Chapter Outline
Benign Squamous Neoplasms 79
Squamous Intraepithelial Lesions of the Vulva (VIN) 81
HPV-related Low- and High-grade Squamous Intraepithelial Lesions (VIN 1–3) 81
High-grade VIN, Differentiated or Simplex Type 86
Squamous Cell Carcinoma 87
Uncommon Subtypes of Squamous Cell Carcinoma 91
Benign Squamous Neoplasms
Condyloma Acuminatum
Definition
Condyloma acuminatum is a benign exophytic lesion caused by infection with low-risk human papillomavirus (HPV) subtypes, principally types 6 and 11.
Clinical Features
Condylomata are asymptomatic, usually multiple and often multifocal, presenting as papillary growths varying in size from barely visible on gross examination to several centimeters.
Microscopic Features
On histologic examination, the lesion consists of complex branching fibrovascular cores covered with acanthotic squamous epithelium, frequently with accompanying hyperkeratosis and parakeratosis. Pathognomonic findings include basal and parabasal hyperplasia, with koilocytic atypia, manifested by enlarged, hyperchromatic nuclei with irregular, wrinkled nuclear membranes accompanied by a region of perinuclear clearing or ‘halo,’ in the upper third of the epithelium ( Figures 4.1 and 4.2 ).
Differential Diagnosis
Immunohistochemical reactivity with Ki-67 in condylomata demonstrates cells active in the cell cycle at all layers of the epithelium, which is helpful to distinguish them from other benign exophytic lesions of the vulva, such as fibroepithelial polyp and seborrheic keratosis. Although warty vulvar intraepithelial neoplasm (VIN) and the warty type of squamous cell carcinoma may show marked koilocytic atypia in the superficial cells, they are distinguished from condyloma by the presence of nuclear atypia and numerous, frequently atypical, mitotic figures in deeper layers of the epithelium. Verrucous carcinoma is grossly similar to condyloma, but is distinguished by its characteristic growth pattern with a pushing invasive border.
Clinical Behavior and Treatment
Condylomata may regress spontaneously, but usually persist and may increase in size or number over time. They are not considered premalignant, and do not progress to high-grade VIN or carcinoma. Small lesions can be treated with topical agents or laser or electro-loop ablation. Extensive lesions may require superficial surgical excision.
Seborrheic Keratosis
Definition
Seborrheic keratosis is a benign, frequently pigmented wart-like growth common on the sun-exposed skin of the elderly and less commonly seen on the hair-bearing skin of the vulva.
Clinical Features
The typical appearance is of an elevated, often macular–papular, flesh-toned or hyperpigmented lesion, which is well demarcated from the surrounding skin, giving the impression of being ‘stuck-on’ to the surface. Because of the superficial, exophytic nature of the lesions, they are prone to irritation and trauma, which may lead to secondary changes of inflammation, erythema, and crusting.
Microscopic Features
The epidermis is thickened by a population of cells with basaloid morphology, without significant nuclear atypia or mitotic activity, and with pronounced surface hyperkeratosis. Pigmentation of the basal and parabasal cells is usually evident. Invaginations of the surface epithelium result in the accumulation of hyperkeratotic material below the surface of the lesion, in what may appear to be cystic spaces, forming the structures known as ‘horn cysts’ ( Figure 4.3 ). Follicular plugging with this hyperkeratosis is also typical. ‘Squamous eddies,’ rounded whorls of squamous cells named for their resemblance to swirling currents in a stream, may be found ( Figure 4.4 ).
Differential Diagnosis
On occasion, reactive changes secondary to trauma or prominence of squamous eddies can be suggestive of squamous cell carcinoma. Key to establishing the correct diagnosis in such cases is the absence of an infiltrative growth pattern. Other entities in the differential diagnosis of seborrheic keratoses on the vulvar skin include condyloma acuminatum, VIN, and melanoma. The papillary architecture and hyperkeratosis of seborrheic keratosis can be suggestive of condyloma, particularly at low power. As seborrheic keratoses are frequently found to contain HPV DNA, some authors have maintained that these lesions are, in fact, variants of condyloma, although this remains controversial. The absence of koilocytic atypia in seborrheic keratosis and of keratin horn cysts in condylomata will usually resolve the diagnosis. The lack of significant nuclear atypia or mitotic activity is also of use to differentiate seborrheic keratosis from VIN and melanoma, with immunohistochemistry of further use in distinguishing the latter.
Clinical Behavior and Treatment
Treatment is identical to that of vulvar condylomata; both excisional and topical treatments are available and effective.
Keratoacanthoma
Definition
Keratoacanthoma is a distinctive keratinocytic neoplasm characterized by rapid growth and spontaneous regression. Although often considered a low-grade variant of squamous cell carcinoma, this view is not universally accepted, and as there have been no reported cases of malignant behavior in cases presenting on the vulva, we present it here as a benign neoplasm.
Clinical Features
Keratoacanthoma characteristically presents as a rapidly growing pink or flesh-colored, firm, well-demarcated dome-shaped lesion with central umbilication. Although common on the sun-exposed skin of the elderly, very few cases occurring on the vulva have been reported.
Microscopic Features
The dome-shaped, umbilicated lesion observed on the skin corresponds to an endophytic proliferation of squamous cells forming a keratin-filled crater-like center rimmed by collarette, or ‘buttressing lips,’ of epidermis. The central squamous cells are well differentiated and tend to become larger toward the center of the proliferation, accumulating abundant glassy, eosinophilic cytoplasm ( Figures 4.5 and 4.6 ). In the early stages of development, mitoses may be numerous and mild to moderate nuclear atypia may be present, but these features regress as the lesion matures, and when well developed only minimal atypia is present. The lesions typically have a rounded, pushing border with a dense inflammatory infiltrate at the base of the lesion.
Differential Diagnosis/Clinical Behavior and Treatment
Focal, small, irregular nests of cells, and less commonly perineural or intravascular invasion adjacent to the pushing border of keratoacanthoma may occasionally be seen. Such seemingly infiltrative patterns can be alarming, but in the absence of other features do not warrant a malignant diagnosis.
Untreated, keratoacanthoma typically increases rapidly in size over a period of weeks to months and then may persist for months until finally undergoing spontaneous involution, usually within six months of eruption. Excision is usually curative, with rare recurrences reported.
Condyloma Acuminatum
Definition
Condyloma acuminatum is a benign exophytic lesion caused by infection with low-risk human papillomavirus (HPV) subtypes, principally types 6 and 11.
Clinical Features
Condylomata are asymptomatic, usually multiple and often multifocal, presenting as papillary growths varying in size from barely visible on gross examination to several centimeters.
Microscopic Features
On histologic examination, the lesion consists of complex branching fibrovascular cores covered with acanthotic squamous epithelium, frequently with accompanying hyperkeratosis and parakeratosis. Pathognomonic findings include basal and parabasal hyperplasia, with koilocytic atypia, manifested by enlarged, hyperchromatic nuclei with irregular, wrinkled nuclear membranes accompanied by a region of perinuclear clearing or ‘halo,’ in the upper third of the epithelium ( Figures 4.1 and 4.2 ).
Differential Diagnosis
Immunohistochemical reactivity with Ki-67 in condylomata demonstrates cells active in the cell cycle at all layers of the epithelium, which is helpful to distinguish them from other benign exophytic lesions of the vulva, such as fibroepithelial polyp and seborrheic keratosis. Although warty vulvar intraepithelial neoplasm (VIN) and the warty type of squamous cell carcinoma may show marked koilocytic atypia in the superficial cells, they are distinguished from condyloma by the presence of nuclear atypia and numerous, frequently atypical, mitotic figures in deeper layers of the epithelium. Verrucous carcinoma is grossly similar to condyloma, but is distinguished by its characteristic growth pattern with a pushing invasive border.
Clinical Behavior and Treatment
Condylomata may regress spontaneously, but usually persist and may increase in size or number over time. They are not considered premalignant, and do not progress to high-grade VIN or carcinoma. Small lesions can be treated with topical agents or laser or electro-loop ablation. Extensive lesions may require superficial surgical excision.
Microscopic Features
On histologic examination, the lesion consists of complex branching fibrovascular cores covered with acanthotic squamous epithelium, frequently with accompanying hyperkeratosis and parakeratosis. Pathognomonic findings include basal and parabasal hyperplasia, with koilocytic atypia, manifested by enlarged, hyperchromatic nuclei with irregular, wrinkled nuclear membranes accompanied by a region of perinuclear clearing or ‘halo,’ in the upper third of the epithelium ( Figures 4.1 and 4.2 ).
Differential Diagnosis
Immunohistochemical reactivity with Ki-67 in condylomata demonstrates cells active in the cell cycle at all layers of the epithelium, which is helpful to distinguish them from other benign exophytic lesions of the vulva, such as fibroepithelial polyp and seborrheic keratosis. Although warty vulvar intraepithelial neoplasm (VIN) and the warty type of squamous cell carcinoma may show marked koilocytic atypia in the superficial cells, they are distinguished from condyloma by the presence of nuclear atypia and numerous, frequently atypical, mitotic figures in deeper layers of the epithelium. Verrucous carcinoma is grossly similar to condyloma, but is distinguished by its characteristic growth pattern with a pushing invasive border.
Clinical Behavior and Treatment
Condylomata may regress spontaneously, but usually persist and may increase in size or number over time. They are not considered premalignant, and do not progress to high-grade VIN or carcinoma. Small lesions can be treated with topical agents or laser or electro-loop ablation. Extensive lesions may require superficial surgical excision.
Seborrheic Keratosis
Definition
Seborrheic keratosis is a benign, frequently pigmented wart-like growth common on the sun-exposed skin of the elderly and less commonly seen on the hair-bearing skin of the vulva.
Clinical Features
The typical appearance is of an elevated, often macular–papular, flesh-toned or hyperpigmented lesion, which is well demarcated from the surrounding skin, giving the impression of being ‘stuck-on’ to the surface. Because of the superficial, exophytic nature of the lesions, they are prone to irritation and trauma, which may lead to secondary changes of inflammation, erythema, and crusting.
Microscopic Features
The epidermis is thickened by a population of cells with basaloid morphology, without significant nuclear atypia or mitotic activity, and with pronounced surface hyperkeratosis. Pigmentation of the basal and parabasal cells is usually evident. Invaginations of the surface epithelium result in the accumulation of hyperkeratotic material below the surface of the lesion, in what may appear to be cystic spaces, forming the structures known as ‘horn cysts’ ( Figure 4.3 ). Follicular plugging with this hyperkeratosis is also typical. ‘Squamous eddies,’ rounded whorls of squamous cells named for their resemblance to swirling currents in a stream, may be found ( Figure 4.4 ).
Differential Diagnosis
On occasion, reactive changes secondary to trauma or prominence of squamous eddies can be suggestive of squamous cell carcinoma. Key to establishing the correct diagnosis in such cases is the absence of an infiltrative growth pattern. Other entities in the differential diagnosis of seborrheic keratoses on the vulvar skin include condyloma acuminatum, VIN, and melanoma. The papillary architecture and hyperkeratosis of seborrheic keratosis can be suggestive of condyloma, particularly at low power. As seborrheic keratoses are frequently found to contain HPV DNA, some authors have maintained that these lesions are, in fact, variants of condyloma, although this remains controversial. The absence of koilocytic atypia in seborrheic keratosis and of keratin horn cysts in condylomata will usually resolve the diagnosis. The lack of significant nuclear atypia or mitotic activity is also of use to differentiate seborrheic keratosis from VIN and melanoma, with immunohistochemistry of further use in distinguishing the latter.
Clinical Behavior and Treatment
Treatment is identical to that of vulvar condylomata; both excisional and topical treatments are available and effective.
Clinical Features
The typical appearance is of an elevated, often macular–papular, flesh-toned or hyperpigmented lesion, which is well demarcated from the surrounding skin, giving the impression of being ‘stuck-on’ to the surface. Because of the superficial, exophytic nature of the lesions, they are prone to irritation and trauma, which may lead to secondary changes of inflammation, erythema, and crusting.
Microscopic Features
The epidermis is thickened by a population of cells with basaloid morphology, without significant nuclear atypia or mitotic activity, and with pronounced surface hyperkeratosis. Pigmentation of the basal and parabasal cells is usually evident. Invaginations of the surface epithelium result in the accumulation of hyperkeratotic material below the surface of the lesion, in what may appear to be cystic spaces, forming the structures known as ‘horn cysts’ ( Figure 4.3 ). Follicular plugging with this hyperkeratosis is also typical. ‘Squamous eddies,’ rounded whorls of squamous cells named for their resemblance to swirling currents in a stream, may be found ( Figure 4.4 ).
Differential Diagnosis
On occasion, reactive changes secondary to trauma or prominence of squamous eddies can be suggestive of squamous cell carcinoma. Key to establishing the correct diagnosis in such cases is the absence of an infiltrative growth pattern. Other entities in the differential diagnosis of seborrheic keratoses on the vulvar skin include condyloma acuminatum, VIN, and melanoma. The papillary architecture and hyperkeratosis of seborrheic keratosis can be suggestive of condyloma, particularly at low power. As seborrheic keratoses are frequently found to contain HPV DNA, some authors have maintained that these lesions are, in fact, variants of condyloma, although this remains controversial. The absence of koilocytic atypia in seborrheic keratosis and of keratin horn cysts in condylomata will usually resolve the diagnosis. The lack of significant nuclear atypia or mitotic activity is also of use to differentiate seborrheic keratosis from VIN and melanoma, with immunohistochemistry of further use in distinguishing the latter.
Keratoacanthoma
Definition
Keratoacanthoma is a distinctive keratinocytic neoplasm characterized by rapid growth and spontaneous regression. Although often considered a low-grade variant of squamous cell carcinoma, this view is not universally accepted, and as there have been no reported cases of malignant behavior in cases presenting on the vulva, we present it here as a benign neoplasm.
Clinical Features
Keratoacanthoma characteristically presents as a rapidly growing pink or flesh-colored, firm, well-demarcated dome-shaped lesion with central umbilication. Although common on the sun-exposed skin of the elderly, very few cases occurring on the vulva have been reported.
Microscopic Features
The dome-shaped, umbilicated lesion observed on the skin corresponds to an endophytic proliferation of squamous cells forming a keratin-filled crater-like center rimmed by collarette, or ‘buttressing lips,’ of epidermis. The central squamous cells are well differentiated and tend to become larger toward the center of the proliferation, accumulating abundant glassy, eosinophilic cytoplasm ( Figures 4.5 and 4.6 ). In the early stages of development, mitoses may be numerous and mild to moderate nuclear atypia may be present, but these features regress as the lesion matures, and when well developed only minimal atypia is present. The lesions typically have a rounded, pushing border with a dense inflammatory infiltrate at the base of the lesion.
Differential Diagnosis/Clinical Behavior and Treatment
Focal, small, irregular nests of cells, and less commonly perineural or intravascular invasion adjacent to the pushing border of keratoacanthoma may occasionally be seen. Such seemingly infiltrative patterns can be alarming, but in the absence of other features do not warrant a malignant diagnosis.
Untreated, keratoacanthoma typically increases rapidly in size over a period of weeks to months and then may persist for months until finally undergoing spontaneous involution, usually within six months of eruption. Excision is usually curative, with rare recurrences reported.
Definition
Keratoacanthoma is a distinctive keratinocytic neoplasm characterized by rapid growth and spontaneous regression. Although often considered a low-grade variant of squamous cell carcinoma, this view is not universally accepted, and as there have been no reported cases of malignant behavior in cases presenting on the vulva, we present it here as a benign neoplasm.
Microscopic Features
The dome-shaped, umbilicated lesion observed on the skin corresponds to an endophytic proliferation of squamous cells forming a keratin-filled crater-like center rimmed by collarette, or ‘buttressing lips,’ of epidermis. The central squamous cells are well differentiated and tend to become larger toward the center of the proliferation, accumulating abundant glassy, eosinophilic cytoplasm ( Figures 4.5 and 4.6 ). In the early stages of development, mitoses may be numerous and mild to moderate nuclear atypia may be present, but these features regress as the lesion matures, and when well developed only minimal atypia is present. The lesions typically have a rounded, pushing border with a dense inflammatory infiltrate at the base of the lesion.
Differential Diagnosis/Clinical Behavior and Treatment
Focal, small, irregular nests of cells, and less commonly perineural or intravascular invasion adjacent to the pushing border of keratoacanthoma may occasionally be seen. Such seemingly infiltrative patterns can be alarming, but in the absence of other features do not warrant a malignant diagnosis.
Untreated, keratoacanthoma typically increases rapidly in size over a period of weeks to months and then may persist for months until finally undergoing spontaneous involution, usually within six months of eruption. Excision is usually curative, with rare recurrences reported.
Squamous Intraepithelial Lesions of the Vulva (VIN)
Definition
About 90% of squamous intraepithelial lesions of the vulva are HPV related, comprising a spectrum of alterations ranging from low-grade squamous intraepithelial lesions VIN (VIN 1), sometimes characterized as ‘flat condyloma,’ to the severe full-thickness dysplasia of high-grade squamous intraepithelial lesion VIN (VIN 3). Recent proposals from both the International Society for the Study of Vulvovaginal Disease (ISVVD) and the College of Pathologists (CAP)/American Society for Colposcopy and Cervical Pathology (ASCCP) have advocated replacement of the older three-tiered system used to describe these lesions with a two-tiered system ( Table 4.1 ).
| 1986 VIN Terminology | 2009 ISSVD Terminology | 2012 CAP/ASCCP Terminology |
|---|---|---|
| VIN 1 | Condyloma HPV changes | Low grade squamous intraepithelial lesion (VIN 1) |
| VIN 2 | VIN, usual type (uVIN) | High grade squamous intraepithelial lesion (VIN 2–3) |
| VIN 3 | VIN, usual type (uVIN) or VIN, differentiated type (dVIN) | High grade squamous intraepithelial lesion (VIN 2–3) or VIN, differentiated type |
HPV-Related Low- and High-Grade Squamous Intraepithelial Lesions (VIN 1–3)
Clinical Features
Patients with HPV-related squamous intraepithelial lesions are usually in their thirties or forties, frequently smokers, and frequently have a history of, or concurrent, multifocal vulvar lesions and/or multicentric oncogenic HPV-related disease, or other sexually transmitted diseases. Pruritus is the most common symptom. Other symptoms may include pain, ulceration, or dysuria. Approximately 20% of patients are asymptomatic, but may have observed an abnormal area on self-examination.
The gross appearance of the lesion is variable. Lesions are usually well demarcated and asymmetric, may appear red, white, pigmented, or mixed, and may be raised, papular, flat, or ulcerated ( Figures 4.7 and 4.8 ).
Pathogenesis/Etiology
The majority of low-grade HPV-related vulvar squamous intraepithelial lesions (LSILs) contain low-risk HPV subtypes, while high-grade lesions (HSILs) typically contain high-risk subtypes, most commonly HPV 16. The estimated time of progression from incident infection to the development of clinical disease has been estimated at 18.5 months.
Microscopic Features
LSIL of the Vulva (VIN 1).
Not all authors agree on the value or significance of the category of LSIL (VIN 1), although there is general agreement that it is a rare and poorly reproducible diagnosis. The controversy stems from disagreement as to the biologic behavior of these lesions. Because of its distinctive, albeit uncommon, morphology and its as yet unclear behavior, we prefer to maintain this diagnostic category for flat-macular lesions with epithelial changes resembling those of exophytic condylomata ( Figure 4.9 ).
HSIL of the Vulva (VIN 2–3).
For descriptive purposes, high-grade HPV-related lesions of the vulva have been divided into warty and basaloid subtypes. Warty lesions ( Figure 4.10A–D ) are characterized by a spiky or undulating surface, giving them a condylomatous gross appearance. The markedly thickened epithelium forms wide, deep rete pegs separated by thin dermal papillae that often closely approach the surface. Disorganization and abundant mitotic figures, including abnormal ones, can be seen in all levels of the epithelium, with evidence of maturation and often koilocytic change in the upper layers. Hyperkeratosis is prominent, often with accompanying parakeratosis. Nuclei are enlarged and hyperchromatic, with irregular nuclear membrane contours and prominent pleomorphism. Multinucleated cells, as well as dyskeratotic cells, may be present. An appreciable amount of eosinophilic cytoplasm is present, and the cell borders are easily delineated. Lesions with this morphology were formerly subclassified as VIN 2 or VIN 3, by determination of the proportion of the epithelium populated by relatively immature cells, with those having immature cells involving no more than two-thirds of the epithelium classified as VIN 2 ( Figure 4.11 ) and those having immature cells involving more than two-thirds of the epithelium as VIN 3.
In contrast to warty lesions, the surface of basaloid lesions is relatively flat. Hyperkeratosis and koilocytosis may be present, but to a lesser degree than is seen in warty lesions. The epithelium is thickened by a relatively uniform population of immature cells with scant cytoplasm, poorly defined cell borders, and enlarged hyperchromatic nuclei ( Figure 4.12 ). As in warty lesions, mitotic activity is readily identified and atypical mitotic figures may be present.
Distinction between warty and basaloid subtypes is not always easy. Mixed forms, containing morphologic features of both types, are not uncommon, and may be designated as such ( Figure 4.13 ), although, as there is no clinical difference between lesions of either morphology, specification is not required for diagnosis.
Routine Biomarkers of Clinical Relevance
Immunohistochemistry for Ki-67 can be useful in identification of LSIL, where it can highlight an abnormal degree of proliferation in a cytologically equivocal lesion. Of greater utility in the diagnosis of HSIL is p16 INK4a ; as a reliable indicator of the presence of high-risk HPV in the vulva, it is strongly positive throughout most of the epithelium in HSIL (VIN 3).
Differential Diagnosis
Although both condyloma acuminatum and warty HSIL (VIN 2–3) may have prominent koilocytic changes, the latter can be distinguished by the presence of atypical, pleomorphic cells in the deeper levels of the epithelium and by the presence of increased mitotic activity, including abnormal mitotic figures, in the upper layers. Seborrheic keratosis and lichen simplex chronicus may have acanthosis and hyperkeratosis, but typically lack the nuclear atypia of HSIL (VIN 2–3). Probably the most common diagnostic dilemma in assessment of HSIL (VIN 2–3) is distinction of truly intraepithelial disease from disease with associated early invasion. This can be complicated by involvement of skin appendages, which may extend quite deeply into the underlying dermis. The distinction rests on the preservation of a distinct epithelial–dermal junction, without an inflammatory response or stromal desmoplasia ( Figure 4.14 ). The border along the basement membrane in intraepithelial lesions should be smooth, while in early invasion irregularly shaped tongues of cells protrude from the basal layer through the basement membrane ( Figure 4.15 ). Often this is accompanied by ‘paradoxical maturation’ of the cells on the invasive front, with the cells enlarging and accumulating more abundant eosinophilic cytoplasm ( Figure 4.16 ). Early invasive nests of squamous cell carcinoma are small, irregularly shaped, and usually accompanied by a desmoplastic response ( Figure 4.17 ).
Intraoperative Consultation and Sampling/Tissue Issues
Proper attention to specimen orientation and sectioning is critical in processing specimens of HSIL (VIN 2–3), whether for frozen or permanent sections. Resections for this disease can be quite large, and often involve margins in multiple anatomic areas, such as perivaginal, periurethral, and perianal, all on the same specimen. Clear orientation by the surgeon is imperative for optimal pathologic evaluation. Pinning larger specimens to a corkboard prior to fixation will help to prevent tangential sections and curling of the edges of the resected tissue, which can make it difficult or impossible to get properly oriented margin sections. When specimens are submitted for the evaluation of margins, whether by frozen section or permanents, it is advisable to take a perpendicular section from the lesion to the nearest margin so that measurement of the nearest distance from the margin is possible. If no gross lesion is appreciable, it may be preferable to perform en face margins, parallel to the surgical excision margins, to ensure complete assessment.
Clinical Behavior and Treatment
The frequency of recurrence for HSIL (VIN 2–3) is estimated at over 50%, and is said to be more likely in patients who continue to smoke after initial diagnosis, in patients with multifocal disease, and in patients with involved margins on the initial resection, although the last association has not been a uniform finding. Several clinical risk factors for the progression of HSIL (VIN 2–3) to carcinoma have been identified, such as patient age, multicentricity, and multifocality of disease, and immunosuppression, but to date the data remain conflicting on all counts. Regardless of what the risk factors for progression may be, rates of progression are reported at 5.7–10%, and, untreated, HSIL (VIN 2–3) has been found to progress to carcinoma within 8 years. Treatment usually consists of wide local partial superficial vulvectomy or laser ablation. Topical treatments are available and currently under investigation, but to date none have been shown to be as effective as surgical treatment.
High-Grade VIN, Differentiated or Simplex Type
Clinical Features
The ‘differentiated’ or ‘simplex’ type of VIN does not have an associated low-grade counterpart; all lesions with this morphology qualify as high grade. This type of VIN is not associated with HPV, and consequently the clinical presentation differs from that of HPV-related lesions in that patients are usually older (postmenopausal), are less often smokers, and rarely have multifocal or multicentric intraepithelial disease, but often have an associated benign vulvar condition, typically lichen sclerosus or lichen simplex chronicus. The symptoms and gross appearances of these lesions do not differ from those described for HPV-related lesions.
Pathogenesis/Etiology
Because of its frequent association with lichen sclerosus, long-standing lichen sclerosus has been implicated by some authors as a precursor lesion to differentiated VIN and associated carcinoma. Also implicated in the development of differentiated VIN is p53 mutation, and many studies have demonstrated the increased expression of p53 in the basal and suprabasal layers of the epithelium in these lesions.
Microscopic Features
In differentiated VIN the most atypical cells are confined to the basal and parabasal layers of the epithelium, while the superficial layers of the epithelium often appear relatively normal, making it easy to overlook. The epithelium may be acanthotic ( Figure 4.18 ), but can also be normal in thickness or even atrophic. An orderly pattern of keratinocyte maturation is present, in contradistinction to the disorder seen in warty and basaloid VIN. The rete pegs are typically elongated, narrow, and branched, and may show an anastomosing pattern ( Figure 4.19 ). The basal cell layer is often expanded by the population of atypical basal and parabasal cells. These cells are characterized by hyperchromatic, irregular, and variably sized nuclei with coarse chromatin and prominent macronucleoli, and a moderate to abundant amount of hypereosinophilic cytoplasm indicative of premature keratinization ( Figure 4.20 ). These cells may form whorled aggregates with or without keratin pearls in the basal portion of the epithelium ( Figures 4.21 and 4.22 ).
Routine Biomarkers of Clinical Relevance
Because differentiated VIN can be so difficult to recognize morphologically, there is great interest in identifying a ‘magic marker,’ which would distinguish it with greater ease. Hence, much has been made of the use of p53 immunostaining in these lesions, which is reported to show positive reactivity for p53 in the majority of the basal epithelial cells with superficial extension of this reactivity in 66–84% of cases. The immunoreactivity, however, is not always consistent throughout the lesion and a similar staining pattern can be seen in several other benign and malignant conditions. Moreover, p53 staining does not necessarily correlate with gene mutation, raising an additional concern as to the significance and utility of this finding. Thus, while p53 immunohistochemical study may be of value in confirming the diagnosis of differentiated VIN, it appears to be neither sensitive nor specific as a marker, and results must be interpreted with caution.
Differential Diagnosis
Differentiated VIN may be difficult to distinguish from the lichen sclerosus and lichen simplex chronicus that so often accompany it, but these benign conditions do not have keratinocyte atypia of the basal cell layers, disturbance of cell maturation, squamous whorls, or keratin pearls. These latter features may be mimicked by seborrheic keratosis; its lack of significant nuclear atypia should distinguish it from VIN.
Intraoperative Consultation and Sampling/Tissue Issues
Specimens should be handled in the same fashion as HPV-related lesions.
Clinical Behavior and Treatment
There is strong evidence that differentiated VIN is more likely to progress than HPV-related VIN, with reported rates of progression of up to 33%, and it appears to do so at a more rapid rate as well. In one study comparing the association of the two types of VIN with preceding, concurrent, or subsequent invasive carcinoma, the rates were found to be 24.2% for high-grade HPV-related VIN and 83.3% for differentiated VIN. Given this very high association, a diagnosis of differentiated VIN often necessitates a more extensive excision than for HPV-related lesions.
Definition
About 90% of squamous intraepithelial lesions of the vulva are HPV related, comprising a spectrum of alterations ranging from low-grade squamous intraepithelial lesions VIN (VIN 1), sometimes characterized as ‘flat condyloma,’ to the severe full-thickness dysplasia of high-grade squamous intraepithelial lesion VIN (VIN 3). Recent proposals from both the International Society for the Study of Vulvovaginal Disease (ISVVD) and the College of Pathologists (CAP)/American Society for Colposcopy and Cervical Pathology (ASCCP) have advocated replacement of the older three-tiered system used to describe these lesions with a two-tiered system ( Table 4.1 ).
| 1986 VIN Terminology | 2009 ISSVD Terminology | 2012 CAP/ASCCP Terminology |
|---|---|---|
| VIN 1 | Condyloma HPV changes | Low grade squamous intraepithelial lesion (VIN 1) |
| VIN 2 | VIN, usual type (uVIN) | High grade squamous intraepithelial lesion (VIN 2–3) |
| VIN 3 | VIN, usual type (uVIN) or VIN, differentiated type (dVIN) | High grade squamous intraepithelial lesion (VIN 2–3) or VIN, differentiated type |
HPV-Related Low- and High-Grade Squamous Intraepithelial Lesions (VIN 1–3)
Clinical Features
Patients with HPV-related squamous intraepithelial lesions are usually in their thirties or forties, frequently smokers, and frequently have a history of, or concurrent, multifocal vulvar lesions and/or multicentric oncogenic HPV-related disease, or other sexually transmitted diseases. Pruritus is the most common symptom. Other symptoms may include pain, ulceration, or dysuria. Approximately 20% of patients are asymptomatic, but may have observed an abnormal area on self-examination.
The gross appearance of the lesion is variable. Lesions are usually well demarcated and asymmetric, may appear red, white, pigmented, or mixed, and may be raised, papular, flat, or ulcerated ( Figures 4.7 and 4.8 ).
Pathogenesis/Etiology
The majority of low-grade HPV-related vulvar squamous intraepithelial lesions (LSILs) contain low-risk HPV subtypes, while high-grade lesions (HSILs) typically contain high-risk subtypes, most commonly HPV 16. The estimated time of progression from incident infection to the development of clinical disease has been estimated at 18.5 months.
Microscopic Features
LSIL of the Vulva (VIN 1).
Not all authors agree on the value or significance of the category of LSIL (VIN 1), although there is general agreement that it is a rare and poorly reproducible diagnosis. The controversy stems from disagreement as to the biologic behavior of these lesions. Because of its distinctive, albeit uncommon, morphology and its as yet unclear behavior, we prefer to maintain this diagnostic category for flat-macular lesions with epithelial changes resembling those of exophytic condylomata ( Figure 4.9 ).
HSIL of the Vulva (VIN 2–3).
For descriptive purposes, high-grade HPV-related lesions of the vulva have been divided into warty and basaloid subtypes. Warty lesions ( Figure 4.10A–D ) are characterized by a spiky or undulating surface, giving them a condylomatous gross appearance. The markedly thickened epithelium forms wide, deep rete pegs separated by thin dermal papillae that often closely approach the surface. Disorganization and abundant mitotic figures, including abnormal ones, can be seen in all levels of the epithelium, with evidence of maturation and often koilocytic change in the upper layers. Hyperkeratosis is prominent, often with accompanying parakeratosis. Nuclei are enlarged and hyperchromatic, with irregular nuclear membrane contours and prominent pleomorphism. Multinucleated cells, as well as dyskeratotic cells, may be present. An appreciable amount of eosinophilic cytoplasm is present, and the cell borders are easily delineated. Lesions with this morphology were formerly subclassified as VIN 2 or VIN 3, by determination of the proportion of the epithelium populated by relatively immature cells, with those having immature cells involving no more than two-thirds of the epithelium classified as VIN 2 ( Figure 4.11 ) and those having immature cells involving more than two-thirds of the epithelium as VIN 3.
