Oral verrucous carcinoma: a diagnostic and therapeutic challenge

Head and neck cancer is the world’s seventh most common cancer with over 870,000 new cases in 2020. Lip and oral cavity malignancies accounted for almost half of them.¹ More than 90% of oral cavity cancers arises from squamous epithelium.² Verrucous carcinoma is a low-grade variant of squamous cell carcinoma (SCC) with specific morphologic, cytokinetic and clinical features.³ It is a locally aggressive tumour and does not metastasize to regional lymph nodes or to distant sites.⁴ In 1941, Friedell and Rosenthal first reported verrucous papillary lesions on the buccal mucosa in eight tobacco chewers.⁵ Seven years later, Ackerman described histopathologic and clinical features of this neoplasm. He defined it as a distinct clinicopathologic entity and introduced a term »verrucous carcinoma«.⁶

Verrucous carcinoma most often arises on mucous membranes of the head and neck region with the oral cavity most commonly involved, particularly buccal mucosa, gum and tongue.³ Oral verrucous carcinoma accounts for 0.57-16.08% of oral squamous cell carcinoma (SCC)^{7, 8, 9} and is predominantly seen in males with the reported mean age at diagnosis between 49 and 69.5 years.^{9, 10, 11} In a study by Koch et al., glottic larynx was the most frequently affected nonoral site.³ Other reported locations in the head and neck region affected by verrucous carcinoma are nasal cavity, paranasal sinuses, nasopharynx, oesophagus and temporal bone.^{12, 13, 14} Verrucous carcinoma on the skin and mucosa of the anogenital region and extremities are described in the literature as well.^15,16

The etiopathogenesis of oral verrucous carcinoma is not completely understood. As in conventional oral SCC, there is a strong association with alcohol consumption and inhaled as well as chewing tobacco use. Other irritants to the oral mucosa such as betel nut chewing, poor oral hygiene, a poorly fitting dental prosthesis and earlier mucosal injuries or scars have also been described as risk factors in the development of oral verrucous carcinoma.^{9,17, 18, 19} There is growing evidence that oral microbiota and its imbalances may play a role in the etiology of oral cancers through activation of smoking and alcohol related carcinogens locally and chronic inflammation systemically.²⁰ Human papillomaviruses (HPVs) have been considered as a possible etiologic factor in verrucous carcinoma, with the reported prevalence of HPV in verrucous carcinoma ranging from 0% to 100%.^{21, 22, 23} However, using highly sensitive and specific molecular methods, it has been shown that HPVs are not associated with the etiopathogenesis of verrucous carcinoma of the head and neck. Furthermore, no evidence of transcriptionally active high-risk α-HPV was found in verrucous carcinoma by real-time polymerase chain reaction (RT-PCR) for HPV E6/E7 messenger ribonucleic acid (mRNA). It appears that verrucous carcinoma of the head and neck is not associated with infection with HPV.^{4,24, 25}

Verrucous carcinoma is characterized by low mitotic activity reflecting in slow growth⁷; hence it can take several years to reach the size that causes symptoms. Patients may report oral discomfort, difficulty chewing or swallowing, and bad breath. Pain usually indicates tumour invasion into the surrounding structures.^26,27

Oral verrucous carcinoma typically appears as an exophytic broad-based lesion with a cauliflower-like warty surface²⁸ as presented in Figure 1. Despite its slow growth, it can reach a significant size and infiltrate adjacent tissues such as muscles and bone.³ However, even when locally advanced, oral verrucous carcinoma has no tendency to metastasize to regional lymph nodes and distant sites.⁴ Cervical lymphadenopathy is commonly seen at initial clinical or radiological examination and is mostly considered reactive secondary to inflammation at the tumour-stromal interface.³

Figure 1

Initial reports of neck metastasis in verrucous carcinoma were later attributed to incorrect pathologic diagnosis or to a presence of foci of conventional SCC of varying degree of differentiation within a verrucous carcinoma. The so-called hybrid verrucous carcinoma was first described by Batsakis et al. in 1982 in three verrucous lesions of the larynx.²⁹ Medina et al. later reported coexistence of verrucous carcinoma and conventional SCC in 20% of 104 patients with oral verrucous carcinoma.³⁰ In contrast to the classic, histologically uniform verrucous carcinoma, a hybrid verrucous carcinoma is capable of metastasizing and must therefore be managed as a more common and aggressive conventional SCC.³¹ However, it is not possible to differentiate these lesions at clinical examination due to similar appearance. Moreover, examination of small tumour samples obtained with biopsy could be misleading as an invasive component is often missed at sampling.³² Gokavarapu et al. reported that 51% of cases preoperatively diagnosed as oral verrucous carcinoma or its benign precursors were actually hybrid lesions.³³ Although multiple biopsies from different areas of the tumour might be helpful to identify invasive component, surgical excision and histopathological examination of whole resection specimen is needed for definitive diagnosis.³² If hybrid verrucous carcinoma is recognized, the pathologist should quantitate each component of the tumour, define the degree of differentiation of the conventional SCC component and comment on depth of the tumour invasion, potential presence of lymphatic or perineural invasion and the adequacy of the resection margins. These features help the clinicians to decide about adjuvant treatment options.³¹

Various mucosal abnormalities including verrucous hyperplasia and dysplasia are frequently found adjacent to the oral verrucous carcinoma supporting the view that verrucous carcinoma develops from precursor lesions.²⁸ Patients with oral verrucous carcinoma are also at high risk of developing metachronous second primary tumours. This can be explained with the concept of »field cancerization« proposed by Slaughter et al. who postulated that prolonged exposure of the upper aerodigestive tract to carcinogens leads to genomic instability even beyond the area of clinically and histopathologically evident mucosal changes.³⁴

Diagnosis of oral verrucous carcinoma is based on a patient’s history, clinical manifestation and histopathologic features of the lesion. However, establishing the correct diagnosis is often difficult due to other oral lesions with often similar verrucous presentation and/or insufficient biopsy specimen as well.⁹ Medical history should include information on the duration of the growth of the lesion and potential etiologic factors (smoking, alcohol abuse). Computed tomography (CT) and/or magnetic resonance imaging (MRI) is helpful to determine local extent of the lesion with potential invasion to surrounding structures and to exclude tumour spread to regional lymph nodes.³⁵

The clinician’s impression of a malignant lesion frequently does not match its benign nature described in the histopathology report. Therefore, biopsies are often repeated, which can significantly delay the start of a treatment.^10,36 Close communication between the clinician and the pathologist is therefore of the utmost importance.³³

Microscopically, verrucous carcinoma consists of filiform projections lined by thick, well-differentiated keratinized squamous epithelium, composed of one to a few layers of basal cells, and multiplied, voluminous spinous cells lacking cytological atypia. It invades the underlying stroma with a well-defined, pushing margin.³⁷ When oral verrucous carcinoma is highly suspicious by clinical appearance, it is recommended that the lesion is surgically excised if not too extensive.³⁸

Lesions in oral cavity with a verrucous appearance may belong to a broad spectrum, extending from verrucous hyperplasia, proliferative verrucous leukoplakia, oral squamous papilloma, oral verrucous carcinoma, hybrid oral verrucous carcinoma to conventional oral SCC with an exophytic growth pattern (Figure 2). It is difficult to distinguish them clinically from each other; they may also coexist.³⁹

Figure 2

Oral verrucous hyperplasia resembles oral verrucous carcinoma both clinically and histopathologically. It presents as a white elevated mucosal plaque or mass with exophytic verrucous surface. In oral verrucous hyperplasia and oral verrucous carcinoma, hyperplastic epithelium is superficial to adjacent normal mucosa, but in oral verrucous carcinoma, broad epithelial processes also extend deeper, exhibiting a pushing-border invasion into the underlying connective tissue but the basement membrane remains intact.⁴⁰ Therefore, it was suggested that oral verrucous carcinoma can be best differentiated from oral verrucous hyperplasia with biopsies taken from the deep portion and the margin of the tumour where adjacent normal mucosa is evident to compare.³³ Oral verrucous hyperplasia is an irreversible precancerous lesion that may transform into oral verrucous carcinoma. Wang et al. reported a 10% of malignant transformation rate in their series of 60 oral verrucous hyperplasia cases. Thus, once diagnosed, oral verrucous hyperplasia should be treated as oral verrucous carcinoma.⁴¹

Proliferative verrucous leukoplakia is an aggressive form of nonhomogeneous multifocal oral leukoplakia characterized by a progressive clinical course with changing clinical and histopathologic features. It is more commonly seen among elderly women. Although etiology of proliferative verrucous leukoplakia remains unclear, it seems that consumption of tobacco and alcohol does not play a role.⁴² Proliferative verrucous leukoplakia usually begins as a single white mucosal plaque that eventually becomes multifocal with exophytic, verrucous or erythematous appearance. Its description includes a histopathological continuum ranging from benign hyperkeratosis to lesions with increasing degree of dysplasia. Therefore, proliferative verrucous leukoplakia has no specific histological features and microscopic findings depend on the histopathologic stage of proliferative verrucous leukoplakia.⁴³ According to the World Health Organization, proliferative verrucous leukoplakia is a potentially malignant disorder with the highest rate of malignant transformation either to oral verrucous carcinoma or conventional oral SCC.⁴² In addition, several authors proposed different clinical and histopathological criteria for diagnosing proliferative verrucous leukoplakia.^44,45 In the meta-analysis by Palaia et al. which included 22 studies with a total of 699 proliferative verrucous leukoplakia patients, a malignant transformation rate of proliferative verrucous leukoplakia was 45.8%.⁴⁶ Thus, once proliferative verrucous leukoplakia is confirmed, active therapy should be undertaken, such as surgery, laser ablation, photodynamic therapy or radiotherapy.⁴⁷ However, proliferative verrucous leukoplakia responds poorly to various treatment modalities and its recurrence rate is high, even after surgical removal.⁴⁸

Squamous cell papilloma (SCP) in the oral cavity appears as a pink to white mucosal exophytic lesion with a warty or granular surface. It is most commonly caused by HPV type 6 and type 11, tends to progress slowly and has a very low risk of becoming malignant. SCP is possible to differentiate from oral verrucous carcinoma microscopically. In contrast to oral verrucous carcinoma which shows epithelial processes with downgrowth into the underlying connective tissue, SCP presents with long, thin and finger-like projections, extending above the mucosal surface. Each of these projections is lined by stratified squamous epithelium and contains a central connective tissue core.⁴⁹

Conventional oral SCC most commonly presents as an ulcerated mucosal lesion with necrotic central area, surrounded by irregular raised and indurated borders. However, an exophytic growth with a smooth, ulcerated or verrucous surface may also be seen.^50,51 In comparison to oral verrucous carcinoma, conventional oral SCC is histopathologically marked by a greater degree of atypia and mitotic activity of the tumour cells and invasion beyond the basement membrane.³¹ It grows more rapidly, frequently metastasizes to the regional and distant sites and has a worse prognosis.⁸ Oral verrucous carcinoma with foci of conventional SCC can be found at histopathological examination, which dictates treatment choices and prognosis.³¹

The development of oral verrucous carcinoma is modulated by genetic predisposition and environmental influences resulting in a wide range of genetic and epigenetic alterations that can be detected by various tumour markers. Molecular mechanisms of oral verrucous carcinoma are therefore increasingly being investigated. Although many different molecules associated with diagnosis, tumour progression and prognosis of oral verrucous carcinoma have been proposed, a reliable and effective biomarker has still not been identified.³⁵

Genetic studies have shown that several genes are differently expressed between oral verrucous carcinoma and oral SCC.⁵² Most investigated markers in carcinogenesis of oral verrucous carcinoma are p53^53,54, Ki-67^53,55,56, cyclin-B1^56,57 and cyclin-D1.⁵⁸ Except for Ki-67, their expression levels were significantly higher in conventional oral SCC than in oral verrucous carcinoma. Tumour suppression markers p21 and p27 may not be of much diagnostic use in distinguishing oral verrucous carcinoma from oral verrucous hyperplasia ⁵⁹ and oral SCC.^54,60 Components of extracellular matrix and basement membrane play an important role in tumour invasion and metastasis. Oral verrucous carcinoma is associated with lower expression of matrix metal-loproteinase 9 (MMP-9)⁵³ and higher expression of laminin⁶¹ in comparison to oral SCC. Laminin and type IV collagen are good markers for basement membrane integrity and their discontinuity is more evident in severe oral epithelial dysplasia than in verrucous carcinoma.⁶¹ Among cell surface proteins, high level of expression of glucose transporter 1 (GLUT-1) in both oral SCC and oral verrucous carcinoma could differentiate them from oral epithelial dysplasia.⁶² Oral SCC could be distinguished from oral verrucous carcinoma based on a higher density of CD68 (marking tumour associated macrophages) and CD31 (marking microvessel density) found in immunohistochemical studies.⁶³ Regarding cytoskeletal proteins, CK20 is highly expressed in oral verrucous carcinoma and oral SCC but not in benign squamous lesions⁶⁴, and CD34 along with α-smooth muscle actin (α-SMA) seem to be helpful in the diagnosis of oral verrucous hyperplasia.⁶⁵ Different expression of desmosomal proteins (up-regulation of plakophilin 1, desmoglein 2, desmoglein 3, desmoplakin), microRNA (miRNA) molecules (up-regulation of miRNA-203, down-regulation of miRNA-125a-5p, miRNA-125b) and proteins (down-regulation of p63) in verrucous carcinoma is useful in differentiation from conventional SCC and detecting foci of SCC in hybrid verrucous carcinoma as well.^37,66

Due to the rarity of oral verrucous carcinoma, treatment recommendations found in the literature is mostly based on case reports and small retrospective case series, and are consequently not uniform. The treatment modalities available include surgery, radiotherapy, chemotherapy, or combinations thereof.

Oral verrucous carcinoma is a rare variant of oral SCC that must be differentiated from conventional SCC due to its locally invasive and non-metastasizing behaviour with a more favourable prognosis. For making a correct diagnosis, close communication between clinician and pathologist is mandatory. Primary surgery with negative surgical margins seems to be the optimal treatment for patients with oral verrucous carcinoma; whether to perform the END remains controversial. The concern about anaplastic transformation after irradiation should not affect the decision on treatment with radiotherapy which is usually proposed to patients with extensive tumours or patients in poor general condition. The role of systemic therapy, particularly immunotherapy and targeted therapy, and non-surgical treatment methods are yet to be defined. Due to rarity of the disease, pooled multi-institutional analyses are warranted to properly address opened questions.