CME/CE

APRIL 2008

Classification of Vulvar Intraepithelial Neoplasia

Natalie A. Saunders, MD; Angela S. Kueck, MD; Hope K. Haefner, MD

The revised classification of vulvar intraepithelial neoplasia represents not only reorganization, but rather a whole new understanding of the disease as an entity distinct from cervical intraepithelial neoplasia with its own etiologic and prognostic patterns.

Continuing Medical Education

GOAL To explore the classification of vulvar intraepithelial neoplasia (VIN) in women relative to its etiologic and prognostic implications. OBJECTIVES To discuss flaws in the first system developed to classify VIN as type 1, 2, or 3. To demonstrate how the new classification of VIN into usual and differentiated types clarifies both diagnostic and prognostic issues. To look at the meaning of the revised classification system in terms of treatment and relationship to vulvar squamous cell carcinoma. ACCREDITATION This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Albert Einstein College of Medicine and Quadrant HealthCom Inc. Albert Einstein College of Medicine is accredited by the ACCME to provide continuing medical education for physicians. This activity has been peer reviewed and approved by Brian Cohen, MD, professor of clinical ObGyn, Albert Einstein College of Medicine. Review date: March 2008. It is designed for -ObGyns, primary care physicians, and nurse practitioners. Albert Einstein College of Medicine designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity. Participants who answer 70% or more of the questions correctly will obtain credit. To earn credit, see the instructions on page 67 and mail your answers according to the instructions on page 68. CONFLICT OF INTEREST STATEMENT The “Conflict of Interest Disclosure Policy” of Albert Einstein College of Medicine requires that authors participating in any CME activity disclose to the audience any relationship(s) with a pharmaceutical or equipment company. Any author whose disclosed relationships prove to create a conflict of interest, with regard to their contribution to the activity, will not be permitted to present. The Albert Einstein College of Medicine also requires that faculty participating in any CME activity disclose to the audience when discussing any unlabeled or investigational use of any commercial product, or device, not yet approved for use in the United States. The authors discuss off-label use of imiquimod for treatment of vulvar intraepithelial neoplasia. Drs Saunders, Kueck, and Haefner report no conflict of interest. Dr Cohen reports no conflict of interest. The staff of CCME of Albert Einstein College of Medicine have no conflicts of interest with commercial interest related directly or indirectly to this educational activity.

The incidence of vulvar intra-epithelial neoplasia (VIN) in the United States is increasing.1 The incidence of VIN alone rose by 411% between 1973 and 2000, from 0.56 cases/100000 women to 2.86 per 100000 women (P<.001).2 Histologically, VIN displays varying degrees of cytoplasmic and nuclear maturation, abnormal nuclei, disruption of normal architecture, and mitotic figures. The classification system for VIN previously paralleled that used for cervical intraepithelial neoplasia.3 Human papillomavirus (HPV) infection is found in association with high-grade VIN in approximately 90% of cases.4 Such infection is especially high in younger women with VIN. Conversely, there is a category of VIN that has not been associated with HPV infection, which tends to occur in older women.

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TERMINOLOGY

The terminology used to classify VIN has undergone considerable change over the years. In 1986, the International Society for the Study of Vulvar Disease (ISSVD) adopted a classification system consisting of 3 categories:5 VIN 1 (mild dysplasia), VIN 2 (moderate dysplasia), and VIN 3 (severe dysplasia). However, as this classification system caused many problems, it was revised in 2004 (Table).

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TABLE. Comparison of Classification Systems for Vulvar Intraepithelial Neoplasia5

The former VIN classification system did not reflect biologic observation. That is, VIN 1 has not been noted to be a precursor for invasive cancer. Rather, the findings in VIN 1 are generally reactive or HPV-related. Also, the diagnosis of VIN 1 is not reproducible among observers. Therefore, the term VIN 1 is no longer used.

In the current classification system, there are 2 types of VIN. The first is known as VIN, usual type (warty, basaloid, and mixed).5 This category includes both VIN 2 and 3, tends to occur in younger women, and is HPV-related. The second is known as VIN, differentiated type. This is seen in the setting of lichen sclerosus or squamous cell hyperplasia (lichen simplex chronicus), and is more common in older women. This is generally not associated with HPV infection. With this high-grade VIN, there is good agreement among observers on the diagnosis.

Recognizing that the natural history of VIN 1, 2, and 3 does not progress as a continuum like cervical intraepithelial neoplasia (CIN), the new system thus eliminated VIN 1 and combined VIN 2 and 3. Furthermore, VIN 1 has not been shown to be a reproducible or reliable diagnosis, and there is likewise no reliable diagnostic distinction between VIN 2 and 3.

Usual Type

The usual type of VIN is HPV-related, and has a demonstrated potential to progress to invasive squamous cell carcinoma (SCC) (Figures 1, 2, 3).6 These VINS can be warty, basaloid, or mixed. The likelihood of such progression depends on certain risk factors, including age; smoking; history of cervical, vaginal, or perianal cancer; HPV; and immunosuppression. This type of VIN presents in younger women, and is the precursor lesion to HPV-associated invasive carcinoma, which is increasing in frequency. Because there is a clear relationship between VIN, usual type, and invasive cancer, adequate treatment and follow-up are imperative.

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FIGURE 1. Vulvar intraepithelial neoplasia, usual type, with brown discoloration in a linear form and some white changes. Image courtesy of Natalie A. Saunders, MD.

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FIGURE 2. Vulvar intraepithelial neoplasia, usual type, with red discoloration involving a large portion of the labium majus and labium minus. Image courtesy of Natalie A. Saunders, MD.

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FIGURE 3. Vulvar intraepithelial neoplasia, usual type, with white-gray color changes and irregular borders. Image courtesy of Natalie A. Saunders, MD.

Differentiated Type

The other, less common type of VIN is the differentiated type, also previously described as VIN, simplex type. The differentiated type of VIN only accounts for 6% to 10% of cases, and underdiagnosis appears to be a widespread problem.7 The terminology for differentiated VIN remains unaffected by the revisions of 2004.3 Clinically, it is frequently associated with SCC, lichen sclerosus, and/or squamous hyperplasia. The lesion is more likely to be unifocal, presenting as an ulcer, warty papule, or hyperkeratotic plaque.5 Differentiated VIN is regarded as a high-grade lesion that always warrants further evaluation and treatment. The largest systematic review looking at the natural history of this type of VIN noted that it will progress to invasive vulvar carcinoma in 9% of untreated patients and 3.3% of treated patients.8 Differentiated VIN often occurs adjacent to invasive squamous cell carcinoma (SCC) of the vulva, and is therefore regarded as the most common precursor to vulvar SCC, with a high risk of progression to an invasive lesion.7

Unlike VIN, usual type, differentiated VIN is generally found in older women. As it is not HPV-related, its successor lesion (SCC) is similarly not HPV-linked. Histologically, differentiated VIN is more subtle than the usual type of VIN, as the squamous cells are well differentiated and often do not extend through the entire thickness of the epidermis. In addition, it is possible that differentiated VIN has a brief intraepithelial phase before it progresses to invasive carcinoma, or it may be mistaken for squamous cell hyperplasia.5 As a result, differentiated VIN is most often discovered during surveillance examinations of women with a history of SCC or lichen sclerosus, and biopsy is more likely to occur at an earlier stage of progression.

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TREATMENT

Surgical treatment remains the mainstay for managing VIN. Therapies include local excision(s), local destruction (laser ablation), and partial/total superficial vulvectomy with or without split-thickness skin grafting. It is also important to consider the location of the lesion, as 75% to 85% of VIN will be found in non-hair-bearing areas. The chosen method of treatment should penetrate to a depth of 1 to 2 mm in non-hair-bearing areas. In hair-bearing areas of the vulva, however, the surgeon may need to extend the depth 3 mm or greater secondary to the amount of disease encompassing the hair follicle.9 Thus, in hair-bearing areas, excision is strongly indicated. Adequate disease-free margins of at least 1 cm should be excised around the lesion as well.

Long-term follow-up is mandatory, as recurrences may develop years later—more often in higher-risk, immunosuppressed patients. Most data suggest that recurrences of VIN, usual type, do not depend on the type of surgery used; the exception to this is cryosurgery, which has a high failure rate.8 There have been reports of using topical therapy with imiquimod for treatment of VIN, usual type, with good initial results, but long-term follow-up data are not available yet.10 The regimen seems to be well tolerated. In one series, complete response was noted in 9/17 patients, with partial response in 5/17 patients.11

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SQUAMOUS CELL CARCINOMA

Vulvar carcinoma accounts for 3% to 5% of all gynecologic malignancies (Figures 4, 5). It is most frequently seen in older white women. There tends to be a bimodal age distribution representing two distinct etiologies of invasive carcinoma; one type is related to HPV and occurs in younger women, while the other pathway is HPV-independent and tends to affect older women. Risk factors include increasing age, smoking, HPV infections, immunosuppression, and other genital cancers. Along with the new VIN terminology, a better understanding of these distinct pathways to invasive carcinoma and their precursors is emerging, leading to increased awareness and earlier diagnosis.

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FIGURE 4. Squamous cell carcinoma, adjacent to the clitoris in a patient with lichen sclerosus. Image courtesy of Natalie A. Saunders, MD.

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FIGURE 5. Squamous cell carcinoma of the vulva. Image courtesy of Natalie A. Saunders, MD.

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CONCLUSION

The term VIN encompasses the entire spectrum of precancerous histologic changes—ie, loss of squamous epithelial maturation associated with enlarged, hyperchromatic nuclei and increased atypical mitoses. One of the main objectives of the ISSVD is the development of nomenclature and classification of vulvar disease, which began in 1986. As more data emerged regarding the biology and natural history of VIN, the ISSVD updated their classification system in 2004 to encompass 2 types of VIN: the usual type and the differentiated type. Ideally, this new terminology will better reflect the natural history of VIN and clarify its role in the development of invasive vulvar carcinoma. Additionally, this more concise classification system should allow for better reproducibility among pathologists and better communication between clinicians.

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Natalie A. Saunders, MD, is Lecturer; Angela S. Kueck, MD, is Assistant Professor; and Hope K. Haefner, MD, is Professor; all in the Department of Obstetrics and Gynecology, The University of Michigan Hospitals, Ann Arbor, MI.

References

1. Abeloff MD. Clinical Oncology, 3^rd ed. Philadelphia, PA: Elsevier Churchill Livingstone; 2004, 2242-2255.
2. Judson PL, Habermann EB, Baxter NN, Durham SB, Virnig BA. Trends in the incidence of invasive and in situ vulvar carcinoma. Obstet Gynecol. 2006;107(5):1018-1022.
3. Wilkinson EJ, Kneale B, Lynch P. Report of the ISSVD Terminology Committee. J Reprod Med. 1986;31:973-974.
4. Buscema J, Naghashfar Z, Sawada E, Daniel R, Woodruff JD, Shah K. The predominance of human papillomavirus type 16 in vulvar neoplasia. Obstet Gynecol. 1988;71(4):601-606.
5. Sideri M, Jones R, Wilkinson E, et al. Squamous vulvar intraepithelial neoplasia: 2004 modified terminology, ISSVD Vulvar Oncology Subcommittee. J Reprod Med. 2005;50(11):807-810.
6. Heller DS. Report of a new ISSVD classification of VIN. J Lower Gen Tract Dis. 2007;11(1):46-47.
7. Hart WR. Vulvar intraepithelial neoplasia: historical aspects and current status. Int J Gynecol Pathol. 2001;20(1):16-30.
8. van Seters M, van Beurden M, de Craen AJ. Is the assumed natural history of vulvar intraepithelial neoplasia III based on enough evidence? A systematic review of 3322 published patients. Gynecol Oncol. 2005;97(2):645-651.
9. Wright VC, Chapman W. Intraepithelial neoplasia of the lower female genital tract: etiology, investigation, and management. Semin Surg Oncol. 1992;8(4):180-190.
10. Jayne CJ, Kaufman RH. Treatment of vulvar intraepithelial neoplasia 2/3 with imiquimod. J Reprod Med. 2002;47(5):395-398.
11. Le T, Hicks W, Menard C, Hopkins L, Fung MF. Preliminary results of 5% imiquimod cream in the primary treatment of vulvar intraepithelial neoplasia grade 2/3. Am J Obstet Gynecol. 2006; 194(2):377-380.

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