p16INK4a expression in actinic keratosis and Bowen's disease

BACKGROUND: Progression of cutaneous squamous neoplasms from actinic keratosis (AK) to Bowen's disease (BD; squamous cell carcinoma in situ) has important implications for clinical management and treatment, thus requiring accurate diagnosis. p16INK4a is a cell cycle regulatory tumour suppressor protein that negatively regulates D-type cyclins in the G1 cell cycle phase via intimate interplay with the retinoblastoma gene. Expression of a paraffin-reactive p16INK4a marker has recently been shown to increase in cervical squamous neoplasms as lesions progress from low-grade dysplasia to squamous cell carcinoma in situ. p16INK4a expression in the progression of squamous cutaneous neoplasia, however, has not been evaluated. OBJECTIVES: To evaluate p16INK4a expression in the progression of squamous cutaneous neoplasia. METHODS: Biopsies of 203 squamous cutaneous neoplasms with unequivocal features of AK (n = 87) and BD (n = 116) as well as a benign squamous control group (verruca vulgaris: n = 10; seborrhoeic keratosis: n = 11; scar tissue: n = 8) obtained between January and December 2001 at Henry Ford Hospital (Detroit, MI, U.S.A.) were immunostained for p16INK4a (Dako; clone E6H4; dilution 1 : 50) using large core (1.5 mm) tissue microarray analysis. Nuclear/cytoplasmic immunoreactivity in > 10% of neoplastic cells was considered positive. RESULTS: Of 203 cases, 166 (81.8%) were interpretable (AK 59; BD 107). Mean patient age was 71.0 years (range 33-93); 57% were male. Sites of involvement were: head and extremities 75.9%, trunk/buttocks 21.7%, genital region 2.4%. p16INK4a immunostaining was positive in 90 of 107 (84.1%) BD cases, four of 59 (6.8%) AK cases and none of 29 benign squamous controls. The sensitivity and specificity of p16INK4a for a diagnosis of BD (vs. benign squamous controls/AK) was 84.1% and 95.5%, respectively (P < 0.0001, Fisher's exact test, two-sided). CONCLUSIONS: p16INK4a is a sensitive and specific marker for distinguishing BD from AK/benign squamous cutaneous lesions and may be helpful as an adjunct to histomorphology in the diagnosis and appropriate clinical management of these lesions.     

Nestin expression in Bowen's disease and Bowen's carcinoma associated with human papillomavirus

Human papillomaviruses (HPVs) have been detected in lesions of Bowen's disease (BD) and Bowen's carcinoma (BC); the invasive tumor retains the cytological characteristics of BD. Previous reports suggest that nestin-expressing hair follicle stem cells are undifferentiated and pluripotent, and nestin expression in some tumors indicates poor differentiation and high grade of malignancy. We identified HPV-DNA in BD (n=25) and BC (n=23) by in situ hybridization (ISH) analysis with INFORM(?) HPV III (Ventana Medical Systems. AZ, USA) and determined nestin expression by indirect immunohistochemical staining with anti-nestin polyclonal antibody (IBL, Gunma, Japan). We detected HPV-DNA in 68% of BD and in 87% of BC. In BD, 13 cases demonstrated the punctuate pattern, and four showed nestin expression. In BC, 19 cases showed the punctuate pattern and 16 showed nestin expression. HPV-DNA integrates into the host genome, and this is observed as the punctuate pattern on ISH. The nestin expression was statistically high in group of BC than BD (P<0.01). These results therefore suggest that HPV-DNA integrated in the genome of tumor cells of these diseases and contributed to malignant alteration. From the standpoint of tumorigenesis, BC might represent one type of poorly differentiated, high-grade squamous cell carcinoma.     

Expression of p53 and p16 in actinic keratosis,bowenoid actinic keratosis and Bowen's disease

Introduction Bowen's disease (BD) and bowenoid actinic keratosis (bAK) have traditionally been differentiated according to the presence or absence of dysplasia in the follicular epithelium. p16 has been suggested to be a useful tool to make the differential diagnosis between BD and AK and as a marker of bad prognosis. Materials Five biopsies of BD, five of AK and five of bAK where stained for p53 and p16. Results All lesions showed positive immunostaining of p53, affecting to the lower two thirdss of the epidermis in BD and bAK, and only the basal layer in non‐bAK. All the BD and bAK cases were positive for p16, showing a similar immunostaining pattern, whereas no staining was observed in non‐bAK. Discussion and conclusion These findings suggest a common pathogenic mechanism for BD and bAK. bAK might have worse prognosis than AK. p16 might not be useful as a tool for differential diagnosis between AK and BD because bAK and BD show an extremely similar immunohistochemical pattern.     

Bowen's disease on the sole: p16INK4a overexpression associated with human papillomavirus type 16

We report a case of Bowen's disease on the sole presenting clinically as an exophytic, blackish-grey, verrucous tumour, and showing human papillomavirus (HPV) type 16 on analysis with polymerase chain reaction. Positive stains for HPV particles by immunohistochemical analysis were limited to several cell nuclei at the upper stratum Malpighii. However, all the tumour cells in the epidermis exhibited strong and diffuse nuclear and cytoplasmic stains for the tumour suppressor protein p16INK4a. We speculate that dysregulation of the retinoblastoma/p16INK4a pathway may be involved in the pathogenesis of the lesion, and p16INK4a overexpression might serve as a useful surrogate marker for identifying Bowen's disease harbouring high-risk types of HPV infection.     

p16,p15及Rb蛋白在皮肤鳞状细胞癌中的表达

目的 :检测p1 6,p1 5及pRb在皮肤鳞癌中的表达及相互关系 ,探讨它们在皮肤鳞癌发生、发展中的作用。方法 :用S-P免疫组化染色法检测 48例皮肤鳞癌和 1 0例正常皮肤中p1 6,p1 5蛋白及pRb的表达。结果 :p1 6,p1 5及pRb在皮肤鳞癌中均有不同程度失表达 ,分别为 1 6/48( 3 3 3 % ) ,7/48( 1 4 6% )及 8/48( 1 6 7% )。而在正常表皮均呈阳性表达 :不同分化皮肤鳞癌中 ,p1 6,p1 5的失表达在低分化鳞癌中显著高于高中分化鳞癌 (P <0 0 5 ) ,pRb表达无显著性差异。结论 :p1 6,p1 5及 /或pRb的表达异常可能与皮肤鳞癌的发生、发展有关。     

p16和pRb在皮肤鳞癌中的表达及其意义

目的：探讨p16、pRb蛋白在皮肤鳞癌中的表达及他们的相互关系和意义。方法：应用免疫组织化学SP法检测40例原发性皮肤鳞癌绀织中p16、pRb的表达：结果：p16、pRb阳性表达率分别为37．5％和52．5％。两者在皮肤鳞癌中的表达呈显著负相关（P=0．011）。结论：在原发性皮肤鳞癌中存在p16和pRb的异常表达现象，两者的表达相互抑制，呈显著负相关。     

Mutant p53 protein is expressed in Bowen's disease.

A total of 26 specimens of histologically determined, cutaneous Bowen's disease from 23 patients were investigated for the incidence of mutant p53 protein expression by an indirect immunoperoxidase technique using the monoclonal antiserum CM1 on paraffin-embedded formalin-fixed tissue sections. Its potential role as a label of cutaneous malignancy was also evaluated: 15 specimens (57.7%) showed nuclear positivity of dysplastic keratinocytes, whereas 11 specimens (42.3%) were immunonegative. Cytoplasmic labeling was never a feature. In general, labeling was predominantly diffuse in distribution although in a significant proportion it was focal. One of two concurrent basal cell carcinomas arising adjacent to plaques of Bowen's disease was immunopositive. Focal immunopositivity of "cytologically normal" adjacent epithelium was seen in six specimens (23%). The study confirms the presence of mutant p53 protein in the majority of nongenital Bowen's disease. Its identification within nuclei of the adjacent "normal" epidermis may represent a potential marker of early (visible) neoplastic transformation.     

Bowen's disease with invasive adnexal carcinoma: the pluripotential nature of Bowen's disease cells

Bowen's disease rarely exhibits multiple combinations of premalignant and/or malignant skin lesions. Bowen's disease with invasive adnexal carcinoma was originally described by Kao, but is not well recognized by clinicians due to its rarity and lack of specific clinical features of this condition. Herein, we describe three unusual cases of Bowen's disease with invasive adnexal carcinoma. The two distinct neoplastic areas exhibited continuity both clinically and histologically. The plaque lesions possessed clinical features typical of Bowen's disease. In cases 1 and 3, we confirmed the adnexal tumor within tumors of Bowen's disease, the diagnosis of which is eccrine porocarcinoma. The tumor in case 2 was characteristic to trichilemmal carcinoma. Immunohistochemically, the tumor cells of Bowen's disease and the adnexal carcinoma differed in antigenicities. The present cases support a notion that Bowen's disease maintains a pluripotential nature.     

外阴HPV相关疾病中p~(53),cyclinD1和ki67蛋白表达及其与HPV感染的关系

目的 探讨人乳头瘤病毒(HPV)在外阴HPV相关疾病—尖锐湿疣(CA)、外阴上皮内瘤变(VIN)和外阴鳞状细胞癌(VSCC)中的感染情况及与p53,cyclinD1,ki67蛋白表达的关系。方法 在110例外阴HPV相关疾病中应用核酸分子快速导流杂交基因分型技术检测HPV16/18,HPV6/11的表达,同时用免疫组化SP法检测p53,cyclinD1,ki67蛋白的表达,并与10例正常组织进行对照。结果 HPV16/18在CA组,VIN组及VSCC组的阳性表达率均高于正常对照组,而且其阳性表达率随外阴上皮恶性程度增加而增加;HPV6/11在CA组及VINⅠ组的阳性表达率均高于VINⅡ组及VINⅢ组和正常对照组;以上差异均有统计学意义(P均<0.05)。HPV6/11在VSCC组无阳性表达,HPV16/18感染与p53,ki67表达呈正相关,与cyclinD1表达无相关性。HPV6/11感染与p53,cyclinD1,ki67表达无相关性。结论 HPV16/18感染与重度外阴上皮内瘤变及外阴鳞状细胞癌密切相关;HPV6/11感染是尖锐湿疣及轻度外阴上皮内瘤变的重要病因。HPV16/18感染与p53,ki67蛋白表达呈正相关,它们在外阴鳞状上皮恶变过程中有着协同的作用。     

The inhibitory effect of UVB irradiation on the expression of p53 and Ki-67 proteins in arsenic-induced Bowen's disease

The aim of this study is to evaluate the effect of ultraviolet B (UVB) on arsenic-induced Bowen's disease. Four patients were irradiated with 750 mJ/cm² of UVB and biopsies were performed before treatment and 2 weeks later. Immunohistochemical stains of p53 and Ki-67 were compared by the labelled-streptavidin method before and after the UVB treatment. We found that the number of p53 and Ki-67 positive cells after the UVB treatment were significantly fewer than those of non-UVB-treated specimens. These results suggest that the UVB inhibitory effect in Bowen's disease needs further studies to clarify its value in potentially retarding the progression of the hyperproliferative status in overt skin cancer on a molecular basis.     

Aneuploidy in Bowen's disease

Distinct aneuploid clones of keratinocytes were detected in six cases of cutaneous Bowen's disease. As Bowen's disease is an accepted precursor of malignancy, aneuploidy may prove to be a useful indicator of the risk of invasive change in dermatoses questionably pre-malignant.     

Dyskeratosis in Bowen's disease

SUMMARY.— Dyskeratosis is a feature of certain benign and malignant epithelial disorders. In Bowen's disease, dyskeratosis is characterized by central displacement, aggregation and condensation of tonofilaments within individual cells at all levels of the epidermis. This premature keratinization is primary and is similar to the benign dyskeratosis observed in keratosis follicularis. Centrally displaced dyskeratotic material was observed intermingled with the mitotic apparatus. Giant cells apparently resulted, since nuclear but not cytoplasmic division was seen. Dyskeratosis may also be secondary, through phagocytosis by one cell of partly or completely keratinized material from other cells. This may result in formation of a second distinct type of giant cell.