Dermatologic Manifestations of Verrucous Carcinoma

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Background

Verrucous carcinoma (VC) refers to a clinicopathologic concept implying a locally aggressive, clinically exophytic, low-grade, slow-growing, well-differentiated squamous cell carcinoma with minimal metastatic potential.

Verrucous carcinoma typically involves the oral cavity, larynx, genitalia, skin, and esophagus.

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.[1] 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 histologic appearance.[2]

Pathophysiology

The pathogenesis of verrucous carcinoma is not yet fully elucidated. Leading theories include human papillomavirus (HPV) infection (anogenital and some oral and sole lesions),[3] chemical carcinogenesis induced by smoking and chewing tobacco,[4] alcohol consumption and betel nut chewing (oral lesions), and chronic inflammation. Schistosomiasis is associated with verrucous carcinoma of the bladder.

Epidemiology

Frequency

The incidence of verrucous carcinoma in the United States and worldwide is unknown.[5]

Mortality/Morbidity

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.

Race

Verrucous carcinoma is reported predominantly in whites.

Sex

Verrucous carcinoma primarily affects men.

Age

Verrucous carcinoma generally occurs in patients aged 55-65 years; however, the anogenital type of verrucous carcinoma has been reported to develop in men aged 18-86 years.

History

Verrucous carcinoma is a slowly growing and locally destructive tumor. The verrucous carcinoma lesion manifests as a verrucous, exophytic, or endophytic mass that typically develops at sites of chronic irritation and inflammation. The verrucous carcinoma tumor enlarges slowly but may be locally destructive and can penetrate deeply into the skin, fascia, and even bone, but it has a low metastatic potential.[6]

Physical

Verrucous carcinoma most commonly involves the oral cavity, larynx, genital area, and soles of the feet. Other areas of involvement are the esophagus, sinonasal track, middle ear, temporal bone, nose, endometrium, and bladder. Based on the different sites of occurrence, verrucous carcinomas are categorized as follows:

Oral verrucous carcinoma (Ackerman tumor, oral florid papillomatosis[7] )

The oral cavity is the most common site of occurrence of verrucous carcinoma and represents 2-12% of all oral carcinomas.[8, 9]

Early lesions appear as white, translucent patches on an erythematous base. They may develop in previous areas of leukoplakia, lichen planus,[10, 11] 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 invasion locally into soft tissues and bone (eg, mandible) may occur. Oral verrucous carcinoma most commonly occurs on the buccal mucosa.[8] Other sites of involvement are the alveolar ridge, upper and lower gingiva, floor of the mouth, tongue, tonsils, and vermilion border of the lip.

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.

Oral verrucous carcinoma involving the hard palate and upper alveolus is considered more aggressive.[8]

In these patients, the majority of the tumors present at advanced stages (III-IV).[8]

Anogenital-type 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.[12] The tumor accounts for 5-24% 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.[12]

The Buschke-Löwenstein tumor is preferentially seen in men and immunocompromised patients.[12] It commonly occurs on the glans penis, mainly in uncircumcised men.

Less commonly, the Buschke-Löwenstein tumor occurs in the bladder[13, 14] or on vaginal, cervical, perianal, scrotal, vulvar, and pelvic organs.

Palmoplantar verrucous carcinoma (epithelioma cuniculatum)[15, 16, 17, 18, 19] }[20]

Verrucous carcinoma of the skin is typically a long-standing, slow-growing, well-circuited tumor that is usually found at the sole of the foot (53%), toes (21%) and heel (16%). Verrucous carcinomas arising from other sites (eg, trunk, extremities, scalp, face, nail apparatus) have also been reported.[21]

Lesions are usually slow growing, exophytic, and locally invasive. Lesions may exhibit hyperkeratosis, ulceration, and sinuses that may draining foul-smelling discharge and cause pain, bleeding, and difficulty walking.

Lesions can often be misdiagnosed for plantar wards that grow slowly into a large exophytic mass.[22]

Cutaneous verrucous carcinoma most often occurs as a single mass or plaque, but multiple verrucous carcinomas on the feet and ankles have been reported.[21]

Verrucous carcinomas of the skin have been reported to develop at sites of long-standing cutaneous scars, including gunshot wounds and burn scars.[22]

Palmoplantar verrucous carcinoma is consider to have a very low incidence of metastases. Nevertheless, in long-standing tumors, underlying structures such as the bone, cartilage, and the tendons can be involved.[22]

Others

Laryngeal verrucous carcinoma usually occurs as a bulky exophytic lesion with a papillomatous appearance that projects from the larynx.[23, 24]

Verrucous carcinomas of the endometrium[25] and the sinonasal track have been reported.[26] Verrucous carcinomas may develop in areas of previous hidradenitis suppurativa.[27] Genital verrucous carcinoma has been associated with genital lichen sclerosus.[28]

Uncommon areas of involvement such as the orbit, middle ear, temporal bone, nose, nasopharynx, and paranasal sinuses, have been reported.

Causes

HPV infection is thought to facilitate or cause verrucous carcinoma. HPV infection is believed to play the predominate role in the development of verrucous carcinoma of the penis, vulva, and periungual region. HPV-16 has been identified frequently in genital and periungual verrucous carcinoma.[29, 30]

HPV types 6 and 11 are found in the Buschke-Löwenstein tumor up to 50% of the time.[12] In oral verrucous carcinomas, HPV types 6, 11, 16, and 18 have been found.[8] In plantar lesions, HPV types 11 and 16 have been associated.[20]

Inflammatory diseases such as long-standing oral ulcerative lichen planus and chronic candidiasis seem to predispose patients to the development of verrucous carcinoma.

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.[8]

Schistosomal infection often is coexistent with verrucous carcinoma of the bladder.

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.[8]

Imaging Studies

Computed tomography or magnetic resonance imaging may be used to demonstrate the exact location and extent of the verrucous carcinoma (VC) tumor for preoperative staging and surgical planning.

Procedures

A skin biopsy always is 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.

Histologic Findings

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, particularly in carcinoma cuniculatum. 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.

Staging

Most verrucous carcinomas are nonmetastatic and are staged based on size, as follows:

Surgical Care

Most physicians treat patients with cutaneous verrucous carcinoma (VC) in their offices. Complete tumor extirpation should be performed at first presentation 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.[31]

Excision with conventional margins[32]

Simple excision is most valuable in the treatment of small verrucous carcinomas of the trunk and extremities and in areas in which tissue sparing is not essential.

Cure rates following simple excision of well-defined T1 lesions can be as high as 95-99%.

A 4-mm margin of healthy tissue is recommended for straightforward lesions.

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. Additionally, more healthy tissue may be excised than is necessary.[8]

Mohs surgery[33, 34, 35]

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 provides a cure rate for verrucous carcinoma of 94-100% and has been of particular value in curing verrucous carcinoma with perineural invasion. MMS offers the added benefit of preserving normal tissue, thus facilitating reconstruction.

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[36]

Cryosurgery using liquid nitrogen is a safe and low-cost procedure for the ablation of selected verrucous carcinomas and is well tolerated by patients.

Cryotherapy has provided a high cure rate for select well-circumscribed superficial verrucous carcinomas. Because of no histologic control, close follow-up is necessary.

This procedure is the least likely to result in cure and is the least preferred intervention.

Curettage and electrodesiccation

Cure rates of 96-99% have been quoted in several large studies for destruction of T0 and T1 verrucous carcinoma (ie, in situ lesions and invasive lesions < 2 cm in diameter). This high cure rate was affected by careful patient selection.

The main disadvantage of curettage and electrodesiccation is a lack of margin control; nonetheless, the procedure is minimally invasive, well tolerated, and effective for in situ lesions without deep involvement.

Curettage and electrodesiccation is most appropriate for slow-growing lesions of the trunk and extremities.

Radiation therapy[37, 38, 39]

Radiation therapy offers the potential advantage of avoiding the trauma and deformity of a surgical procedure, but it has occasionally been associated with transformation to high-grade squamous carcinoma.

Ionizing radiation therapy is used mainly as a treatment for primary cutaneous carcinoma in patients who cannot tolerate surgery (eg, elderly patients).

Cure rates for T1 lesions range from 85-95%.

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 of middle aged.

Radiation therapy is expensive and requires multiple visits. The procedure is blind to histologic margin control. 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 considerations

Other treatments that have been used for cutaneous verrucous carcinomas with variable success include topical or systemic chemotherapy (bleomycin, 5-fluorouracil, cisplatin, methotrexate), carbon-dioxide laser, intralesional interferon alfa, imiquimod, and photodynamic therapy.[40]

In oral verrucous carcinoma in the presence of clinical lymphadenopathy and if the pathological diagnosis is uncertain, neck treatment should be considered.[8]

If bone involvement is suspected, radiography or computed tomography scanning should be performed.

Further Outpatient Care

Verrucous carcinoma (VC) usually is cured with appropriate therapy. However, recurrence of cutaneous carcinoma with clear surgical margins has been reported. In addition, patients are at risk for developing additional verrucous carcinoma and squamous cell carcinoma and should be evaluated with skin examinations at 3- to 12-month intervals.

Prognosis

In most cases of verrucous carcinomas, regardless of the variant, the clinical outcome is rarely an aggressive course. Most patients with verrucous carcinoma have a good prognosis. 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.[8] 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.

Author

Bassam Zeina, MD, PhD, Consulting Staff, Department of Dermatology, Milton Keynes Hospital, UK

Disclosure: Nothing to disclose.

Coauthor(s)

Nicole Sakka, MBBS, Foundation Year 2, Royal Liverpool and Broadgreen University Hospital, Liverpool, UK

Disclosure: Nothing to disclose.

Sohail Mansoor, MBBS, MSc, Dermatologist and Lead Physician in Dermatologic Surgery, Department of Dermatology, Barnet Hospital, UK

Disclosure: Nothing to disclose.

Specialty Editors

Kelly M Cordoro, MD, Assistant Professor of Clinical Dermatology and Pediatrics, Department of Dermatology, University of California, San Francisco School of Medicine

Disclosure: Nothing to disclose.

Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA

Disclosure: Nothing to disclose.

John G Albertini, MD, Consulting Staff, Dermatologic Surgery, The Skin Surgery Center; Program Director, ACGME Accredited Fellowship in Procedural Dermatology

Disclosure: Nothing to disclose.

Glen H Crawford, MD, Assistant Clinical Professor, Department of Dermatology, University of Pennsylvania School of Medicine; Chief, Division of Dermatology, The Pennsylvania Hospital

Disclosure: Nothing to disclose.

Chief Editor

William D James, MD, Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

Disclosure: Elsevier Royalty Other

Additional Contributors

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, Mohsin Ali, MBBS, FRCP, MRCP, to the development and writing of this article.

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