Currently, the pathogenesis of vulvar cancer is dichotomous. Usual-type VIN(uVIN) are usually defined by high-risk HPV infection. Differentiated vulvar intraepithelial neoplasia(dVIN)are associated with TP53 mutations. However, there are a significant, albeit small, subset of vulvar carcinomas exhibits the absence of HPV infection and mutations in TP53. In such occasions, the term ‘atypical verruciform hyperplasia’ is often applied. In 2017, CP Crum et al propose using the term ‘DE-VIL’ to redefine these atypical verruciform lesion group owing to their unique morphologic and genetic characteristics relative to differentiated and usual VIN .
DVIN, VAAD and DE-VIL were belong to the precursor lesions of HPV-independent VSCC. DE-VIL show prominent acanthosis and papillomatosis, but minimal atypia. Complete loss of the granular layer in some areas often been showed in DE-VIL. Due to its presence of plaque-like parakeratosis, lack of atypia, lack of premature keratinisation and the background of lichen sclerosus(LS) as seen in dVIN, it is different from dVIN. Meanwhile, high nuclear-to-cytoplasmic ratios, pleomorphism, hyperchromasia, apoptotic bodies and mitoses are also absent, hinting that DE-VIL is completely different from uVIN. In this study, our case report showed the similar features,meeting the criteria for DE-VIL.However, an interesting detection was that small significant cytological atypia extending into the upper layers of the epithelium was showed in the vicinity of verruciform lesion, mimicking HSIL. And the same immunochemical patterns was showed in this small lesion when compared with the verruciform lesion.Whether it is a rare subtype of DE-VIL or only a accompanying status is still pending. To date, no other study had reported this phenomenon. Someone suggested that the morphological features of HPV-independent and HPV-associated precursor lesions can overlap, based on HE Staining. Perhaps, it can be used to explain that phenomenon in our case report.
As the important differential diagnosis of DE-VIL,VAAD should been paid more attention for gynaecological pathologists. Although a vast majority of VAAD lesions displayed histologic overlap with DE-VIL. Some molecular studies showed that they maybe two unique entities. Specifically, VAAD has been showed a high percentage of HRAS (71.4%) and NOTCH1 (28.6%) mutations. However, DE-VILs are associated with activating PIK3CA mutations, which have been revealed in 73% of lesions, and only 7% of lesions have identified HRAS mutations . Some authors prefer the term DE-VIL over VAAD when the criteria for DE-VIL are met for diagnostic purposes. Due to the rare occurrence of DE-VIL, further studies are required to reveal the difference between these lesions.
A growing number of relevant studies have focused on genetic and epigenetic alterations in vulvar cancer. TP53 mutations and HPV status may play important roles in the carcinogenesis of VSCC. There were many studies reported positive expression of p53 in 66–100% of dVIN[11–13]. Meanwhile, Trietsch et al stated TP53 mutations were showed in 3% of HPV-positive VIN and 21% of HPV-negative VIN . So it was obvious that part of HPV-independent VSCC did’t follow the TP53 pathway. DE-VIL exhibited the absence of HPV infection and mutations in TP53, it was concordant with that result. On the other hand, as a surrogate marker for high-risk HPV infection, the positive expression of P16 associated extremely well with high-risk HPV status [11,12,14 ]. The positive staining pattern must be strong, diffuse and continuous (nuclear and cytoplasmic). Otherwise, we should assess the negative staining of P16. Our case showed wild-type p53 immunostaining and negative expression of P16,so further support the diagnosis of DE-VIL.
Positive staining of Ki-67 in the basal and suprabasilar layers was showed in uVIN and dVIN . The staining for Ki-67 is much more conspicuous in uVIN and the full thickness of the epithelium was usually been stained[6, 11, 15]. In contrast to the basal expression seen in LS, positive staining of Ki-67 in dVIN were showed in the basal layer and a thin parabasal layer. In our case, Ki-67 stains the nearly full thickness of the epithelium, suggesting that DE-VIL maybe play an important role in the development of vulvar SCC. Moreover, no lymphatic metastasis or recurrence has been showed in our case to date.Therefore, complete excision and monitoring for progression is recommended in all cases of DE-VIL.
In a conclusion, as the precursor lesions of HPV-independent VSCC, DE-VIL demonstrated considerable morphologic overlap with VAAD, so additional study was required to delineate if they are independent entity. Meanwhile, DE-VIL was too difficult to diagnosis due to the lack of sufficient evidence. Therefore, we should pay more and more attention for DE-VIL. Moreover, an interesting phenomenon was found in our report: a small lesion showed similar morphologic feature to HSIL nearby the lesion of DE-VIL.However, it showed same immunochemical patterns with DE-VIL. Explanation of this phenomenon is still unclear, so further investigation is needed.