Vulvar squamous cell carcinoma guidelines do not include tissue-sparing techniques as a treatment option
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What is known about this subject in regard to women and their families? Current National Comprehensive Cancer Network guidelines for early-stage vulvar squamous cell carcinoma (SCC; T1a ≤1 mm invasion) and high-grade squamous intraepithelial lesion recommend wide local excision (at least 1 cm) as the primary treatment modality. Current excisional margins are often associated with disfigurement and functional deficits with psychologic, social, and sexual ramifications. What is new from this article as messages for women and their families? We propose a new category of very early vulvar SCC (high-grade squamous intraepithelial lesion, differentiated vulvar intraepithelial neoplasia, T1a) to be considered in vulvar cancer treatment guidelines that would include vulvar organ-sparing approaches. Tissue-sparing procedures dermatologists commonly utilize may be reasonable treatment modalities for some patients with very early vulvar SCC. We aim to bring increased awareness to the role tissue-sparing approaches can play in very early vulvar SCC and their utility in preserving vulvar function and preventing morbidity. National Comprehensive Cancer Network (NCCN) guidelines for early-stage vulvar squamous cell carcinoma (SCC; T1a ≤1 mm invasion) recommend wide local excision (WLE) as the primary treatment modality.1 The guidelines incorporate a footnote on high-grade squamous intraepithelial lesions (HSIL) and recommend WLE for these lesions as well. For these early-stage SCCs, there is no recommendation for sentinel lymph node biopsy or lymphadenectomy as the risk of nodal metastases is less than 1%.1 The guidelines on margin control for WLE state that efforts should be made to obtain surgical margins (at least 1 cm) at time of primary surgery. However, the guidelines also highlight that studies have called into question these margins, suggesting narrower margins as current excisional margins are often associated with disfigurement and functional deficits with psychologic, social, and sexual ramifications.2,3 There is precedence for inclusion of tissue-sparing procedures in NCCN guidelines previously. For example, Penile Cancer guidelines include a section on "Principles of Penile Organ-Sparing Approaches" as well as "Primary Radiation/Chemoradiation Therapy (Penile Preservation)" which state that Tis, Ta, and T1 penile cancer may be amenable to conservative modalities, including topical therapy, WLE, laser therapy, glansectomy, external beam radiation therapy, brachytherapy, and Mohs micrographic surgery (MMS). Topical regimens, laser devices, and settings are included. We suggest that the management of some cases of early vulvar SCC could benefit from an interdisciplinary approach between dermatology and gynecologic oncology. As NCCN Vulvar Cancer guidelines do not include tissue-sparing techniques for vulvar SCC, and dermatologists are not currently represented on the guideline committee, gynecologists may be less comfortable referring a patient for multidisciplinary evaluation with dermatology. However, the tissue-sparing procedures dermatologists commonly utilize may be reasonable treatment modalities for some patients with very early vulvar SCC, where larger excisions may be associated with increased morbidity. Such procedures may have utility for the following: HSIL, HPV-independent differentiated vulvar intraepithelial neoplasia, and T1a vulvar SCC. For example, reports available on use of MMS for select cases of SCC have found this may be an effective modality as a first-line therapy in select cases and in some treatment-refractory cases: 38 cases of vulvar SCC were treated with MMS with 4 reporting recurrence, however most cases were not early SCC, as the average tumor size was 18 mm and multiple had been treated with prior modalities including excision.4 Unfortunately, prospective studies on MMS for early vulvar SCC are lacking. Future studies should focus on efficacy and patient-reported outcomes with use of other tissue-sparing modalities for early vulvar SCC. Herein, we propose a new category of very early vulvar SCC (HSIL, differentiated vulvar intraepithelial neoplasia, T1a) to be considered in vulvar cancer treatment guidelines that would include vulvar-organ sparing approaches (Fig. 1). We aim to bring increased awareness to the role tissue-sparing approaches can play in very early vulvar SCC and their utility in preserving vulvar function and preventing morbidity. We encourage increased multidisciplinary collaboration between dermatology, gynecology, and other pertinent specialties to consider incorporation of tissue-sparing modalities into future guidelines, providing additional treatment options for patients with a diagnosis of very early vulvar SCC.Fig. 1.: Current and proposed NCCN Guidelines for vulvar SCC. *Special circumstances may allow the use of topical, laser, or radiation therapy. NCCN, National Comprehensive Cancer Network; SCC, squamous cell carcinoma; EBRT, external beam radiation therapy; HSIL, high-grade squamous intraepithelial lesions; dVIN, differentiated vulvar intraepithelial neoplasia; ILN, inguinal lymph nodes.Conflicts of interest None. Funding None. Study approval N/A. Author contributions CAV: Participated in writing of the paper and manuscript preparation. IIS: Participated in figure design and manuscript preparation. ANE: Participated in writing of the paper and manuscript preparation. CNK: Participated in writing of the paper and manuscript preparation.Keywords:
Wide local excision
Vulvar intraepithelial neoplasia
Vulvar neoplasm
Squamous intraepithelial lesion
Vulvar Carcinoma
Abstract Paraffin‐embedded sections of vulvar squamous‐cell carcinomas and of normal vulvar tissues were examined for HPV types 6, 11, 16, 18 and 33 by the polymerase chain reaction. Overall, 19 of 62 tumours harboured HPV DNA of types 16, 18 or 33. HPV types 6 and 11 were not detected. HPV DNA was found in 61% of tumours with adjacent intraepithelial neoplasia (VIN III), and in 13% of tumours without associated VIN III. HPV DNA was not detected in any of 101 normal vulvar tissues. HPV DNA was found more often in younger women, in patients with VIN III‐associated tumours, and in those with multicentric anogenital neoplasia. This points to the existence of a subset of vulvar carcinomas preceded by intraepithelial neoplasia, with HPV as a major factor in carcinogenesis. HPV also seems to be an important factor in the development of multiprimaries in these patients. The 2 groups of patients with vulvar carcinoma did not differ with regard to prognosis, as estimated by the risk of recurrence after primary surgery.
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Usual vulvar intraepithelial neoplasia (VIN) is a chronic high-risk HPV-related disorder,which is causally associated with basaloid and warty carcinoma.Differentiated VIN is not a chronic HPV-related disease,which is correlated with keratinizing squamous carcinoma(KSC),vulvar KSC have a significantly worse prognosis.Patients with vulvar condylomata acuminate and VIN may exist in cervical intraepithelial neoplasias.Therefore,we should do cervical pathological examination.Vaccination against HPV oncoproteins has been used for HPV-related diseases.
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Vulvar cancer is the fourth most common gynecologic cancer, most frequently diagnosed in postmenopausal women. There are two independent pathways for the most common type of vulvar cancer, squamous cell carcinoma (SCC). The warty type of vulvar SCC is usually preceded by the typical vulvar intraepithelial neoplasia (VIN), with integrated human papillomavirus. In contrast, well-differentiated keratinizing vulvar SCC is preceded by differentiated VIN and chronic inflammation. Preinvasive (VIN) lesions are usually surgically excised or ablated with laser or chemical destruction. Early-stage (stage I/II) invasive squamous cell vulvar carcinoma is surgically staged and treated with a lymph node sampling/dissection and a radical wide local excision. Treatment of advanced-stage disease (III/IV) is individualized, depending on the size, location, and lymph node status. The survival of patients with vulvar cancer correlates with the stage of the disease, with lymph node status being the single most important prognostic factor.
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We read this very interesting article by Wakeham et al. evaluating the impact of HPV in patients with vulvar neoplasms.1 The authors observed that the presence of high-risk HPV type(s) in patients affected by vulvar intraepithelial neoplasia (VIN) is associated with an increased risk of developing vulvar carcinoma. The authors observed that all cases of VIN progressed to vulvar cancer are related to HPV16. Moreover, high-risk HPV positivity was demonstrated to be a valid biomarker correlating with better survival outcomes in patients with vulvar squamous cell cancer.1 Growing evidence suggested that HPV status had a great impact on patients' outcomes.2, 3 However, the role of HPV status in VIN and vulvar cancer is not fully addressed. Recently, our study group investigated how primary (pre-treatment) type-specific HPV influence the risk of persistence/recurrence in patients treated for VIN usual type (also known as VIN2+).4 In agreement with Wakeham et al. we observed that HPV16 is the most common HPV type detected in VIN usual type (detected in 15 out of the 62 patients studied). However, in contrast to the background, we observed that pretreatment infection from HPV31 and HPV33 correlated with an increased risk of VIN usual type persistence/recurrence after primary treatment; while pretreatment infection from HPV16 is not associated with this risk, independently.4 We speculated that HPV31 and HPV33 might correlate with multifocal and suddenly growing lesions in contrast to more aggressive (and more evident) lesions related to HPV16.5 However, our investigation is just focused on VIN usual type; while the study from Wakeham et al. aimed to test the impact of type-specific HPV infection on patients with both VIN and vulvar cancer.1 Further studies are warranted in order to assess the risk of VIN, VIN usual type and vulvar cancer outcomes on the basis of type-specific HPV infection. In fact, various type-specific HPV infections might have a different risk of progression and recurrence in vulvar lesions, thus identifying HPV type(s) involved might play an important prognostic and potentially therapeutic role in those patients.
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Vulvar Clinic, Department of Gynecologic Oncology, Green Lane/National Women's Hospital, Auckland, New Zealand. Obstet Gynecol 1994:84:741-745
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Human papillomavirus (HPV) is a necessary cause for cervical cancer, and it has been associated with vulvar and vaginal cancer and vulvar (VIN) and vaginal (VaIN) and anal (AIN) intraepithelial neoplasia. We assessed the prevalence of HPV (and the types) to estimate the possible effect of a HPV vaccine on lower genital tract disease prevention.Two hundred fifty-eight samples of VIN, VaIN, AIN, and vulvar cancer from 241 women were included in the study. The diagnosis of surgical samples was made using published histomorphologic criteria. The DNA was extracted for HPV detection and typed using polymerase chain reaction and sequencing.The analyses were performed on 210 intraepithelial neoplasia samples (VIN2/3, VaIN2/3, AIN2/3) and 48 vulvar carcinoma samples. Human papillomavirus DNA was detected in 92%, 91%, 89%, and 60% of the VIN, VaIN, AIN, and vulvar carcinoma samples, respectively. High-risk HPV types 16 or 18 were detected in 76%, 64%, 81%, and 42% of the VIN2/3, VaIN2/3, AIN, and vulvar carcinoma samples. Women with HPV-positive samples were younger than those with HPV-negative samples (46 years compared with 55 years and 51 years compared with 61 years, for the VIN2/3 and vulvar carcinoma samples, respectively). Human papillomavirus-positive vulvar carcinoma was more frequent in women aged younger than 56 years (77%), than in those aged 56 years or older (41%).Based on the data obtained in this study, widely-implemented prophylactic HPV vaccination could make an important contribution to the reduction of the risk for cervical cancer and could also prevent about half the vulvar carcinomas in younger women and about two thirds of the intraepithelial lesions in the lower genital tract.II-3.
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Evaluation of vulvar intraepithelial neoplasia (VIN) and early vulvar cancer risk factor occurrence, frequency, localization and development.A clinical study carried out on 293 women aged 23-76 years with VIN and vulvar cancer stage I and in a control group of 115 cytologically and colposcopically negative women.Clinical, colposcopic and morphological evaluation of the localization of VIN and vulvar carcinoma stage I concomitant with intraepithelial neoplasia in other parts of the lower genital tract. Anamnestic inquiry regarding risk factors. In situ hybridisation technique for HPV detection. Thomson's method for blood serum vitamin A level assessment.An increased frequency of VIN and Ca stage I, especially in young women, has been observed in the past 15 years. In a group of young women under 45 years of age, those lesions were multifocal in 43 cases (63.2%), and unifocal in 25 patients (36.8%). In women over 45 years of age, multifocal lesions occurred in 35 (31.8%), and unifocal in 75 patients (68.2%). HPV infections concomitant with VIN and vulvar cancer stage I occurred in 61.5% of young women and in 17.5% of older females. VIN and stage I vulvar carcinoma coexisted with cervical intraepithelial neoplasia and cervical and/or vaginal cancer in 14 women (7.9%). The risk factor for VIN and early vulvar carcinoma occurrence in young women was different than in older patients. Long-term follow-up of VIN 1 and VIN 2 showed that in over 1/3 of cases the lesions were persistent or recurred after a transient remission. Progression depended not only on dysplasia stage, but also on histological pattern.
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In this updated systematic review and meta-analysis, we estimate the pooled prevalence of human papillomavirus (HPV) DNA and HPV type distribution in squamous cell carcinoma of the vulva (vulvar cancer) and vulvar intraepithelial neoplasia (VIN). PubMed, Embase and Cochrane Library databases were used to identify studies published between 1990 and 2015 and using a PCR-based or hybrid capture test to evaluate the presence of HPV DNA in vulvar cancer or VIN. Pooled estimates of the HPV prevalence with corresponding 95% confidence intervals (CI) were calculated based on a random effects model. The I2 statistic was used to describe the amount of heterogeneity. In meta-regression analyses, potential sources of heterogeneity were evaluated. We identified 92 eligible papers, comprising altogether 5,015 cases of vulvar cancer (64 papers) and 2,764 cases of VIN (48 papers). The pooled prevalence of HPV in vulvar cancer was 39.7% (95% CI: 35.1-44.4%). Overall, 76.3% (95% CI: 70.1-82.1%) of VIN lesions tested HPV-positive, while the HPV prevalence in new subcategories of VIN, uVIN and dVIN, was 86.2% (95% CI: 73.5-95.5%) and 2.0% (95% CI: 0-10.0%), respectively. Substantial between-study heterogeneity was observed (vulvar cancer: I2 = 88.4%; VIN: I2 = 90.7%) with the largest variation between geographical regions. Among HPV-positive cases, the predominant high-risk HPV type was HPV16, followed by HPV33 and HPV18. HPV6 was detected as a single infection in a small subset of VIN and vulvar cancer samples. Thus, HPV vaccination targeting these HPV types may prevent a substantial number of vulvar lesions.
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