Verrucous Carcinoma: A Review of the Literature with Emphasis on Treatment Options

Headnote

Abstract

Ackerman's tumor or verrucous carcinoma (VC) is a unique clinico-pathological variant of squamous cell carcinoma, occurring mainly in the oral cavity and larynx; buccal mucosa being the most commonly involved site. Since VC was first reported by Ackerman, there has been ongoing discussion regarding the preferred treatment. There is a considerable controversy in the literature regarding anaplastic transfonnation of verrucous carcinoma following chemotherapy, cryosurgery, laser surgery, and even after multiple conventional operations, resulting in a more aggressive behaviour. A detailed review about the different managementmodalities are being discussedin this paper along with a case report.

Keywords: Carcinoma, verrucous, treatment.

Introduction

Verrucous carcinoma is defined as "A warty variant of squamous cell carcinoma characterized predominantly by exophytic overgrowth of well differentiated keratinizing epithelium having minimal atypia and with locally destructive pushing margins at its interface with underlying connective tissue". It is an uncommon but distinct variety of well differentiated squamous cell carcinoma (SCC) and was first delineated as a clinico-pathologic entity by Ackerman in the year 1948.1 It is also called as Ackerman's Tumor, Snuff Dipper's Tumor, Buscke Lowenstein Tumor, Florid Oral Papillomatosis, Epithelioma Cuniculatum or Carcinoma Cuniculatum.2

Predominantly being a squamous mucosal lesion, verrucous carcinoma may also be found on cutaneous surfaces. Whether the carcinoma occur in the upper aero-digestive tract (Verrucous Carcinoma), the genitalia (Condyloma Acuminatum), or on extremities (Carcinoma Cuniculatum), they are essentially the same neoplasm with slow growing, locally invasive and non-metastasizing behaviour. The mucosal membrane of head and neck are sites of predilection, with the oral cavity and larynx being atrisk.3

The oral cavity is the most common site of occurrence. In addition, it is known to occur in the larynx, pyriform sinus, esophagus, nasal cavity and paranasal sinuses, external auditory meatus, lacrimal duct, skin, scrotum, penis, vulva, vagina, uterine cervix, perineum, and the leg. This tumor is predominantlyseeninmaleswhoareover 50 years.

The macroscopic appearance of Ackerman's tumor depends on several factors like duration of lesion, degree of keratinization and the changes in adjacent mucosa. The fully developed carcinoma is an exophytic gray to red bulky lesion with a rough, shaggy, papillomatous surface. Theterm"Verrucous"isusedbecauseofits fine, finger like surface projections.4 It may grow through soft tissue of cheeks, penetrate into mandible or maxilla and invade perineural space.5 Regional lymph node metastasis is rare and distant metastasis has not been reported.

Since VC was first reported by Ackerman, there has been ongoing discussion regarding the preferred treatment. A sincere effort has been made to discuss the different treatmentmodalities available forits management.1

Case report

A 50-year-old male patient presented with an expohytic growth on anterior mandibular gingiva, with a rough, shaggy and papillomatous surface for aperiod of 6 months withhistory of tobacco chewing. The growth was 2.0cmx 1.0cm in its greatest dimensions and was not associated with trauma, oral bleeding, dysphagia or any speech problem. On palpation, the growth was greyish white, non-friable, non-tender, with well defined raised margins and no infiltrative induration (Figure la). Cervical lymph nodes were not palpable. The differential diagnosis included proliferative verrucous leukoplakia and VC. An incisional biopsy was performed and tissue was obtained from the center of the mass. Care was taken to perform the biopsy down to the underlying bone, including the periosteum. Histopathologic^ examination revealed features of verrucous carcinoma depicting bulbous, elephant foot like rete pegs extending into deeper tissues lacking cytological atypia. Occasional mitotic figures were present. (Figure lb).The patient underwent wide-excision taking safe oncological margin, under general anesthesia and reconstruction of the defect was done by collagen graft (Figure 2a, 2b). Patient was followed up for 6 months; healing was satisfactory and there were no signs of recurrence (Figure 3a, 3b). After complete assessment of the defect, patient was sent to the Department of Prosthodontics for complete mouth rehabilitation.

Discussion

Verrucous carcinoma most of the times go unrecognized or unchallenged due to benign indolent tumor behaviour. Clinical leukoplakia often characterizes the mucosa from which the neoplasm originates. Verrucous carcinoma appears to be a part of histologic continum of leukoplakia with verrucous hyperplasia as a part of the spectrum while other consider verrucous hyperplasia as a distinct clinico-pathological entity with its characteristics.3'6 In the oral cavity, verruccous carcinoma constitutes 2 to 4.5% of all forms of squamous cell carcimonas seen mainly in males above 50 years of age and having a close connection with use of tobacco, especially chewing or snuff dipping.78 This is also associated with high incidence (37.7%) of second primary tumor synchronous or metachronous, mainly in oral mucosa.9 Verrucous carcinoma has excellent prognosis because of its slow growth and gravity with which it metastasizes to regional lymph nodes.4 Later in the course the contiguous structure may be involved and adjacent tissues including bone and cartilage may be invaded and destroyed. Microscopically, verruccous carcinoma is usually broad based and locally invasive with papillary fronds consisting of highly differentiated squamous cell lacking usual criteria of malignancy. Rarely mitosis is seen. Surface is usually covered by keratin layers. The invasive margin is invariably a slow 'pushing' one along with inflammatory reaction in the stroma.3 The cell kinetics of verrucous carcinoma are distinctive, containing a thick zone of non-proliferating, non keratinizing cells between the basal germinativelayerofnormalsquamousmucosa, lacking the S-phase cells.10 In contrast, non-verrucous squamous cell carcinoma manifests S-phase cells distribution throughout non keratinized zones. It is likely that most of the cases reported in the past as oral florid papillomatosis represent early and non-invasive stage of verrucous carcinoma."

Because of deceptive benign appearance of neoplastic cells, an accurate pathological diagnosis requires a sufficient biopsy specimen that contains infiltrative features of verrucous carcinoma. A focus of conventional invasive squamous cell carcinoma within the verrucous carcinoma is seen in 20% of patients akin to the phenomenon of anaplastic transformation in larynx.3 Clinico-pathological characteristics of verrucous carcinoma has been summarized in Table 1.

Treatment modalities include surgery, radiation therapy, chemotherapy, cryotherapy, laser therapy, photodynamic therapy and treatment with recombinant^-interferon. Surgical excision remains the preferred treatment for the primary lesion.12

Surgery: Anaplastic transformation resulting in a more aggressive behaviour has been shown to occur as a result of chemotherapy, cryosurgery, laser surgery, and even after multiple conventional operations." A review of NCDB data with specific attention to localized cases of oral VC demonstrated 85% and 42% 5-year survival rates after surgery and radiation therapy, respectively14 Further, improved outcomes were not seen with the addition of radiation therapy as an adjuvant to surgery. Although these data clearly suggest better outcomes with surgical intervention, defmitivestatementscannotbemadewithoutthebenefitof randomized trials, which are difficult to conduct in these rare tumors. Adegreeoftreatment selection bias also has to be factored into the analysis of treatment outcomes, because irradiation alone is often chosen for patients with extensive disease that would be difficult to resect primarily or in patients with significant co-morbidities who would tend to have lower 5-year survival data.14 Irrespective of treatment, there is a 26%-57% incidence of recurrence. Therefore, close long-term follow-up is necessary. There is no consensus with respect to the size of surgical margins necessary to decrease the risk of recurrence. Certainly with extensive gingival involvement, consideration should be given to segmental or marginal osseous resection. Resection of VC involving tooth bearing mucosa must include adjacent alveolus to ensure that any periodontal extension, including alveolar involvement, is adequately treated. A reviewofeightcasesofgingivalVCdemonstratedhistolo-gicevidenceofbonyinvasioninthreepatients(37.5%).15

Radiation: Transformation of VC to anaplastic or poorly differentiated squamous cell carcinoma has been described after radiation therapy. This phenomenon was first reported by Perez and co-workers in 1966 when they noted its occurrence in 8 of 17 patients with VC.16 In an effort to examine the efficacy of radiation therapy as a primary modality in the treatment of VC, Ferlito and colleagues critically evaluated 148 patients with histologically confirmed VC managed with radiation therapy" Most of these patients experienced treatment failure with persistence or recurrence and with a local control rate of only 43.2% (64 of 148 patients). These findings corroborate the observation that radiation therapy is less effective than surgery, because VC, although not radioresistant, is less radiosensitive than squamous cell carcinoma. Of the 148 cases treated with primary radio-therapy, 10 cases (6.7%) of true anaplastic transformation were identified. The prognosis of anaplastic transformation after treatment with radiation therapy is dismal.

Photodynamic therapy: Photodynamic therapy using haematoporphyrins is effective in animal models and has been used to treat head and neck cancers and premalignant lesions in humans.18 22 Photodynamic therapy (PDT) involves using a specific wavelength of light to activate a photosensitising drug that is retained in the lesion. This produces a photochemical reaction resulting in the generation of reactive products such as singlet oxygen that damages the tissue. PDT appears effective in the management of superficial epithelial lesions. However, there is the major disadvantage of skin photosensitivity for about 6 weeks after administration of the photosensitiser.

Laser: Since the early 1970s, C02 laser has proved to be an effective method of treatment for patients with several types of oral lesions, including early squamous cell carcinoma. However, few reports have appeared in the literature regarding the use of C02 in oral VC. The primary advantages of C02 laser treatment include prompt hemo-stasis, wound sterilization and the sealing of adjacent lymphatic vessels.23 This latter property potentially reduces the spread of malignant cells and may be useful in preventing metastasis during the treatment of a patient with squamous cell carcinoma.24 Surgical time is greatly shortened and according to results reported by other studies, the healing process is usually faster and less painful compared with that following electrosurgery and cryosurgery techniques.25'26

Cryosurgery: Cryosurgery uses freezing temperatures to achieve specific effects on tissues. It has been used as the treatment of choice, as an alternative method, or as an adjunct to othermethods for diverse benign andmahgnant lesions.27 32 Advantages of cryosurgery include bloodless treatment, very low incidence of infection, and a relative lack of scarring and pain.33 It has been widely used by dermatologists on skin lesions. Although there have been several reports on the cryosurgical treatment of oral lesions, it is, nevertheless, not widely used by oral and maxillofacial surgeons.5'3437 Simple cryosurgery includes the dipstick (cotton-wool swab) technique and the open spray technique. The open-spray technique emits a fine spray of a cryogen on the target area. There is no contact between the instrument and the tissue, thus preventing the instrument from sticking to the tissue. It is therefore particularly useful for irregular, large, widespread, and multiple lesions and for those with bleeding surfaces. Cryosurgery does not involve the removal of tissue and its technique is not as exactly reproducible as excisional surgery. Because of the lack of precision in cryosurgery, there can be difficulty in judging the final volume of tissue necrosis. Inadequate destruction of the lesion requires another procedure. Therefore multiple treatments to achieve complete eradication of the lesion are needed when cryosurgery is used alone. By tangentially excising the exophytic component of the lesion, the proliferative elements within the submucous layer may be more directly exposed to the cryosurgery, accounting for the high success rates in treating verrucous lesions. An additional advantage of the method is the ability to obtain histologic confrrm-ation of the diagnosis. The primary advantages of the present technique are their ease of use, very low morbidity, limited post-operative care, no sophisticated equipment required, and most of all the satisfactory results.

Interferon therapy: Interferon (IFN) is an antiviral and anti-angiogenic agent that is used in a variety of conditions, including life-threatening hemangiomas and several types of malignant tumors. IFN is produced by recombinant DNA technology or is purified from cultured human cells. Among other effects, IFN suppresses the production of fibroblast growth factors (FGF), which are involved in neo-angiogenesis in tumors. Treatment with IFN is lengthy and challenging. However, with appropriate monitoring, dose modifications, and aggressive supportive care, it can be given safely and is manageable for the majority of patients. The two most common side effects of IFN are flu-like symptoms (fever, chills, muscle and joint aches) and fatigue.38

Our treatment choice was complete surgical excision. VC is an indolent low-grade carcinoma with a deceptively benign histologic appearance. Not withstanding the potential for slow growth and lack of metastasis, the pattern of local invasion and the risk of progression to squamous cell carcinoma dictate an aggressive approach with complete surgical excision. VC involving tooth-bearing mucosa should especially be treated with excision of underlying alveolus. Unfortunately, recurrence is common, and long-term vigilant surveillance is necessary.

There is a considerable controversy in the literature regarding 'anaplastic transformation' of verrucous carcino- ma following irradiation, chemotherapy, cryo-surgery, laser surgery as small proportion of verrucous carcinoma are reported to have changed their biological behaviour from indolent low grade locally destructive lesion to a highly malignant, metastasizing and fatal tumor, with extremely short latent period of transformation.5'39'40'16 Other authors don't believe in this 'dedifferentiation' phenomenon and account this observation to presence of 'Hybrid tumors' which is presence of foci of less differentiated squamous cell carcinoma within verrucous carcinoma.3'9 Because of reported incidence of anaplastic transformation many centers recommend wide field surgical resection with good onco-clearance as preferred treatment modality, While others recommend that verrucous carcinoma should be treated as other squamous cell carcinomas with the treatment modality determined by effectiveness of control without regarding the potential risk of its developing into a far more aggressive lesion.3'41

Conclusion

For proper diagnosis of verrucous carcinoma, deeper tissue biopsies with adequate surgical margins are necessary since these may harbor the foci of well differentiated squamous cell carcinoma. In all cases of verrucous carcinoma, surgery should be done if the procedure has acceptable morbidity. Irradiation might be the second choice of treatment for verrucous carcinoma, where surgery could not be performed. The effectiveness of preoperative chemotherapy for advanced verrucous carcinoma of the tongue has been reported. However, the effect of chemotherapy onverrucous carcinoma hasnotbeen thoroughly estimated at this moment of time. So, surgery is the first choice for the treatment of verrucous carcinoma and radiotherapy or chemotherapy has only a complementary role to surgical procedure.

References

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Disclosure : The authors report no conflicts of interest.