Vulval superficial myofibroblastoma with lymphocytic and eosinophilic infiltrate.

We present the case of a vulval superficial myofibroblastoma with a lymphocytic and eosinophilic rim in a woman in her late 20s. The tumour presented in pregnancy as a cystic lesion with pain and increasing size. While the histopathology of superficial myofibroblastomas has been well defined in the literature, to our knowledge, there has been no documentation of the presence of an inflammatory infiltrate of lymphocytes and eosinophils surrounding and within the tumour. This may potentially act as a diagnostic or prognostic reference.

Nonsclerotic Lichen Sclerosus: Definition of a Concept and Pathologic Description.

OBJECTIVE: Nonsclerotic lichen sclerosus (NSLS) refers to the clinicopathologic situation of examination findings consistent with lichen sclerosus (LS) but without dermal sclerosis on microscopy. This review aims to describe the features of NSLS and provide a classification framework. METHODS: The International Society of the Study of Vulvovaginal Diseases tasked the Difficult Pathologic Diagnoses Committee with development of consensus documents for conditions with problematic histopathology. The Difficult Pathologic Diagnoses Committee reviewed the literature on NSLS and formulated descriptions and diagnostic criteria, then approved by the International Society of the Study of Vulvovaginal Diseases membership. RESULTS: Nonsclerotic LS may be categorized into 4 histopathologic subtypes: lichenoid dermatitis, hypertrophic lichenoid dermatitis, dermal fibrosis without acanthosis, and dermal fibrosis with acanthosis. Each has a pathologic differential diagnosis of 1 or more entities, so clinical correlation is required for final diagnosis of LS. There is no evidence to support a reliable association between absent sclerosis and clinical appearance, duration, or oncogenic potential of LS. CONCLUSIONS: Pathologists and clinicians should be familiar with the concept of NSLS and its implications for patient management. Use of the term "early LS" to indicate a lack of sclerosis in presumed LS should be abandoned. Clinical correlation is required to confirm LS from among the differential diagnoses.

Mass Spectrometry Proteomic Analysis of Four p53 Patterns in Differentiated Vulvar Intraepithelial Neoplasia.

OBJECTIVE: The histopathologic diagnostic criteria of differentiated vulvar intraepithelial neoplasia (dVIN), the precursor of human papillomavirus-independent squamous cell carcinoma, are basal atypia, a negative or non-block-positive p16, and a supportive p53 immunohistochemistry (IHC). Several different patterns of supportive p53 IHC have been described. This study aims to determine the relationship between p53 IHC patterns and mass spectrometry analysis of cellular proteins in dVIN. METHODS: Four patterns of p53 IHC were studied: overexpression, cytoplasmic, wild type, and intermediate expression between wild type and overexpression. For each pattern, tissue samples of 4 examples were subjected to mass spectrometry. RESULTS: The protein profile within each p53 IHC pattern shared common features. Each of the 4 p53 patterns had a distinguishable protein profile when compared with the other 3 patterns. CONCLUSIONS: The distinguishable protein profiles in different p53 IHC patterns suggest diverse mechanisms of TP53 dysfunction. Subtyping dVIN by p53 IHC is worthy of further study because varied protein expression profiles may translate into different clinical behavior.

The Clinicopathologic Challenge of Nonneoplastic Vulvar Acanthosis.

OBJECTIVE: The aim of the study was to evaluate clinicopathologic features of cases demonstrating an acanthotic tissue reaction not clearly consistent with psoriasis, lichen simplex chronicus, mycosis, or condyloma. MATERIALS AND METHODS: This is a retrospective pathologic case series of biopsies reported as "benign acanthotic lesion" and "acanthotic tissue reaction" that lacked a clear diagnosis on expert review. Cases with nuclear atypia were excluded. Clinical and histopathologic data were collected, immunohistochemistry for p16 and p53 were obtained, and molecular testing for 28 common anogenital human papillomavirus (HPV) genotypes was undertaken. RESULTS: There were 17 cases with a median age of 47 years. Unilaterality and medial location were clinical reasons for diagnostic difficulty. Histopathologic uncertainty often related to lack of papillary dermal fibrosis to support lichen simplex chronicus or psoriasiform lesions without parakeratosis, subcorneal pustules, and/or mycotic elements. Firm pathologic diagnoses were not possible, but 3 groups emerged: favoring chronic dermatitis, favoring psoriasis, and unusual morphologies. p16 results were negative or nonblock positive while p53 was normal or basal overexpressed. Human papillomavirus testing was negative in 12, low positive for HPV 16 in 1, unassessable in 3, and not requested in 1. CONCLUSIONS: There is a group of acanthotic tissue reactions that cannot be classified with standard histopathologic assessment. Further clinicopathologic research into unilateral acanthotic lesions may provide insight into separation of psoriasis and mycosis when organisms are absent. Once nuclear atypia is excluded, immunohistochemistry for p16 and p53 and HPV molecular testing do not assist in diagnostic identification.

Desquamative Inflammatory Vaginitis and Plasma Cell Vulvitis Represent a Spectrum of Hemorrhagic Vestibulovaginitis.

OBJECTIVE: The aim of the study was to identify whether desquamative inflammatory vaginitis (DIV) and plasma cell vulvitis (PCV) are distinct clinicopathologic entities. MATERIALS AND METHODS: The pathology database identified biopsies described as "vaginitis" or "vulvitis" occurring in nonkeratinized epithelium or mucocutaneous junction. Exclusions were age less than 18 years, unavailable slides or records, concurrent neoplasia, or histopathology consistent with other entities. Clinical data included demographics, symptoms, examination, microbiology, treatment, and response. Histopathologic review documented site, epithelial thickness and characteristics, infiltrate, and vascular abnormalities. Cases were analyzed according to histopathologic impression of DIV or PCV based on previous pathologic descriptions. RESULTS: There were 36 specimens classified as DIV and 18 as PCV from 51 women with mean age of 51 years; 3 (6%) had concurrent biopsies with both. Pain was more common in PCV, but rates of discharge, itch, and bleeding were comparable. Rates of petechiae or erythema were similar and vaginal examination was abnormal in 72% of PCV cases. All DIV and 33% of PCV occurred in squamous mucosa; the remaining PCV cases were from mucocutaneous junction. Mean epithelial thickness, rete ridge appearance, exocytosis, and spongiosis were similar in DIV and PCV. Epithelial erosion, wide-diameter lesions, plasma cells, and stromal hemosiderin occurred in both but were more common in PCV. Lymphocyte-obscured basal layer, narrow-diameter lesions, hemorrhage, and vascular congestion were seen in both, but more common and marked in DIV. CONCLUSIONS: Desquamative inflammatory vaginitis and PCV have overlapping symptoms, signs, and histopathologic features. They may represent a single condition of hemorrhagic vestibulovaginitis with varying manifestations according to location and severity.

Vulval squamous cell carcinoma arising from hidradenitis suppurrativa.

A 47- year-old woman developed a rapidly enlarging vulvar mass. Although the clinical appearance suggested malignancy, its lack of atypia and invasion on initial superficial biopsy delayed the pathological diagnosis. It was not until a large incisional biopsy was performed that showed the diagnosis of verrucous squamous cell carcinoma (VSCC) involving pre-existing sinuses of hidradenitis suppurativa (HS). VSCC arising in HS is very rare and often leads to death in published cases. This case demonstrates the challenge in pathological diagnosis of this condition which impacted time to treatment.

Erosive Lichen Sclerosus-A Clinicopathologic Subtype.

OBJECTIVE: The aim of the study was to identify whether erosive lichen sclerosus (LS) is a distinct clinicopathologic subtype. MATERIALS AND METHODS: The pathology database was searched for "erosion," "erosive," "ulcer," and "lichen sclerosus." Inclusion criteria were histopathologic diagnosis of LS and erosion or ulcer overlying a band of hyalinization and/or fibrosis. Exclusions were concurrent neoplasia and insufficient tissue. Histopathologic review documented site, epithelial thickness, adjacent epidermal characteristics, infiltrate, and dermal collagen abnormality. Clinical data included demographics, comorbidities, examination findings, microbiologic results, treatment, and response. RESULTS: Ten examples of erosive LS and 15 of ulcerated LS occurred in 24 women with a mean age of 67 years. Ulcerated LS was associated with diabetes and nontreatment at time of biopsy. Clinicians identified red patches in all but 1 case of erosive LS. Ulcerated LS was documented as fissure, ulcer, or white plaque, with 8 (53%) described as lichenified LS with epidermal breaches. Erosive LS favored hairless skin with normal adjacent stratum corneum sloping gently into erosion, whereas most ulcers in LS had an abrupt slope from hair-bearing skin. All cases were treated with topical steroids; 2 patients with erosive LS and 10 with ulcerated LS also had oral antifungals, topical estrogen, antibiotics, and/or lesional excision. Treatment yielded complete resolution in 50%. CONCLUSIONS: Erosive LS is an unusual clinicopathologic subtype characterized by red patches on hairless skin seen microscopically as eroded epithelium overlying a band of hyalinized or fibrotic collagen. In contrast, ulcerated LS is usually a traumatic secondary effect in an uncontrolled dermatosis.

Diagnostic Criteria for Differentiated Vulvar Intraepithelial Neoplasia and Vulvar Aberrant Maturation.

OBJECTIVE: The aim of the study was to describe the features required for diagnosis of differentiated vulvar intraepithelial neoplasia (dVIN) and vulvar aberrant maturation (VAM). MATERIALS AND METHODS: The International Society of the Study of Vulvovaginal Diseases tasked the difficult pathologic diagnoses committee to develop consensus recommendations for clinicopathologic diagnosis of vulvar lichen planus, lichen sclerosus, and dVIN. The dVIN subgroup reviewed the literature and formulated diagnostic criteria that were reviewed by the committee and then approved by the International Society of the Study of Vulvovaginal Diseases membership. RESULTS: Differentiated vulvar intraepithelial neoplasia is the immediate precursor of human papillomavirus (HPV)-independent vulvar squamous cell carcinoma and shows a spectrum of clinical and microscopic appearances, some overlapping with HPV-related neoplasia. The histopathologic definition of dVIN is basal atypia combined with negative or nonblock-positive p16 and basal overexpressed, aberrant negative, or wild-type p53. The most common pattern of dVIN is keratinizing with acanthosis, aberrant rete ridge pattern, and premature maturation. The morphologic spectrum of keratinizing dVIN includes hypertrophic, atrophic, acantholytic, and subtle forms. A few dVIN cases are nonkeratinizing, with basaloid cells replacing more than 60% of epithelium. Vulvar aberrant maturation is an umbrella term for lesions with aberrant maturation that arise out of lichenoid dermatitis and lack the basal atypia required for dVIN. CONCLUSIONS: Evaluation of women at risk for dVIN and VAM requires a collaborative approach by clinicians and pathologists experienced in vulvar disorders. Close surveillance of women with lichen sclerosus and use of these recommendations may assist in prevention of HPV-independent squamous cell carcinoma through detection and treatment of dVIN and VAM.

Clinicopathologic Diagnosis of Differentiated Vulvar Intraepithelial Neoplasia and Vulvar Aberrant Maturation.

OBJECTIVE: The aim of the study was to describe the demographic, clinical, and histopathologic features of differentiated vulvar intraepithelial neoplasia (dVIN) and vulvar aberrant maturation (VAM). METHODS: Specimens from 2010 to 2020 reported as dVIN or VAM were reviewed. Clinical data included age, rurality, symptoms, and evidence of lichen sclerosus (LS). Histopathologic data included epithelial thickness, keratinization, architectural and dyskeratotic features, stroma, p16, and p53. Differentiated vulvar intraepithelial neoplasia and VAM were distinguished by assessment of basal nuclear chromatin, enlargement, pleomorphism, and mitoses. RESULTS: One hundred twenty women with a median age of 71 years had 179 examples of dVIN and VAM. Squamous cell carcinoma was concurrent in 66% and associated with rurality. Ten percent were asymptomatic, and all but 3 had evidence of LS. Differentiated vulvar intraepithelial neoplasia showed a range of thickness, architecture, and dyskeratosis; its unifying !feature was basal atypia. Differentiated vulvar intraepithelial neoplasia displayed hyperchromasia in 83% and easily observed mitoses in 70%. Nonkeratinizing morphology, subcategorized into basaloid and intermediate, occurred in 24% of women with dVIN. Traditional dVIN represented 62% of keratinizing cases; the remainder were atrophic (13%), hypertrophic (13%), acantholytic (8%), or subtle (5%). Vulvar aberrant maturation had abnormal stratum corneum, acanthosis, premature maturation, and enlarged vesicular nuclei. Null p53 helped distinguish dVIN from VAM and dermatoses. CONCLUSIONS: The morphology of dVIN encompasses nonkeratinizing and keratinizing types, the latter subdivided into traditional, acantholytic, atrophic, hypertrophic, and subtle. Diagnosis relies on basal atypia with supportive p16 and p53. Atypia exists on a biologic spectrum with mild abnormalities of VAM and reactive change. Identification of dVIN and VAM requires collaboration between clinicians and pathologists experienced in vulvar disorders.

Anogenital High-Grade Squamous Intraepithelial Lesion Comorbid With Vulvar Lichen Sclerosus and Lichen Planus.

OBJECTIVE: The aim of the study was to describe the clinicopathologic features of vulvovaginal or anal high-grade squamous intraepithelial lesion (HSIL) comorbid with lichen sclerosus and/or lichen planus (LS/LP). METHODS: The local pathology database identified 37 consecutive cases from 2007 to 2019 of vulvar, vaginal, or anal HSIL among women who had a histopathologic diagnosis of vulvar LS/LP. Cases had p16 and p53 immunoperoxidase stains. Clinical data included age, relative location of HSIL and LS/LP, immune-modifying conditions, tobacco use, treatment type, and follow-up. Histopathologic data included HSIL morphology categorized as warty-basaloid or keratinizing, p16 and p53 patterns within HSIL, and features of LS/LP. RESULTS: The mean age was 69 years with a median follow-up up 42 months. Lichen sclerosus, alone or in combination with LP, was the comorbid dermatosis in 89%. Lichen sclerosus/lichen planus was overlapping or adjacent to HSIL in two-thirds of cases and located separately in the remainder. Rates of tobacco use and immunologic dysfunction were each 40%. In cases of co-located LS and HSIL, sclerosis was absent under the neoplasia in 57%. Twenty-four percent of HSIL cases showed keratinizing morphology; block-positive p16 and suprabasilar-dominant p53 helped distinguish HSIL from human papillomavirus-independent neoplasia. CONCLUSIONS: Histopathologic identification of comorbid HSIL and LS/LP may be challenging because of keratinizing morphology and loss of diagnostic features of LS. Clinicopathologic correlation and use of p16 and p53 are essential to achieve an accurate diagnosis and enact disease-specific management plans.

Clinicopathologic Diagnostic Criteria for Vulvar Lichen Planus.

OBJECTIVE: The aim of the study was to describe the clinical and histopathologic features required for a clinicopathologic diagnosis of vulvar lichen planus (LP), which is divided into 3 types: erosive, classic, and hypertrophic. MATERIALS AND METHODS: The International Society of the Study of Vulvovaginal Diseases tasked the Difficult Pathologic Diagnoses committee with development of a consensus document for the clinicopathologic diagnosis of vulvar LP, lichen sclerosus, and differentiated vulvar intraepithelial neoplasia. The LP subgroup reviewed the literature and formulated diagnostic criteria, then approved by the International Society of the Study of Vulvovaginal Diseases membership. RESULTS: The clinicopathologic diagnosis of erosive LP incorporates 5 criteria: (a) a well-demarcated, glazed red macule or patch at labia minora, vestibule, and/or vagina, (b) disease affects hairless skin, mucocutaneous junction, and/or nonkeratinized squamous epithelium, (c) evidence of basal layer damage, categorized as degenerative or regenerative, (d) a closely applied band-like lymphocytic infiltrate, and (e) absent subepithelial sclerosis. The clinicopathologic diagnoses of classic and hypertrophic LP each require a characteristic clinical appearance accompanied by hyperkeratosis, hypergranulosis, acanthosis, basal layer degeneration, a closely applied lymphocytic infiltrate, and absent dermal sclerosis, with hypertrophic LP showing marked epithelial abnormality compared with classic LP. CONCLUSIONS: Clinicopathological correlation yields the most reliable diagnosis of vulvar LP. Disease appearance overlaps with other physiologic, dermatologic, infectious, and neoplastic entities; a low threshold for biopsy at all morphologically distinct areas is recommended. Use of the histopathologic criteria described in this document may reduce the nondiagnostic biopsy rate for clinically diagnosed LP.

Symbiotic collision tumour of the scalp: squamous cell carcinoma and malignant melanoma.

Cutaneous collision tumours are the co-existence of two tumours of different histopathological morphologies that coincide at the same or adjacent anatomical sites. A large scalp nodule excised from a 70 year-old man revealed a collision tumour composed of cells of squamous carcinoma (SCC) and malignant melanoma. Immunohistochemistry using dual staining for melanoma and squamous cell carcinoma demonstrated an unusual pattern; nests of melanoma cells surrounded by a layer of squamous carcinoma cells. The unique architecture observed in the case suggested a relationship between the two tumours.

A Clinicopathologic Study and Descriptive Analysis of "Atypical Endosalpingiosis".

"Atypical endosalpingiosis" (AE) is a diagnostic term used variably among pathologists to denote peritoneal lesions exhibiting architectural changes and/or cytologic atypia intermediate between endosalpingiosis and primary peritoneal serous borderline tumor (SBT). AE is a contentious entity and is not recognized in the current World Health Organisation Classification. We report a series of 10 cases classified as AE, in attempt to further characterize this lesion. The patients ranged in age from 24 to 72 yr (mean, 39.7 yr) and the commonest presenting complaint was abdominal pain. Operative findings usually comprised small peritoneal nodules and/or fibrous adhesions, predominantly involving the pelvis. The lesions were either mesothelial or submesothelial in location and typically exhibited mixed tubular and papillary architecture, sometimes with minor components of solid, cribriform or single cell growth. Epithelial multilayering was present in all cases but usually involved <25% of the lesion. There was mild nuclear atypia and mitoses were infrequent or absent. No infiltrative growth was seen. The stroma was usually inflamed and psammoma bodies were consistently present. Features which prompt a diagnosis of AE rather than endosalpingiosis include architectural alterations, usually in the form of papillae, epithelial multilayering, and mild nuclear atypia. While the extent of these findings is often less than occurs in primary peritoneal SBT or in extraovarian implants in association with an ovarian SBT, robust histologic criteria for distinction of AE from SBT do not exist. Despite this, the term AE may be of use when dealing with atypical peritoneal proliferations resembling SBT but which are limited in extent or fall just short of criteria for an unequivocal diagnosis of primary peritoneal SBT. In our series, lesions diagnosed as AE did not result in adverse clinical outcome (follow-up in 8 patients from 4 to 84 mo). Further study is required to determine whether a diagnostically reproducible and clinically relevant intermediate lesion exists between endosalpingiosis and SBT.

PARAGON (ANZGOG-0903): a phase 2 study of anastrozole in asymptomatic patients with estrogen and progesterone receptor-positive recurrent ovarian cancer and CA125 progression.

OBJECTIVE: A subset of patients with recurrent ovarian cancer (ROC) may benefit from antiestrogen therapy with higher response rates reported in tumors that are strongly estrogen receptor (ER)-positive (ER⁺). PARAGON is a basket trial that incorporates 7 phase 2 trials investigating the activity of anastrozole in patients with ER⁺ and/or progesterone receptor (PR)-positive (PR⁺) recurrent/metastatic gynecological cancers. METHODS: Postmenopausal women with ER⁺ and/or PR⁺ ROC, who were asymptomatic and had cancer antigen 125 (CA125) progression after response to first line chemotherapy, where chemotherapy was not clinically indicated. Patients received anastrozole 1 mg daily until progression or unacceptable toxicity. RESULTS: Fifty-four patients were enrolled (52 evaluable). Clinical benefit at three months (primary endpoint) was observed in 18 patients (34.6%; 95% confidence interval [CI]=23%-48%). Median progression-free survival (PFS) was 2.7 months (95% CI=2.1-3.1). The median duration of clinical benefit was 6.5 months (95% CI=2.8-11.7). Most patients progressed within 6 months of starting anastrozole but 12 (22%) continued treatment for longer than 6 months. Anastrozole was well tolerated. In the exploratory analysis, ER histoscores and the intensity of ER staining did not correlate with clinical benefit rate or PFS. CONCLUSION: A subset of asymptomatic patients with ER⁺ and/or PR⁺ ROC and CA125 progression had durable clinical benefit on anastrozole, with acceptable toxicity. Anastrozole may delay symptomatic progression and the time to subsequent chemotherapy. The future challenge is to identify the subset of patients most likely to benefit from an aromatase inhibitor and whether the clinical benefit could be increased by the addition of other agents.

PARAGON: A Phase II study of anastrozole in patients with estrogen receptor-positive recurrent/metastatic low-grade ovarian cancers and serous borderline ovarian tumors.

OBJECTIVE: Treatment options are limited for patients with recurrent/metastatic low-grade ovarian cancers (LGOCs) and serous borderline ovarian tumors (SBOTs) as response rates to chemotherapy are low. A subset of patients appears to derive clinical benefit from antiestrogens, but most studies have been retrospective and clinical benefit rates (CBR) remain uncertain. The primary aim of PARAGON was to prospectively investigate the CBR of anastrozole, an aromatase inhibitor, in patients with estrogen receptor (ER) and/or progesterone receptor (PR) positive LGOC and SBOT. METHODS: Post-menopausal women with ER-positive and/or PR-positive recurrent/metastatic LGOCs and SBOTs and evaluable disease by RECIST v1.1 or GCIG CA125 criteria were treated with anastrozole 1 mg daily until progression or unacceptable toxicity. RESULTS: Thirty-six patients were enrolled. Clinical benefit at 3 months (primary endpoint) was observed in 23 patients (64%, 95% CI 48%-78%) and was similar at 6 months (61%, 95% CI 43%-75%). The median duration of clinical benefit was 9.5 months (95% CI 8.3-25.8). Best study response was partial response by RECIST in 5 patients (14%), stable disease in 18 patients (50%) with progressive disease in 13 patients (36%). Median PFS was 11.1 months (95% CI 3.2-11.9). Anastrozole was well-tolerated. Patients with evidence of clinical benefit at 3 months reported less pain, fatigue, and improved physical and role functioning as early as 1 month of commencing treatment. CONCLUSIONS: Anastrozole was associated with a CBR of 61% of patients with recurrent ER-positive and/or PR-positive LGOC or SBOT for at least 6 months with acceptable toxicity.

Phase 2 study of anastrozole in recurrent estrogen (ER)/progesterone (PR) positive endometrial cancer: The PARAGON trial - ANZGOG 0903.

BACKGROUND: The clinical benefit rate with aromatase inhibitors and the impact of treatment on quality of life (QOL) in endometrial cancer is unclear. We report the results of a phase 2 trial of anastrozole in endometrial cancer. METHODS: Investigator initiated single-arm, open label trial of anastrozole, 1 mg/d in patients with ER and/or PR positive hormonal therapy naive metastatic endometrial cancer. Patients were treated until progressive disease (PD) or unacceptable toxicity. The primary end-point was clinical benefit (response + stable disease) at 3 months. Secondary endpoints include progression-free survival (PFS), quality of life (QOL) and toxicity. RESULTS: Clinical benefit rate in 82 evaluable patients at 3 months was 44% (95% CI: 34-55%) with a best response by RECIST of partial response in 6 pts. (7%; 95% CI: 3-15%). The median PFS was 3.2 months (95% CI: 2.8-5.4). Median duration of clinical benefit was 5.6 months (95% CI: 3.0-13.7). Treatment was well tolerated. Patients who had clinical benefit at 3 months reported clinically significant improvements in several QOL domains compared to those with PD; this was evident by 2 months including improvements in: emotional functioning (39 vs 6%: p = 0.002), cognitive functioning (45 vs 19%: p = 0.021), fatigue (47 vs 19%: p = 0.015) and global health status (42 vs 9%: p = 0.003). CONCLUSION: Although the objective response rate to anastrozole was relatively low, clinical benefit was observed in 44% of patients with ER/PR positive metastatic endometrial cancer and associated with an improvement in QOL.

Clinical and molecular classification of vulvar squamous pre-cancers.

Vulvar intraepithelial neoplasia (VIN) is a precursor to vulvar squamous cell carcinoma and is defined histopathologically by the presence of atypia. VIN has been classified into two types: usual vulvar intraepithelial neoplasia (uVIN), which is also referred to as a vulvar high-grade squamous intra-epithelial lesion (HSIL), and differentiated VIN (dVIN). The former is associated with chronic infection by sub-types of the human papilloma virus (HPV), whereas dVIN is HPV-independent and frequently associated with lichen sclerosus. The distinction is important because dVIN has a greater risk of, and more rapid transit to, vulvar squamous cell carcinoma. Furthermore, dVIN-associated vulvar cancers have an increased risk of recurrence and higher mortality than those arising from HSIL. Molecular characterization of vulvar squamous cell carcinoma precursors using next-generation sequencing is a relatively novel, but rapidly advancing field. This review appraises recent studies that have investigated the risks of progression to vulvar malignancy associated with HSIL and dVIN, the prognosis of HPV-dependent and HPV-independent vulvar squamous cell carcinomas, and conducted next generation sequencing mutation analyses to elucidate the genomic profiles underlying VIN. These studies suggest that HSIL and dVIN are characterized by different underlying molecular alterations that may have important implications for treatment and follow-up of women diagnosed with vulvar squamous cell cancer.