vaginal, cervical, perianal, scrotal, and pelvic organs.
Verrucous carcinoma of the foot (epithelioma cuniculatum)[8, 23, 24]
Verrucous carcinoma of the skin is typically a long-standing, slow-growing tumor that is usually found at the sole of the foot and, less frequently, the toes or heels.
Lesions are usually slow growing, exophytic, and locally invasive. Lesions may exhibit hyperkeratosis, ulceration, and sinuses that may drain foul-smelling discharge and cause pain, bleeding, and difficulty walking.
Lesions can often be misdiagnosed for plantar warts that grow slowly into a large exophytic mass.
Verrucous carcinoma of the foot most often occurs as a single mass or plaque, but multiple verrucous carcinomas on the feet and ankles have been reported.
Verrucous carcinoma of the foot is considered to have a very low incidence of metastases. Nevertheless, in long-standing tumors, underlying structures such as the bone, cartilage, and tendons can be involved.
Other cutaneous sites (cutaneous verrucous carcinoma)[4, 8, 24]
Verrucous carcinomas arising from other cutaneous sites beyond the foot (eg, scalp, face, nail apparatus, arm) have also been reported.[26, 24, 27, 28]
These tumors, like their counterparts encountered on the sole of the foot, tend to present as slowly enlarging, locally aggressive, exophytic masses with low metastatic potential.
Cutaneous verrucous carcinoma has been reported to develop at sites of inflammation or scarring such as decubitus ulcers, gunshot wounds, burn scars, lupus vulgaris scars, and areas affected by hidradenitis suppurativa.[8, 29]
HPV may play a role in the development of verrucous carcinoma. HPV types 6 and 11 are most frequently associated with the Buschke-Löwenstein tumor. In plantar lesions, HPV type 16 has been reported. Finally, HPV type 33 has been reported in a verrucous carcinoma of the scalp.
Despite the presence of HPV strains within some lesions of verrucous carcinoma, a causal relationship has not been proven and remains controversial.[31, 32]
Inflammation appears to sometimes play a role in the development of verrucous carcinoma. For instance, cutaneous verrucous carcinoma may develop at sites of inflammation or scarring such as decubitus ulcers or areas affected by hidradenitis suppurativa.[8, 29] In addition, lichen sclerosus may predispose patients to the development of penile verrucous carcinomas. Similarly, verrucous carcinomas of the oral cavity have been reported to develop in patients with long-standing oral ulcerative lichen planus and chronic candidiasis.
Associations in oral verrucous carcinoma have been found in patients who chewed or inhaled tobacco and betel nuts, dipped snuff, and/or consumed alcohol. Lesions developed at the sites where tobacco was habitually placed in the mouth.
Furthermore, oral verrucous carcinoma is associated with poor dental hygiene, ill-fitting dentures, and low socioeconomic status. Oral verrucous carcinoma has a higher incidence in males and in immunocompromised patients.
Schistosomal infection often is coexistent with verrucous carcinoma of the bladder.
Computed tomography or magnetic resonance imaging may be used to demonstrate the exact location and extent of the verrucous carcinoma for preoperative staging and surgical planning.
A skin biopsy is always required for definitive diagnosis of verrucous carcinoma, despite the fact that the diagnosis is suspected strongly on clinical grounds.
Biopsy is performed routinely in the physician's office using a local anesthetic.
All skin biopsy specimens obtained to diagnose verrucous carcinoma must reach at least the depth of the mid dermis to allow for determination of the presence or absence of invasive disease.
A deep (scoop) shave biopsy, a punch biopsy, an incisional biopsy, or an excisional biopsy may be performed.
Pathology readings preferably are made by a dermatopathologist who has extensive experience with verrucous carcinoma.
Regardless of site of origin, verrucous carcinomas share the same histological features. Verrucous carcinoma of all types may resemble a verruca superficially, with hyperkeratosis, parakeratosis, acanthosis, papillomatosis, and granular cell layer vacuolization. A characteristic feature is the blunt projections of well-differentiated epithelium surrounded by edematous stroma and chronic inflammatory cells that extend into the dermis, sometimes forming sinuses filled with keratin. Cutaneous verrucous carcinomas may be confused with warty carcinomas, but the higher-grade cytological atypia and the more infiltrative growth pattern of warty carcinomas can help to differentiate.
Although most verrucous carcinomas are nonmetastatic, staging is still based on the tumor, nodes, metastases (TNM) staging system. The specifics of staging vary based on the anatomic site, with slightly different criteria for oral, anal, and penile lesions. No specific staging system exists for cutaneous verrucous carcinoma; however, the seventh edition of the American Joint Committee for Cancer Staging Manual does propose a staging system for cutaneous squamous cell carcinomas and other cutaneous carcinomas, as follows :
Most physicians treat patients with cutaneous verrucous carcinoma in their offices. Complete tumor removal should be performed expeditiously because verrucous carcinoma can recur, metastasize, and, ultimately, cause death. Recurrent verrucous carcinoma carries a relatively poor prognosis.
Surgical excision and Mohs micrographic (MMS) surgery represent the treatments of choice for cutaneous verrucous carcinomas.[36, 37]
Surgical excision 
Complete surgical resection with clear margins is recommended once the diagnosis of verrucous carcinoma has been established.
Standard excision with permanent conventional sections is a highly effective treatment for many verrucous carcinomas. The depth of the excision should include the subcutaneous fat because even small verrucous carcinomas may extend into the subcutaneous fat.
The disadvantages of excision with an arbitrary margin are that in some cases, the pathology reveals a subclinical positive margin, requiring further surgery. In extensive tumors with inflammatory changes, the surgical margin may be difficult to define. Furthermore, incomplete surgical resection can lead to acceleration in the growth of the tumor. Finally, as opposed to tissue-sparing modalities, more healthy tissue may be excised than is necessary.
Mohs surgery [39, 40, 41]
A dermatologic surgeon usually offers MMS. The main advantage of MMS over simple excision in the extirpation of cutaneous verrucous carcinoma is the ability to examine all excision margins (deep and lateral) and to carefully map residual foci of invasive carcinoma.
MMS allows for tissue preservation, thus facilitating reconstruction; this can be of particular benefit in sensitive areas of the body such as the anogenital region where preservation of sexual function and body image are of great importance.
MMS is performed routinely in an outpatient setting with the patient under local anesthesia.
MMS is not widely available outside the United States.
A multidisciplinary approach using MMS performed in conjunction with a plastic surgeon, otolaryngologist, and radiation oncologist may allow for the complete removal of deeply invasive verrucous carcinoma, preservation of vital structures, and facilitation of the reconstruction of a large operative defect.
Because of its many advantages, MMS is the procedure of choice for verrucous carcinoma for which tissue preservation is needed. Furthermore, surgery for verrucous carcinoma using MMS may be an integral component in the management of certain verrucous carcinomas that otherwise would be beyond the experience of the cutaneous surgeon.
Cryosurgery [42, 43]
Cryosurgery using liquid nitrogen is a safe and low-cost procedure for the ablation of selected verrucous carcinomas and is well tolerated by patients.
The major disadvantage of cryosurgery is the lack of histologic control and lack of precision in application of treatment, which often leads to the need for multiple treatments. Initial shave excision of the bulk of the tumor may allow for more direct therapy and thus, a higher cure rate.
This procedure is the least likely to result in cure and, therefore, is not a preferred intervention.
Radiation therapy [44, 45, 46]
Radiation therapy offers the potential advantage of avoiding the trauma and deformity of a surgical procedure, but it remains a controversial modality, owing to its potential association with transformation to a high-grade squamous carcinoma. Although reported in earlier literature, the association between radiation and anaplastic transformation of verrucous carcinoma appears to be less frequent than previously reported.[48, 49]
Ionizing radiation therapy is used mainly as a treatment for primary cutaneous carcinoma in patients who cannot tolerate surgery (eg, elderly patients).
Although the initial cosmetic result following radiation often is good, the long-term result frequently is poor, with atrophy, hypopigmentation, and telangiectasia. Some patients treated with radiation also develop radiation necrosis. This risk increases over time.
Radiation therapy is not advocated for use over bony structures because of the risk of osteoradionecrosis. Radiation therapy is not advocated for patients who are young or middle aged.
Radiation therapy is expensive and requires multiple visits. The procedure is blind to histologic margin control and may be linked to anaplastic transformation. For these reasons, the use of radiation as primary therapy for verrucous carcinoma generally is restricted to older patients who cannot tolerate or who refuse surgery.
Other treatments that have been used for cutaneous verrucous carcinomas with variable success include curettage and electrodessication, topical or systemic chemotherapy (bleomycin, 5-fluorouracil, cisplatin, methotrexate), carbon dioxide laser, intralesional interferon-alfa, imiquimod, and photodynamic therapy.
The main pitfall in the diagnostic evaluation is taking an inadequate biopsy specimen, leading some to advise the use of excisional biopsy whenever the diagnosis of verrucous carcinoma is suspected. Additionally, in some cases, the carcinoma is so well differentiated that the pathologist may read the tissue as pseudoepitheliomatous hyperplasia. Verrucous carcinoma has the potential to cause substantial morbidity and even mortality, and physicians who diagnose and treat verrucous carcinoma are held legally accountable for their actions.
Failure to ensure adequate patient follow-up care is a pitfall because primary treatment of verrucous carcinoma is not a guarantee of cure. Not informing patients of the potential morbidity associated with verrucous carcinoma may lead to the lesion being regarded as trivial and not requiring follow-up care. The courts hold the physician, not the patient, responsible for appropriate follow-up care. Missed appointments for patients with verrucous carcinoma before or following surgery may indicate a worried or angry patient and should be followed up with a phone call to reschedule and, if necessary, with a certified letter.
Failure to outline all possible risks prior to verrucous carcinoma surgery is another pitfall. Surgery for patients with verrucous carcinoma may cause bleeding, infection, scar formation, deformity, and nerve damage. Removal of deeply invasive lesions may lead to substantial morbidity, including pain syndromes and paralysis. If a surgical complication develops, the physician who performed the primary procedure is held legally responsible, regardless of who handles the complication. Any patient with lesions that are outside the realm of comfort of an individual physician should be referred to another physician.
Verrucous carcinoma usually is cured with appropriate therapy. However, recurrence of cutaneous carcinoma with clear surgical margins has been reported. In addition, patients with a history of verrucous carcinoma should be evaluated with regular skin examinations at 3- to 12-month intervals.