Association of Plantar Warts Genotype and Treatment Method

By: Daniel Lowe, B.A., Theresa Schneider, B.A., Ashley Dikis, DPM FACFAS

Des Moines University Medicine and Health Sciences

            Verrucae, or warts, are the result of an infection from the human papillomavirus (HPV). The virus infects the epidermis, thus causing thickening and results in a benign epidermal neoplasm. Warts typically infect children and young adults with the mode of transmission being direct contact. Lesions may form anywhere along the plantar aspect of the foot, though often are located at areas of maximum pressure, such as the metatarsal heads or the heel. A thick overlying hyperkeratotic tissue layer is often present, with disruption of surrounding dermatoglyphics. Dark spots are visualized within the lesion, representing areas of punctate hemorrhaging, seen in Figure 1. 1-3 Diagnosis is traditionally achieved via physical examination with the noted presence of these distinguishing characteristics, though dermoscopy can be useful in improving diagnostic accuracy. 4

Figure 1. Patient present with a plantar wart showing the common characteristics: hyperkeratotic tissue, disruption of surrounding dermatoglyphics, and punctate hemorrhaging.

            HPV has more than 100 subtypes.1 According to Planell-Mas et al., the most common types of HPV within plantar warts are HPV-57 (37.1%), HPV-27 (23.8%), HPV-1a (20.9%), HPV-2 (15.2%), and HPV-65 (2.8%).5 Al-Awadhi et al. analyzed plantar warts using real-time PCR and found HPV-27b to be the most common at 46.4%, HPV-57c at 25.8%, HPV-1a at 13.4%, HPV-2 at 9.3%, HPV-65 at 2%, followed by HPV 1a and HPV 27b at 3.1%. 6

            Current available evidence suggests some HPV genotypes of a plantar wart may have clinical distinction. Planell-Mas et al. found statistical significance in the correlation of HPV-57 favoring females and HPV-1a favoring men. After analyzing samples obtained through their study, they also noted that HPV genotypes within the alpha genus were only found in those patients over the age of 21, while genotypes from the mu genus were detected in all ages.  While warts in the alpha genus developed over a prolonged time (6 months to more than a year), those in the mu genus often developed in less than a year.5 Excluding the work reported by Planell-Mas and colleagues, there are no other publications that delineate the HPV-genotype of the plantar wart and the clinical presentation. This presents a challenge to make this determination without a PCR modality.  

            A systematic review by Garcia-Oreja et al. reported the average cure rate for treatment methods consisted of: cryotherapy (45.61%), salicylic acid (13.6%), cantharidin-podophyllum-salicylic acid formulation (97.82%), laser (79.36%), topical antivirals (72.45%), intralesional bleomycin (83.37%), and intralesional immunotherapy (68.14%).  Within the studies, the cryotherapy and salicylic acid were typically first-line treatment with low cure rates.7 They did note the issue of heterogeneity in study design, efficacy results, study size, treatment period and follow-up as a significant limitation in comparison of the available data, indicating a need for future robust randomized control trials.7 This study demonstrates the baseline treatment method for all genotypes being grouped together as one.

            At present, the question remains unanswered as to whether a correlation between treatment method and the HPV-genotype of a plantar wart exists. Hogendoorn et al. found a significant association of plantar warts with the genotype HPV 2  and HPV 27 having a decreased treatment response compared to HPV 1 with use of monochloroacetic acid or the combination of cryotherapy and salicylic acid (Figure 2).8

            A study by Bruggink et al. reported HPV 1 has better outcomes in the wait-and-see method with a cure rate at 58%, compared to HPV 2, 27, and 57 at 7%. For HPV 2, 27, and 57 the cure rate using cryotherapy was 11% and 25% with salicylic acid. For HPV 1, the cryotherapy cure rate occurred at 65% and 92% for salicylic acid (Figure 3).9

           Fichman et al. compared genotypes found in verruca vulgaris, also known as the common wart, and the treatment outcomes seen with pulsed dye laser therapy. They compared the clearance rate of HPV types 2, 10, and 57. HPV-2 clearance occurred at 75.6%, HPV–10 was 80%, and finally HPV-57 was 95.6% (Figure 4). No statistically significant difference was noted between outcomes of viral types with pulsed dye laser therapy.10 Although there was no statistical significance present between clearance rate for pulsed dye laser, when compared to Bruggink’s study within HPV 2 and 57, the clearance rates are higher than either the wait-and-see method, cryotherapy, or salicylic acid.

         Planell-Mas and colleagues also looked at the heal rates for plantar warts using 1064 laser and cooling. Within this study laser treatment demonstrated the following results: HPV-1 100% cured, HPV-2 50% cured, HPV-27 85.7% cured, HPV-57 94.1% cured, and HPV-65 100% cured (Figure 5).11

          A physician can easily determine a plantar wart genotype. Koning demonstrated that genotyping a wart via swabbing had a 100% specificity, compared to biopsy, and a 96% sensitivity. Utilizing this technique, a physician can simply use a sterile swab and send the sample to pathology, allowing for the ability to determine genotype in the outpatient clinic setting.12 

            At this time, HPV-1 demonstrates the best outcomes with the wait-and-see method when compared to first line treatment methods, suggesting monitoring may be advised before proceeding with intervention.9 Further research is needed to investigate the best treatment method for other common HPV genotypes (HPV 2, 27, 57, and 65). Based on these studies, 1064 nm laser and cooling demonstrates the highest clearance rate compared to monochloroacetic acid or a combination therapy of cryotherapy and salicylic acid within the HPV genotyping of 2, 27, 57, and 65. New research needs to compare a greater diversity of treatment methods within the different genotypes to limit the vast number of treatment methods currently available. Future patient encounters may begin with a swab of a plantar wart to determine the best treatment modality. The goal would be to offer more detail in diagnosis, guide therapy in an evidence-based fashion, and overall improve outcomes.  Ultimately this should reduce treatment time, potentially decrease cost, and improve patient satisfaction. 

References
  1. Habif T. Clinical Dermatology. Elsevier Health Sciences, 2015
  2. Ferri FF. Ferri’s Fast Facts in Dermatology: A Practical Guide to Skin Diseases and Disorders. Elsevier Health Sciences, 2017
  3. Marks JG, Miller JJ. Lookingbill and Marks’ Principles of Dermatology. Elsevier Health Sciences, 2017
  4. Bhatti A, Chowdhary S, Ferrise T, Govardhanam N, Parish A, Tropper Y, Vlahovic TC. Plantar Verruca and Dermoscopy: An Update. Clin in Podiatr Med Surg 2021; 38:513-520
  5. de Planell‐Mas E, Martínez-Garriga B, Zalacain AJ, Vinuesa T, Viñas M. Human papillomaviruses genotyping in plantar warts. J Med Virol 2017; 89:902-907
  6. Al-Awadhi R, Nawaf A, Wassim C. Prevalence of HPV Genotypes in adult male patients with cutaneous warts: a cross-sectional study. Med Princ and Pract 2020; 29:458-464
  7. García‐Oreja S, Álvaro-Afonso FJ, García-Alvarez Y, García-Morales E, Sanz-Corbalán I, Martínez JLL. Topical treatment for plantar warts: A systematic review. Dermatol Ther 2021; 34
  8. Hogendoorn GK, Bruggink SC, de Koning MNC, Eekhof JAH, Hermans KE, Rissman R, Burggraaf J, Wolterbeek R, Quint KD, Kouwenhoven STP, Bouwes Bavinck JN. Morphological characteristics and human papillomavirus genotype predict the treatment response in cutaneous warts. Br J Dermatol 2018; 178:253-260
  9. Bruggink SC, Gussekloo J, de Koning MNC, Feltkamp MCW, Bouwes Bavinck JN, Quint WGV, Assendelft WJJ, Eekhof JAH. HPV type in plantar warts influences natural course and treatment response: secondary analysis of a randomised controlled trial. J Clin Virol 2013; 57:227-232
  10. Fichman Y, Levi A, Hodak E, Halachmi S, Mazor S, Wolf D, Caplan O, Lapidoth M. Efficacy of pulsed dye laser treatment for common warts is not influenced by the causative HPV type: a prospective study. Lasers Med Sci 2018; 33:773-777
  11. de Planell-Mas E, Martínez-Garriga B, Viñas M, Zalacain-Vicuña AJ. Efficacy of the Treatment of Plantar Warts Using 1064 nm Laser and Cooling. Int J Environ Res Public Health. 2022 Jan 12;19(2):801.
  12. de Koning MN, Khoe LV, Eekhof JA, Kamp M, Gussekloo J, Ter Schegget J, Bouwes Bavinck JN, Quint WG. Lesional HPV types of cutaneous warts can be reliably identified by surface swabs. J Clin Virol. 2011 Oct;52(2):84-7.

About the Authors

This online journal article was written by Daniel Lowe of De Moines University’s Podiatric Medicine program and by Theresa Schneider of De Moines University’s Osteopathic Medicine program. Daniel Lowe will receive his D.P.M. degree in 2023, and Theresa Schneider will receive her D.O. degree in 2023. Both students collaborated with Ashley Dikis D.P.M., FACFAS.

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