VIN Definitions & Epidemiology

Vulvar cancer makes up 3% to 5% of all female genital cancers and has been identified as 1 of 12 cancers rising in incidence between 1992 and 1998. In this time period, combined carcinoma-in-situ (also called VIN3 or VIN usual) and invasive vulvar carcinoma were found to increase 2.4% per year, with the increase most pronounced in younger women (Howe, 2000). This report did not, however, differentiate between VIN3 and invasive cancer. In a more recent analysis of the SEER database, a national population-based cancer registry, the two were considered separately. While the rates of vulvar carcinoma-in-situ increased 411% between 1973 and 2000, rates of invasive vulvar cancer rose only 20% (Judson, 2006). Although the progression of VIN3 to vulvar cancer is often likened to that of CIN3 to cervical carcinoma, the development of these cancers may be more dissimilar than previously thought. For example, oncogenic HPV, while found in close to 100% of squamous cell cancers of the cervix, has been detected in only approximately 40% of vulvar carcinomas.

In a published systematic review on the natural history of VIN3 in over 3,000 patients, van Seters (2005) reported that 6.5% were found to have invasive squamous cell carcinoma on evaluation, with 3.3% developing carcinoma over the course of follow up. Although the potential for progression to vulvar carcinoma is clear, the behavior of VIN3 did not mimic that of CIN3 (where progression rates for untreated disease have been reported to approach 70%, and peak cancer rates occur roughly 20 years following the peak seen for CIN3). If HPV-related VIN3 progressed reliably to vulvar cancer, two outcomes would be expected if this disease behaved similarly to cervical cancer. First, a peak in the incidence of vulvar cancer would be expected approximately 5 to 20 years after the peak seen in VIN3 and second, a leveling of the incidence of invasive vulvar cancer would be seen with age. Neither, in fact, occurred. In-situ disease peaked in the fifth decade of life and declined thereafter, while the incidence of vulvar cancer began to increase rapidly after age 60, never stabilizing (Judson, 2006).

Clinically, then, two distinct types of vulvar carcinoma begin to emerge. As opposed to the typical keratinizing vulvar squamous carcinomas seen in older women (in which oncogenic HPV infection ranges from 2-23%), HPV-related basaloid and warty carcinomas (75-100% of which harbor HPV) tend to arise in younger women. As a result, the risk factors typically associated with HPV-related disease (e.g., number of sexual partners, early age at first coitus, history of abnormal Pap smears), while applicable to women with HPV-associated vulvar cancers, do not hold for those with keratinizing carcinomas.

As with vulvar carcinoma, two distinct clinicopathologic subtypes of VIN exist: usual VIN and differentiated VIN. Differentiated VIN, typically HPV negative, is seen most frequently in older women with other epithelial disorders such as lichen sclerosus or lichen simplex chronicus. As compared to VIN usual, differentiated VIN is associated with a higher risk of progression to invasive squamous cell carcinoma of the vulva.

OLD TERMINOLOGY
VULVAR INTRAEPITHELIAL NEOPLASIA (VIN)

     1.  Squamous type (with or w/o HPV change)

a.  VIN I
b.  VIN II
c.  VIN III (Squamous cell CIS, Bowen's disease, Erythroplasia of Queyrat, CIS simplex)

a.  Paget’s Disease
b.  Melanoma in Situ

NEW TERMINOLOGY
SQUAMOUS VIN TERMINOLOGY (ISSVD 2004)

VIN, usual type

VIN, warty type
VIN, basaloid type
VIN, mixed (warty/basaloid) type

VIN, differentiated type

Note: The occasional example of VIN that cannot be classified into either of the above VIN categories (usual type and differentiated type) may be classified as VIN, unclassified type (or VIN, NOS). The rare VIN of pagetoid type may be classified as such, or placed in this category.

VIN usual commonly presents in young women, often in their 30s and 40s. It tends to be multifocal and is strongly associated with cigarette smoking. The similarities of the warty and basaloid subtypes are numerous and include association with high-risk HPV types, particularly HPV 16, multicentric involvement of the lower genital tract, absence or near absence of p53 expression (involved in tumor suppression) and premalignancy (although regression is less likely and progression to invasion more likely with the basaloid type). While warty-basaloid VIN has been divided into basaloid and warty subtypes, a distinction which may be clinically relevant, the reproducibility of this subclassification has not yet been proven (Scurry, 2006).

Warty-basaloid VIN has historically been graded using the same criteria as for cervical intraepithelial neoplasia or CIN, with cellular maturation decreasing and the presence of mitotic figures increasing from the lower third of the epithelium to all epithelial layers as grade increases. Unlike CIN1, however, the diagnosis of VIN1 is rarely made, non-reproducible, and of unclear biological potential. The changes seen in VIN1 cannot reliably be distinguished from HPV changes and can mimic the reactive changes seen with inflammation or differentiated VIN. VIN2 is similarly uncommon, and VIN2 and 3 are not reproducibly distinguished and clinically behave similarly. Accumulating evidence, then, suggests a one-grade system for warty-basaloid VIN (with VIN1 as a term being removed altogether and VIN2 and 3 consolidated into one category termed VIN) may be most appropriate, although consensus on the use of such terminology has not been uniformly endorsed (Scurry, 2006).