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Verrucous carcinoma of the vulva: Patterns of care and treatment outcomes

Verrucous carcinoma of the vulva: Patterns of care and treatment outcomes INTRODUCTIONVerrucous carcinoma (VC) of the vulva is a rare form of squamous cell carcinoma that accounts for approximately 1% of vulvar tumors.1,2 VC was first classified as a form of squamous cell carcinoma by Ackerman in 1948 in a case of VC of the oral cavity.3 In 1963 Goethals et al. first suggested involvement of the female genital tract, and in 1966 Kraus and Perez‐Mesa reported the first two cases of vulvar verrucous carcinoma.4,5 Grossly, verrucous carcinoma is fungating and cauliflower like. Histologically, VC commonly displays organized keratinocytes, acanthosis, parakeratosis, or orthokeratosis, with minimal cellular atypia.6,7 Blunt invasion with bulbous rete ridges is a characteristic finding.8,9 Unlike well‐differentiated SCC, there is no cytologic atypia, invasion by irregular‐shaped nests of carcinoma, or desmoplastic stromal response in VC.10 Verrucous carcinoma can be associated with local recurrences; however, distant metastases from VC are uncommon.11,12 Most cases begin with a small wart that progressively enlarges over several months. Chief complaints at the time of initial presentation range from concern for abnormal lesions, itching, and discomfort, to hindrance of daily activities depending on the size and extent of local lesion involvement.The incidence of invasive vulvar carcinoma in the United States has been increasing over the past three decades across all age groups of women, among all races, and in all geographic regions.13 Theories of increased immunosuppressed populations, miscoded cases, and environmental factors have been suggested to explain the changing incidence of vulvar carcinoma. Verrucous vulvar carcinoma is more commonly diagnosed in post‐menopausal women.8,14 VC is a well‐differentiated form of vulvar SCC, with most cases unrelated to infection with human papilloma virus (HPV).12 While the relationship between VC and HPV has been debated,9,15,16 some studies have suggested that a portion of VC cases are related to HPV.17Treatment of VC is centered around primary site surgery, with attention toward taking wide margins to prevent local recurrence.18 Since lymph node metastases are rare in VC, radical vulvectomy is sufficient in the majority of cases, and systemic lymph node dissection is generally not performed.18,19 Some cases of VC may coexist with SCC, in which a lymphadenectomy would be warranted in addition to primary site surgery.20 In an extensive literature review by Liu et al., 15% (10/67) of cases of VC coexisted with well‐differentiated SCC.2 This evidence of coexisting histologies places an emphasis on the importance of thorough histologic evaluation to achieve an accurate and complete diagnosis. There have been some cases of patients receiving radiotherapy and subsequent transformation to SCC or anaplastic transformation.19,21–24 The current paradigm regarding treatment for VC is that wide local excision is associated with a favorable prognosis.The purpose of this study was to perform an analysis of the National Cancer Database (NCDB) (1) to assess the incidence of verrucous vulvar carcinoma, (2) to compare patient, tumor, and treatment characteristics between VC and vulvar SCC, and (3) to analyze factors associated with OS in verrucous carcinoma of the vulva.METHODSDatabaseThis study analyzed data from the National Cancer Database (NCDB). The NCDB includes about 70% of all cases of cancer diagnosed in the United States every year. Extensive demographic data as well as disease and treatment details are provided for each de‐identified patient. Increased numbers of institutions are participating in recording cancer cases with the NCDB. In 2008, 1430 Commission on Cancer (CoC) programs reported to the NCDB, but in 2020 nearly 1500 CoC programs were participating.25Patient cohortThe NCDB included 621 patients diagnosed with VC and 45 043 patients diagnosed with SCC. Patients who were diagnosed with verrucous vulvar carcinoma or vulvar SCC between the years of 2004 and 2016 were included. The inclusion criteria for this analysis are shown in the CONSORT diagram in Figure 1.1FIGURECONSORT diagram describing inclusion criteriaStatistical analysisBaseline patient demographics were obtained from the NCDB including age, race, tumor size and stage, surgical intervention, and adjuvant therapy. Statistical analysis was performed comparing cases of SCC to cases of VC by the chi‐squared test to evaluate differences in disease characteristics at diagnosis, surgical management, and adjuvant treatments. To evaluate changes in incidence across years, linear regression models were used to fit the logarithm of the number of cases as a function of year; a model using the ratio of VC to SCC cases was also considered to compare changes in the two histologies. The Kaplan–Meier method and log rank tests were performed to evaluate the differences in OS between VC and SCC and OS with regard to lymph node surgery in VC treatment. Patients diagnosed in 2016 had unknown survival status and were excluded from survival analyses. Propensity score weighted analysis was used to evaluate OS between VC and SCC while balancing confounding variables. A multivariable Cox proportional hazards model was utilized to assess the impact of various demographic factors and treatment methods on OS in the VC patients. All analyses were performed using the R project for statistical computing software, version 3.6.2. Statistical significance was defined by α < .05.RESULTSIncidence rates and demographics of VC compared to SCCSCC diagnoses reported in the NCDB demonstrate an approximately 2.0% increase each year from 2004 to 2016 (CI 1.3% to 2.7%, p < .0001) as shown by Figure 2A. Conversely, the incidence of VC has remained stable, with diagnoses decreasing by a non‐significant 1.3% per year (CI 4.2% decrease to 1.6% increase; p = .344) from 2004 to 2016 as demonstrated in Figure 2B. To control for the potential effect of changing NCDB reporting rates, we considered the ratio of VC to SCC cases. As shown in Figure 2C, VC diagnoses are significantly declining by 3.2% per year relative to the number of SCC diagnoses (CI 0.4% to 6.0%; p = .0285).2FIGUREIncidence of vulvar cancer. (A) Squamous cell carcinoma. (B) Verrucous carcinoma. (C) Number of verrucous carcinomas per 100 squamous cell carcinoma casesA comparison of patient demographics between SCC and VC demonstrated many significant differences (Table 1). The age distribution between the two cohort subsets was statistically significantly different (p < .0001). Of all women diagnosed with SCC, 63.3% were under the age of 70. In contrast, 59.4% of women with VC were diagnosed at age 70 or over, and throughout the time period examined there was no change in the mean age of diagnosis for VC patients (p = .563). A significantly larger portion of the VC patients had a non‐zero Charlson/Deyo comorbidity score (VC: 34% vs. SCC: 27%, p < .0001). There were no significant differences between SCC and VC diagnoses based on race (p = .2044) or Hispanic origin (p = .4830).1TABLECohort demographics comparing squamous cell carcinoma and verrucous vulvar carcinomaSquamous cellVerrucousNPropNPropp‐valueHistology45 04399%6211%<.0001Age<50987222%6110%50–59974322%7412%60–69891920%11719%70–79803018%14023%≥80847919%22937%Race.2044White39 84388%56190%Black39619%427%Other12393%183%Hispanic origin.4830Non‐Hispanic43 49997%59696%Hispanic15443%254%Charlson/Deyo Comorbidity Score<.0001Absent32 88173%40966%Present12 12627%21234%Tumor Size<.0001< 2 cm11 15236%12225%2.0–3.9 cm916930%17135%4.0–5.9 cm487116%9319%≥ 6 cm539318%9620%Unknown14 458139Grade<.0001110 15734%33287%214 33948%4010%≥ 3526918%113%Unknown15 278238TNM pathologic stage<.00010626121%133%114 25549%23663%2323011%9826%3442915%205%411414%103%Unknown15 727244Lymph vascular invasion<.0001No LVSI15 66889%21797%Invasion199711%63%Unknown27 378398Primary site surgery<.0001No surgery611414%285%Surgery38 87686%59395%Unknown530Regional lymph node surgery<.0001No surgery26 67360%48278%Surgery18 11740%13822%Unknown2531Chemotherapy<.0001No chemo37 58286%57196%Chemo606014%244%Unknown140126Radiotherapy<.0001No radiation34 55277%57293%Radiation10 08223%407%Unknown4099Abbreviations: cm, centimeter; N, number; Prop, proportion, LVSI, lymph vascular invasion; TNM, tumor‐node‐metastasis.Tumor characteristics and treatment modalitiesSeveral tumor characteristics of SCC and VC were significantly different. Verrucous carcinomas tended to be slightly larger than squamous cell carcinomas (p < .0001), with 39% of verrucous carcinomas measuring at least 4 cm in size, compared to 34% of squamous cell carcinomas being 4 cm or larger. Tumor grade was significantly different (p < .0001) with the vast majority of VC (87%) being grade 1; in contrast, only 34% of SCC cases were grade 1. Comparison of TNM (tumor‐node‐metastasis) pathologic group staging between the two histologies also demonstrated a significant difference (p < .0001). The majority of VC cases were stage 1 or 2 (63% and 26%, respectively), with a limited number of stage 3 and 4 cases (5% and 3%, respectively). In contrast, a larger proportion of SCC patients were diagnosed with stage 3 or 4 disease (15% and 4%, respectively). Lymph vascular invasion was seen in a higher portion of SCC patients (11%) compared to VC patients (3%).Treatment approaches were also significantly different between SCC and VC (p < .0001). Primary site surgery was done in a larger portion of VC patients (95%) compared to those with SCC (86%). Regional lymph node surgery was more often performed in patients with SCC (40%) in comparison to those with VC (22%). Adjuvant therapy such as chemotherapy or radiation therapy were more commonly used in cases of SCC. Chemotherapy was used more frequently in cases of SCC (14%) than VC (4%); similarly, radiotherapy was used in a much higher proportion of SCC (23%) compared to VC patients (7%).Overall survival of SCC compared to VCThere was a statistically significant difference in the Kaplan–Meier survival curves between patients diagnosed with squamous cell carcinoma compared to those diagnosed with verrucous vulvar carcinoma (p = 0.0266; Figure 3A). Five‐year survival rates where similar between the two histologies (SCC 64.8% and VC 63.4%). However, VC patients had statistically better survival soon after diagnosis (between years 1 and 2.5) but worse survival past year 7. Propensity score weighted analysis, which reweighted the SCC cohort to match the characteristics of the VC patients, demonstrated a trend toward improved OS in VC patients (p = 0.0794; Figure 3B).3FIGUREOverall survival by histology. (A) Kaplan Meier survival analysis. (B) Propensity score weighted analysisFactors affecting OS in VC patientsA Cox proportional hazards analysis was performed to evaluate factors affecting OS in patients diagnosed with verrucous carcinoma (Table 2). Overall survival was significantly worse in VC patients who were older and in those who had a non‐zero Charlson/Deyo comorbidity score. Compared to patients younger than 50 years, those between the ages of 70–79 years had significantly worse OS (adjusted hazard ratio [aHR] 4.65; CI 2.22–9.75; p < .0001), as did patients ≥80 years (aHR 8.96; CI 4.35–18.45; p < .0001). A non‐zero Charlson/Deyo comorbidity score was associated with an aHR of 1.68 (CI 1.28–2.20; p = .0002). Regarding tumor characteristics, patients with at least grade 3 tumors also had significantly worse OS compared to those with grade 1 tumors (aHR 3.88; CI 1.57–9.57; p = .0032). Additionally, patients with pathologic stage 4 VC had significantly worse OS compared to VC patients with stage 1 disease (aHR 28.7; CI 3.37–244.07; p = .0021).2TABLECox proportional hazards model for OS in patients with verrucous vulvar carcinomaAdj HR95% CIp‐valuesAge (years)<.0001<50Reference50–591.560.683.61.296560–692.561.185.53.016870–794.652.229.75<.0001≥808.964.3518.45<.0001Race.2000WhiteReferenceBlack1.720.993.00.0564Other1.060.432.65.8963Hispanic origin.7256Non‐HispanicReferenceHispanic0.880.411.86.7299Charlson/Deyo comorbidity score.0002AbsentReferencePresent1.681.282.20.0002Tumor size.5760<2 cmReference2.0–3.9 cm1.180.801.76.40364.0–5.9 cm1.420.922.18.1135≥6 cm1.240.791.96.3491Unknown1.320.842.07.2321Grade.05501Reference21.330.812.20.2572≥33.881.579.57.0032Unknown1.100.831.46.5151TNM pathologic stage.00060Reference13.040.4122.78.278324.300.5632.77.159133.070.3725.71.3010428.703.37244.07.0021Unknown3.320.4524.68.2404Lymph vascular invasion.6294No LVSIReferenceInvasion0.490.073.70.4894Unknown1.110.731.70.6209Primary site surgery<.0001No surgeryReferenceSurgery0.190.110.33<.0001Regional lymph node surgery.0341No surgeryReferenceSurgery0.670.470.96.0298Unknown0.000.00Inf.0034Chemotherapy.1252No chemoReferenceChemo0.440.191.02.0560Unknown1.150.522.55.7290Radiotherapy.0121No radiationReferenceRadiation1.901.043.47.0360Unknown0.210.041.09.0636Diagnosis year.3865HR per year1.030.971.09.3865Abbreviations: 95% CI, 95% confidence interval; Adj HR, adjusted hazard ratio; cm, centimeter; HR, hazard ratio; LVSI, lymph vascular invasion; OS, overall survival; TNM, tumor‐node‐metastasis.Different treatment modalities also had a significant effect on OS in VC patients (Table 2). Patients treated with surgery to the primary site had a significant improvement in OS compared to those with no primary site surgery (aHR 0.19; CI 0.11–0.33; p < .0001). On univariate analysis, there was a trend in improved 5‐year OS in VC patients treated with regional lymph node surgery plus surgery at the primary site compared to primary site surgery alone (73.5% vs. 63.4%, respectively, p = .1686) (Figure 4). Cox proportional hazards analysis demonstrated a significant improvement in OS in women who were treated with surgery to the regional lymph nodes (aHR 0.67; CI 0.47–0.96; p = .0298) when controlling for other confounders. When excluding VC patients who were not treated with surgery to the primary site, the combination of primary site surgery plus regional lymph node surgery also improved OS compared to treatment with primary site surgery alone on multivariate analysis (aHR 0.67; CI 0.46–0.97; p = .0357). Patients who received chemotherapy had a trend toward improved OS (aHR 0.44; CI 0.19–1.02; p = .0560), while VC patients who received radiotherapy had significantly worse OS (aHR 1.90; CI 1.04–3.47; p = .0360).4FIGUREOverall survival by lymph node surgeryDISCUSSIONIncidence rates of verrucous vulvar carcinomaThe incidence of vulvar SCC has significantly increased from 2004 to 2016. This trend could be due to the increase in risk factors throughout the population. Cigarette smoking, BMI > 30, and menopausal hormones have all been associated with an increased risk of vulvar SCC.26 The number of VC cases diagnosed annually is trending down, but this could be impacted by differing levels of NCDB case capture between 2004 to 2016. In particular, NCDB reporting rates have increased which could mask a true decrease in VC incidence if more recent cases are reported at a higher frequency. Relative to the number of SCC cases reported in the NCDB, VC cases are significantly declining.Patient demographicsMost studies have concluded that VC is diagnosed in patients at a later age than SCC,2,27,28 and our results are consistent with this observation. While there have been case reports of VC patients diagnosed at a younger age,29 our results do not support a trend toward a decreasing age of diagnosis of verrucous vulvar carcinoma.Differing tumor characteristics and treatment modalitiesRegional lymph node surgery was performed more commonly in SCC cases, which is expected since lymph node metastases rarely occur in VC.18,19 Lymphadenectomy is generally recommended with a primary tumor infiltration depth > 1 mm.30 Verrucous carcinoma is rarely infiltrative, which may account for the decreased rate of lymph node surgery. In our analysis, primary site surgical intervention was performed in the vast majority of VC, and results showed that a smaller proportion of SCC cases received surgery (85% SCC, 95% VC). The observed high rate of primary site surgery in VC cases is likely because wide local excision with adequate margins is the current standard of care for VC.18 Furthermore, because VC is more often diagnosed at an earlier stage than SCC, complete resection of the primary tumor without performing an excessively morbid surgery (i.e., pelvic exenteration) is more likely in cases of VC.Chemotherapy and radiotherapy were used more frequently in SCC compared to VC, with only 4% and 7% of VC patients receiving chemotherapy or radiotherapy, respectively. This is most likely due to the increased propensity of SCC to metastasize to regional and distant sites compared to VC.11,12 Additionally, radiotherapy in VC treatment has been associated with anaplastic transformation and possible progression to invasive SCC.19,21–24LimitationsWe acknowledge limitations to this study. First, large population‐based data sets are prone to missing and inadequate data. Rather than excluding patients with missing covariates from our overall survival model, we simply treated “unknown” as a distinct category so that all patients were included in the analysis. For completeness, we did choose to continue to report these values since they were a part of the model fitting. In general, we are not confident that the data are actually missing at random. Many of the aHRs for missing values were greater than 1 indicating missing data may be associated with greater hazard of death, although these terms are not always significant. We suspect that missing values may be correlated with poorer patient care which may then be correlated with poorer survival, but to avoid making any explicit assumptions, we have chosen to treat missing values as its own category. Additionally, the NCDB only lists one histologic diagnosis per patient, and, thus, an evaluation of patients with a coexistence of VC and SCC could not be performed. Second, the vast majority of VC patients are diagnosed at an early stage and grade, and these patients are overwhelmingly treated with surgery without chemotherapy or radiotherapy. Thus, any statistical comparison of VC based on stage, grade, and treatment other than surgery should be interpreted with caution. Third, a study performed in 2017 analyzed the accuracy of histology code reporting in central cancer registries, and subtypes of vulvar SCC were not consistently recorded with proper histologic codes when compared to the pathology reports.31 These findings expose a limitation in the study of rare subtypes of SCC, including verrucous vulvar carcinoma.ConclusionsWhile the incidence of vulvar SCC has increased since 2004, the incidence of VC has remained stable. Compared to SCC, VC was significantly more likely to be diagnosed in older women and treated with surgery alone. We found that there was an improvement in OS in VC patients treated with both primary site and regional lymph node surgery compared to primary site surgery alone.ACKNOWLEDGMENTSThe data used in this study are derived from a deidentified National Cancer Database file. The American College of Surgeons and the Commission on Cancer have not verified and are not responsible for the analytic or statistical methodology employed or the conclusions drawn from these data by the investigators.CONFLICT OF INTERESTThe authors have stated explicitly that there are no conflicts of interest in connection with this article.AUTHOR CONTRIBUTIONSConceptualization, S.M.D., L.B.R., and S.R.S.; Methodology, J.T.G.; Formal analysis, S.M.D., L.B.R., S.R.S., and J.T.G.; Critical analysis, S.M.D., L.B.R., S.R.S., and J.T.G.; Statistical analysis, J.T.G; Drafting/final editing, S.M.D., L.B.R., S.R.S., and J.T.G.; Supervision, S.R.S.ETHICS STATEMENTThe study was found to be exempt from Institutional Review Board (IRB) review through 45 CFR 46.116 (D) by our institution's Biomedical Institutional Review Board.DATA AVAILABILITY STATEMENTThe data that supports the findings of this study are available in the National Cancer Database.REFERENCESBornstein J, Bogliatto F, Haefner HK, et al. The 2015 International Society for the Study of Vulvovaginal disease (ISSVD) terminology of vulvar squamous intraepithelial lesions. Obstet Gynecol. 2016;127:264‐268.Liu G, Li Q, Shang X, et al. Verrucous carcinoma of the vulva: a 20 year retrospective study and literature review. J Low Genit Tract Dis. 2016;20:114‐118.Ackerman LV. Verrucous carcinoma of the oral cavity. Surgery. 1948;23:670‐678.Goethals PL, Harrison EG Jr, Devine KD. Verrucous squamous carcinoma of the oral cavity. Am J Surg. 1963;106:845‐851.Kraus FT, Perezmesa C. Verrucous carcinoma. Clinical and pathologic study of 105 cases involving oral cavity, larynx and genitalia. Cancer. 1966;19:26‐38.Brisigotti M, Moreno A, Murcia C, Matias‐Guiu X, Prat J. Verrucous carcinoma of the vulva. A clinicopathologic and immunohistochemical study of five cases. Int J Gynecol Pathol. 1989;8:1‐7.Scurry J, Wilkinson EJ. Review of terminology of precursors of vulvar squamous cell carcinoma. J Low Genit Tract Dis. 2006;10:161‐169.Finan MA, Barre G. Bartholin's gland carcinoma, malignant melanoma and other rare tumours of the vulva. Best Pract Res Clin Obstet Gynaecol. 2003;17:609‐633.Watkins JC. Human papillomavirus‐independent squamous lesions of the vulva. Surg Pathol Clin. 2019;12:249‐261.Wenig BM. Ear and temporal bone. In: Weidner N, ed. Mod Surg Pathol; Elsevier; 2009:295‐325.Hoang LN, Park KJ, Soslow RA, Murali R. Squamous precursor lesions of the vulva: current classification and diagnostic challenges. Pathology. 2016;48:291‐302.Nascimento AF, Granter SR, Cviko A, Yuan L, Hecht JL, Crum CP. Vulvar acanthosis with altered differentiation: a precursor to verrucous carcinoma? Am J Surg Pathol. 2004;28:638‐643.Bodelon C, Madeleine MM, Voigt LF, Weiss NS. Is the incidence of invasive vulvar cancer increasing in the United States? Cancer Causes Control. 2009;20:1779‐1782.Campaner AB, Cardoso FA, Fernandes GL, Veasey JV. Verrucous carcinoma of the vulva: diagnosis and treatment. An Bras Dermatol. 2017;92:243‐245.Asiaf A, Ahmad ST, Mohammad SO, Zargar MA. Review of the current knowledge on the epidemiology, pathogenesis, and prevention of human papillomavirus infection. Eur J Cancer Prev. 2014;23:206‐224.Crowther ME, Shepherd JH, Fisher C. Verrucous carcinoma of the vulva containing human papillomavirus‐11. Case Rep Br J Obstet Gynaecol. 1988;95:414‐418.Rando RF, Sedlacek TV, Hunt J, Jenson AB, Kurman RJ, Lancaster WD. Verrucous carcinoma of the vulva associated with an unusual type 6 human papillomavirus. Obstet Gynecol. 1986;67:70S‐75S.Zhang W, Wang Y, Chen W, et al. Verrucous carcinoma of the vulva: a case report and literature review. Am J Case Rep. 2019;20:551‐556.Andersen ES, Sorensen IM. Verrucous carcinoma of the female genital tract: report of a case and review of the literature. Gynecol Oncol. 1988;30:427‐434.Haidopoulos D, Diakomanolis E, Rodolakis A, Voulgaris Z, Vlachos G, Michalas S. Coexistence of verrucous and squamous carcinoma of the vulva. Aust N Z J Obstet Gynaecol. 2005;45:60‐63.Boutas I, Sofoudis C, Kalampokas E, Anastasopoulos C, Kalampokas T, Salakos N. Verrucous carcinoma of the vulva: a case report. Case Rep Obstet Gynecol. 2013;2013:932712‐932713.Crowther ME, Lowe DG, Shepherd JH. Verrucous carcinoma of the female genital tract: a review. Obstet Gynecol Surv. 1988;43:263‐280.Demian SD, Bushkin FL, Echevarria RA. Perineural invasion and anaplastic transformation of verrucous carcinoma. Cancer. 1973;32:395‐401.Proffitt SD, Spooner TR, Kosek JC. Origin of undifferentiated neoplasm from verrucous epidermal carcinoma of oral cavity following irradiation. Cancer. 1970;26:389‐393.Bilimoria KY, Stewart AK, Winchester DP, Ko CY. The National Cancer Data Base: a powerful initiative to improve cancer care in the United States. Ann Surg Oncol. 2008;15:683‐690.Brinton LA, Thistle JE, Liao LM, Trabert B. Epidemiology of vulvar neoplasia in the NIH‐AARP study. Gynecol Oncol. 2017;145:298‐304.Saraiya M, Unger ER, Thompson TD, et al. US assessment of HPV types in cancers: implications for current and 9‐valent HPV vaccines. J Natl Cancer Inst. 2015;107:djv086.Smith JS, Backes DM, Hoots BE, Kurman RJ, Pimenta JM. Human papillomavirus type‐distribution in vulvar and vaginal cancers and their associated precursors. Obstet Gynecol. 2009;113:917‐924.Bouquet de Joliniere J, Khomsi F, Gothuey JM, et al. Verrucous carcinoma of the vulva: a case report and review of the literature. Front Surg. 2016;3:8.Alkatout I, Schubert M, Garbrecht N, et al. Vulvar cancer: epidemiology, clinical presentation, and management options. Int J Womens Health. 2015;7:305‐313.Siegel DA, Wilson R, Wilkinson EJ, et al. Evaluation of the vulvar cancer histology code reported by central cancer registries: importance in epidemiology. Arch Pathol Lab Med. 2017;141:139‐143. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Cancer Reports Wiley

Verrucous carcinoma of the vulva: Patterns of care and treatment outcomes

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Abstract

INTRODUCTIONVerrucous carcinoma (VC) of the vulva is a rare form of squamous cell carcinoma that accounts for approximately 1% of vulvar tumors.1,2 VC was first classified as a form of squamous cell carcinoma by Ackerman in 1948 in a case of VC of the oral cavity.3 In 1963 Goethals et al. first suggested involvement of the female genital tract, and in 1966 Kraus and Perez‐Mesa reported the first two cases of vulvar verrucous carcinoma.4,5 Grossly, verrucous carcinoma is fungating and cauliflower like. Histologically, VC commonly displays organized keratinocytes, acanthosis, parakeratosis, or orthokeratosis, with minimal cellular atypia.6,7 Blunt invasion with bulbous rete ridges is a characteristic finding.8,9 Unlike well‐differentiated SCC, there is no cytologic atypia, invasion by irregular‐shaped nests of carcinoma, or desmoplastic stromal response in VC.10 Verrucous carcinoma can be associated with local recurrences; however, distant metastases from VC are uncommon.11,12 Most cases begin with a small wart that progressively enlarges over several months. Chief complaints at the time of initial presentation range from concern for abnormal lesions, itching, and discomfort, to hindrance of daily activities depending on the size and extent of local lesion involvement.The incidence of invasive vulvar carcinoma in the United States has been increasing over the past three decades across all age groups of women, among all races, and in all geographic regions.13 Theories of increased immunosuppressed populations, miscoded cases, and environmental factors have been suggested to explain the changing incidence of vulvar carcinoma. Verrucous vulvar carcinoma is more commonly diagnosed in post‐menopausal women.8,14 VC is a well‐differentiated form of vulvar SCC, with most cases unrelated to infection with human papilloma virus (HPV).12 While the relationship between VC and HPV has been debated,9,15,16 some studies have suggested that a portion of VC cases are related to HPV.17Treatment of VC is centered around primary site surgery, with attention toward taking wide margins to prevent local recurrence.18 Since lymph node metastases are rare in VC, radical vulvectomy is sufficient in the majority of cases, and systemic lymph node dissection is generally not performed.18,19 Some cases of VC may coexist with SCC, in which a lymphadenectomy would be warranted in addition to primary site surgery.20 In an extensive literature review by Liu et al., 15% (10/67) of cases of VC coexisted with well‐differentiated SCC.2 This evidence of coexisting histologies places an emphasis on the importance of thorough histologic evaluation to achieve an accurate and complete diagnosis. There have been some cases of patients receiving radiotherapy and subsequent transformation to SCC or anaplastic transformation.19,21–24 The current paradigm regarding treatment for VC is that wide local excision is associated with a favorable prognosis.The purpose of this study was to perform an analysis of the National Cancer Database (NCDB) (1) to assess the incidence of verrucous vulvar carcinoma, (2) to compare patient, tumor, and treatment characteristics between VC and vulvar SCC, and (3) to analyze factors associated with OS in verrucous carcinoma of the vulva.METHODSDatabaseThis study analyzed data from the National Cancer Database (NCDB). The NCDB includes about 70% of all cases of cancer diagnosed in the United States every year. Extensive demographic data as well as disease and treatment details are provided for each de‐identified patient. Increased numbers of institutions are participating in recording cancer cases with the NCDB. In 2008, 1430 Commission on Cancer (CoC) programs reported to the NCDB, but in 2020 nearly 1500 CoC programs were participating.25Patient cohortThe NCDB included 621 patients diagnosed with VC and 45 043 patients diagnosed with SCC. Patients who were diagnosed with verrucous vulvar carcinoma or vulvar SCC between the years of 2004 and 2016 were included. The inclusion criteria for this analysis are shown in the CONSORT diagram in Figure 1.1FIGURECONSORT diagram describing inclusion criteriaStatistical analysisBaseline patient demographics were obtained from the NCDB including age, race, tumor size and stage, surgical intervention, and adjuvant therapy. Statistical analysis was performed comparing cases of SCC to cases of VC by the chi‐squared test to evaluate differences in disease characteristics at diagnosis, surgical management, and adjuvant treatments. To evaluate changes in incidence across years, linear regression models were used to fit the logarithm of the number of cases as a function of year; a model using the ratio of VC to SCC cases was also considered to compare changes in the two histologies. The Kaplan–Meier method and log rank tests were performed to evaluate the differences in OS between VC and SCC and OS with regard to lymph node surgery in VC treatment. Patients diagnosed in 2016 had unknown survival status and were excluded from survival analyses. Propensity score weighted analysis was used to evaluate OS between VC and SCC while balancing confounding variables. A multivariable Cox proportional hazards model was utilized to assess the impact of various demographic factors and treatment methods on OS in the VC patients. All analyses were performed using the R project for statistical computing software, version 3.6.2. Statistical significance was defined by α < .05.RESULTSIncidence rates and demographics of VC compared to SCCSCC diagnoses reported in the NCDB demonstrate an approximately 2.0% increase each year from 2004 to 2016 (CI 1.3% to 2.7%, p < .0001) as shown by Figure 2A. Conversely, the incidence of VC has remained stable, with diagnoses decreasing by a non‐significant 1.3% per year (CI 4.2% decrease to 1.6% increase; p = .344) from 2004 to 2016 as demonstrated in Figure 2B. To control for the potential effect of changing NCDB reporting rates, we considered the ratio of VC to SCC cases. As shown in Figure 2C, VC diagnoses are significantly declining by 3.2% per year relative to the number of SCC diagnoses (CI 0.4% to 6.0%; p = .0285).2FIGUREIncidence of vulvar cancer. (A) Squamous cell carcinoma. (B) Verrucous carcinoma. (C) Number of verrucous carcinomas per 100 squamous cell carcinoma casesA comparison of patient demographics between SCC and VC demonstrated many significant differences (Table 1). The age distribution between the two cohort subsets was statistically significantly different (p < .0001). Of all women diagnosed with SCC, 63.3% were under the age of 70. In contrast, 59.4% of women with VC were diagnosed at age 70 or over, and throughout the time period examined there was no change in the mean age of diagnosis for VC patients (p = .563). A significantly larger portion of the VC patients had a non‐zero Charlson/Deyo comorbidity score (VC: 34% vs. SCC: 27%, p < .0001). There were no significant differences between SCC and VC diagnoses based on race (p = .2044) or Hispanic origin (p = .4830).1TABLECohort demographics comparing squamous cell carcinoma and verrucous vulvar carcinomaSquamous cellVerrucousNPropNPropp‐valueHistology45 04399%6211%<.0001Age<50987222%6110%50–59974322%7412%60–69891920%11719%70–79803018%14023%≥80847919%22937%Race.2044White39 84388%56190%Black39619%427%Other12393%183%Hispanic origin.4830Non‐Hispanic43 49997%59696%Hispanic15443%254%Charlson/Deyo Comorbidity Score<.0001Absent32 88173%40966%Present12 12627%21234%Tumor Size<.0001< 2 cm11 15236%12225%2.0–3.9 cm916930%17135%4.0–5.9 cm487116%9319%≥ 6 cm539318%9620%Unknown14 458139Grade<.0001110 15734%33287%214 33948%4010%≥ 3526918%113%Unknown15 278238TNM pathologic stage<.00010626121%133%114 25549%23663%2323011%9826%3442915%205%411414%103%Unknown15 727244Lymph vascular invasion<.0001No LVSI15 66889%21797%Invasion199711%63%Unknown27 378398Primary site surgery<.0001No surgery611414%285%Surgery38 87686%59395%Unknown530Regional lymph node surgery<.0001No surgery26 67360%48278%Surgery18 11740%13822%Unknown2531Chemotherapy<.0001No chemo37 58286%57196%Chemo606014%244%Unknown140126Radiotherapy<.0001No radiation34 55277%57293%Radiation10 08223%407%Unknown4099Abbreviations: cm, centimeter; N, number; Prop, proportion, LVSI, lymph vascular invasion; TNM, tumor‐node‐metastasis.Tumor characteristics and treatment modalitiesSeveral tumor characteristics of SCC and VC were significantly different. Verrucous carcinomas tended to be slightly larger than squamous cell carcinomas (p < .0001), with 39% of verrucous carcinomas measuring at least 4 cm in size, compared to 34% of squamous cell carcinomas being 4 cm or larger. Tumor grade was significantly different (p < .0001) with the vast majority of VC (87%) being grade 1; in contrast, only 34% of SCC cases were grade 1. Comparison of TNM (tumor‐node‐metastasis) pathologic group staging between the two histologies also demonstrated a significant difference (p < .0001). The majority of VC cases were stage 1 or 2 (63% and 26%, respectively), with a limited number of stage 3 and 4 cases (5% and 3%, respectively). In contrast, a larger proportion of SCC patients were diagnosed with stage 3 or 4 disease (15% and 4%, respectively). Lymph vascular invasion was seen in a higher portion of SCC patients (11%) compared to VC patients (3%).Treatment approaches were also significantly different between SCC and VC (p < .0001). Primary site surgery was done in a larger portion of VC patients (95%) compared to those with SCC (86%). Regional lymph node surgery was more often performed in patients with SCC (40%) in comparison to those with VC (22%). Adjuvant therapy such as chemotherapy or radiation therapy were more commonly used in cases of SCC. Chemotherapy was used more frequently in cases of SCC (14%) than VC (4%); similarly, radiotherapy was used in a much higher proportion of SCC (23%) compared to VC patients (7%).Overall survival of SCC compared to VCThere was a statistically significant difference in the Kaplan–Meier survival curves between patients diagnosed with squamous cell carcinoma compared to those diagnosed with verrucous vulvar carcinoma (p = 0.0266; Figure 3A). Five‐year survival rates where similar between the two histologies (SCC 64.8% and VC 63.4%). However, VC patients had statistically better survival soon after diagnosis (between years 1 and 2.5) but worse survival past year 7. Propensity score weighted analysis, which reweighted the SCC cohort to match the characteristics of the VC patients, demonstrated a trend toward improved OS in VC patients (p = 0.0794; Figure 3B).3FIGUREOverall survival by histology. (A) Kaplan Meier survival analysis. (B) Propensity score weighted analysisFactors affecting OS in VC patientsA Cox proportional hazards analysis was performed to evaluate factors affecting OS in patients diagnosed with verrucous carcinoma (Table 2). Overall survival was significantly worse in VC patients who were older and in those who had a non‐zero Charlson/Deyo comorbidity score. Compared to patients younger than 50 years, those between the ages of 70–79 years had significantly worse OS (adjusted hazard ratio [aHR] 4.65; CI 2.22–9.75; p < .0001), as did patients ≥80 years (aHR 8.96; CI 4.35–18.45; p < .0001). A non‐zero Charlson/Deyo comorbidity score was associated with an aHR of 1.68 (CI 1.28–2.20; p = .0002). Regarding tumor characteristics, patients with at least grade 3 tumors also had significantly worse OS compared to those with grade 1 tumors (aHR 3.88; CI 1.57–9.57; p = .0032). Additionally, patients with pathologic stage 4 VC had significantly worse OS compared to VC patients with stage 1 disease (aHR 28.7; CI 3.37–244.07; p = .0021).2TABLECox proportional hazards model for OS in patients with verrucous vulvar carcinomaAdj HR95% CIp‐valuesAge (years)<.0001<50Reference50–591.560.683.61.296560–692.561.185.53.016870–794.652.229.75<.0001≥808.964.3518.45<.0001Race.2000WhiteReferenceBlack1.720.993.00.0564Other1.060.432.65.8963Hispanic origin.7256Non‐HispanicReferenceHispanic0.880.411.86.7299Charlson/Deyo comorbidity score.0002AbsentReferencePresent1.681.282.20.0002Tumor size.5760<2 cmReference2.0–3.9 cm1.180.801.76.40364.0–5.9 cm1.420.922.18.1135≥6 cm1.240.791.96.3491Unknown1.320.842.07.2321Grade.05501Reference21.330.812.20.2572≥33.881.579.57.0032Unknown1.100.831.46.5151TNM pathologic stage.00060Reference13.040.4122.78.278324.300.5632.77.159133.070.3725.71.3010428.703.37244.07.0021Unknown3.320.4524.68.2404Lymph vascular invasion.6294No LVSIReferenceInvasion0.490.073.70.4894Unknown1.110.731.70.6209Primary site surgery<.0001No surgeryReferenceSurgery0.190.110.33<.0001Regional lymph node surgery.0341No surgeryReferenceSurgery0.670.470.96.0298Unknown0.000.00Inf.0034Chemotherapy.1252No chemoReferenceChemo0.440.191.02.0560Unknown1.150.522.55.7290Radiotherapy.0121No radiationReferenceRadiation1.901.043.47.0360Unknown0.210.041.09.0636Diagnosis year.3865HR per year1.030.971.09.3865Abbreviations: 95% CI, 95% confidence interval; Adj HR, adjusted hazard ratio; cm, centimeter; HR, hazard ratio; LVSI, lymph vascular invasion; OS, overall survival; TNM, tumor‐node‐metastasis.Different treatment modalities also had a significant effect on OS in VC patients (Table 2). Patients treated with surgery to the primary site had a significant improvement in OS compared to those with no primary site surgery (aHR 0.19; CI 0.11–0.33; p < .0001). On univariate analysis, there was a trend in improved 5‐year OS in VC patients treated with regional lymph node surgery plus surgery at the primary site compared to primary site surgery alone (73.5% vs. 63.4%, respectively, p = .1686) (Figure 4). Cox proportional hazards analysis demonstrated a significant improvement in OS in women who were treated with surgery to the regional lymph nodes (aHR 0.67; CI 0.47–0.96; p = .0298) when controlling for other confounders. When excluding VC patients who were not treated with surgery to the primary site, the combination of primary site surgery plus regional lymph node surgery also improved OS compared to treatment with primary site surgery alone on multivariate analysis (aHR 0.67; CI 0.46–0.97; p = .0357). Patients who received chemotherapy had a trend toward improved OS (aHR 0.44; CI 0.19–1.02; p = .0560), while VC patients who received radiotherapy had significantly worse OS (aHR 1.90; CI 1.04–3.47; p = .0360).4FIGUREOverall survival by lymph node surgeryDISCUSSIONIncidence rates of verrucous vulvar carcinomaThe incidence of vulvar SCC has significantly increased from 2004 to 2016. This trend could be due to the increase in risk factors throughout the population. Cigarette smoking, BMI > 30, and menopausal hormones have all been associated with an increased risk of vulvar SCC.26 The number of VC cases diagnosed annually is trending down, but this could be impacted by differing levels of NCDB case capture between 2004 to 2016. In particular, NCDB reporting rates have increased which could mask a true decrease in VC incidence if more recent cases are reported at a higher frequency. Relative to the number of SCC cases reported in the NCDB, VC cases are significantly declining.Patient demographicsMost studies have concluded that VC is diagnosed in patients at a later age than SCC,2,27,28 and our results are consistent with this observation. While there have been case reports of VC patients diagnosed at a younger age,29 our results do not support a trend toward a decreasing age of diagnosis of verrucous vulvar carcinoma.Differing tumor characteristics and treatment modalitiesRegional lymph node surgery was performed more commonly in SCC cases, which is expected since lymph node metastases rarely occur in VC.18,19 Lymphadenectomy is generally recommended with a primary tumor infiltration depth > 1 mm.30 Verrucous carcinoma is rarely infiltrative, which may account for the decreased rate of lymph node surgery. In our analysis, primary site surgical intervention was performed in the vast majority of VC, and results showed that a smaller proportion of SCC cases received surgery (85% SCC, 95% VC). The observed high rate of primary site surgery in VC cases is likely because wide local excision with adequate margins is the current standard of care for VC.18 Furthermore, because VC is more often diagnosed at an earlier stage than SCC, complete resection of the primary tumor without performing an excessively morbid surgery (i.e., pelvic exenteration) is more likely in cases of VC.Chemotherapy and radiotherapy were used more frequently in SCC compared to VC, with only 4% and 7% of VC patients receiving chemotherapy or radiotherapy, respectively. This is most likely due to the increased propensity of SCC to metastasize to regional and distant sites compared to VC.11,12 Additionally, radiotherapy in VC treatment has been associated with anaplastic transformation and possible progression to invasive SCC.19,21–24LimitationsWe acknowledge limitations to this study. First, large population‐based data sets are prone to missing and inadequate data. Rather than excluding patients with missing covariates from our overall survival model, we simply treated “unknown” as a distinct category so that all patients were included in the analysis. For completeness, we did choose to continue to report these values since they were a part of the model fitting. In general, we are not confident that the data are actually missing at random. Many of the aHRs for missing values were greater than 1 indicating missing data may be associated with greater hazard of death, although these terms are not always significant. We suspect that missing values may be correlated with poorer patient care which may then be correlated with poorer survival, but to avoid making any explicit assumptions, we have chosen to treat missing values as its own category. Additionally, the NCDB only lists one histologic diagnosis per patient, and, thus, an evaluation of patients with a coexistence of VC and SCC could not be performed. Second, the vast majority of VC patients are diagnosed at an early stage and grade, and these patients are overwhelmingly treated with surgery without chemotherapy or radiotherapy. Thus, any statistical comparison of VC based on stage, grade, and treatment other than surgery should be interpreted with caution. Third, a study performed in 2017 analyzed the accuracy of histology code reporting in central cancer registries, and subtypes of vulvar SCC were not consistently recorded with proper histologic codes when compared to the pathology reports.31 These findings expose a limitation in the study of rare subtypes of SCC, including verrucous vulvar carcinoma.ConclusionsWhile the incidence of vulvar SCC has increased since 2004, the incidence of VC has remained stable. Compared to SCC, VC was significantly more likely to be diagnosed in older women and treated with surgery alone. We found that there was an improvement in OS in VC patients treated with both primary site and regional lymph node surgery compared to primary site surgery alone.ACKNOWLEDGMENTSThe data used in this study are derived from a deidentified National Cancer Database file. The American College of Surgeons and the Commission on Cancer have not verified and are not responsible for the analytic or statistical methodology employed or the conclusions drawn from these data by the investigators.CONFLICT OF INTERESTThe authors have stated explicitly that there are no conflicts of interest in connection with this article.AUTHOR CONTRIBUTIONSConceptualization, S.M.D., L.B.R., and S.R.S.; Methodology, J.T.G.; Formal analysis, S.M.D., L.B.R., S.R.S., and J.T.G.; Critical analysis, S.M.D., L.B.R., S.R.S., and J.T.G.; Statistical analysis, J.T.G; Drafting/final editing, S.M.D., L.B.R., S.R.S., and J.T.G.; Supervision, S.R.S.ETHICS STATEMENTThe study was found to be exempt from Institutional Review Board (IRB) review through 45 CFR 46.116 (D) by our institution's Biomedical Institutional Review Board.DATA AVAILABILITY STATEMENTThe data that supports the findings of this study are available in the National Cancer Database.REFERENCESBornstein J, Bogliatto F, Haefner HK, et al. 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Journal

Cancer Reports – Wiley

Published: Oct 1, 2022

Keywords: gynecologic cancer; National Cancer Database; verrucous; vulva

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