Basal Atypia Research Articles

Incidence and Clinicopathologic Characteristics of Human Papillomavirus-independent Invasive Squamous Cell Carcinomas of the Cervix: A Morphologic, Immunohistochemical, and Human Papilloma-Virologic Study of 670 Cases.

We aimed to determine the frequency of human papillomavirus-independent (HPVI) cervical squamous cell carcinoma (SCC) and to describe clinicopathologic characteristics. Among 670 patients with surgically treated SCCs in an established multi-institutional cohort, 447 had available tissue. Tissue microarrays were constructed and studied by in situ hybridization (ISH) for high-risk and low-risk human papillomavirus (HPV) mRNA and immunohistochemistry for p16 and p53. Tumors were HPVI if negative by HPV ISH and they failed to show diffuse p16 positivity by immunohistochemistry, and human papillomavirus-associated (HPVA) if positive by HPV ISH. Ten HPVI SCCs and 435 HPVA SCCs were identified; 2 cases were equivocal and excluded from analysis. The overall rate of HPVI SCC was low (2%) but was higher among older patients (7% in patients above 60y of age and 17% in patients above 70y of age). Compared with HPVA, patients with HPVI SCC were significantly older (median age, 72 vs. 49, P <0.001) and diagnosed at a higher stage (40% vs. 18% with stage III/IV disease, P =0.055). p53 expression was varied; 2 cases (20%) had null expression and 8 (80%) had wild-type expression. HPVI SCCs were heterogenous, with keratinizing, nonkeratinizing, and warty morphologies observed. Several cases had a precursor lesion reminiscent of differentiated vulvar intraepithelial neoplasia, with prominent basal atypia and hypereosinophilia or a basaloid-like morphology. Two patients (20%) had distant recurrences within 12 months, and 3 (30%) died of disease during follow-up. HPVI SCCs are rare tumors that are more common among older patients with higher stage disease and have important clinical and histologic differences from HPVA SCCs.

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

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. 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. 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. 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.

Pseudoepitheliomatous keratotic and micaceous balanitis: a series of eight cases.

Pseudoepitheliomatous keratotic and micaceous balanitis (PEKMB) is a clinicopathological entity characterized clinically by micaceous scale on the glans, and histologically by acanthosis, hyperkeratosis and pseudoepitheliomatous hyperplasia. We present a series of eight cases of this rare condition, the first series of more than two cases to be reported. To determine the clinical and histological characteristics of cases of PEKMB, and evaluate treatments used and clinical course. This monocentric case series was conducted at the University College London Hospitals tertiary male genital dermatology clinic between April 2018 and August 2020. Eight patients with PEKMB were evaluated. Data were collected on demographics, clinical presentation, histological features, presence of human papilloma virus (HPV), history of lichen sclerosus, treatment of PEKMB and subsequent response, and presence or development of squamous cell carcinoma (SCC) or penile intraepithelial neoplasia (PeIN) during follow-up. Eight Caucasian males presented with clinical and histological evidence of PEKMB. Seven had a background of lichen sclerosus; two had failed treatment with superpotent topical steroids and four had symptoms for three or more years prior to circumcision. There was no clinical or histological relationship with HPV infection, and p16 staining was negative. HPV PCR, performed in two cases, was negative. Basal atypia, insufficient to amount to PeIN, was present in six patients. One patient progressed to PeIN during follow-up, and no patient progressed to invasive malignancy. Five patients were treated successfully with glans resurfacing and split skin graft reconstruction. Our observations demonstrate that PEKMB represents a form of chronic, undiagnosed or misdiagnosed, inadequately treated or treatment refractory, unstable lichen sclerosus. The significant potential for squamous carcinogenesis (differentiated PeIN and verrucous carcinoma) can be mitigated by timely diagnosis and treatment. Glans resurfacing and split skin graft reconstruction appears to be a successful treatment modality in patients with refractory disease.

Verruciform xanthoma of the vulva in the context of lichen sclerosus: A mimicker of HPV and p53-independent intraepithelial neoplasia

A 67-year-old woman presented with a 2 x 1.5 cm white, asymptomatic verrucous plaque on the left labia minora. She was known for vulvar lichen sclerosus et atrophicus (LSA) for 1.5 years, treated with high-potency topical corticosteroids. A biopsy of the verrucous lesion demonstrated a small fragment of parakeratotic vulvar epithelium with papillomatosis and moderate basal atypia, spongiosis and mitoses. Neutrophils were present, forming microabscesses in the stratum corneum. The granular layer was lost in those acanthotic areas. The differential diagnosis included vulvar verruciform lichen simplex chronicus, verrucous carcinoma, vulvar acanthosis with altered differentiation, differentiated exophytic vulvar intraepithelial neoplasia or verruciform xanthoma. We demonstrate how accurately diagnosing verruciform xanthoma in the context of inflammatory dermatoses of genital sites is crucial to avoid overtreating as a preneoplastic mimicker lesion.

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

ObjectiveThe 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 MethodsThe 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.ResultsDifferentiated 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.ConclusionsEvaluation 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.

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). 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. 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. 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.

Molecular characterization of invasive and in situ squamous neoplasia of the vulva and implications for morphologic diagnosis and outcome.

Human papillomavirus (HPV)-independent vulvar squamous cell carcinoma (VSCC) is an aggressive clinical entity. Current diagnostic guidelines for premalignant lesions are ambiguous, and their molecular profile and progression events are still unclear. We selected 75 samples, from 40 patients, including 33 VSCC, 8 verrucous carcinomas (VC), 13 differentiated-type vulvar intraepithelial neoplasia (dVIN), 11 suspicious for dVIN (?dVIN), 6 differentiated exophytic vulvar intraepithelial lesions (DE-VIL), 2 vulvar acanthosis with altered differentiation (VAAD), and 2 usual-type vulvar intraepithelial neoplasia (uVIN/HSIL). Invasive and precursor lesions were matched in 29 cases. Clinical information, p16 immunohistochemistry, and mutation analysis were performed on all lesions. All dVIN, ?dVIN, DE-VIL, and VAAD were p16 negative, all uVIN/HSIL were p16 positive. In the HPV-independent group, mutations were identified in 6 genes: TP53 (n = 40), PIK3CA (n = 20), HRAS (n = 12), MET (n = 5), PTEN (n = 4), and BRAF (n = 1). TP53 mutations occurred in 73% (22/30) VSCC, 85% (11/13) dVIN, 70% (7/10) ?dVIN and no VC (0/8), DE-VIL (0/6) nor VAAD (0/2). Basal atypia was the only reliable feature of TP53 mutations. ?dVIN lesions that were non-acanthotic and atypical but obscured by inflammation, all harbored TP53 mutations. In lesions without TP53 mutations, PIK3CA (50% VC, 33% DE-VIL, 100% VAAD, 40% VSCC) and HRAS (63% VC, 33% DE-VIL, 0% VAAD, 20% VSCC) mutations were found. Mutational progression from in situ to invasive was seen (7/26, 27%) and usually involved TP53 (4/26, 15%). Cases with TP53 and PIK3CA co-mutations had the worse clinical outcomes (p < 0.001). We recommend testing for p53 in all HPV-independent lesions suspicious for dVIN, even in the presence of marked inflammation or non-acanthotic skin, particularly when close to a margin. VC, VAAD, and DE-VIL, were almost never mutated for TP53, but instead often harbored PIK3CA and HRAS mutations. In VSCC, combined TP53 and PIK3CA mutations may inform prognosis.

Classic Vulvar Intraepithelial Neoplasia With Superimposed Lichen Simplex Chronicus: A Unique Variant Mimicking Differentiated Vulvar Intraepithelial Neoplasia.

High-grade vulvar intraepithelial neoplasia, a precursor lesion to vulvar squamous cell carcinoma, is subdivided into 2 types, classic or usual vulvar intraepithelial neoplasia (CVIN) and differentiated vulvar intraepithelial neoplasia (DVIN). CVIN, which is a human papilloma virus (HPV)-dependent lesion, is typically distinguished from DVIN, a p53 mutation-dependent process, by its distinct histomorphologic and immunohistochemical characteristics. However, distinguishing between the 2 entities becomes challenging in cases of CVIN with superimposed inflammatory changes, especially lichen simplex chronicus (LSC). Twelve cases of DVIN, 9 cases of LSC, and 9 cases of CVIN with superimposed LSC were assessed for a number of morphologic features, including hyperkeratosis, hypergranulosis, acanthosis, hypercellularity, abnormal maturation (i.e. abnormal keratinization close to the base and/or dyskeratosis), hyperchromasia, and basal atypia. Immunohistochemistry for p53, p16, and MIB-1 was performed for all cases. When sufficient tissue was available, HPV genotyping was performed for cases of CVIN with superimposed LSC. DVIN uniformly demonstrated abnormal maturation, and atypia involving the basal cell layer; they were all p16 negative and demonstrated p53 positivity of moderate to strong intensity in a basal and parabasal distribution. CVIN with superimposed LSC frequently displayed hyperchromasia involving the basal 3 to 4 cell layers, basal to full-thickness atypia, and apoptosis. CVIN with superimposed LSC demonstrated intense p16 positivity extending from the basal cells to the mid-epithelium and a reduction or loss of staining in maturing keratinocytes. P53 staining revealed a unique pattern of parabasal and mid-epithelial weak to moderate staining with sparing of the basal layer. Cases of LSC demonstrated heterogenous p53 positivity and were negative for p16. MIB-1 staining showed a similar range of positivity for all diagnoses. HPV genotyping revealed HPV 16 in all 5 cases of CVIN with LSC that underwent testing. We conclude that, although CVIN with superimposed LSC can closely resemble DVIN, morphologic features such as nuclear hyperchromasia uniformly involving the basal 3 to 4 cell layers, apoptosis, and absent or less pronounced cytoplasmic maturation are more suggestive of CVIN with superimposed LSC. In cases where the morphology remains ambiguous, immunohistochemistry for both p16 and p53 can be helpful. In particular, p53 parabasal and mid-epithelial staining without involvement of the basal layer appears to be a characteristic finding in CVIN with superimposed LSC. MIB-1 staining is of little utility in distinguishing between these entities and should not be routinely performed.

The use of cytospin monolayer technique in the cytological diagnosis of vulval and anal disease.

This pilot study investigated the use of the non-invasive cytospin monolayer technique in the diagnosis and screening of neoplastic and non-neoplastic vulval disease. Twenty-three patients (age range 34-86 years) attending a vulval disease clinic had brush cytology performed. The samples were prepared with a cytospin monolayer technique and the slides Papanicolaou-stained. Subsequent cytological interpretation and diagnosis were performed without knowledge of the clinical history and correlated with follow-up biopsy histopathology from each patient. Twenty-eight cytospin samples were analysed in total, of which 11 (39%) contained dyskaryotic cells which were assessed and a predicted VIN/AIN grade given. Ten of 11 samples (91%) reported as dyskaryotic had VIN/AIN on biopsy histology. One of 11 samples (9%) was reported as containing occasional squamous cells with borderline nuclear features and, although the corresponding biopsy did not show VIN, basal atypia was reported. One patient had features suggesting invasive carcinoma on cytology which was verified on subsequent biopsy. The 15 cases in which no dyskaryotic cells were identified did not show VIN or AIN on subsequent histology. Two cases were acellular and considered inadequate for cytological interpretation. The cytospin monolayer technique allows the diagnosis of neoplastic from non-neoplastic vulval disease. It is a quick, inexpensive and non-invasive method that may have a role in diagnosis, screening and surveillance of patients.

Comparison of histological features of vulvar lichen sclerosis with and withoutadjacent squamous cell carcinoma

Scurry J, Vanin K, Ostor A. Comparison of histologicalfeatures of vulvar lichen sclerosis with and without adjacent squamous cellcarcinoma. Int J Gynecol Cancer 1997; 7: 392–399. To compare the histological features of vulvar lichen sclerosis with andwithout adjacent squamous cell carcinoma, sections of 132 consecutive cases ofvulvar squamous cellcarcinoma were examined to determine the characteristics of the epidermisadjacent to the carcinoma. Where lichen sclerosis was observed, its featureswere compared to those ofvulvar lichen sclerosis from 86 women without associated carcinoma. Lichensclerosis was seen in adjacent skin of 63 of 132 (48%) women with vulvarsquamous cell carcinoma. In61 of these 63, the epidermis was also significantly thickened. The changescausing the thickened epidermis could not be distinguished from superimposedlichen simplex chronicus in21 women. In the other 40, the main, but not the only, distinguishing featurewas differentiated vulvar intraepithelial neoplasia (basal atypia), which wasseen in 33. Otherdifferences were alterations in the ratios of hyperkeratosis, granulosis,acanthosis, and irregular prolongation of rete ridges. In lichen sclerosiswithout cancer, 73 women hadassociated epidermal thickening and in 69 of these the changes could not bedistinguished from superimposed lichen simplex chronicus; the other 4 showeddifferentiated andundifferentiated vulvar intraepithelial neoplasia in two women each. Weconclude that epidermal thickening is common in vulvar lichen sclerosis,whether occurring alone or inassociation with squamous cell carcinoma. Superimposed lichen simplex chronicuscannot fully explain the histological features of the epidermal thickening inlichen sclerosis inthe majority of women with carcinoma, but can do so in the majority of womenwithout carcinoma. In individual cases, however, there are no definitehistological criteria to distinguish hyperplasia from superimposed lichensimplex chronicus.

Vulvar intraepithelial neoplasia: Age, morphological phenotype, papillomavirus DNA, and coexisting invasive carcinoma

Recent studies suggest that subsets of vulvar intraepithelial neoplasia (VIN) may be distinguished based on morphological presentation, the presence or absence of human papillomavirus (HPV) nucleic acids, and patient age. We analyzed 65 VIN lesions, including 15 with associated squamous cell carcinoma, to determine the relationship between pathological parameters associated with common types of VIN (multinucleation, koilocytosis, verruco-papillary morphology, diffuse atypia), rarer variants (differentiation, basal atypia), patient age, and papillomavirus nucleic acids. For all lesions higher mean ages were observed in patients with lesions that were associated with cancer and with well differentiated VIN variants with basal atypia only. A strong negative correlation with HPV nucleic acids was observed for differentiated variants with basal atypia ( P = .002). In the common or “classic” VIN group patients with lesions with koilocytotic atypia, multinucleation, and verruco-papillary morphology were generally younger. However, no parameter or group of parameters defined a subset of patients with a significantly lower mean age or lesions with a higher index of HPV nucleic acids. Three of six lesions of lichen sclerosus (LS)—associated VIN, including one involving invasive carcinoma in elderly women, contained HPV nucleic acids; all three lesions exhibited the features of classic VIN. The finding of HPV across a broad age range suggests that this virus may play a role in vulvar neoplasia at any point in life. The direct demonstration of HPV nucleic acids within three LS-associated VINs is intriguing because it links two distinct risk factors to the same neoplasm.