Molecular Subtypes of Vulvar Squamous Cell Carcinoma: The Significance of HPV-Independent/p53 Wild Type

Abstract

Vulvar carcinoma is a rare disease, meeting the criteria for a "rare cancer", but its incidence is increasing, especially in women <60 years of age. Squamous cell carcinoma (VSCC) accounts for the overwhelming majority of vulvar carcinomas and is the focus of this review. As with many cancers, the increased understanding of molecular events during tumorigenesis has led to the emergence of the molecular subclassification of VSCC, which is subclassified into tumors that arise secondary to high-risk human papillomavirus infection (HPV-associated, or HPVa) and those that arise independently of HPV (HPVi), most commonly in the setting of a chronic inflammatory condition of the vulvar skin. This latter group of HPVi VSCC arises in most cases secondary to mutations in TP53, but recently, attention has focused on the uncommon TP53 wild-type HPVi VSCC. These three molecular subtypes of VSCC (HPVa, HPVi p53 abnormal, and HPVi p53 wild type), as well as their precursor lesions, cannot be diagnosed based on a routine histopathological examination or immunostaining for p53 and p16 as surrogate markers for TP53 mutation and high-risk HPV infection, respectively, are required. The molecular subtyping of VSCC shows high reproducibility and provides important prognostic information. HPVa VSCC has the most favorable prognosis, while HPVi VSCC with TP53 mutations (p53abn) has the worst prognosis, and HPVi VSCC with wild-type TP53 (p53wt) has an intermediate prognosis. In this review, we discuss the evidence supporting this molecular subclassification and its implications for the diagnosis and treatment of VSCC and its precursors.

Keywords: classification; human papillomavirus; molecular; p16; p53; prognosis; radiation therapy; squamous cell carcinoma; surgery; vulvar cancer.

Figure 1

(a) Subdivision of squamous cell carcinomas of the lower female genital tract based on HPV association according to the recommendations of the WHO classification 2020 [28]; (b): Classification of VSCC from morphology-based to morpho-molecular classification, depending on the etiology of the disease, using p16 and p53 immunohistochemistry [10,12,14,20].

Figure 2

Summary of the recently described three-tiered molecular classification of VSCC and its precursors (please see text) (uVIN = usual VIN; dVIN = differentiated VIN; vaVIN = verrucous VIN).

Figure 3

Patterns of p16 overexpression in non-keratinizing (a) and keratinizing (b) VSCC, so-called block-like staining. Note that the keratinized areas stain negative for a p16 pattern (asterisk; see text).

Figure 4

An algorithmic approach for the three-tiered molecular subclassification of VSCC using p16 and p53 immunohistochemistry [14]. ISH = in situ hybridization.

Figure 5

Immunohistochemical classification of VSCC into its molecular subtypes (for details, please see the text and Figure 4 and Figure 6 and Table 1).

Figure 6

Algorithmic approach in routine pathology workup for the three-tiered molecular classification of VSCC [10,14,40].

Figure 7

A 57-year-old woman with a poorly differentiated squamous cell carcinoma ((a); FIGO stage IVA) with p16 block-type staining overexpression (b) and p53 wild-type expression staining pattern (scattered; (c)) on immunohistochemistry, treated using hypofractionated radiation with a total dose of 38 Gy and sequential chemotherapy consisting of 5 cycles of carboplatin AUC 5 and paclitaxel 175 mg/m². (d) Prior treatment: 25 cm × 10 cm exophytic superficially ulcerated tumor. (e) Partial clinical response after three months of treatment. (f) Complete local clinical response after 10 months. There was no local recurrence within 363 months of follow-up.

Figure 8

Summary of the three-tiered molecular classification of VSCC.