Verrucous Hyperplasia Case report and differential diagnosis

Verrucous hyperplasia (VH) is a rare exophytic oral mucosal lesion which can transform into verrucous carcinoma (VC), its malignant but clinically similar counterpart. These entities can be distinguished by the lack of invasive growth in VH cases; as such, it is essential to include a margin with adequate depth when performing a biopsy of the epithelium of the lesion. We report an 80-year-old male patient who presented to the Bapuji Dental College & Hospital, Davangere, Karanataka, India, in 2011 with a warty whitish-pink growth on the inside of his cheek. The patient was treated with wide surgical excision of the lesion and a diagnosis of VH was made based on histopathological features. There was no evidence of recurrence at a five-year follow-up. This report highlights the histological variations, pathogenesis and differential diagnosis of VH.

].It was firm in consistency and nontender upon palpation.There was no evidence of discharge and no ulcerations were observed on the surface of the lesion, nor in the surrounding mucosa which appeared normal.An extraoral examination revealed an enlarged submandibular lymph node, which was mobile and non-tender upon palpation.
The lesion was treated with wide surgical excision.Histopathological examination of a biopsy specimen revealed a hyperplastic stratified squamous epithelium arranged in the form of exophytic papillary projections, with underlying fibrovascular connective tissue [Figure 2A].The epithelium exhibited hyperparakeratinisation with a few koilocytes seen in the superficial layers.The rete ridges had a broad 'elephant's foot' shape and were at the same level as that of the adjoining normal epithelium [Figure 2B].Some of the cells in the basal layer of the epithelium exhibited dysplastic features.In addition, the underlying connective tissue revealed dense chronic inflammatory cell infiltrates, chiefly concentrated in the juxta-epithelial areas.As a result of these features, a final diagnosis of VH was made.The patient was subsequently followed-up periodically over the next five years with no sign of recurrence [Figure 3].

Discussion
Clinically, VH presents as a warty or papillary fungating exophytic mucosal mass which can sometimes ulcerate and is predominantly pink in colour with a partly whitish surface. 4The average age at first presentation is between 30-60 years old. 4,5Previous research has indicated the buccal mucosa to be the most common site for VH; this may potentially be correlated with usage of quid (i.e.clumps of chewing tobacco) which is usually placed in this region of the mouth. 5,6In contrast, Shear et al. found that the gingiva and alveolar mucosa were the most common sites among 68 cases of VH. 3 Hazarey et al. reported that placement of tobacco-betel-lime quid (i.e. a mixture of slaked lime, chewing tobacco and betel leaf pieces) in the buccal vestibule was the most predominant habit associated with VH growth. 6ang et al. similarly observed that 91% of 60 patients with VH chewed areca nut quid (i.e. a mixture of areca nut, betel leaf pieces and chewing tobacco). 5moking was reported to be the second most common aetiological factor in these two studies. 5,6ear et al. classified two histological patterns of VH, including the "sharp" variety (comprised of heavily keratinised, long and narrow verrucous processes) and the "blunt" variety (comprised of less heavily keratinised, broader and flatter verrucous processes). 3The former may potentially be referred to as verrucous leukoplakia due to its predominantly white colour resulting from the heavy keratinisation. 3However, no difference in prognosis has been reported according to these patterns.In contrast, Wang et al. classified VH into plaque-type and mass-type lesions and identified significant differences in their malignant transformation rates. 5Plaque-type VH was defined as horizontally-proliferating epithelial hyperplasia resulting in an elevated plaque-like lesion with a verrucous surface, while mass-type VH lesions displayed single or multiple protuberant masses of  to the adjacent normal epithelium; furthermore, the broadened epithelial ridges lie above the adjacent normal epithelium in VH, whereas similar rete ridges display an endophytic growth pattern in VC cases. 6In addition, the verrucous processes in VC often bring a margin of normal epithelium down with them into the underlying connective tissue. 3he histogenesis of VH as proposed by Shear et al. is summarised in Figure 4. 3 It has been proposed that leukoplakia, if left untreated, may transform into VH or VC over time. 3Moreover, VH can be confused with proliferative verrucous leukoplakia (PVL), a variant of non-homogenous leukoplakia in which the lesions eventually assume an exophytic verrucous appearance. 8While the term VH refers to both clinical and histopathological features, PVL is unequivocally accepted as a clinical term used to define a specific type of non-homogenous leukoplakia with a verrucous surface. 4Histologically, PVL displays clinical foci of hyperkeratosis that progressively spread and become multifocal.Many cases of PVL are extremely resistant to treatment and progress to invasive cancer. 8In cases of papillary squamous cell carcinoma (PSCC), VC can be distinguished by its intact basement membrane which contrasts with the focal or early invasion seen in PSCC; furthermore, the epithelium in PSCC cases is significantly dysplastic when compared with the almost 'bland' cytological features of the epithelium of VC lesions. 92][3] Slootweg et al. concluded that VH probably epithelial hyperplasia, with very little connective tissue at the core and a verrucous surface. 5istopathologically, all variants of VH exhibit verrucous projections of the hyperplastic epithelium which lie superficially to the adjacent epithelium. 3,5owever, there are considerable similarities between VH and VC lesions.The latter is defined as a warty, papillary or fungating exophytic lesion with broad and intact intrusions of rete ridges. 3According to previous research, keratin plugging in the centre of epithelial invaginations is a histological hallmark of VC; however, Slootweg et al. reported that the presence of keratin plugging is not obligatory for a VC diagnosis. 4,7Although dysplasia is rarely seen, mitotic figures are more common. 4The distinction between VH and VC is histological, based on the location of the hyperplastic epithelium in relation   represents a morphological variant of VC after noting an association between VH and SCC in 37% of 27 patients. 4Chen et al. reported high expression of inducible nitric oxide synthase (iNOS) proteins and messenger ribonucleic acid in VH lesions and concluded that an iNOS-dependent mechanism may be involved in the malignant transformation of VH. 10,11 Additionally, the higher expression of interleukin-1β and glutathione S-transferase pi isoenzymes and the allelic loss at 19 loci on seven different chromosome arms may also play an important role in the malignant transformation of VH. [12][13][14] Tumour protein p53, epidermal growth factor receptor and human epidermal growth factor receptor 3 expression can also be used to differentiate VH from VC and SCC. 15,16Although Greer Jr et al. found an association between the human papilloma virus and VH, the role of the virus in the malignant transformation of VH has yet to be confirmed. 17n terms of treatment modality, surgery alone is the most common method of management for both VC and VH cases, due to their overlapping clinicopathological features. 18,19However, it is important to ensure wide surgical excision of the lesion with adequate soft tissue margins so as to avoid recurrence.Although sporadic cases of cervical and distant metastasis have been reported, the overall rate of metastasis is insignificant. 20An incorrect histological diagnosis or the presence of occult foci indicating SCC has been proposed to justify the metastatic nature of lesions otherwise characteristic of VC; as such, thorough sampling of the surgical specimen is highly recommended. 20,21

Conclusion
Distinction between VC and VH lesions can only be made histologically, by comparing the level of the rete ridges of the epithelium of the lesion with that of the adjacent normal epithelium.In addition, VH cases may also be confused with verrucous leukoplakia.Thus, biopsies of verrucous lesions should include the adjacent normal epithelium in order to ensure correct diagnosis.As VH has the potential for malignant transformation, patients should be treated in a similar manner to those with VC.

Figure 2 :
Figure 2: Photomicrographs of haematoxylin and eosin stains at x100 magnification showing (A) papillary projections (arrow) with keratin plugging (asterisk) in the clefts and (B) broad 'elephant's foot' rete ridges (arrows) at the same level as that of the adjacent normal epithelium.

Figure 1 :
Figure 1: Intraoral photograph showing a whitish-pink sessile exophytic lesion on the buccal mucosa of an 80-year-old male patient.

Figure 3 :
Figure 3: Intraoral photograph of the buccal mucosa of an 85-year-old male patient showing no evidence of recurrence of verrucous hyperplasia five years after wide surgical excision of the lesion.

Figure 4 :
Figure 4: Flowchart depicting the histogenesis of verrucous hyperplasia as proposed by Shear et al.3