Non-invasive diagnosis of early cutaneous squamous cell carcinoma.

Early cutaneous squamous cell carcinoma (cSCC) can be challenging to diagnose using clinical criteria as it could present similar to actinic keratosis (AK) or Bowen's disease (BD), precursors of cSCC. Currently, histopathological assessment of an invasive biopsy is the gold standard for diagnosis. A non-invasive diagnostic approach would reduce patient and health system burden. Therefore, this study used non-invasive sampling by tape-stripping coupled with data-independent acquisition mass spectrometry (DIA-MS) proteomics to profile the proteome of histopathologically diagnosed AK, BD and cSCC, as well as matched normal samples. Proteomic data were analysed to identify proteins and biological functions that are significantly different between lesions. Additionally, a support vector machine (SVM) machine learning algorithm was used to assess the usefulness of proteomic data for the early diagnosis of cSCC. A total of 696 proteins were identified across the samples studied. A machine learning model constructed using the proteomic data classified premalignant (AK + BD) and malignant (cSCC) lesions at 77.5% accuracy. Differential abundance analysis identified 144 and 21 protein groups that were significantly changed in the cSCC, and BD samples compared to the normal skin, respectively (adj. p < 0.05). Changes in pivotal carcinogenic pathways such as LXR/RXR activation, production of reactive oxygen species, and Hippo signalling were observed that may explain the progression of cSCC from premalignant lesions. In summary, this study demonstrates that DIA-MS analysis of tape-stripped samples can identify non-invasive protein biomarkers with the potential to be developed into a complementary diagnostic tool for early cSCC.

Bowen disease on the dorsum of the foot associated with human papillomavirus type 16.

A 94 years old Japanese female was presented to our hospital with a skin lesion on her left foot. A physical examination found a markedly hyperkeratotic reddish-brown plaque, measuring 3 cm in diameter. A biopsy specimen showed prominent papillomatosis, hyperkeratosis, and atypical keratinocytes throughout the epidermis. Individual cell keratinization, multinucleated keratinocytes, and many keratinocytes with clear cytoplasm were seen. We excised the lesion, and the skin grafting was used for covering the skin defect. We investigated whether human papillomavirus (HPV) was present in the lesion, and HPV 16 DNA was detected using the polymerase chain reaction. Immunohistochemical analysis showed several HPV-positive cells in the upper epidermis. In addition, the tumor cells showed strong and diffuse expression of p16INK4a. Bowen disease (BD) is an intraepidermal squamous cell carcinoma. The precise pathogenesis of BD is unclear, but it involves various factors. HPV infection is one of these factors and is a well-known cause of BD of the genitalia and fingers. It has been shown that some BD lesions occurring at other locations are also associated with HPV. Dysregulation of the Rb/p16INK4a pathway is considered to play an important role in HPV-induced BD, but the precise mechanism remains to be elucidated. J. Med. Invest. 69 : 152-154, February, 2022.

Expression and significance of mammalian target of rapamycin in cutaneous squamous cell carcinoma and precancerous lesions.

The aim of this study is to explore the role of mammalian target of rapamycin (mTOR) in cutaneous squamous cell carcinoma (CSCC), Bowen's disease (BD), and actinic keratosis (AK) with squamous cell differentiation abnormality and its relationship with the degree of tumor proliferation. Thirty cases of clinical paraffin specimens of CSCC, BD, and AK were each collected from Jinhua Fifth Hospital, while 30 cases of normal skin specimens surgically resected in Department of Plastic Surgery were selected as controls. The expressions of mTOR and Ki-67 in tissues were detected by immunohistochemical staining. The positive expression rate of mTOR in the CSCC group was higher than those in the BD group and AK group (P < 0.05), while it was higher in the BD group and AK group than in the normal skin group (P < 0.05). The CSCC group had a higher positive expression rate of Ki-67 than the AK group (P < 0.01). The results of logistic regression analysis showed that the pathogenic site [odds ratio (OR) = 1.189, 95% confidence interval (95%CI): 1.028-1.381, P = 0.021], course of disease (OR = 2.059, 95%CI: 1.036-4.087, P = 0.043), and differentiation degree (OR = 1.325, 95%CI: 1.169-1.512, P = 0.001) were independent factors for the positive expression of mTOR. OR>1, indicating that the factor is a risk factor. The expression levels of mTOR in CSCC, BD, and AK were positively correlated with the expression level of Ki-67 (r = 0.827, P < 0.01, r = 0.608, P < 0.01, r = 0.368, P = 0.045). These results suggest that mTOR may be involved in the pathogenesis of CSCC, and related to the proliferation degree of CSCC, as an index reflecting the proliferation status of CSCC.

Different Immunohistochemical Localization of Fatty Acid Binding Protein 5 in Actinic Keratosis Compared with That in Bowen's Disease: A Retrospective Study.

ABSTRACT: Actinic keratosis (AK) and Bowen's disease (BD) are common premalignant lesions of invasive squamous cell carcinoma that have different pathogenesis and clinical significance. Fatty acid-binding protein 5 (FABP5) is responsible for keratinocyte homeostasis and differentiation; however, no study has revealed its expression in AK and BD. Our study aimed to investigate the differential expression and significance of FABP5 in these lesions. Patients with pathologically confirmed cases of AK (n = 37) and BD (n = 12) were included in this study. FABP5 immunostaining pattern was assessed in the normal skin, AK and BD lesions, with a focus on the staining patterns of basal cells, atypical keratinocytes, and uninvolved epidermal keratinocytes. All patients with AK showed negative FABP5 expression in the atypical cells in the basal layer, whereas the uninvolved upper layers showed diffuse, strong FABP5 expression, regardless of the grade of AK. All patients with BD showed heterogeneous and diffuse FABP5 expression in atypical cells of all layers of the epidermis. This study is the first to investigate the role of FABP5 in premalignant skin lesions. The unique immunohistochemical localization of the FABP5 can be a helpful diagnostic marker, and altered fatty acid metabolism may be the key in understanding the different pathophysiology of AK and BD.

Bowen disease with matrical differentiation: Report of an exceptional histopathologic presentation.

Matrical differentiation is the distinctive feature of pilomatricoma and other purely matrical adnexal neoplasms; additionally, foci of matrical differentiation have been also described in hybrid cysts of Gardner syndrome, as well as in a wide variety of benign and malignant cutaneous tumors, including basal cell carcinoma. We report an exceptional case of Bowen disease exhibiting multiple foci of matrical differentiation, as confirmed by means of immunohistochemical studies. Several types of divergent, non-squamous differentiation have been exceptionally reported in cutaneous squamous cell carcinoma in situ (cSCCIS), including sebaceous, mucinous/glandular, poroid, tricholemmal, and neuroendocrine differentiation; matrical differentiation may be added to this list. Our findings further emphasize the undifferentiated nature of neoplastic cells in cSCCIS.

Data Independent Acquisition Proteomic Analysis Can Discriminate between Actinic Keratosis, Bowen's Disease, and Cutaneous Squamous Cell Carcinoma.

Actinic keratosis, Bowen's disease and cutaneous squamous cell carcinoma (cSCC) are heterogeneous keratinocytic skin lesions. Biomarkers that can accurately stratify these lesion types are needed to support a new paradigm of personalized and precise management of skin neoplasia. In this paper, we used a data independent acquisition proteomics workflow, sequential window acquisition of all theoretical mass spectra, to analyze formalin-fixed paraffin-embedded samples of normal skin and keratinocytic skin lesions, including well-differentiated, moderately differentiated and poorly differentiated cSCC lesions. We quantified 3,574 proteins across the 93 samples studied. Differential abundance analysis identified 19, 5, and 6 protein markers exclusive to actinic keratosis, Bowen's disease and cSCC lesions, respectively. Among cSCC lesions of various levels of tumor differentiation, 118, 230, and 17 proteins showed a potential as biomarkers of well-differentiated, moderately differentiated and poorly differentiated cSCC lesions, respectively. Bioinformatics analysis revealed that actinic keratosis and cSCC lesions were associated with decreased apoptosis, and Bowen's disease lesions with over-representation of the DNA damage repair pathway. Differential expression of alternatively spliced FGFR2, Rho guanosine triphosphatase signaling, and RNA metabolism proteins were associated with the level of cSCC tumor differentiation. Proteome profiles also separated keratinocytic skin lesion subtypes on principal components analysis. Overall, protein markers have excellent potential to discriminate keratinocytic skin lesion subtypes and facilitate new diagnostic and therapeutic strategies.

Hypergranulotic dyscornification: 30 cases of a striking epithelial reaction pattern.

BACKGROUND: Hypergranulotic dyscornification (HD) is a rarely reported histological reaction pattern that may be observed in solitary benign keratoses. OBJECTIVE AND METHODS: We retrospectively reviewed all cases described as displaying "hypergranulotic dyscornification" at our institution between January 1st 1990 to September 1st 2018. We excluded cases that on retrospective review displayed changes of epidermolytic hyperkeratosis. We conducted electron microscopy (EM) of two lesions. RESULTS: Thirty cases were identified in our search. Eleven patients were men and 19 were women. Their mean age was 56.9 ± 21.2 years. In contrast to previous reports, we found that HD does not spare the head and neck area. Frequent clinical impressions were inflamed seborrheic keratosis, Bowen disease or inflamed verruca. The most distinctive histopathologic finding was the presence of a prominent granular layer with clumped perinuclear keratohyaline granules. Some cases had mounds of rounded, anucleate glassy eosinophilic corneocytes in the stratum corneum. We observed one case of incidental HD occurring in an epidermoid cyst. EM of HD showed dense perinuclear bands which appeared to match areas of positive staining by keratin immunohistochemistry, without evidence of pale cytoplasmic areas devoid of keratin filaments, characteristic of epidermolytic hyperkeratosis. CONCLUSION: HD is a reproducible finding in some benign keratoses, probably because of abnormal keratinization. Awareness of this unique reaction pattern will help prevent misdiagnosis.

Clonal highlights: Clonal seborrheic keratoses often demonstrates p16 expression.

BACKGROUND: At times, distinguishing Bowen disease (BD) and benign seborrheic keratosis (SK) is histologically challenging, especially when SK shows clonal features (clonal seborrheic keratosis [CSK]). While p16 is often reported as positive in BD and negative in SK, p16 expression in CSK is rarely studied. Here we investigate p16 immunohistochemistry in CSK, SK, and BD. METHODS: p16 immunohistochemistry with pattern of expression was noted for 14 CSK, 12 SK, and 18 BD. The degree of inflammation among lesions with respect to p16 expression was also noted. RESULTS: When examining p16 staining in clonal nests of CSK, 57% showed diffuse or patchy/diffuse positivity, 21% showed patchy positivity, and 21% showed clusters of single positive cells. 67% of BD showed diffuse positivity, 11% showed patchy/diffuse positivity, 17% showed patchy positivity, and 6% were negative. 25% of SK showed focal areas of patchy to full thickness positivity, 25% showed moderate number of positive single cells with or without patchy staining, and 50% showed negative/scattered single cell positivity. CONCLUSION: Our findings support that p16 positivity limited to clonal nests in CSK is normal. p16 positivity in clonal nests of CSK in isolation without concurrent atypical histologic features should not be used to support a diagnosis of BD.

Bowen disease with invasive mucin-secreting sweat gland differentiation: Report of a case and review of the literature.

Bowen disease (BD) with divergent adnexal differentiation is a rare composite cutaneous tumor featuring different phenotypic elements. Sebaceous, poroid and trichilemmal invasive components have been described in this setting and very infrequent reports of mucinous glandular differentiation are extant. Clinically, these tumors are not sufficiently distinctive to enable recognition without histopathological evaluation. From a microscopic perspective, care must be taken to exclude a collision tumor as well as other combined cutaneous neoplasms featuring squamous and glandular differentiation. Direct continuity between the two epithelial phenotypes helps to establish the correct diagnosis and generates interesting speculation about the pathogenesis of these and other epithelial skin tumors. We describe a case of BD in continuity with an invasive adenocarcinoma exhibiting mucinous sweat gland differentiation on the face of an elderly man. Details of the case are outlined with the objective of adding to a scant literature on this topic.

Mast Cells Are a Marked Source for Complement C3 Products That Associate with Increased CD11b-Positive Cells in Keratinocyte Skin Carcinomas.

By using immunohistochemistry and antibodies that identify complement C3c (in C3 and C3b) or CD11b receptor, we report that the proportion C3c+ mast cells and the number of CD11b+ cells are increased in basal cell carcinoma (BCC). Instead, only CD11b+ cells are increased in squamous cell carcinoma/Bowen's disease, and only slightly so in actinic keratosis. Only C3c+ mast cells are increased in psoriasis. Furthermore, C3c+ mast cells correlated positively with CD11b+ cells, and iC3b immunoreactivity was detected around tryptase+ mast cells. Therefore, mast cells may convey immunoregulatory signals through C3, C3b, and iC3b to CD11b+ cells, especially in BCC.

ΔNp63 promotes abnormal epidermal proliferation in arsenical skin cancers.

Arsenic is known to perturb epidermal homeostasis and induce abnormal keratinocyte proliferation, leading to skin carcinogenesis. P63 and its isoforms are essential to regulate epidermal homeostasis. This study aimed to investigate the role of p63 isoforms in abnormal epidermal proliferation induced by arsenic. Using arsenic-induced Bowen's disease (As-BD; an intraepidermal carcinoma) as a disease model, we found that in As-BD, the expression of proliferating basal keratinocytes marker cytokeratin 14 (CK14) and N-terminal truncated p63 isoform (ΔNp63; proliferation regulator) was increased, however, that of the differentiation marker cytokeratin 10 (CK10) and full-length p63 isoform (TAp63; differentiation regulator) was decreased in squamous cells as compared with healthy subjects. These observations were recapitulated in the arsenic-treated skin equivalents (SEs). The SEs showed that arsenic increased epidermal thickness, induced abnormal proliferation, and increased ΔNp63 expression in squamous cells as compared with the control. Treatment of cultured normal human epidermal keratinocytes (HKCs) with arsenic increased CK14 and △Np63 expressions, but decreased TAp63 and CK10 expressions. Furthermore, knockdown of ΔNp63 by RNA interference abrogated arsenic-induced CK14 expression and recovered the reduction of TAp63 and CK10 caused by arsenic. These findings indicated that ΔNp63 is a pivotal regulator in the abnormal cell proliferation in arsenical cancers.

Expression of Minichromosome Maintenance Proteins in Actinic Keratosis and Squamous Cell Carcinoma.

Minichromosome maintenance (MCM) proteins are a group of proteins involved in DNA replication and cell-cycle regulation. Because they are associated with DNA through G1 into S phase, MCM proteins are potentially specific indicators of cell proliferation that could be valuable markers of dysplasia, and preinvasive and invasive malignant tumors. To analyze MCM protein expression patterns in actinic keratosis (AK), Bowen disease (BD), and cutaneous squamous cell carcinoma (SCC), we performed immunohistochemical staining of MCM2, -5, and -7 on tissue microarray blocks from 91 AK, 50 BD, and 174 SCC samples. The distribution and semiquantitatively assessed number of positive cells were analyzed in relation to the type of the lesion and the SCC prognostic parameters (grade, diameter, and thickness). Basal expression of all 3 proteins was observed more frequently in AK, whereas the distribution in BD was predominantly diffuse (P<0.001). All 3 proteins showed peripheral distribution in most well-differentiated SCC and diffuse distribution in poorly differentiated tumors (P<0.001). Using the 50% cut-off value, there was a statistically significant difference among AK, BD, and SCC (P<0.001). In addition, all MCM proteins showed highly significant differences (P<0.001) between well-differentiated SCC and both moderately and poorly differentiated SCC. The diffuse distribution and 50% cut-off value of positive cells revealed statistically significant associations of all MCM proteins with SCC thicker than 6 mm. Our results suggest a role for MCM proteins in the progression of in situ keratinocytic lesions and their association with high-risk features in SCC.

Significant Role of Collagen XVII And Integrin ß4 in Migration and Invasion of The Less Aggressive Squamous Cell Carcinoma Cells.

Collagen XVII and integrin α6ß4 have well-established roles as epithelial adhesion molecules. Their binding partner laminin 332 as well as integrin α6ß4 are largely recognized to promote invasion and metastasis in various cancers, and collagen XVII is essential for the survival of colon and lung cancer stem cells. We have studied the expression of laminin γ2, collagen XVII and integrin ß4 in tissue microarray samples of squamous cell carcinoma (SCC) and its precursors, actinic keratosis and Bowen's disease. The expression of laminin γ2 was highest in SCC samples, whereas the expression of collagen XVII and integrin ß4 varied greatly in SCC and its precursors. Collagen XVII and integrin ß4 were also expressed in SCC cell lines. Virus-mediated RNAi knockdown of collagen XVII and integrin ß4 reduced the migration of less aggressive SCC-25 cells in horizontal scratch wound healing assay. Additionally, in a 3D organotypic myoma invasion assay the loss of collagen XVII or integrin ß4 suppressed equally the migration and invasion of SCC-25 cells whereas there was no effect on the most aggressive HSC-3 cells. Variable expression patterns and results in migration and invasion assays suggest that collagen XVII and integrin ß4 contribute to SCC tumorigenesis.

Potential role of the OVOL1-OVOL2 axis and c-Myc in the progression of cutaneous squamous cell carcinoma.

OVOL1 and OVOL2 are ubiquitously conserved genes encoding C2H2 zinc-finger transcription factors in mammals. They promote epithelial cell proliferation, differentiation, and mesenchymal-to-epithelial transition, coordinately mediated via the Wnt signaling pathway. We previously reported that human OVOL1 and OVOL2 were preferentially expressed in the normal epidermis and hair follicles as well as their tumors, and found that OVOL1 is upregulated in Bowen's disease and downregulated in cutaneous squamous cell carcinoma. The aims of this study were to elucidate the potential role of the OVOL1-OVOL2 axis in Bowen's disease and squamous cell carcinoma, and to reveal the relationship between OVOL and c-Myc, a proto-oncogene that plays a pivotal role in the malignancy of epithelial tumors. We investigated 20 Bowen's disease and 20 squamous cell carcinoma clinical samples and a human squamous cell carcinoma cell line (A431) using immunohistochemical staining and molecular biological approaches. Immunohistochemical analysis revealed that OVOL1 was upregulated in Bowen's disease and markedly downregulated in squamous cell carcinoma; conversely, c-Myc was downregulated in Bowen's disease and upregulated in squamous cell carcinoma. OVOL2 was markedly upregulated in the nucleus of Bowen's disease cells, but the distribution of OVOL2 expression in squamous cell carcinoma varied widely; OVOL2 was typically expressed in the cytoplasm, but only sporadically in the nucleus. Furthermore, knockdown of OVOL1 using a specific small interfering RNA increased the mRNA and protein levels of c-Myc and OVOL2. Knockdown of OVOL2 did not significantly affect the mRNA and protein levels of either c-Myc or OVOL1. These results suggest that OVOL1 is an upstream suppressor of c-Myc and OVOL2, and the OVOL1-OVOL2 axis is a modulator of c-Myc, coordinately regulating the invasiveness of cutaneous squamous cell carcinoma. Taken together, this study suggests that the OVOL1-OVOL2 axis is a key modulator of c-Myc expression in the shift from in situ epidermal malignancy (Bowen's disease) to invasive squamous cell carcinoma.

Electroacupuncture ameliorates abnormal defaecation and regulates corticotrophin-releasing factor in a rat model of stress.

OBJECTIVE: To examine the effect of electroacupuncture (EA) treatment on abnormal defaecation in a rat model of chronic heterotypic stress (CHS) and investigate the underlying mechanisms. METHODS: 20 male Sprague-Dawley rats were randomly divided into three groups: normal (n=6), CHS (n=7), and CHS+EA (n=7). Rats in the CHS group and CHS+EA groups received four different types of stressors for 7 days. For rats in the CHS+EA group, EA was applied at ST36 in the bilateral hind legs for 30 min before each stress-loading session. Rats in the normal group did not receive stressors or EA treatment. The faecal pellets of each rat were collected and weighed at a fixed time every day. Protein expression of corticotrophin-releasing factor (CRF) in the hypothalamus and colorectal tissues was measured by Western blotting at the end of the experiment on the 7th day. RESULTS: After 7 consecutive days of CHS, the number of faecal pellets, faecal wet weight, and faecal water content were significantly increased in the CHS group compared with the normal group (p=0.035, p=0.008 and p=0.008, respectively). All three parameters were significantly decreased in CHS+EA versus CHS groups (p=0.030, p=0.011 and p=0.006, respectively). Stress significantly increased CRF expression in both the hypothalamus and colorectal tissues. The excessive CRF responses seen following CHS were significantly suppressed by EA treatment. CONCLUSIONS: EA treatment can ameliorate stress loading induced abnormal defaecation in rats and decrease protein expression of CRF centrally (hypothalamus) and peripherally (colorectal tissues), suggesting a potentially therapeutic role for EA in stress-related responses.

Human papillomavirus infection and p16 expression in the immunocompetent patients with extragenital/extraungual Bowen's disease.

BACKGROUND: The role of human papillomaviruses (HPV) in the development of squamous cell carcinoma (SCC) has been established for anogenital lesions but still remains controversial for carcinomas in other sites. The aim of this study was to determine the α-HPV and ß-HPV prevalence and their association with p16 expression, sun exposure, and clinicopathological findings in patients with Bowen's disease (BD). METHODS: One hundred sixty nine skin biopsy specimens from 157 immunocompetent patients with extragenital/extraungual BD were examined for HPV status and p16 expression. The presence of koilocyte-like changes, solar elastosis and papillomatosis was recorded for each specimen. RESULTS: BD was diagnosed more often in potentially sun-exposed sites with prevalence 73.6 % and a remarkable predilection for the head and neck region. High risk α-HPV or ß-HPV were detected in 34.7 % of lesions and ß-HPV infections dominated over α-HPV. Higher prevalence of koilocyte-like changes and papillomatosis was found in HPV-positive specimens but it was not statistically significant. The expression of p16 was detected in 79.8 % of lesions and displayed no correlation with the HPV status. HPV-positivity tended to be detected more often in sun-protected sites. Dual infections by α-HPV/ß-HPV genera and mixed α-HPV infections were not detected, while 37.5 % of ß-HPV positive specimens were infected by two or more ß-HPV genotypes. HPV 9 was significantly associated with mixed ß-HPV infections. CONCLUSIONS: HPV may play an etiological role at least in some SCC in situ arising in extragenital sites. Sunprotected sites may be more dependent on HPV-mediated co-carcinogenesis than sun exposed areas. The presence of the p16-expression, papillomatosis or koilocyte-like change is not a reliable marker of HPV infection in SCC in situ.

Role of mitochondria, ROS, and DNA damage in arsenic induced carcinogenesis.

The International Agency for Research on Cancer (IARC) declared arsenic a class I carcinogen. Arsenic exposure induces several forms of human cancers, including cancers of skin, lung, liver, and urinary bladder. The majority of the arsenic-induced cancers occur in skin. Among these, the most common is Bowen's disease, characterized by epidermal hyperplasia, full layer epidermal dysplasia, leading to intraepidermal carcinoma as well as apoptosis, and moderate dermal infiltrates, which require the participation of mitochondria. The exact mechanism underlying arsenic induced carcinogenesis remains unclear, although increased reactive oxidative stresses, leading to chromosome abnormalities and uncontrolled growth, and aberrant immune regulations might be involved. Here, we highlight how increased mitochondrial biogenesis and oxidative stress lead to mitochondrial DNA damage and mutation in arsenic induced cancers. We also provide therapeutic rationale for targeting mitochondria in the treatment of arsenic induced cancers.

Limitations of Ber-EP4 for distinction of Bowen disease from basal cell carcinoma.

BACKGROUND: Diagnostic differentiation between Bowen disease a variant of squamous cell carcinoma in situ (SCCIS) and basal cell carcinoma (BCC) can be difficult on the basis of hematoxylin and eosin (routine) staining in small or fragmented biopsy samples. Ber-EP4 staining is diagnostically reliable for differentiation between BCC and cutaneous squamous cell carcinoma [Dasgeb et al. Biomark Cancer, 5: 7, (2013); Tellechea et al. Am J Dermatopathol, 15: 452 (1993)]. The objective of this study was to determine the usefulness of Ber-EP4 staining for differentiation of SCCIS from BCC. METHODS: Here, we performed immunohistochemistry with a Ber-EP4 antibody in 76 cases of Bowen type of SCCIS. As positive controls we selected 16 cases of BCC. RESULTS: A positive reaction was obtained for Ber-EP4 in the secretory portion of eccrine and apocrine glands and in follicular germinative cells at the lower end of catagen hairs of normal skin tissue. All BCC samples tested were positive. Of the Bowen type SCCIS samples, 26.3% reacted positively (at least 5% positive staining of neoplastic cells). In 3/76 cases (3.9%) more than 50% of the tumor cells expressed Ber-EP4. CONCLUSION: We conclude that Ber-EP4 expression is not always helpful to distinguish between Bowen type of SCCIS and BCC, as Ber-EP4 expression in Bowen type SCCIS is not infrequent.

Cytokeratin 17 immunoexpression in actinic keratosis (bowenoid and nonbowenoid) and in Bowen disease.

Cytokeratin (CK) 17 immunoexpression has been investigated in nonmelanoma skin cancer as well as in many preinvasive epithelial malignancies. However, there is not any previous study of CK17 immunoexpression in actinic keratosis (AK) or Bowen disease in nonimmunocompromised patients. We evaluated CK17 immunoexpression in 20 cases of AK (10 nonbowenoid and 10 bowenoid) as well as in 10 cases of Bowen disease. We identified expression of CK17 in the superficial layers above the atypical foci. In some cases, there were foci of expression by the full thickness of the epidermis, which was the predominant pattern in very few cases (1 Bowen disease and 1 bowenoid AK). In addition, 1 case of bowenoid AK showed CK17 expression in a "skyline" pattern in the basal layer of the epidermis. Cytokeratin 17 immunostaining did not allow us to distinguish between the 3 entities studied. However, the immunostaining allowed us to distinguish atypical foci in the biopsies, even if atypicality was minimal. In addition, CK17 was useful in identifying surgical borders involved by disease in cases in which the hematoxylin-eosin was difficult to evaluate. Cytokeratin 17 immunoexpression might have a role in evaluating surgical borders in some cases of AK and Bowen disease.

Orthokeratotic Bowen disease: a histopathologic, immunohistochemical and molecular study.

BACKGROUND: Some examples of Bowen disease lack the characteristic broad parakeratosis making their histopathologic diagnosis particularly difficult in small and incomplete biopsies. MATERIALS AND METHODS: The archives of our dermatopathology laboratory were searched for cases of Bowen disease with >75% orthokeratosis (orthokeratotic Bowen disease) and classic Bowen disease (>25% parakeratosis). Selected specimens were evaluated histopathologically, using immunohistochemical stains (CK10, CK7, Bcl-2, p16 and Ki-67) and by DNA amplification/sequencing for human papilloma virus (HPV) subtypes. RESULTS: Among 102 consecutive samples 14 cases of orthokeratotic Bowen disease were identified. In comparison with 24 examples of classic Bowen disease, the orthokeratotic examples occurred more frequently in female and younger patients (p = 0.04 and 0.008, respectively) but shared most of the histopathologic features of classic Bowen disease except a preserved granular layer and relative absence of the eyeliner sign (p < 0.0001 and p = 0.042, respectively). Immunohistochemical staining patterns were similar between the two groups. HPV types 11, 16 and 58 were identified from five cases of orthokeratotic Bowen disease. CONCLUSION: Orthokeratotic Bowen disease is a distinct variant of squamous cell carcinoma in situ associated with HPV infection in less than half of the cases studied.