Radiol Oncol 2023; 57(1): 1-11. doi: 10.2478/raon-2023-0015 1 review Oral verrucous carcinoma: a diagnostic and therapeutic challenge Nejc Kristofelc1, Nina Zidar2, Primoz Strojan3,4 1 Department of Otorhinolaryngology, General Hospital Dr. Franc Derganc Nova Gorica, Šempeter pri Gorici, Slovenia 2 Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia 3 Department of Radiation Oncology, Institute of Oncology, Ljubljana, Slovenia 4 Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia Radiol Oncol 2023; 57(1): 1-11. Received 17 December 2022 Accepted 29 January 2023 Correspondence to: Nejc Krištofelc, M.D., Department of Otorhinolaryngology, General Hospital Dr. Franc Derganc Nova Gorica, Ulica padlih borcev 13 A, SI-5290 Šempeter pri Gorici, Slovenia. E-mail: nejc.kristofelc@bolnisnica-go.si Disclosure: No potential conflicts of interest were disclosed. This is an open access article distributed under the terms of the CC-BY license (https://creativecommons.org/licenses/by/4.0/). Background. Verrucous carcinoma is a low-grade variant of squamous cell carcinoma with specific morphologic, cytokinetic and clinical features. Despite low mitotic activity and slow growth, it can infiltrate adjacent tissues in advanced stages but does not metastasize. The most frequently affected site is the oral cavity. The following article provides latest updates in the etiology, clinical presentation, diagnostics and treatment options in oral verrucous car- cinoma and discusses the existing dilemmas linked to this unique malignancy. Conclusions. Oral verrucous carcinoma must be differentiated from conventional squamous cell carcinoma due to its less aggressive behaviour with a more favourable prognosis. Close communication between clinician and patholo- gist is mandatory for making a correct diagnosis. Primary surgery with negative surgical margins seems to be the most successful treatment. However, management recommendations are not uniform since they are mostly based on case reports and small retrospective case series. Prospective and pooled multi-institutional studies are therefore needed. Key words: verrucous carcinoma; oral verrucous carcinoma; squamous cell carcinoma; diagnostics; differential diagnosis; treatment Introduction 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 epitheli- um.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 me- tastasize to regional lymph nodes or to distant sites.4 In 1941, Friedell and Rosenthal first report- ed verrucous papillary lesions on the buccal mu- cosa in eight tobacco chewers.5 Seven years later, Ackerman described histopathologic and clinical features of this neoplasm. He defined it as a dis- tinct clinicopathologic entity and introduced a term »verrucous carcinoma«.6 Verrucous carcinoma most often arises on mu- cous membranes of the head and neck region with the oral cavity most commonly involved, particu- larly buccal mucosa, gum and tongue.3 Oral ver- rucous carcinoma accounts for 0.57-16.08% of oral squamous cell carcinoma (SCC)7–9 and is predomi- nantly seen in males with the reported mean age at diagnosis between 49 and 69.5 years.9–11 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 Radiol Oncol 2023; 57(1): 1-11. Kristofelc N et al. / Review of oral verrucous carcinoma2 verrucous carcinoma are nasal cavity, paranasal sinuses, nasopharynx, oesophagus and temporal bone.12-14 Verrucous carcinoma on the skin and mu- cosa of the anogenital region and extremities are described in the literature as well.15,16 Etiology 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 to- bacco use. Other irritants to the oral mucosa such as betel nut chewing, poor oral hygiene, a poorly fit- ting dental prosthesis and earlier mucosal injuries or scars have also been described as risk factors in the development of oral verrucous carcinoma.9,17–19 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 papillomavi- ruses (HPVs) have been considered as a possible etiologic factor in verrucous carcinoma, with the reported prevalence of HPV in verrucous carcino- ma ranging from 0% to 100%.21–23 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 tran- scriptionally 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 Clinical presentation Verrucous carcinoma is characterized by low mi- totic 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 cauliflow- er-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 me- tastasize 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 in- flammation at the tumour-stromal interface.3 Initial reports of neck metastasis in verrucous carcinoma were later attributed to incorrect patho- logic diagnosis or to a presence of foci of convention- al SCC of varying degree of differentiation within a verrucous carcinoma. The so-called hybrid ver- rucous carcinoma was first described by Batsakis et al. in 1982 in three verrucous lesions of the lar- ynx.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 ver- rucous carcinoma, a hybrid verrucous carcinoma is capable of metastasizing and must therefore be managed as a more common and aggressive con- ventional SCC.31 However, it is not possible to dif- ferentiate 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 FIGURE 1. Verrucous carcinoma of the right buccal mucosa (clinical stage T2N0M0) in an 81-year-old male patient. He presented with a whitish exophytic tumour mass of the inner side of the right cheek and without suspicious lymph nodes on the neck. The lesion was noticed by the patient a month before initial examination, and it occasionally hurt, but he had no problems feeding. Due to associated diseases, he was treated with radiotherapy (55 Gy, 2.2 Gy/ fraction) and concurrent intravenous chemotherapy (vinblastine 2 mg, day 1; methotrexate 50 mg, day 2; bleomycin 15 mg, days 2 and 3). The patient died of injury 5.5 years after completion of treatment for verrucous carcinoma with no evidence of malignant disease in oral cavity. Radiol Oncol 2023; 57(1): 1-11. Kristofelc N et al. / Review of oral verrucous carcinoma 3 verrucous carcinoma or its benign precursors were actually hybrid lesions.33 Although multiple biop- sies from different areas of the tumour might be helpful to identify invasive component, surgical ex- cision and histopathological examination of whole resection specimen is needed for definitive diagno- sis.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 pres- ence of lymphatic or perineural invasion and the adequacy of the resection margins. These features help the clinicians to decide about adjuvant treat- ment options.31 Various mucosal abnormalities including ver- rucous hyperplasia and dysplasia are frequently found adjacent to the oral verrucous carcinoma supporting the view that verrucous carcinoma de- velops from precursor lesions.28 Patients with oral verrucous carcinoma are also at high risk of de- veloping 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 Diagnostics and differential diagnosis Diagnosis of oral verrucous carcinoma is based on a patient’s history, clinical manifestation and his- topathologic features of the lesion. However, estab- lishing 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 informa- tion on the duration of the growth of the lesion and potential etiologic factors (smoking, alcohol abuse). Computed tomography (CT) and/or magnetic reso- nance imaging (MRI) is helpful to determine local extent of the lesion with potential invasion to sur- rounding 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 de- scribed in the histopathology report. Therefore, bi- opsies are often repeated, which can significantly delay the start of a treatment.10,36 Close communi- cation between the clinician and the pathologist is therefore of the utmost importance.33 Microscopically, verrucous carcinoma con- sists 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 cy- tological atypia. It invades the underlying stroma with a well-defined, pushing margin.37 When oral verrucous carcinoma is highly suspicious by clini- cal appearance, it is recommended that the lesion is surgically excised if not too extensive.38 Lesions in oral cavity with a verrucous appear- ance may belong to a broad spectrum, extending from verrucous hyperplasia, proliferative verru- cous leukoplakia, oral squamous papilloma, oral verrucous carcinoma, hybrid oral verrucous carci- noma to conventional oral SCC with an exophytic growth pattern (Figure 2). It is difficult to distin- guish them clinically from each other; they may also coexist.39 Oral verrucous hyperplasia resembles oral ver- rucous carcinoma both clinically and histopatho- logically. 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 sug- gested 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 transfor- mation rate in their series of 60 oral verrucous hyperplasia cases. Thus, once diagnosed, oral ver- rucous hyperplasia should be treated as oral ver- rucous carcinoma.41 Proliferative verrucous leukoplakia is an ag- gressive 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 verru- cous leukoplakia remains unclear, it seems that consumption of tobacco and alcohol does not play a role.42 Proliferative verrucous leukoplakia usu- ally begins as a single white mucosal plaque that eventually becomes multifocal with exophytic, verrucous or erythematous appearance. Its de- Radiol Oncol 2023; 57(1): 1-11. Kristofelc N et al. / Review of oral verrucous carcinoma4 scription 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 de- pend on the histopathologic stage of proliferative verrucous leukoplakia.43 According to the World Health Organization, proliferative verrucous leu- koplakia 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 dif- ferent clinical and histopathological criteria for di- agnosing proliferative verrucous leukoplakia.44,45 In the meta-analysis by Palaia et al. which included 22 studies with a total of 699 proliferative verru- cous leukoplakia patients, a malignant transfor- mation 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, photo- dynamic therapy or radiotherapy.47 However, pro- liferative 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 cav- ity 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 differenti- ate from oral verrucous carcinoma microscopical- ly. 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, extend- ing above the mucosal surface. Each of these pro- jections 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 cen- tral area, surrounded by irregular raised and indu- rated borders. However, an exophytic growth with a smooth, ulcerated or verrucous surface may also be seen.50,51 In comparison to oral verrucous carci- noma, 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 dic- tates treatment choices and prognosis.31 FIGURE 2. Histopathology images of oral verrucous lesions. Squamous cell papilloma (A) exophytic lesion, composed of finger-like projections, lined by non-keratinizing stratified squamous epithelium and a central connective tissue core. Verrucous hyperplasia (B) exophytic lesion, composed of hyperplastic keratinizing squamous epithelium with no invasion into the underlying stroma. Verrucous carcinoma (C) exophytic tumour, resembling verrucous hyperplasia, but with invasive growth, consisting of broad epithelial islands and processes, with no atypia, exhibiting a pushing-border into the underlying stroma. A B C Radiol Oncol 2023; 57(1): 1-11. Kristofelc N et al. / Review of oral verrucous carcinoma 5 Molecular biomarkers The development of oral verrucous carcinoma is modulated by genetic predisposition and environ- mental influences resulting in a wide range of ge- netic and epigenetic alterations that can be detect- ed by various tumour markers. Molecular mecha- nisms of oral verrucous carcinoma are therefore increasingly being investigated. Although many different molecules associated with diagnosis, tu- mour progression and prognosis of oral verrucous carcinoma have been proposed, a reliable and ef- fective 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 mark- ers in carcinogenesis of oral verrucous carcinoma are p5353,54, Ki-6753,55,56, cyclin-B156,57 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 diagnos- tic 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 inva- sion 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 base- ment 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 trans- porter 1 (GLUT-1) in both oral SCC and oral ver- rucous carcinoma could differentiate them from oral epithelial dysplasia.62 Oral SCC could be dis- tinguished from oral verrucous carcinoma based on a higher density of CD68 (marking tumour associated macrophages) and CD31 (marking mi- crovessel 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 plakophi- lin 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 differen- tiation from conventional SCC and detecting foci of SCC in hybrid verrucous carcinoma as well.37,66 Treatment Due to the rarity of oral verrucous carcinoma, treatment recommendations found in the litera- ture 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. Surgery Wide surgical excision is usually considered the treatment of choice because of the wide spectrum of reconstruction possibilities of the resulting tis- sue defect in the oral cavity with good functional results, and encouraging locoregional control and survival rates.17,38,67 However, there is ongoing de- bate about the optimal width of surgical margins and the need for elective neck dissection (END). Similar to conventional oral SCC, clinical surgical margin of 10–15 mm and histological margin of at least 5 mm are still generally considered sufficient to not increase the risk of local recurrence of oral verrucous carcinoma68-70, although no worse out- comes were reported in patients with close histo- logical margins (i.e. less than 5 mm) who did not receive adjuvant radiotherapy.10 Since histological- ly pure oral verrucous carcinoma does not metas- tasize, END is usually not performed during pri- mary surgery but is indicated in hybrid oral ver- rucous carcinoma and when microvascular flap is used for reconstruction of tumour defect.10,67,68 Some authors advocate a selective supraomo- hyoid neck dissection (neck levels I–III) also in patients with advanced primary tumour stages (cT3–4) and/or clinically overt lymphadenopathy. However, in several studies, no patient with END had histologically proven nodal metastasis.10,17,38,71 Radiotherapy Oral verrucous carcinoma is thought to be less sensitive to radiotherapy than conventional oral SCC.72,73 Radiotherapy targets DNA in rapidly di- viding cells, whereas studies on cytokinetic char- acteristics of verrucous carcinoma have shown that only low proportion of tumour cells are in S-phase compartment of the cell cycle during which DNA is synthesized, corresponding to a low mitotic ac- Radiol Oncol 2023; 57(1): 1-11. Kristofelc N et al. / Review of oral verrucous carcinoma6 tivity of this tumour and reduced susceptibility to irradiation.29 Mohan et al. demonstrated that pa- tients with oral verrucous carcinoma who received postoperative radiotherapy trended toward worse disease-specific survival (DSS) than those with oral SCC, suggesting relative radioresistance of oral verrucous carcinoma.7 Studies reporting local control rate and survival rate for upfront surgery and primary radiotherapy are summarized in Table 1 and Table 2. However, a fair comparison between oncologi- cal results of surgery and radiotherapy is diffi- cult to make due to obvious lack of well-designed prospective studies or even comparisons. In most series, patients were recruited over a longer time period which resulted in suboptimal treatments in at least part of these patients. Thus, local control and survival rates of irradiated patients must be interpreted with caution and understanding that irradiation techniques and fractionation schemes used in the past changed significantly over time. Nevertheless, radiotherapy is an acceptable alter- native to surgery for patients who refuse proposed operation or are medically unfit for major surgery as well as in whom surgery would cause an im- portant functional and/or cosmetic impairment.77 In cases of radiotherapy failure, surgical salvage remains an option.78 In the past, radiotherapy was burdened with the phenomenon of anaplastic transformation which assumed the possibility of conversion of verrucous carcinoma to a less-differentiated SCC after irradiation.79 In older literature, its incidence has been reported to be as high as 30%.80 Recently, different authors questioned the concept of this phenomenon and raised the possibility of hybrid lesions containing foci of conventional SCC that had been missed at the initial biopsy and not con- trolled by irradiation, resulting in tumour recur- rence.3,79,81 This hypothesis is further justified by the reports of anaplastic transformation following primary surgery as well, probably due to the same reason as in the case of radiotherapy, i.e. an incor- rect histopathologic diagnosis.73 Postoperative radiotherapy The benefit of postoperative radiotherapy (PORT) in oral verrucous carcinoma is controversial. The decision about PORT usually follows recommen- dations for patients with conventional oral SCC (i.e. positive or close surgical margins, pT3–T4 primary tumour, perineural and lymphovascular invasion).67,82 Analysing the SEER database, how- ever, Mohan et al. demonstrated a statistically significant improvement in DSS in patients solely operated compared to those receiving surgery and PORT.7 In a recent retrospective cohort study of the National Cancer Database (NCDB), Naik et al. showed that positive surgical margins were as- sociated with significantly worse overall survival (OS) (hazard ratio [HR] 2.85, P = 0.006).82 However, TABLE 1. Primary surgery in the treatment of oral verrucous carcinoma - review of the literature series Authors and study year Number of patients Local control (%) Survival Follow-up time Kraus and Perezmesa, 196674 64 55 (85.9) N.S. N.S. Medina et al, 198430 90 74 (82.2) N.S. At least 2 years Jyothirmayi et al, 19978 11 N.S. 5-year DFS 68% Median 56 months (range 7–110) Koch et al, 20013 484 N.S. 5-year RSR 85.7% N.S. Kang et al, 200338 38 38 (100) at 3 years 3-year OSR 94.7% Median 37.5 months (range 13–76) Walvekar et al, 200917 101 80 (79.2) 5-year DFS 77.6% Median 4.61 years (range 0.5–14.3) Huang et al, 200967 39 38 (97.4) 5-year CSS 89.1% Median 90 months (range, 13–171) Candau-Alvarez et al, 201468 13 12 (92.3) OSR 92.9% for a mean follow- up of 2 years Mean 24.8 months (range 6–53) Franklyn et al, 201710 22 21 (95.5) (recurrence in a patient with hybrid OVC) N.S. Median 24 months CSS = cancer specific survival; DFS = disease free survival; N.S. = not specified; OSR = overall survival rate; OVC = oral verrucous carcinoma; RSR = relative survival rate Radiol Oncol 2023; 57(1): 1-11. Kristofelc N et al. / Review of oral verrucous carcinoma 7 in those patients the use of PORT showed no OS benefit (HR 3.12, P = 0.072). These findings suggest that the role of PORT is limited in oral verrucous carcinoma, favouring surgical re-resection, when feasible, over adjuvant radiotherapy in patients with adverse pathologic features or clinically overt residual tumour after surgery.82 Chemotherapy Experiences with chemotherapy, alone or in com- bination with other modalities, in oral verrucous carcinoma are scarce.83 Chemotherapy can be im- plemented in a neo-adjuvant setting to reduce tu- mour size before subsequent surgery, which is ex- pected to be less extensive and mutilating, result- ing in better functional and cosmetic outcome.84 It can also be used as a salvage treatment for patients with recurrent disease and to palliate symptoms in advanced tumours not suitable for aggressive radical treatment.85,86 Although the data on the use of older chemotherapy drugs are available in the literature, there is no information on the use of modern drugs (targeted agents, check-point in- hibitors) in oral verrucous carcinoma. Encouraging results were reported by Wu et al. using intra-arterial methotrexate infusion as a primary therapy in 15 patients with oral verru- cous carcinoma. Despite locally advanced T3–4 tumours in eight of these patients, a complete tu- mour remission was observed in all patients who were without disease recurrence at a mean follow- up of 42 months.83 Karkazoglou et al. reported on 12 oral verrucous carcinoma patients who had also been treated with methotrexate, given by various routes and in different doses, because of either the extent of the tumour or poor general condition of the patient. Only one patient failed to respond. Authors concluded that methotrexate reduced morbidity and improved quality of life with mini- mal and reversible toxicity.87 Preliminary observa- tions in two elderly patients with locally advanced oral verrucous carcinoma showed that single cy- cle of oral fluoropyrimidine capecitabine induced rapid and clinically significant response with near complete resolution of oral lesions within 3 weeks of initiating therapy. A durable partial response was seen at 6 months and 1 year and was associ- ated with significant improvement in life quality with acceptable toxicity profile.88 Chemoradiotherapy In addition, chemotherapy can be given simultane- ously with radiotherapy. In a group of 12 patients with previously untreated verrucous carcinoma of different head and neck mucosal sites, concurrent chemoradiotherapy with at least two cycles of in- travenous vinblastine, methotrexate and bleomy- cin and radiotherapy dose of 44–70 Gy (median 65.2 Gy) resulted in local control (median follow- up of 3.4 years) in 11 patients, nine of whom had advanced T3–4 tumours.85 Authors concluded that concomitant chemotherapy seems to successfully compensate lower effectiveness of radiotherapy in verrucous carcinoma and even allows reduction of TABLE 2. Primary radiotherapy in the treatment of oral verrucous carcinoma - review of the literature series Authors and study year Number of patients Local control rate with primary radiotherapy (%) Surgical salvage Local control rate with primary radiotherapy and salvage surgery (%) Survival Follow-up time Kraus and Perezmesa, 196674 13 0 (0) 8/13 7 (53.8) N.S. N.S. Memula et al, 198075 32 19 (59.4) 6/13 25 (78.1) 5-year DFS 31% N.S. Medina et al, 198430 12 7 (58.3) 3/5 10 (83.3) N.S. At least 2 years Nair et al, 198876 50 22 (44) at 3 years 4/28 N.S. 3-year DFS 44% At least 3 years Vidysagar et al, 199236 107 55 (51.4) (residual disease in 19 patients, recurrence in 33 patients) 20/52 N.S. 5-year DFS 49% Range 6–60 months Jyothirmayi et al, 19978 42 16 (38.1) (residual disease in 10 patients, recurrence in 16 patients) 9/26 N.S. 5-year DFS 66% Median 56 months (range 7–110) Koch et al, 20013 33 N.S. N.S. N.S. 5-year RSR 41.8% N.S. DFS = disease free survival; N.S. = not specified; OVC = oral verrucous carcinoma; RSR = relative survival rate Radiol Oncol 2023; 57(1): 1-11. Kristofelc N et al. / Review of oral verrucous carcinoma8 radiation dose bellow the standard 66–70 Gy, and, therefore, alleviates its toxicity and contributes to organ sparing.84 Promising results of chemoradio- therapy were also reported by Yoshimura et al. us- ing 5-fluorouracil and its analogues.89 Non-surgical techniques Non-surgical methods are well established treat- ment modalities in low risk nonmelanoma skin cancers and to some extent in oral benign and precancerous lesions but there are only a few case reports regarding their use in oral verrucous car- cinoma. Cryotherapy acts by freezing a lesion in situ which leads to disruption of cell membranes, dam- age of tumour vasculature, activation of cytotoxic immune mechanisms and finally cell necrosis.90 Yeh et al. reported clinically complete response to shave excision and subsequent cryotherapy with liquid nitrogen in 11 of 18 patients with oral ver- rucous hyperplasia and oral verrucous carcinoma. After a mean follow-up of 23 months, recurrence was found in three cases and all were successfully treated by the same technique.91 Photodynamic therapy (PDT) is based on topi- cal or systemic administration of an exogenous photosensitiser which increases tumour tissue sensitiveness to light of a specific wavelength.92 It mediates tumour destruction by creating oxygen free radicals, damaging tumour vasculature and activating immune response against tumour cells. Chen et al. reported a complete clinical regression and no tumour recurrence at 6 months follow-up after 22 cycles of PDT using topical 5-aminole- vulinic acid followed by multiple fractionated ir- radiations with LED red light in a 56-year-old male with oral verrucous carcinoma extending from mouth angle to buccal mucosa.93 In order to bet- ter expose deeper part of the lesion under mucosal surface to cryotherapy or PDT and make a defini- tive histopathologic diagnosis, its exophytic part may initially be removed with debulking methods such as shave or laser excision.91 CO2 laser destructs a lesion with tissue vapori- zation and is therefore proposed for treatment of tumours involving cosmetically critical areas such as lips, where wide surgical excision may lead to unacceptable aesthetic and/or functional impair- ment.94 Several authors reported good clinical re- sponse with complete tumour removal and no re- currence in a follow-up from 15 to 48 months.94-96 Described procedures are non-invasive and can be safely carried out in a local anaesthesia in the outpatient clinic. Other reported advantages are short procedure duration, ability to treat multifo- cal lesions, limited pain and scarring, fast homeo- stasis and healing process, low risk of secondary infection and little or no side effects.91,93,95 However, their effect is limited by a depth of agent penetra- tion, which therefore makes them suitable only for a treatment of superficial oral lesions.92 They also lack working precision since it is difficult to judge the final extent of tissue necrosis during a proce- dure. Moreover, tumour resolution can only be assessed clinically and not histopathologically.91 Large-scale clinical studies with longer follow-up are further necessary to evaluate their effective- ness in the management of oral verrucous carci- noma. Conclusions Oral verrucous carcinoma is a rare variant of oral SCC that must be differentiated from conventional SCC due to its locally invasive and non-metastasiz- ing behaviour with a more favourable prognosis. For making a correct diagnosis, close communica- tion between clinician and pathologist is manda- tory. Primary surgery with negative surgical mar- gins seems to be the optimal treatment for patients with oral verrucous carcinoma; whether to per- form 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 pa- tients 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. Acknowledgments This review was funded by the Slovenian Research Agency (ARRS), grant number P3-0307. References 1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mor- tality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71: 209-49. doi: 10.3322/caac.21660 Radiol Oncol 2023; 57(1): 1-11. Kristofelc N et al. / Review of oral verrucous carcinoma 9 2. Van Dijk BAC, Brands MT, Geurts SME, Merkx MAW, Roodenburg JLN. Trends in oral cavity cancer incidence, mortality, survival and treatment in the Netherlands. Int J Cancer 2016; 139: 574-83. doi: 10.1002/ijc.30107 3. Koch BB, Trask DK, Hoffman HT, Karnell LH, Robinson RA, Zhen W, et al. National survey of head and neck verrucous carcinoma: patterns of presentation, care, and outcome. Cancer 2001; 92: 110-20. doi: 10.1002/1097-0142(20010701)92:1<110::AID-CNCR1298>3.0.CO;2-K 4. Patel KR, Chernock RD, Zhang TR, Wang X, El-Mofty SK, Lewis JSJ. Verrucous carcinomas of the head and neck, including those with associated squamous cell carcinoma, lack transcriptionally active high-risk human papillomavirus. Hum Pathol 2013; 44: 2385-92. doi: 10.1016/j.humpath.2013.07.011 5. Friedell HL, Rosenthal LM. The etiologic role of chewing tobacco in cancer of the mouth: report of eight cases treated with radiation. J Am Med Assoc 1941; 116: 2130-5. doi: 10.1001/jama.1941.02820190006002 6. Ackerman LV. Verrucous carcinoma of the oral cavity. Surgery 1948; 23: 670- 8. PMID: 18907508 7. Mohan S, Pai SI, Bhattacharyya N. Adjuvant radiotherapy is not supported in patients with verrucous carcinoma of the oral cavity. Laryngoscope 2017; 127: 1334-8. doi: 10.1002/lary.26443 8. Jyothirmayi R, Sankaranarayanan R, Varghese C, Jacob R, Nair MK. Radiotherapy in the treatment of verrucous carcinoma of the oral cavity. Oral Oncol 1997; 33: 124-8. doi: 10.1016/S0964-1955(96)00059-0 9. Rekha KP, Angadi PV. Verrucous carcinoma of the oral cavity: a clinico- pathologic appraisal of 133 cases in Indians. Oral Maxillofac Surg 2010; 14: 211-8. doi: 10.1007/s10006-010-0222-0 10. Franklyn J, Janakiraman R, Tirkey AJ, Thankachan C, Muthusami J. Oral verrucous carcinoma: ten year experience from a tertiary care hospital in India. Indian J Med Paediatr Oncol 2017; 38: 452-5. doi: 10.4103/ijmpo. ijmpo_153_16 11. Alonso JE, Kuan EC, Arshi A, St. John MA. A population-based analysis of verrucous carcinoma of the oral cavity. Laryngoscope 2018; 128: 393-7. doi: 10.1002/lary.26745 12. Alonso JE, Han AY, Kuan EC, Suh JD, John MAS. Epidemiology and sur- vival outcomes of sinonasal verrucous carcinoma in the United States. Laryngoscope 2018; 128: 651-6. doi: 10.1002/lary.26790 13. Sweetser S, Jacobs NL, Wong Kee Song LM. Endoscopic diagnosis and treat- ment of esophageal verrucous squamous cell cancer. Dis Esophagus 2014; 27: 452-6. doi: 10.1111/j.1442-2050.2012.01434.x 14. Miller ME, Martin N, Juillard GF, Bhuta S, Ishiyama A. Temporal bone verru- cous carcinoma: outcomes and treatment controversy. Eur Arch Oto-Rhino- Laryngology 2010; 267: 1927-31. doi: 10.1007/s00405-010-1281-4 15. Prince ADP, Harms PW, Harms KL, Kozlow JH. Verrucous carcinoma of the foot: a retrospective study of 19 cases and analysis of prognostic factors influencing recurrence. Cutis 2022; 109: E21-8. doi: 10.12788/cutis.0499 16. Koch H, Kowatsch E, Hödl S, Smola MG, Radl R, Hofmann T, et al. Verrucous carcinoma of the skin: long-term follow-up results following surgical therapy. Dermatol Surg 2004; 30: 1124-30. doi: 10.1111/j.1524-4725.2004.30338.x 17. Walvekar RR, Chaukar DA, Deshpande MS, Pai PS, Chaturvedi P, Kakade A, et al. Verrucous carcinoma of the oral cavity: a clinical and pathological study of 101 cases. Oral Oncol 2009; 45: 47-51. doi: 10.1016/j.oraloncol- ogy.2008.03.014 18. Gokavarapu S, Parvataneni N, Charan CR, Puthamakula S, Kulkarni G, Reddy BS. Multi centricity of oral verrucous carcinoma: a case series of 22 cases. Indian J Otolaryngol Head Neck Surg 2015; 67: 138-42. doi: 10.1007/ s12070-015-0835-6 19. Rahali L, Omor Y, Mouden K, Mahdi Y, Elkacemi H, Elmajjaoui S, et al. Oral verrucous carcinoma complicating a repetitive injury by the dental prosthesis: a case report. Pan Afr Med J 2015; 20: 297. doi: 10.11604/ pamj.2015.20.297.6135 20. Ahn J, Chen CY, Hayes RB. Oral microbiome and oral and gastrointestinal cancer risk. Cancer Causes Control 2012; 23: 399-404. doi: 10.1007/s10552- 011-9892-7 21. Johnson TL, Plieth DA, Crissman JD, Sarkar FH. HPV detection by polymerase chain reaction (PCR) in verrucous lesions of the upper aerodigestive tract. Mod Pathol 1991; 4: 461-5. 22. Fliss DM, Noble-Topham SE, McLachlin M, Freeman JL, Noyek AM, van Nostrand AW, et al. Laryngeal verrucous carcinoma: a clinicopathologic study and detection of human papillomavirus using polymerase chain reac- tion. Laryngoscope 1994; 104: 146-52. doi: 10.1288/00005537-199402000- 00005 23. Mitsuishi T, Ohara K, Kawashima M, Kobayashi S, Kawana S. Prevalence of human papillomavirus DNA sequences in verrucous carcinoma of the lip: genomic and therapeutic approaches. Cancer Lett 2005; 222: 139-43. doi: 10.1016/j.canlet.2004.09.019 24. del Pino M, Bleeker MCG, Quint WG, Snijders PJF, Meijer CJLM, Steenbergen RDM. Comprehensive analysis of human papillomavirus prevalence and the potential role of low-risk types in verrucous carcinoma. Mod Pathol 2012; 25: 1354-63. doi: 10.1038/modpathol.2012.91 25. Odar K, Kocjan BJ, Hošnjak L, Gale N, Poljak M, Zidar N. Verrucous carcinoma of the head and neck - not a human papillomavirus-related tumour? J Cell Mol Med 2014; 18: 635-45. doi: 10.1111/jcmm.12211 26. Terada T. Verrucous carcinoma of the oral cavity: a histopathologic study of 10 Japanese cases. J Maxillofac Oral Surg 2011; 10: 148-51. doi: 10.1007/ s12663-011-0197-x 27. Kamath VV, Varma RR, Gadewar DR, Muralidhar M. Oral verrucous carci- noma. An analysis of 37 cases. J Craniomaxillofac Surg 1989; 17: 309-14. doi: 10.1016/s1010-5182(89)80059-9 28. Sonalika W, Anand T. Oral verrucous carcinoma: a retrospective analysis for clinicopathologic features. J Cancer Res Ther 2016; 12: 142-5. doi: 10.4103/0973-1482.172709 29. Batsakis JG, Hybels R, Crissman JD, Rice DH. The pathology of head and neck tumors: verrucous carcinoma, part 15. Head Neck Surg 1982; 5: 29-38. doi: 10.1002/hed.2890050107 30. Medina JE, Dichtel W, Luna MA. Verrucous-squamous carcinomas of the oral cavity: a clinicopathologic study of 104 cases. Arch Otolaryngol 1984; 110: 437-40. doi: 10.1001/archotol.1984.00800330019003 31. Devaney KO, Ferlito A, Rinaldo A, El-Naggar AK, Barnes L. Verrucous carci- noma (carcinoma cuniculatum) of the head and neck: what do we know now that we did not know a decade ago? Eur Arch Otorhinolaryngol 2011; 268: 477-80. doi: 10.1007/s00405-011-1495-0 32. Gokavarapu S, Rao.S LMC, Tantravahi US, Gundimeda SD, Rao TS, Murthy S. Oral hybrid verrucous carcinoma: a clinical study. Indian J Surg Oncol 2014; 5: 257-62. doi: 10.1007/s13193-014-0345-0 33. Gokavarapu S, Chandrasekhara Rao LM, Patnaik SC, Parvataneni N, Raju KVVN, Chander R, et al. Reliability of incision biopsy for diagnosis of oral verrucous carcinoma: a multivariate clinicopathological study. J Maxillofac Oral Surg 2015; 14: 599-604. doi: 10.1007/s12663-014-0715-8 34. Slaughter DP, Southwick HW, Smejkal W. Field cancerization in oral strati- fied squamous epithelium; clinical implications of multicentric origin. Cancer 1953; 6: 963-8. doi: 10.1002/1097-0142(195309)6:5<963::aid- cncr2820060515>3.0.co;2-q 35. Peng Q, Wang Y, Quan H, Li Y, Tang Z. Oral verrucous carcinoma: from mul- tifactorial etiology to diverse treatment regimens (review). Int J Oncol 2016; 49: 59-73. doi: 10.3892/ijo.2016.3501 36. Vidyasagar MS, Fernandes DJ, Kasturi DP, Akhileshwaran R, Rao K, Rao S, et al. Radiotherapy and verrucous carcinoma of the oral cavity: a study of 107 cases. Acta Oncol 1992; 31: 43-7. doi: 10.3109/02841869209088264 37. Odar K, Boštjančič E, Gale N, Glavač D, Zidar N. Differential expression of microRNAs miR-21, miR-31, miR-203, miR-125a-5p and miR-125b and proteins PTEN and p63 in verrucous carcinoma of the head and neck. Histopathology 2012; 61: 257-65. doi: 10.1111/j.1365-2559.2012.04242.x 38. Kang CJ, Chang JTC, Chen TM, Chen IH, Liao CT. Surgical treatment of oral verrucous carcinoma. Chang Gung Med J 2003; 26: 807-12. PMID: 14765750 39. Alkan A, Bulut E, Gunhan O, Ozden B. Oral verrucous carcinoma: a study of 12 cases. Eur J Dent 2010; 4: 202-7. doi: 10.1055/s-0039-1697831 40. Zhu LK, Ding YW, Liu W, Zhou YM, Shi LJ, Zhou ZT. A clinicopathological study on verrucous hyperplasia and verrucous carcinoma of the oral mucosa. J Oral Pathol Med 2012; 4: 131-5. doi: 10.1111/j.1600-0714.2011.01078.x 41. Wang YP, Chen HM, Kuo RC, Yu CH, Sun A, Liu BY, et al. Oral verrucous hy- perplasia: histologic classification,prognosis, and clinical implications. J Oral Pathol Med 2009; 38: 651-6. doi: 10.1111/j.1600-0714.2009.00790.x Radiol Oncol 2023; 57(1): 1-11. Kristofelc N et al. / Review of oral verrucous carcinoma10 42. Warnakulasuriya S, Kujan O, Aguirre-Urizar JM, Bagan JV, González-Moles MÁ, Kerr AR, et al. Oral potentially malignant disorders: a consensus report from an international seminar on nomenclature and classification, con- vened by the WHO collaborating centre for oral cancer. Oral Dis 2021; 27: 1862-80. doi: 10.1111/odi.13704 43. Moussa M, Salem H, ElRefai SM. Oral proliferative verrucous leukoplakia: the unsolved paradox. Madridge J Dent Oral Surg 2017; 2: 55-8. doi: 10.18689/mjdl-1000114 44. Cerero-Lapiedra R, Baladé-Martínez D, Moreno-López LA, Esparza-Gómez G, Bagán J V. Proliferative verrucous leukoplakia: a proposal for diagnostic criteria. Med Oral Patol Oral Cir Bucal 2010; 15: 839-45. PMID: 20173704 45. Carrard VC, Brouns EREA, van der Waal I. Proliferative verrucous leukopla- kia: a critical appraisal of the diagnostic criteria. Med Oral Patol Oral Cir Bucal 2013; 18: 411-3. doi: 10.4317/medoral.18912 46. Palaia G, Bellisario A, Pampena R, Pippi R, Romeo U. Oral proliferative ver- rucous leukoplakia: progression to malignancy and clinical implications. Systematic review and meta-analysis. Cancers 2021; 13: 4058. doi: 10.3390/ cancers13164085 47. Capella DL, Gonçalves JM, Abrantes AAA, Grando LJ, Daniel FI. Proliferative verrucous leukoplakia: diagnosis, management and current advances. Braz J Otorhinolaryngol 2017; 83: 585-93. doi: 10.1016/j.bjorl.2016.12.005 48. Proaño-Haro A, Bagan L, Bagan J V. Recurrences following treatment of proliferative verrucous leukoplakia: A systematic review and meta-analysis. J Oral Pathol Med 2021; 50: 820-8. doi: 10.1111/jop.13178 49. Alan H, Agacayak S, Kavak G, Ozcan A. Verrucous carcinoma and squamous cell papilloma of the oral cavity: report of two cases and review of literature. Eur J Dent 2015; 9: 453-6. doi: 10.4103/1305-7456.163224 50. Santosh ABR, Boyd D, Laxminarayana KK. Proposed clinico-pathological classification for oral exophytic lesions. J Clin Diagnostic Res 2015; 9: ZE01-8. doi: 10.7860/JCDR/2015/12662.6468 51. Bouckaert, Munzhelele TI, Feller L, Lemmer J, Rag K. The clinical character- istics of oral squamous cell carcinoma in patients attending the Medunsa Oral Health Centre, South Africa. Integr Cancer Sci Ther 2016; 3: 575-8. doi: 10.15761/ICST.1000207 52. Wang YH, Tian X, Liu OS, Fang XD, Quan HZ, Xie S, et al. Gene profiling analysis for patients with oral verrucous carcinoma and oral squamous cell carcinoma. Int J Clin Exp Med 2014; 7: 1845-52. 53. Mohtasham N, Babakoohi S, Shiva A, Shadman A, Kamyab-Hesari K, Shakeri MT, et al. Immunohistochemical study of p53, Ki-67, MMP-2 and MMP-9 ex- pression at invasive front of squamous cell and verrucous carcinoma in oral cavity. Pathol Res Pract 2013; 209: 110-4. doi: 10.1016/j.prp.2012.11.002 54. Vallonthaiel AG, Singh MK, Dinda AK, Kakkar A, Thakar A, Das SN. Expression of cell cycle-associated proteins p53, pRb, p16, p27, and correlation with survival: A comparative study on oral squamous cell carcinoma and ver- rucous carcinoma. Appl Immunohistochem Mol Morphol AIMM 2016; 24: 193-200. doi: 10.1097/PAI.0000000000000179 55. Zargaran M, Eshghyar N, Baghaei F, Moghimbeigi A. Assessment of cel- lular proliferation in oral verrucous carcinoma and well-differentiated oral squamous cell carcinoma using Ki67: a non-reliable factor for differential diagnosis? Asian Pac J Cancer Prev 2012; 13: 5811-5. doi: 10.7314/ap- jcp.2012.13.11.5811 56. de Spíndula-Filho JV, da Cruz AD, Oton-Leite AF, Batista AC, Leles CR, de Cássia Gonçalves Alencar R, et al. Oral squamous cell carcinoma versus oral verrucous carcinoma: an approach to cellular proliferation and negative relation to human papillomavirus (HPV). Tumour Biol 2011; 32: 409-16. doi: 10.1007/s13277-010-0135-4 57. Patil GB, Hallikeri KS, Balappanavar AY, Hongal SG, Sanjaya PR, Sagari SG. Cyclin B1 overexpression in conventional oral squamous cell carcinoma and verrucous carcinoma - a correlation with clinicopathological features. Med Oral Patol Oral Cir Bucal 2013; 18: e585-90. doi: 10.4317/medoral.18220 58. Menaka TR, Ravikumar SS, Dhivya K, Thilagavathi N, Dinakaran J, Kalaichelvan V. Immunohistochemical expression and evaluation of cyclin D1 and minichromosome maintenance 2 in oral squamous cell carcinoma and verrucous carcinoma. J Oral Maxillofac Pathol 2022; 26: 44-51. doi: 10.4103/jomfp.jomfp_446_21 59. Lin HP, Wang YP, Chiang CP. Expression of p53, MDM2, p21, heat shock protein 70, and HPV 16/18 E6 proteins in oral verrucous carcinoma and oral verrucous hyperplasia. Head Neck 2011; 33: 334-40. doi: 10.1002/ hed.21452 60. Adegboyega PA, Boromound N, Freeman DH. Diagnostic utility of cell cycle and apoptosis regulatory proteins in verrucous squamous carcinoma. Appl Immunohistochem Mol Morphol AIMM 2005; 13: 171-7. doi: 10.1097/01. pai.0000132190.39351.9b 61. Arduino PG, Carrozzo M, Pagano M, Broccoletti R, Scully C, Gandolfo S. Immunohistochemical expression of basement membrane proteins of ver- rucous carcinoma of the oral mucosa. Clin Oral Investig 2010; 14: 297-302. doi: 10.1007/s00784-009-0296-y 62. Angadi VC, Angadi P V. GLUT-1 immunoexpression in oral epithelial dyspla- sia, oral squamous cell carcinoma, and verrucous carcinoma. J Oral Sci 2015; 57: 115-22. doi: 10.2334/josnusd.57.115 63. El-Rouby DH. Association of macrophages with angiogenesis in oral ver- rucous and squamous cell carcinomas. J Oral Pathol Med 2010; 39: 559-64. doi: 10.1111/j.1600-0714.2010.00879.x 64. Gao HW, Ho JY, Lee HS, Yu CP. The presence of Merkel cells and CD10- and CD34-positive stromal cells compared in benign and malignant oral tumors. Oral Dis 2009; 15: 259-64. doi: 10.1111/j.1601-0825.2009.01518.x 65. Paral KM, Taxy JB, Lingen MW. CD34 and α smooth muscle actin distinguish verrucous hyperplasia from verrucous carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol 2014; 117: 477-82. doi: 10.1016/j.oooo.2013.12.401 66. Odar K, Zidar N, Bonin S, Gale N, Cardesa A, Stanta G. Desmosomes in verru- cous carcinoma of the head and neck. Histol Histopathol 2012; 27: 467-74. doi: 10.14670/HH-27.467 67. Huang TT, Hsu LP, Hsu YH, Chen PR. Surgical outcome in patients with oral verrucous carcinoma: long-term follow-up in an endemic betel quid chew- ing area. ORL 2009; 71: 323-8. doi: 10.1159/000267306 68. Candau-Alvarez A, Dean-Ferrer A, Alamillos-Granados FJ, Heredero Jung S, García-García B, Ruiz-Masera JJ, et al. Verrucous carcinoma of the oral mucosa: an epidemiological and follow-up study of patients treated with surgery in 5 last years. Med Oral Patol Oral Cir Bucal 2014; 19: 506-11. doi: 10.4317/medoral.19683 69. Verma DK, Bansal S, Gupta D, Bansal A. Neck dissection in verrucous carcinoma: a surgical dilemma. IJSS Case Reports Rev 2015; 1: 42-5. doi: 10.17354/cr/2015/28 70. Rath S, Gandhi AK, Rastogi M, Agarwal A, Singhal A, Sharma V, et al. Treatment pattern and outcomes in verrucous carcinoma of oral cavity: a single institutional retrospective analysis from a tertiary cancer center and review of literature. Indian J Otolaryngol Head Neck Surg 2022; 74(Suppl 2): 1790-6. doi: 10.1007/s12070-020-01798-w 71. Sadasivan A, Thankappan K, Rajapurkar M, Shetty S, Sreehari S, Iyer S. Verrucous lesions of the oral cavity treated with surgery: analysis of clinico- pathologic features and outcome. Contemp Clin Dent 2012; 3: 60-3. doi: 10.4103/0976-237X.94548 72. Lundgren JA, van Nostrand AW, Harwood AR, Cullen RJ, Bryce DP. Verrucous carcinoma (Ackerman’s tumor) of the larynx: diagnostic and therapeutic considerations. Head Neck Surg 1986; 9: 19-26. doi: 10.1002/ hed.2890090105 73. Ferlito A, Rinaldo A, Mannarà GM. Is primary radiotherapy an appropriate option for the treatment of verrucous carcinoma of the head and neck? J Laryngol Otol 1998; 112: 132-9. doi: 10.1017/s0022215100140137 74. Kraus FT, Perezmesa C. Verrucous carcinoma: clinical and pathologic study of 105 cases involving oral cavity, larynx and genitalia. Cancer 1966; 19: 26-38. doi: 10.1002/1097-0142(196601)19:1<26::aid-cncr2820190103>3.0.co;2-l 75. Memula N, Ridenhour GDL. Radiotherapeutic management of oral verru- cous carcinoma. Oncol Biol Phys 1980; 6: 1404. 76. Nair MK, Sankaranarayanan R, Padmanabhan TK, Madhu CS. Oral verrucous carcinoma. Treatment with radiotherapy. Cancer 1988; 61: 458-61. doi: 10.1002/1097-0142(19880201)61:3<458::aid-cncr2820610309>3.0.co;2-t 77. Chang BA, Katz S, Kompelli AR, Nathan CAO. Is primary radiotherapy an acceptable treatment modality for verrucous carcinoma of the larynx? Laryngoscope 2019; 129: 1964-5. doi: 10.1002/lary.27985 78. Huang SH, Lockwood G, Irish J, Ringash J, Cummings B, Waldron J, et al. Truths and myths about radiotherapy for verrucous carcinoma of larynx. Int J Radiat Oncol Biol Phys 2009; 73: 1110-5. doi: 10.1016/j.ijrobp.2008.05.021 79. Tharp ME, Shidnia H. Radiotherapy in the treatment of verrucous car- cinoma of the head and neck. Laryngoscope 1995; 105: 391-6. doi: 10.1288/00005537-199504000-00011 Radiol Oncol 2023; 57(1): 1-11. Kristofelc N et al. / Review of oral verrucous carcinoma 11 80. Demian SD, Bushkin FL, Echevarria RA. Perineural invasion and anaplastic transformation of verrucous carcinoma. Cancer 1973; 32: 395-401. doi: 10.1002/1097-0142(197308)32:2<395::aid-cncr2820320217>3.0.co;2-e 81. Schwade JG, Wara WM, Dedo HH, Phillips TL. Radiotherapy for verrucous carcinoma. Radiology 1976; 120: 677-9. doi: 10.1148/120.3.677 82. Naik AN, Silverman DA, Rygalski CJ, Zhao S, Brock G, Lin C, et al. Postoperative radiation therapy in oral cavity verrucous carcinoma. Laryngoscope 2022; 132: 1953-61. doi: 10.1002/lary.30009 83. Wu CF, Chen CM, Shen YS, Huang IY, Chen CH, Chen CY, et al. Effective eradi- cation of oral verrucous carcinoma with continuous intraarterial infusion chemotherapy. Head Neck 2008; 30: 611-7. doi: 10.1002/hed.20751 84. Strojan P, Ferlito A, Wu CF, Rinaldo A. Intraarterial chemotherapy: a valid option in the treatment of verrucous carcinoma? Eur Arch Oto-Rhino- Laryngology 2010; 267: 835-7. doi: 10.1007/s00405-009-1178-2 85. Strojan P, Šoba E, Budihna M, Auersperg M. Radiochemotherapy with vinblastine, methotrexate, and bleomycin in the treatment of verrucous car- cinoma of the head and neck. J Surg Oncol 2005; 92: 278-83. doi: 10.1002/ jso.20422 86. De Keukeleire S, De Meulenaere A, Deron P, Huvenne W, Fréderic D, Bouckenooghe O, et al. Verrucous hyperplasia and verrucous carcinoma in head and neck: use and benefit of methotrexate. Acta Clin Belg 2021; 76: 487-91. doi: 10.1080/17843286.2020.1752455 87. Karagozoglu KH, Buter J, Leemans CR, Rietveld DHF, Van Den Vijfeijken S, Van Der Waal I. Subset of patients with verrucous carcinoma of the oral cavity who benefit from treatment with methotrexate. Br J Oral Maxillofac Surg 2012; 50: 513-8. doi: 10.1016/j.bjoms.2011.09.011 88. Salesiotis A, Soong R, Diasio RB, Frost A, Cullen KJ. Capecitabine induces rapid, sustained response in two patients with extensive oral verrucous carcinoma. Clin Cancer Res 2003; 9: 580-5. 89. Yoshimura Y, Mishima K, Obara S, Nariai Y, Yoshimura H, Mikami T. Treatment modalities for oral verrucous carcinomas and their outcomes: contribution of radiotherapy and chemotherapy. Int J Clin Oncol 2001; 6: 192-200. doi: 10.1007/PL00012104 90. Yu CH, Lin HP, Cheng SJ, Sun A, Chen HM. Cryotherapy for oral precan- cers and cancers. J Formos Med Assoc 2014; 113: 272-7. doi: 10.1016/j. jfma.2014.01.014 91. Yeh CJ. Treatment of verrucous hyperplasia and verrucous carcinoma by shave excision and simple cryosurgery. Int J Oral Maxillofac Surg 2003; 32: 280-3. doi: 10.1054/ijom.2002.0331 92. Chen HM, Yu CH, Lin HP, Cheng SJ, Chiang CP. 5-Aminolevulinic acid-mediat- ed photodynamic therapy for oral cancers and precancers. J Dent Sci 2012; 7: 307-5. doi: 10.1016/j.jds.2012.03.023 93. Chen HM, Chen CT, Yang H, Lee MI, Kuo MYP, Kuo YS, et al. Successful treat- ment of an extensive verrucous carcinoma with topical 5-aminolevulinic acid-mediated photodynamic therapy. J Oral Pathol Med 2005; 34: 253-6. doi: 10.1111/j.1600-0714.2004.00267.x 94. Hsu CK, Lee JYY, Yu CH, Hsu MML, Wong TW. Lip verrucous carcinoma in a pregnant woman successfully treated with carbon dioxide laser surgery. Vol. 157, The British journal of dermatology. Br J Dermatol 2007; 157: 813-5. doi: 10.1111/j.1365-2133.2007.08078.x 95. Azevedo LH, Galletta VC, de Paula Eduardo C, de Sousa SOM, Migliari DA. Treatment of oral verrucous carcinoma with carbon dioxide laser. J Oral Maxillofac Surg 2007; 65: 2361-6. doi: 10.1016/j.joms.2006.10.024 96. Lee CN, Huang CC, Lin IC, Lee JYY, Ou CY, Wong TW. Recalcitrant lip verrucous carcinoma successfully treated with acitretin after carbon dioxide laser abla- tion. JAAD case reports 2018; 4: 576-8. doi: 10.1016/j.jdcr.2018.02.002