We have a “ring around the collar” problem

(1)

EDITORIAL

We have a “ring around the collar” problem

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy in the world and is associated with significant morbidity and mortality. Oral cavity squamous cell carcinoma (OCSCC) represents about a third of the 50,000 cases of HNSCC in the United States, and almost half of the 600,000 worldwide cases.^1,2Despite the numerous therapeutic advances, the long-term survival of patients with human papillomavirus (HPV) negative SCC remains modest. Because OCSCC is often preceded by premalignant lesions, patients with this disease benefit the most from screening and early detection. Because premalignant oral lesions cannot be accurately identified solely on the basis of their clinical characteristics, the gold standard is biopsy and histologic evaluation. However, from a diagnostic and clinical management perspective, the definition of oral premalignancy is problematic. Classic oral epithelial dysplasia (OED) is currently considered premalignant and at risk for progressing to SCC. However, the major- ity of these lesions will not progress to cancer, even over prolonged periods. Several studies have under- scored this concept. Mincer et al. evaluated patients with OED and followed them for up to 8 years. Only 11% of the lesions underwent malignant transformation during the observation period.³Likewise, Arduino et al. demon- strated that the 1-year outcomes of patients with OED were highly variable, with 40% of the lesions disappear- ing, 20% remaining stable, 7% progressing to OCSCC, and 33% of the patients developing new lesions.⁴ Finally, in a meta-analysis, the overall malignant transformation rate in nearly 1000 patients with OED was 12%.⁵ Given this relatively low rate of transformation and the limited chemopreventive options, intervention has largely been conservative in nature and limited to risk reduction with careful follow-up.

However, a potentially more ominous premalignant oral condition has entered the fray. First described by Hansen, proliferative verrucous leukoplakia (PVL) appears to be a unique type of oral premalignancy.⁶ Although data regarding the natural history of this disease are limited, there is a growing impression that the incidence of PVL may be on the rise. This is disconcerting on several levels because there are considerable unknowns with respect to the biology, clinical presentation, histo- pathologic diagnosis, treatment, and prognosis of this condition. In short, we have a great deal of work before us.

From a biologic/etiologic perspective, we have much to discern regarding the contributing factors and the molecular mechanisms driving transformation and progression.

The limited data, to date, suggest that the 2 conditions may utilize different pathways of progression compared with classic OED and OCSCC.^7,8 Clinically, PVL presents as multifocal, nonhomogeneous, relentlessly growing/expanding leukoplakia. Importantly, compared with classic OED, PVL has a significantly higher rate of recurrence and malignant transformation (as high as 75%) as well as the development of second primary tumors. One can readily appreciate that this condition represents a unique and worrisome form of oral premalignancy.^{6,9 12} Although PVL often affects the gingiva and buccal mucosa initially, it typically spreads to

Fig. 1. Representative clinical presentation of “ring around the collar” demonstrating the multifocal appearance of proliferative verrucous leukoplakia (PVL) involving the maxillary gingiva.

1 Vol. 129 No. 1 January 2020

(2)

other locations of the oral cavity. The gingival lesions have been described by Dr. Donald Cohen and his Uni- versity of Florida colleagues as “ring around the collar”

(Figure 1). I happen to like this colloquial clinical phrase when discussing this condition with general practitioners because it provides a striking visual clinical representation that seems to be limited to PVL. From a more scientifi- cally objective perspective, in spite of numerous attempts, criteria for the clinical terminology and presentation of this condition are still in development.^{6,13 15} Currently, there is lack consensus within the field of pathology with respect to the diagnostic criteria and the most appropriate diagnostic term for this condition. For example, the inter- esting pilot study by Upadhyaya et al. nicely demon- strated the challenges of diagnosing PVL and the subsequent downstream implications to patient management, underscoring the need for standardized diagnostic terminology and criteria.¹⁶Finally, from a treatment perspective, numerous different treatment modalities, includ- ing topical treatment, radiation, laser ablation, simple excision, and block resection, have been attempted.^{6,10,17 23} However, we currently do not have an evidence-based standard of care.

In summary, PVL is a unique and aggressive form of oral premalignancy, which, more often than not, pro- gresses to cancer. As discussed above, many aspects of this relatively new condition continue to remain largely unknown to us. Importantly, it represents a clinical conundrum that will require a true multispecialty collaborative effort by general practitioners, pathologists, oncologists, and surgeons to establish consistent clinical/histologic diagnostic criteria as well as evidence- based treatment guidelines. I hope that this editorial will serve to gratefully acknowledge the outstanding individuals currently investigating PVL and as an invi- tation to inquisitive investigators from all specialties to join the fray as we seek to combat this perplexing condition.

Mark W. Lingen, DDS, PhD, FRCPath Editor-in-Chief

https://doi.org/10.1016/j.oooo.2019.10.011

REFERENCES

1.Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Can- cer J Clin. 2019;69:7-34.

2.Warnakulasuriya S. Global epidemiology of oral and oropharyn- geal cancer. Oral Oncol. 2009;45:309-316.

3.Mincer HH, Coleman SA, Hopkins KP. Observations on the clinical characteristics of oral lesions showing histologic epithelial dysplasia. Oral Surg Oral Med Oral Pathol. 1972;33:389-399.

4.Arduino PG, Surace A, Carbone M, et al. Outcome of oral dysplasia: a retrospective hospital-based study of 207 patients with a long follow-up. J Oral Pathol Med. 2009;38:540-544.

5. Mehanna HM, Rattay T, Smith J, McConkey CC. Treatment and follow-up of oral dysplasia—a systematic review and meta-analysis. Head Neck. 2009;31:1600-1609.

6. Hansen LS, Olson JA, Silverman S. Jr. Proliferative verrucous leukoplakia. A long-term study of thirty patients. Oral Surg Oral Med Oral Pathol. 1985;60:285-298.

7. Okoturo EM, Risk JM, Schache AG, Shaw RJ, Boyd MT.

Molecular pathogenesis of proliferative verrucous leukoplakia: a systematic review. Br J Oral Maxillofac Surg. 2018;56:780-785.

8. Koh J, Kurago ZB. Expanded expression of Toll-like receptor 2 in proliferative verrucous leukoplakia. Head Neck Pathol. 2019 Mar 19.

https://doi.org/10.1007/s12105-019-01028-y. [Epub ahead of print].

9. Morton TH, Cabay RJ, Epstein JB. Proliferative verrucous leukoplakia and its progression to oral carcinoma: a review of the literature. J Oral Pathol Med. 2007;36:255-261.

10. Silverman S. Jr., Gorsky M. Proliferative verrucous leukoplakia:

a follow-up study of 54 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1997;84:154-157.

11. Upadhyaya JD, Fitzpatrick SG, Islam MN, Bhattacharyya I, Cohen DM. A retrospective 20-year analysis of proliferative verrucous leukoplakia and its progression to malignancy and associ- ation with high-risk human papillomavirus. Head Neck Pathol.

2018;12:500-510.

12. Bagan J, Murillo-Cortes J, Poveda-Roda R, Leopoldo-Rodado M, Bagan L. Second primary tumors in proliferative verrucous leukoplakia: a series of 33 cases. Clin Oral Investig. 2019 Aug 22.

https://doi.org/10.1007/s00784-019-03059-9. [Epub ahead of print].

13. Cerero-Lapiedra R, Balade-Martınez D, Moreno-Lopez LA, Esparza-Gomez G, Bagan JV. Proliferative verrucous leukoplakia: a proposal for diagnostic criteria. Med Oral Patol Oral Cir Bucal. 2010;15:e839-e845.

14. Carrard VC, Brouns ER, van der Waal I. Proliferative verrucous leukoplakia: a critical appraisal of the diagnostic criteria. Med Oral Patol Oral Cir Bucal. 2013;18:e411-e413.

15. Villa A, Menon RS, Kerr AR, et al. Proliferative leukoplakia: pro- posed new clinical diagnostic criteria. Oral Dis. 2018;24:749-760.

16. Upadhyaya JD, Fitzpatrick SG, Cohen DM, et al. Inter-observer variability in the diagnosis of proliferative verrucous leukoplakia:

clinical implications for oral and maxillofacial surgeon understand- ing: a collaborative pilot study. Head Neck Pathol. 2019 Apr 10.

https://doi.org/10.1007/s12105-019-01035-z. [Epub ahead of print].

17. Poveda-Roda R, Bagan JV, Jimenez-Soriano Y, Dıaz-Fernandez JM, Gavalda-Esteve C. Retinoids and proliferative verrucous leukoplakia (PVL). A preliminary study. Med Oral Patol Oral Cir Bucal. 2010;15:e3-e9.

18. Bagan JV, Jimenez Y, Sanchis JM, et al. Proliferative verrucous leukoplakia: high incidence of gingival squamous cell carcinoma. J Oral Pathol Med. 2003;32:379-382.

19. Bagan JV, Jimenez-Soriano Y, Diaz-Fernandez JM, et al. Malig- nant transformation of proliferative verrucous leukoplakia to oral squamous cell carcinoma: a series of 55 cases. Oral Oncol.

2011;47:732-735.

20. Martinez-Lopez A, Blasco-Morente G, Perez-Lopez I, et al. Suc- cessful treatment of proliferative verrucous leukoplakia with 5%

topical imiquimod. Dermatol Ther. 2017;30:1-2.

21. Zakrzewska JM, Lopes V, Speight P, Hopper C. Proliferative verrucous leukoplakia: a report of ten cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996;82:396-401.

22. Fettig A, Pogrel MA, Silverman S. Jr., Bramanti TE, Da Costa M, Regezi JA. Proliferative verrucous leukoplakia of the gingiva. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2000;90:723-730.

23. Borgna SC, Clarke PT, Schache AG, et al. Management of proliferative verrucous leukoplakia: justification for a conservative approach. Head Neck. 2017;39:1997-2003.

EDITORIAL OOOO

2 ^Lingen January 2020