Clinical and Pathological Features in Women with Vulvar Squamous Intraepithelial Neoplasia: A Single Center Experience from China

doi:10.21203/rs.3.rs-2831158/v1

Objective: This study aimed to investigate the optimal depth of vulvar intraepithelial neoplasia (VIN) and involved skin appendages to provide evidence for treatment.

Methods: The study retrospectively enrolled and analyzed the clinical characteristics of all VINs in the obstetrics and gynecology department of a university hospital from January 1, 2019, to December 30, 2021. The study further explored the thickness of epithelium and skin appendages of 285 women with low-grade VIN (VIN 1) and 285 women with high-grade VIN (VIN 2/3).

Results: The study included 1,474 VINs: 1,139 (80%) VIN 1 and 335 (20%) VIN 2/3 cases. The VIN 1 and VIN 2/3 groups showed a significant difference in HPV infection (P<0.01) but not in cytology (P=0.499). The majority (89.90%, 1,325) of the cases occurred in one area of the vulva, whereas 10.11% had multifocal areas. VIN commonly occurred on the posterior fourchette (76.85%), labia majora (11.61%), and labia minora (9.92%). The VIN 2/3 groupreported a significantly higher positive rate for concurrent Cervical and Vaginal intraepithelial neoplasia (160 of 285) compared with the VIN 1 group (321 of 953) (P=0.000). The involved epithelial thicknesses in VIN 2/3 and VIN 1 were 0.69±0.44 and 0.49±0.23 mm, respectively, both greater than their noninvolved epithelial thickness (0.31±0.19 and 0.32±0.10 mm, p<0.001 and p<0.001, respectively). In circumstances of appendage involvement, VIN thickness was 1.98±0.64 mm.

Conclusions: VIN thickness was generally ≤1 mm for the superficial lesions in non-hairy areas. Lesions extending onto hairy areas were about 3 mm, destroying involved skin appendages.

Vulvar intraepithelial neoplasia

Vulva

HPV

Squamous intraepithelial lesion

Treatment

Thickness

In 2015, the International Society for the Study of Vulvovaginal Disease proposed a revised classification of vulvar intraepithelial neoplasia (VIN) terminology to include low-grade squamous intraepithelial lesion (LSIL) and high-grade squamous intraepithelial lesion (HSIL) subtypes, and VIN differentiated type^[1]. LSIL and HSIL correspond to the previous VIN 1 and VIN 2/3 nomenclature, respectively. VIN 2/3 is more common in younger women^[2] and considered a premalignant condition, which is related to the invasive squamous cell carcinomas of the vulva (VSCC) that account for over 80% of malignancies in the vulva.

Management of VIN remains challenging owing to the lack of clear consensus regarding the best treatment modality. Current treatment options for VIN are local surgical excision, topical chemotherapy, and photodynamic and laser ablation. Local surgical excision, in the form of vulvectomy, is disfiguring, emotionally distressing, and a cause for sexual problems for many women. Indeed, the apparently rising incidence of VIN in younger women and the need for conservation therapy have been noted. Alternative, conservative, topical chemotherapy with immune-modulating agents and antiviral therapy have varying disadvantages, such as high rates of ulceration and unclear success response rates ranging from 26–70%^[3–5]. Photodynamic therapy has shown numerous limits, such as high rate of treatment failure, immunosuppressive effects, and consequent increases in direct and non-direct costs^[6]. Laser vaporization, which uses a high-energy light beam, has been proposed as a surgical treatment for a variety of VIN. This has met with varying success, with reports of being generally well tolerated, having satisfactory healing, and causing minimal sexual dysfunction^[7].

However, these treatments may lead to residual lesions and VIN recurrence. The depth of treatment is a crucial aspect of therapy because an appropriate treatment rarely causes adverse reactions and can be repeated. Notably, different areas of the vulva have different skin structure. Few studies have investigated the depth of epithelial and involved appendages, and the results are uniform. They measured small sample sizes and suggested that depths of 1.0 mm and 2.0–2.5 mm in non-hairy and hairy sites, respectively, were appropriate for successful treatment^{[8, 9]}. Thus, a large-sample study with VIN lesions of more precise thickness is needed to help guide clinical treatment. In this study, we aimed to explore the depth of the involved and noninvolved vulvar epithelium and appendages in women with VIN and provide data regarding epithelial destruction during treatment.

Patients

This is a single-center retrospective study carried out in a large OB/GYN hospital in China. From January 1, 2019 to December 30, 2021, we enrolled subjects who underwent colposcopy-directed biopsies or vulvar surgical vulvectomy. We included patients diagnosed with VIN 1 and VIN 2/3. Patients with an incomplete medical history, VIN with warty (condyloma acuminata) type, and those who were lost to follow-up were excluded. Approval was obtained from the relevant institutional review board before data extraction was commenced, and all women provided consent to participate in the study. Finally, a total of 285 patients with VIN 2/3 were enrolled in the study. Considering the large number of VIN 1, we randomly selected 285 VIN 1 patients who were diagnosed in the same period as the VIN 2/3 patients.

Cytology and Human Papillomavirus Testing

Cervical or vaginal cytology tests were interpreted and reported by two pathology specialists based on the 2014 Bethesda System. Human papillomavirus testing was performed using fluorescence-based multiplex realtime HPV DNA genotyping kit (Bioperfectus, Jiangsu, China), which can detect high-risk HPV types (16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 73, 82) and low-risk HPV types (6,11, 81).

Pathology

We examined tissue specimens from 570 patients with VIN 1 and VIN 2/3. Specimens were collected from biopsies or local surgical vulvectomy that were fixed in buffered formalin and embedded in paraffin. We stained 4-µm sections of paraffin-processed samples with hematoxylin and eosin. Two experienced pathologists scanned and reviewed all digital slides. All margin diagnoses were negative for intraepithelial lesion or invasive cancer. To compare the vulvar epithelium thickness between before and after formalin fixation, we selected seven radical vulvectomy samples (International Federation of Gynecology and Obstetrics phase I, VSCC), each of which had a frozen section diagnosis of vulvar margin and their corresponding formalin-fixed and paraffin-embedded (FFPE) samples. In total, we retrieved 21 paired sections from those cases.

Surface keratinization or surface separated from the epidermis easily made the use of the surface as a reference point inaccurate. As such, we started vertical measurements at the junction of the stratum corneum with the stratum granulosum and extended to the basal layer. We measured multiple foci and recorded the maximum values. We also obtained the thicknesses of the involved and noninvolved epithelium or appendages in the same section. All available data were recorded, including patient history of cytology, HPV, disease, and age.

Statistical Analysis

Statistical analyses were performed using SPSS for Windows, Version 16.0 (SPSS Inc., Chicago, IL). We applied independent samples t-test and chi-squared test to compare the difference in groups. P values < 0.05 were considered statistically significant.

In table1, a total of 1,474 women were diagnosed with VIN who received vulvar biopsies or local surgical vulvectomy from January 1, 2019 to December 30, 2021. Of them, 1,139 (80%) and 335 (20%) were VIN 1 and VIN 2/3 cases, respectively. The average age for patients with VINs was 42.72 ± 14.31 years. In addition, the women were significantly older in the VIN 2/3 group compared with the VIN1 group (P <0.01). We also found a significant difference in HPV infection (P <0.01) but not in cytology (P = 0.499) between the VIN 1 and VIN 2/3 groups. Almost 90% (1,325 of 1,474) of the cases had lesions on one vulvar area, whereas 10.11% (149) of the cases had multifocal areas. In our sample, VIN was commonly found on the posterior fourchette (76.85%), labia majora (11.61%), and labia minora (9.92%). We recorded 1,374 of 1,678 (77.83%) VIN lesions in non-hairy areas and 372 (22.17%) in hairy areas. We found cervical squamous intraepithelial neoplasia (CIN) or/and vaginal squamous intraepithelial neoplasia (VaIN) in 38.85% (481 of 1,238) VINs who had no CIN/VaIN history. We noted a significantly higher positive rate for concurrent CIN and VaIN in the VIN 2/3 group (56.14%,160 of 285) compared with the VIN 1 group (33.68%, 321 of 953) (P = 0.000).

We randomly selected 285 cases of VIN 1 who were diagnosed in the same period as VIN 2/3 patients, all of whom had no history of CIN/VaIN. The clinical characteristics of the women with VIN 1 and VIN 2/3 are shown in Supplementary 1. In the VIN 1 group, six cases had two lesion sites, on the posterior fourchette and labia majora. In the VIN 2/3 group, 20 cases had the same two lesion sites, and three cases had three lesion sites, the posterior fourchette, labia majora, and perianal areas. For the VIN 1 group, CIN/VaIN 1 was detected in 35 (12.28%) cases and CIN/VaIN 2/3 in 8 (2.81%) cases. Two subjects (0.70%) also had squamous cell carcinoma of the cervix (SCC). For the VIN 2/3 group, CIN/VaIN 1, CIN/VaIN 2/3, SCC, and vaginal squamous carcinoma (VaSCC) were detected in 90 (31.6%), 59 (20.7%), 8 (2.8%), and 3 (1.1%) subjects, respectively.

Table 2, Figure 1 and Figure 2 give the epithelial thickness of VINs in different sites. We examined 291 and 309 sections of tissue from 285 cases with VIN 1 and 285 cases with VIN 2/3, respectively. Of the 600 tissue sections, VIN was found on the posterior fourchette (45.33%), labia majora (18.83 %), and labia minora (14.83%). The maximum depth of epithelial lesions was 1.6 mm in VIN 1 and 2.75 mm in VIN 2/3. A significant difference was detected in VIN 2/3 across all vulvar sites between involved and noninvolved epithelial thickness (P<0.05). The involved epithelial thickness in the VIN 1 group was greater compared with the noninvolved, except for the clitoris, urethral opening, and navicular fossa. The thickness of the involved epithelium was 0.69 ± 0.44 mm and 0.49 ± 0.23 mm in the VIN 2/3 and VIN 1 groups, respectively (p = 0.000). However, the depth of the noninvolved epithelium was projected to be similar in any grade of VIN. We found that 32.81% (187 of 570) of VINs were involved in hairy areas. The rate of involvement in hairy areas was 28.07% (80 of 285) in VIN 1 and 37.54% (107 of 285) in VIN 2/3. The most common non-hairy lesions were in the posterior fourchette in both VIN 2/3 and VIN 1, whereas the labia majora was the most common area in hairy areas. We noted a significant difference in epithelial thickness between VINs in non-hairy and hairy sites (0.52 ± 0.30 mm vs. 0.78 ± 0.45 mm, P <0.001).

Table 3 shows the depth of involved epithelial and skin appendages in VIN and noninvolved tissue. Compared with nondysplastic samples, we found no significant difference in the depth of the stratum corneum in VIN groups. The thickness of involved skin appendages in VIN ranged from 0.91 to 5.44 mm (mean depth, 1.98 ± 0.64 mm), whereas that of noninvolved skin appendages ranged from 0.26 to 4.38 mm (mean depth, 1.66 ± 0.85mm). In only one patient did VIN appear to affect hair follicles; the depth reached 5.44 mm. The thickness of involved epithelial VIN skin appendages was consistently greater than that of involved epithelium at the same section (1.98 ± 0.61 mm vs. 1.01 ± 0.52 mm, P <0.001). Hair follicles represented the most commonly involved appendage, followed by sebaceous glands. The involvement of sweat glands was not detected in any VINs (see Figure 3).

As shown in Supplementary 2, the involved epithelial thickness in all grades of VIN was consistently greater than that of noninvolved epithelial thickness across all age groups. We observed a decreasing tendency with age in both noninvolved and involved groups in all grades of VIN, which was statistically significant (P <0.001 for all comparisons). In comparisons between the VIN 2/3 and VIN 1 groups, the differences in the involved epithelial thickness were statistically significant for any different age group, premenopausal women, and postmenopausal women (P <0.001 for all comparisons). Comparisons of the noninvolved epithelial thickness showed no subgroup-level (age, premenopausal and postmenopausal group) significant differences between the VIN 2/3 and VIN 1 groups (P >0.05 for all comparisons).

To compare the vulvar epithelium thickness before and after the FFPE treatment of samples, we enrolled 21 pairs of frozen and corresponding FFPE-treated sections. The epithelial thickness was 0.32 ± 0.18 mm for the frozen and 0.31 ± 0.11 mm for the FFPE sections, indicating no significant difference in changes in size caused by tissue fixation (P = 0.56).

Our study showed that the value of cytology results was limited in identifying the severity of VIN lesions, given that these results showed no differences between the VIN 1 and VIN 2/3 groups. However, when the cytological results yield HSIL⁺, care should be taken to avoid missing serious lesions under colposcopy. In our study, most VINs were associated with HPV infection, consistent with other studies that reported HPV positivity rates over 80%^[10–13]. This fact confirms a cause-and-effect relation.

VINs tend to be multifocal and multicentric, and about 18–56% of VINs had cervix, vaginal, and anal lesions at the same time^[14–18]. In our study, 31.58% of VIN2/3 cases were concurrent with LSIL, 20.27% with HSIL, 2.81% with SCC, and 1.05% with VaSCC. VIN 2/3 cases are more likely to be accompanied by cervical and vaginal lesions. Our data supported the concept that HPV-related disease can manifest throughout the multicentric disease of lower female genital tract rather than being confined to one particular organ. Thus, finding VIN on clinical examination should prompt a thorough examination from the cervix to the perianal area^[19]. Meanwhile, owing to the lack of effective screening methods for VIN 2/3, comprehensive and careful examination of vulvar and perianal areas is the main method for the early detection of VIN 2/3.

The involved epithelial thickness was ≤ 1 mm in 87.67% (526 of 600) of VIN cases, although 61 (of 301, 20.37%) cases of VIN 2/3 and 13 (of 291, 4.47%) cases of VIN1 showed thickness greater than 1 mm. The number of VIN 2/3 lesion sites with depths > 1 mm in hairy sites (including the labia majora and perianal areas) is expected to be high (at 49 of 97 cases). Meanwhile, 53.85% (7 of 13) VIN 1 cases occurred in hairy sites (including the labia majora and perianal areas). Therefore, a treatment depth of 1 mm may be sufficient for most cases of VIN. However, patients with hairy lesions should be monitored. According to our results, more than half of the patients had lesion depths of 1–3 mm when in circumstances of lesions in hairy sites.

In our results, lesions in hairy sites were thicker compared with non-hairy areas. Histologically, non-hairy sites include the clitoris, labia minora, and posterior fourchette, which have a corresponding absence of hair follicles and sweat glands. Hair-bearing skin of the inter-labial grooves, labia majora, lateral perineal, and perianal areas consist of skin appendages, including hair follicles, sebaceous glands, and apocrine and exocrine sweat glands. The upper parts of the hair root sheath and lining of the sebaceous gland duct are susceptible to extension of epithelium lesions owing to their being contiguous with the surface epithelium and composed of similar cells. The ducts of the exocrine and apocrine glands are lined by their own independent epithelium, which is not contiguous with the surface epithelium. Involvement of hair root sheaths to depths of 0.8–2.5 mm has been documented^[20]. Involvement of the sebaceous duct occurs less often, secondary to that of the sheath.

Baggish and Dorsey suggested a uniform depth of 3 mm for vaporization for all areas of the vulva^[21]. Buckley et al. conducted a study of 28 patients with skin appendages involved and described that CO₂ laser eradication of the skin to a depth of 5 mm can eliminate all atypical epithelium in skin appendages. However, it is unclear whether the tissues between 5 and 10 mm should also be destroyed to ensure that no appendages remain, as the appendages may penetrate deeper than 5 mm^[22]. Based on our results, the depth of lesions extended to appendages was much deeper than that of involved epithelium in the same section. We found that superficial lesions in non-hairy areas were vaporized to ≤ 1 mm, but lesions extending onto hairy areas were vaporized to 3 mm to destroy involved skin appendages. Our results were similar to previous findings that was from a study with only 29 patients and only 5 cases with involved skin appendages^[23]. However, in our study, only one case with involved appendages was detected with a lesion depth over 5 mm. Therefore, we could not offer evidence for treatment with a depth of༞5mm for VIN patients.

The goals for VIN treatment should be to completely destroy the lesion, improve symptoms, exclude invasion, preserve normal vulvar anatomy and function, and avoid recurrences^[24]. VIN has a recurrence rate of 20–36.7% despite treatment^{[25, 26]}, with 2–15% progressing to vulvar cancer^{[27, 28]}. The risk factors for the recurrence and progression of VIN remain poorly understood. To eliminate VIN and avoid recurrences, health care professionals must understand the structure of the skin and recognize the involvement of appendages.

To sum up, epithelial VIN 2/3 lesions were thicker than epithelial VIN 1 lesions, especially in hairy areas. The depth of the involvement appendages was higher than the thickness of the epithelium lesion in the same section. The lesion depth of hairy areas is 1–3 mm with or without appendage involvement, deeper than the lesion depth of non-hairy areas at about 1 mm. Hence, the removal of involved epithelium and appendages would be suitable for treatment.

Conflicts of interest/Competing interests: The authors declare no competing interests.

Author contribution

Conceptualization: Long Sui,, Chao Wang, and Qing Cong

Methodology: Jingjing Xiao, Ziren Chen, Yinping Xiao

Formal analysis and investigation: Jingjing Xiao, Ziren Chen, Yinping Xiao

Writing - original draft preparation: Jingjing Xiao

Writing - review and editing: Jingjing Xiao

Funding acquisition: Qing Cong

Resources: Long Sui,, Chao Wang, and Qing Cong

Supervision: Long Sui,, Chao Wang, and Qing Cong

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Table 1. Clinical Characteristics of the 1474 Women with Vulvar Intraepithelial Neoplasia
	Total	VIN2/3		VIN1		P
	n=1474	n=335		n=1139		P
Age(y)	42.72±14.31	44.69±14.75		41.28±13.82		0.007
Cytology						0.499
≤LSIL	1279	287	85.67%	992	87.09%
≥HSIL	195	48	14.33%	147	12.91%
HPV infection						0.008
Yes	1357	320	95.52%	1037	91.04%
NO	117	15	4.48%	102	8.96%
Number of lesion site						<0.001
1	1325	301	89.85%	1024	89.90%
≥2	149	34	10.15%	115	10.10%
Lesion site						<0.001
non-hairy
Posterior forchette	1036	182	46.79%	854	66.25%
labia minora	182	58	14.91%	124	9.62%
Navicular fossa	52	14	3.60%	38	2.95%
Urethral opening	29	13	3.34%	16	1.24%
clitoris	7	4	1.03%	3	0.23%
hairy
labia majora	240	80	20.57%	160	12.41%
interlabial grooves	68	9	2.31%	59	4.58%
perianal areas	64	29	7.46%	35	2.72%
Accompanied with cervical/vaginal SIL						0.002
Yes	481	160	56.14%	321	33.68%
NO	757	125	43.86%	632	66.32%
History with CIN/VaIN						0.538
Yes	236	50	14.93%	186	16.33%
NO	1238	285	85.07%	953	83.67%
HSIL, high-grade squamous intraepithelial lesion; LSIL: low-grade squamous intraepithelial lesion; ≤LSIL: atypical squamous cells of undetermined significance, no intraepithelial or malignant lesions, or low-grade squamous intraepithelial lesion; SIL: squamous intraepithelial lesion.

Table 2. Involved and Noninvolved Vulvar Epithelial Thickness in Patients of Different Sites
Site		VIN2/3						VIN1
Site	total	No. patients	Involved	(range)	Noninvolved	(range)	P	No. patients	Involved	(range)	Noninvolved	(range)	P
Non-hariy	413	202	0.59±0.36	0.15-2.37	0.30±0.20	0.08-1.20	<0.001	211	0.46±0.31	0.15-1.40	0.31±0.10	0.18-0.64	<0.001
Posterior forchette	272	153	0.62±0.39	0.15-2.37	0.30±0.21	0.08-1.2	<0.001	119	0.50±0.24	0.29-1.40	0.33±0.11	0.22-0.64	<0.001
labia minora	89	26	0.47±0.22	0.25-1.19	0.30±0.20	0.10-0.70	0.006	63	0.42±0.16	0.15-0.80	0.26±0.05	0.18-0.37	<0.001
clitoris	14	5	0.59±0.05	0.51-0.65	0.31±0.09	0.23-0.47	<0.001	9	0.43±0.14	0.28-0.65	0.36±0.10	0.26-0.51	0.224
Navicular fossa	19	10	0.54±0.31	0.36-1.40	0.27±0.07	0.11-0.47	0.023	9	0.30±0.10	0.15-0.43	0.23±0.03	0.19-0.28	0.059
Urethral opening	19	8	0.52±0.13	0.31-0.7	0.27±0.13	0.11-0.50	0.002	11	0.48±0.19	0.28-0.82	0.36±0.10	0.26-0.51	0.072
Hariy	187	107	0.92±0.51	0.1-2.75	0.33±0.18	0.12-1.18	<0.001	80	0.58±0.27	0.24-1.60	0.36±0.11	0.21-0.78	<0.001
interlabial grooves	35	10	0.66±0.25	0.40-1.10	0.30±0.11	0.15-0.47	0.001	25	0.52±0.21	0.30-1.00	0.31±0.07	0.21-0.45	<0.001
labia majora	113	70	0.95±0.52	0.25-2.75	0.30±0.19	0.12-1.18	<0.001	43	0.63±0.29	0.32-1.6	0.37±0.11	0.27-0.64	<0.001
perianal areas	39	27	0.93±0.52	0.10-1.82	0.40±0.16	0.18-0.91	<0.001	12	0.57±0.27	0.24-1.15	0.41±0.14	0.28-0.78	0.048
Total	600	309	0.69±0.44	0.10-2.75	0.31±0.19	0.08-1.2	<0.001	291	0.49±0.23	0.15-1.60	0.32±0.10	0.18-0.78	<0.001
VIN: Vulvar Intraepithelial Neoplasia

Table 3. Depth of Epithelial and Skin Appendages in Vulvar Intraepithelial Neoplasia and Noninvolved tissue
	VIN			Non-involved			P
Diagnosis	No. patients	Mean±SD(mm)	Range(mm)	No. patients	Mean±SD(mm)	Range(mm)	P
Stratum Corneum	57	0.10±0.06	0.04-0.25	47	0.08±0.08	0.01-0.52	0.331
Epidermis	57	1.01±0.52	0.25-2.75	57	0.28±0.16	0.12-1.08	<0.001
Appendage	57	1.98±0.61	0.91-5.44	186	1.66±0.85	0.26-4.38	/
Hair Follicles	45	2.05±0.66	0.91-5.44	56	1.86±0.99	0.31-4.38	0.271
Sebaceous Gland	12	1.71±0.29	0.98-2.1	63	1.77±0.60	0.79-3.33	0.715
Sweat Gland	/	/	/	67	1.40±0.87	0.26-4.12	/

Supplementary.docx

Clinical and Pathological Features in Women with Vulvar Squamous Intraepithelial Neoplasia: A Single Center Experience from China

Status:

Version 1

Abstract

Figures

Introduction

Materials And Methods

Patients

Cytology and Human Papillomavirus Testing

Pathology

Statistical Analysis

Results

Discussion

Declarations

References

Tables

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