The earliest description of intraepithelial neoplasia of the vulva was published in France in 1922 [1]. As these lesions were increasingly recognized, they came to be known as “Bowen disease” due to their similarity to lesions described in the nonvulvar skin first described by Bowen in 1912 [2]. Similar terms such as “Bowen dermatosis” [3] were also used in reference to vulvar intraepithelial disease in the earliest pathologic literature. By the 1950s, terms such as “intraepithelial carcinoma” [4]) and “carcinoma in situ” [5], thought to better represent the biology of the lesions, were added to the repertoire. The first recognition that there seemed to be more than one type of intraepithelial neoplasia of the vulva came in 1961, with the publication of two seminal papers by Abell and Gosling [6, 7] in which they described both a more common “Bowen’s type” and a less common “simplex” type of intraepithelial carcinoma. By the 1970s, all of these terms, in addition to a variety of other clinically derived terms such as “erythroplasia of Queyrat,” “leukoplakia,” “leukoplakic vulvitis,” and “bowenoid papulosis,” were all being used to describe intraepithelial lesions of the vulva. It was, at the same time, becoming increasingly clear that not all of these lesions exhibited the same biologic behavior.

By this time, it was also becoming evident that intraepithelial lesions of the vulva, as of the cervix, consisted of both full-thickness lesions with severe nuclear atypia and high proliferation and of lesser degrees of intraepithelial changes. In 1976, the ISSVD published the first of several reports on the nomenclature of vulvar diseases [8], with the intent to establish a more uniform and clinically relevant terminology. The report introduced the term “squamous carcinoma in situ” to refer to the most severe lesions with severe, full-thickness cellular abnormalities and classified less severe abnormalities under the heading of “hyperplastic dystrophy with atypia,” which were subdivided into mild, moderate, and severe categories.

Around the same time the ISSVD made this first attempt to standardize the diagnostic terminology of vulvar lesions, major advances were beginning in the understanding of cervical disease which would come to impact the understanding of vulvar disease. In the cervix, squamous lesions had long been categorized as either dysplasias, which were not considered malignant, or carcinoma in situ, which was malignant by definition. But during the 1960s, it became increasingly evident that carcinoma in situ was not, in fact, a distinct histopathologic and biologic entity. In 1973, Richart introduced a new terminology for cervical intraepithelial disease which eliminated the term. The precursors of cervical carcinoma, he argued, were better understood as a single disease process evolving through a spectrum of morphologic changes that he termed cervical intraepithelial neoplasia (CIN) [9]. In 1982, Crum and Richart introduced the term “vulvar intraepithelial neoplasia” (VIN) for description of vulvar squamous lesions, reflecting the growing understanding that these lesions were pathogenetically similar to those of the cervix [10, 11]. The term was accepted by the ISSVD in 1986 [12] when it recommended that that term be used for all squamous intraepithelial lesions of the vulva, with lesions subcategorized into three tiers of severity, designated VIN I, VIN II, and VIN III. To incorporate those relatively uncommon vulvar intraepithelial lesions previously referred to predominantly as the “simplex” type, a subcategory termed VIN III, differentiated type, was included. This differentiated VIN lesion did not have a counterpart in the cervix.

For the next 18 years, aside from a revision in 1989 recommending the replacement of the roman numerals with Arabic ones [13], the ISSVD nomenclature remained stable; however, competing systems of nomenclature were introduced. In 1994, the World Health Organization (WHO), in the second edition of “Histologic Typing of Female Genital Tract Tumors” [14], addressing the issue of inconsistent terminology for vulvar lesions, accepted VIN 1–3 as an acceptable alternative for three of the four tiers in its preferred terminology of dysplasia/carcinoma in situ for intraepithelial neoplasia of the vulva. In this system, lesions were categorized as mild dysplasia (VIN 1), moderate dysplasia (VIN 2), severe dysplasia (VIN 3), and carcinoma in situ, the latter of which included a subset of “carcinoma in situ, simplex type.” This publication also introduced the overarching term “squamous intraepithelial lesion” into the mix as a general term to cover all of the described subcategories with the exception of “carcinoma in situ, simplex type.”

Up to this point, the evolution of nomenclature for intraepithelial neoplasia closely mirrored that of the uterine cervix. The majority of intraepithelial lesions of the vulva showed a morphology similar to those of the cervix, and especially as it became clear that lesions in both sites were strongly associated with oncogenic human papillomavirus (HPV), the carcinogenicity of which was becoming increasingly well understood, it was tempting to try to fit vulvar lesions into that new paradigm.

While there were certainly many important similarities between intraepithelial neoplasias of the vulva and cervix, significant differences prevented consideration of the two as completely analogous. To begin with, there was the mysterious entity of the “differentiated” or “simplex” lesions, which did not have a morphologic counterpart in the cervix and showed little association with HPV, suggesting an alternative etiology must exist for them. There was also the unexplained difference in the low-grade lesions of these different sites, with low-risk HPV-type-related exophytic condylomata appearing commonly on the vulva but rarely in the cervix, while flat low-grade squamous intraepithelial neoplasias were common on the cervix but rare on the vulva. By far the most significant and troubling issue, however, was that as research into the association of HPV with cervical and vulvar disease progressed, the association in vulvar lesions proved considerably weaker than that in the cervix. While almost all CIN 2 and 3 lesions, as well as associated cervical squamous carcinomas and even a significant portion of CIN 1, consistently demonstrated the presence of high-risk HPV viral subtypes [15–17], the findings in vulvar lesions were less consistent. Studies reported a wide range, from 53 % to 92 % [18–21], of VIN 2 and 3 lesions to contain high-risk HPV viral DNA, but the average HPV positivity rate was considerably lower than in the cervix. What was even more troublesome was that significantly fewer vulvar squamous cell carcinomas than VIN cases were HPV positive, with studies finding anywhere from 0 to 48 % [18, 21–26] and averaging on the lower side of this range.

The perplexing failure of oncogenic HPV to explain vulvar intraepithelial squamous lesions as well as it did for cervical intraepithelial lesions led some investigators to look more closely at vulvar cancers and their associated precursors. In so doing, it became evident that there was, in fact, a significant difference in morphology between HPV-positive and HPV-negative tumors, as there was for their associated intraepithelial lesions. HPV-negative tumors tended to be well-differentiated, keratinizing squamous cell carcinomas [19, 22, 23] and to be associated with adjacent non-neoplastic vulvar dermatoses like squamous hyperplasia or lichen sclerosus [27, 28], or the differentiated type of VIN as an associated intraepithelial component [28]. HPV-positive tumors tended to show a warty or basaloid pattern and to have associated VIN 3 with similar morphology in a large percentage of cases [18, 19, 22, 23, 25, 29]. Epidemiologic data also showed significant differences between women with HPV-positive tumors and those with HPV-negative ones, with the former presenting about 20 years earlier [22, 23, 29] and more often also affected by other HPV-related disease of the cervix, vagina, or vulva [20, 27, 30–32]. The evidence was building that squamous carcinoma of the vulva was less homogeneous than that of the cervix. Taken together, the morphologic, virologic, and epidemiologic data suggested that, unlike in the uterine cervix, there was not just one pathway to squamous carcinoma of the vulva, but two, with two distinct intraepithelial precursor lesions, only one of which was related to HPV [23, 25, 33], as summarized in Table 9.2.

By this time, advances in the understanding of HPV pathogenesis in the cervix had led to further change in how cervical squamous intraepithelial lesions were viewed. The biologic evidence supported the existence of only two, rather than three, types of lesions. Thus began a shift, first in the reporting of cervical cytology specimens and subsequently in reporting tissue biopsies, to the classification of lesions into either “low-grade” (CIN 1) or “high-grade” (CIN 2–3) categories. This shift was justified not only on the grounds that it better reflected the biologic evidence, but also that it allowed for more reproducible diagnosis [34, 35] and was more practical, given that most clinicians already treated CIN 2 and CIN 3 lesions the same way.

The evolving understanding of how HPV influenced the development of cervical cancer , and that there were both HPV-dependent and non-HPV-dependent pathways to vulvar carcinoma , led to yet another revision in terminology for vulvar disease. In 2003, the WHO revised its terminology to favor the use of VIN over the synonyms of dysplasia and carcinoma in situ, defining both warty and basaloid types associated with HPV, which were further classified into VIN 1, 2, and 3, and maintaining the previous terminology of “carcinoma in situ, simplex type” for lesions with a differentiated morphology [36]. In 2004, the ISSVD undertook more drastic revisions, abandoning the category of VIN 1 altogether and combining VIN 2 and 3 into one category of simply “VIN” [37, 38]. In this system, VIN is subclassified into two categories, the usual type, abbreviated “uVIN,” and the differentiated type, abbreviated “dVIN,” and uVIN is further subclassifiable as warty, basaloid, or warty/basaloid if desired. The decision to abolish the category of VIN 1 has been controversial, but the justifications given were that the diagnosis is rare without an accompanying higher-grade lesion [39], that it is poorly reproducible [34, 40], and that, unlike in the cervix, evidence is lacking that it may progress to a higher-grade lesion [37, 41]. The same arguments which had been used to support the combination of CIN 2 and 3 into one category of “high-grade” lesions were found to be applicable to VIN 2 and VIN 3 [34, 39], at least the HPV-related types, and ultimately to all HPV-related lesions of the lower anogenital tract. It is for this reason that a recent proposal has been made to standardize the nomenclature for all HPV-related lesions of the lower anogenital tract ; the Lower Anogenital Squamous Terminology Standardization Project (LAST) proposes that a two-tier system of LSIL and HSIL be used to refer to all HPV-related squamous intraepithelial lesions of the vulva, vagina, cervix, anus, perianal area, and penis [42], rather than the organ-specific intraepithelial neoplasia nomenclatures, with the option to maintain that specific nomenclature in parentheses; thus, lesions formerly categorized as VIN 2 or 3 or uVIN in ISSVD terminology would be designated HSIL (VIN 2–3). This system pertains only to HPV-related lesions, so it makes no recommendation as to terminology for differentiated lesions of the vulva. Most recently, the WHO has adopted identical terminology, retaining the term “differentiated-type VIN” for those lesions not related to HPV [43].

As is evident from the terminology used and from their earliest descriptions, intraepithelial lesions have always been recognized as preinvasive lesions. This understanding was based initially on morphologic grounds, and later supported by the observation that these lesions were observed adjacent to invasive disease in 7–25 % of cases examined [4, 7, 44], and further supported by the observation that when followed over time a significant proportion of patients with these lesions developed squamous carcinoma [6, 44]. These observations continued to be made over the ensuing decades, and the strength of the association of VIN with carcinoma has even increased over time, as more attention has been paid to vulvar disease and interventions have been initiated earlier in the disease process, with later studies reporting the presence of intraepithelial disease adjacent to vulvar carcinoma in 20–100 % of cases [18, 27, 45–54]. This strong association remains compelling evidence that VIN is a precancerous lesion. But association does not prove causation, as the association of squamous hyperplasia, lichen sclerosis, and other non-neoplastic vulvar dermatoses with vulvar carcinoma has been noted to be as strong, if not stronger than that of VIN. It has not been until relatively recently that the underlying biology of VIN has begun to come to light, and there is a tremendous amount still to discover, but these investigations have continued to provide additional support to the long-held understanding of VIN as a precancerous lesion.