Human papillomavirus-associated increase in p16INK4A expression in penile lichen sclerosus and squamous cell carcinoma.

BACKGROUND: Human papillomaviruses (HPVs) are sexually transmitted human carcinogens that may play a role in the oncogenesis of penile cancer. OBJECTIVES: To investigate the role of HPV infection and expression of the tumour suppressor protein p16INK4A in the pathogenesis of penile cancer. METHODS: By means of polymerase chain reaction amplification and reverse hybridization line probe assay to detect HPV infection, and immunohistochemical staining for p16INK4A and Ki67, we analysed 26 penile squamous cell carcinomas (SCCs) and 20 independent penile lichen sclerosus (LS) lesions from 46 patients. RESULTS: HPV DNA was found in 54% of penile SCCs and 33% of penile LS cases in single and multiple infections. High-risk HPV 16 was the predominant HPV type detected. No relationship between Ki67 expression and HPV infection was observed. Strong immunostaining for p16INK4A correlated with HPV 16/18 infection in both penile LS and penile SCC. In our penile SCC series the cancer margins were also associated with penile LS in 13 of 26 lesions, and HPV was detected in seven of the 13 SCC cases associated with LS and in six of the 11 SCC lesions not involving LS. CONCLUSIONS: Our study shows a high prevalence of HPV 16 and p16INK4A expression in penile lesions, consistent with an active role for HPV in interfering with the retinoblastoma pathway. High-risk HPV infection could be involved in the tumorigenic process in 50% of penile cancers, and the use of prophylactic HPV vaccines has the potential to prevent these cancers.     

Immunohistochemical staining of p16 in squamous cell carcinomas of the genital and extragenital area

Background and objectivesPositive immunostaining for the tumor suppressor protein p16 is associated with the presence of mucosal or αsubtypes of human papillomavirus (HPV) in cervical and genital squamous cell carcinoma (SCC). The aim of this study was to determine whether p16 immunostaining is also associated with mucosal HPV in extragenital SCC.Material and methodsParaffin sections of lesions located in the genital region (8 genital warts, 3 intraepidermal SCCs, and 7 invasive SCCs) and extragenital area (29 intraepidermal SCCs corresponding to Bowen disease and 10 invasive SCCs) were stained for p16 by immunohistochemistry. Mucosal HPV was detected by polymerase chain reaction (PCR).ResultsIn the genital area, p16 immunostaining was negative in genital warts and positive in all 3 intraepidermal SCCs and 2 invasive SCCs (29%). Mucosal HPV was detected in 6 genital warts and 2 intraepidermal SCCs (100% after exclusion of 3 lesions that could not be analyzed by PCR) and in the 2 invasive SCCs that were positive for p16. In the extragenital area, 19 intraepidermal SCCs (95%) and 2 invasive SCCs (20%) were immunopositive for p16. Mucosal HPV was detected in 4 intraepidermal SCCs (p16 immunopositive) and 1 invasive SCC (p16 immunonegative). In intraepidermal SCCs, p16 immunostaining facilitated the identification of dermal microinfiltration or invasion of normal skin appendages.ConclusionsAccording to our results, unlike in genital SCCs, p16 immunopositivity is independent of the presence of HPV in extragenital SCCs. Compared with intraepidermal SCCs, the absence of p16 protein in invasive SCCs in the extragenital area would indicate progression of the disease.     

Cutaneous manifestations of dabrafenib (GSK2118436): a selective inhibitor of mutant BRAF in patients with metastatic melanoma

Background Inhibitors of mutant BRAF are emerging as standard of care in patients with metastatic melanoma carrying relevant oncogenic mutations. Cutaneous reactions are frequent and significant. We conducted a systematic prospective dermatological review of all patients enrolled at a single institution in the phase I/II clinical trial of the mutant BRAF inhibitor dabrafenib (GSK2118436). Objectives To identify the cutaneous manifestations of the BRAF inhibitor dabrafenib; to form diagnostic criteria to standardize the diagnosis of verrucal keratotic squamoproliferative lesions; and to bring awareness to the medical community of the importance of dermatological assessment of patients taking dabrafenib. Methods Patients enrolled in the phase I/II trial (n = 43) were monitored for the development of new skin lesions. Each new lesion was photographed, a clinical diagnosis recorded and, where appropriate, a biopsy taken. Human papillomavirus (HPV) and p16 immunohistochemistry analyses were performed. Results The most frequently observed lesions were verrucal keratotic squamoproliferative lesions (49%), Grover’s disease (27%) and reactive hyperkeratotic lesions on the soles, at points of friction (22%). Eighteen squamous cell carcinomas (SCCs) occurred in 20% of patients. Most SCCs appeared between weeks 6 and 24 following commencement of therapy on both sun‐damaged and nonsun‐damaged skin. All SCCs were well differentiated, five were of the keratoacanthoma type, and two were SCC in situ. Other lesions observed included seborrhoeic keratoses, epidermal cysts, acneiform eruptions, hair loss and changes in hair structure. HPV was negative in 15 of the 16 tissues studied and p16 expression was higher in SCCs compared with verrucal keratoses. Conclusions Administration of the mutant BRAF inhibitor dabrafenib is associated with induction of keratinocytic proliferation, which in some cases develops features of low‐grade malignancy. Highly oncogenic HPV infection is unlikely to be a contributor to the formation of SCCs or verrucal keratoses.     

Multiple human papillomavirus-16 associated digital squamous-cell carcinomas in an immunocompetent woman with prior human papillomavirus-related genital carcinoma

High-risk subtype human papillomavirus (HPV) infection, which is known to contribute to the oncogenesis of anogenital squamous-cell carcinoma (SCC), is detected in the majority of digital SCCs. Evidence suggests a genital-digital route of transmission of high-risk HPV, and most HPV-related digital SCCs occur near the nail unit in immunocompetent adults. As early HPV-related SCC commonly appears as a verrucous periungual papule, a biopsy should be considered if such a lesion persists or occurs in an individual who is likely to inoculate their digits with high-risk HPV from digital-genital contact with themselves or sexual partners. We present a 60-year-old woman, who has a personal history of vulvar and cervical SCC and an appreciable disease burden from SCCs that involved five digits of her hands.     

Characterization of skin lesions induced by skin‐tropic α‐ and β‐papillomaviruses in a patient with epidermodysplasia verruciformis

Epidermodysplasia verruciformis (EV) is a rare, lifelong, autosomal recessive skin disease associated with an unusual susceptibility to infections with ubiquitous β‐human papillomaviruses (β‐HPVs), and in some cases also skin‐tropic α genotypes. In this case report, HPV infection patterns were correlated with pathology and clinical manifestations of skin lesions from a patient with EV, without loss‐of‐function mutations in the EVER genes. HPV infection was investigated by both polymerase chain reaction (PCR) and laser capture microdissection (LCM) PCR, alongside immunofluorescence for the viral proteins E4 and L1. Analysis of eyebrow hair bulbs revealed multiple β‐genus HPV infections, including HPV20 and HPV24, which were consistently found in all 11 skin lesions on the patient. Six lesions were also positive for the skin tropic α‐genotype, HPV27. Clear‐cut differences between two wart‐like lesions, one caused by a skin‐tropic α‐genotype and the other by β‐genotypes (as detected by LCM PCR) are shown, including the high cellular proliferation rate in β‐HPV‐induced lesions. Widespread expression of the early protein E4 was also evident in skin lesions positive for HPV20 by LCM PCR in both tumours and nearby intraepidermal proliferative areas. L1 expression was restricted to areas of intraepidermal proliferation showing productive infection. The patient's inability to control HPV infections is conclusive to the uncontrolled replication of few genotypes from both α and β genera, which cause proliferative lesions with clear‐cut clinical and histological features.     

Anal carcinoma in human immunodeficiency virus‐positive men: results of a prospective study from Germany

Background Anal intraepithelial neoplasia (AIN), a human papillomavirus (HPV)‐associated potential precursor lesion of anal cancer, is frequent among human immunodeficiency virus (HIV)‐positive men who have sex with men (MSM). There is a paucity of data published on the progression of high‐grade AIN to invasive cancer as well as on clinical and virological characteristics comparing anal margin and anal canal carcinoma. Objectives To search for anal carcinoma and AIN in a large series of HIV‐positive MSM, to assess treatment response of anal carcinoma, and to analyse lesional HPV spectrum of anal cancers. Methods Detection of anal carcinoma and AIN was performed using cytology, high‐resolution anoscopy, and histology in case of abnormal findings. Additionally, HPV analyses for 36 high‐ and low‐risk α‐HPV types were performed in patients with anal carcinoma. Results In total, 446 German HIV‐positive MSM were examined within an observation period of 5 years and 10 months. Of these, 116 (26·0%) patients had normal findings, 163 (36·5%) had low‐grade AIN, 156 (35·0%) had high‐grade AIN, and 11 (2·5%) had anal carcinoma as evidenced by the highest grade of cytology/histology. Five patients with anal cancer, who had refused treatment of their precancerous lesions, had progressed from high‐grade AIN to invasive cancer within a median time of 8·6 months. All anal cancers carried high‐risk α‐HPV types. All five squamous cell carcinomas (SCCs) of the anal canal were HPV16 positive. In contrast, only one of the four anal margin SCCs were HPV16 positive (HPV31, HPV33 and HPV33 + HPV68 were found in the other three anal margin SCCs). HPV59 was found in two adenocarcinomas, one of which additionally carried HPV33. In contrast to the cancer biopsies, a broad spectrum of surface high‐ and low‐risk HPV types was found in anal swabs of the patients. Surgical excision resulted in long‐term disease control of all anal margin carcinomas, whereas combined chemoradiotherapy in carcinomas of the anal canal was associated with high recurrence rates, high toxicity, and high mortality. Conclusions Anal carcinoma and AIN are frequent in HIV‐positive men, even in patients participating in anal cancer prevention programmes. High‐grade dysplasia in these patients can progress to invasive cancer within a short period of time. Anal margin carcinoma and anal canal carcinoma differ substantially in their lesional HPV spectrum, prognosis and treatment response.     

Penile intraepithelial neoplasia: histopathological evaluation,HPV typing,clinical presentation and treatment

Background Genital human papillomavirus (HPV) infection in male patients can cause great variety of lesions, most of which are benign, but some are categorised as penile intraepithelial neoplasia (PIN). Objectives The aims of the present work were to: (i) perform HPV testing and correlate to histopathology from genital HPV‐induced lesions in men; and (ii) determine the clinical presentation and treatment of PIN. Methods Men attending the venereological clinic at Karolinska Hospital for surgical treatment of genital HPV infection were included. Two biopsies were taken from each patient, one for histopathology and one for HPV typing using PCR. Patients exhibiting PIN were selected for further analysis. Lesions were described, and treatment and follow‐up data were recorded. Results Forty‐seven of 303 (16%) male HPV patients exhibited PIN lesions. Nineteen were afflicted with lesions denominated as PIN I, 13 had PIN II lesions and 15 had PIN III lesions. Macular lesions were most common (n = 27). Ninety‐three percent of the analysed PIN lesions were HPV‐positive. Three of twelve (25%) HPV‐positive PIN III lesions contained only low‐risk HPV types compared to 13 of 19 (68%) PIN I lesions. In addition, 9 of 12 (75%) HPV‐positive PIN III lesions contained high‐risk HPV types compared to 6 of 19 (32%) PIN I lesions (P = 0.029). HPV 6 and HPV 16 were the most prevalent genotypes. A mean of four surgical treatment sessions was performed during a treatment period of mean 27 months. Conclusions PIN is highly HPV‐positive, can show differing clinical pictures and is difficult to treat.     

Isolated extragenital HPV-thirties-group-positive bowenoid papulosis in an AIDS patient

We report a case of extragenital bowenoid papulosis in a man with AIDS. The lesions occurred on the anterolateral aspects of the neck, and were not associated with clinical genital or periungual involvement. In situ hybridization demonstrated abundant HPV DNA within the thirties group (31/33/35), in the absence of HPV-16 or -18.     

Human papillomavirus type 56‐associated Bowen disease

Summary Background Some cases of human papillomavirus (HPV) type 56 infection in Bowen disease have been reported. However, the incidence and clinical characteristics are still unclear. Objective To clarify the prevalence of HPV type 56‐positive Bowen disease in our department and to characterize the clinical manifestations. Methods Sixty‐eight specimens of Bowen disease were examined by polymerase chain reaction using HPV consensus primers, and the amplified products were subjected to DNA sequence analyses. Moreover, positive samples were investigated by in situ hybridization. These findings were used to clarify the clinical characteristics of HPV‐positive Bowen disease. Results  Eight out of 68 specimens (12%) of Bowen disease were HPV‐positive, of which six specimens were HPV type 56‐positive. The HPV type 56‐positive lesions were characterized by a longitudinal melanonychia or a deeply pigmented keratotic lesion. The remaining two specimens were genital Bowen disease in which HPV type 16 was detected. In situ hybridization demonstrated the positive cells in the upper layer of epidermis. The HPV type 56 detected in the samples of longitudinal melanonychia can be divided into at least into two types. Conclusions This study determined the prevalence of HPV type 56‐positive Bowen disease. Longitudinal melanonychia is the most characteristic manifestation of HPV type 56‐associated Bowen disease.     

Human papillomavirus in cutaneous squamous cell carcinoma and cervix of a patient with psoriasis and extensive ultraviolet radiation exposure

"High-risk" human papillomaviruses (HPVs) are associated with intraepithelial neoplasia and cancer of the uterine cervix. HPV has also been found in nonmelanoma skin cancer (NMSC), especially in squamous cell carcinomas (SCCs) of immunosuppressed patients. Recently, lesions of psoriasis have been shown to harbor HPV, and patients with psoriasis often have a history of extensive therapy with ultraviolet radiation (UVR). UVR is the major known risk factor in the occurrence of NMSC, in which HPV may be a cofactor for SCC. We report an otherwise healthy, nonimmunosuppressed patient with psoriasis who had a history of extensive exposure to UVR and experienced multiple SCCs on UV-exposed body sites. By the polymerase chain reaction method, we detected HPV in 5 of 9 SCCs. Automated sequencing showed HPV types 12 and 17. Only 1 of 3 normal skin specimens was HPV positive (HPV type 17). This positive specimen was from UV-exposed skin; one of the two HPV-negative, normal skin specimens was located on a body site not exposed to sun. In addition, HPV type 62 was found in a brush specimen of the uterine cervix. This case report suggests an association between psoriasis, HPV infection, and UVR exposure, in onset of SCC.     

Altered gene expression in squamous cell carcinoma arising from congenital unilateral linear porokeratosis

Congenital unilateral linear porokeratosis (CULP) is a rare disorder of keratinization that shares clinical and molecular similarities with psoriasis. It also has an increased risk for malignant transformation to cutaneous squamous cell carcinoma (SCC). We investigated the expression of psoriasin, human beta‐defensin‐2, cathelicidin antimicrobial peptide/LL‐37, e‐cadherin, involucrin, p16^INK4a, p53, cyclin D1 and microchromosome maintenance protein 7 in healthy skin and in lesions of psoriasis, CULP and SCC from the same patient. p16^INK4a was overexpressed in CULP but not in the subsequent SCC. Psoriasin was overexpressed in psoriasis, CULP and SCC compared with healthy skin. Speculatively, p16^INK4a and psoriasin could be involved in the pathogenesis of CULP. Moreover, psoriasin may play a role in the malignant transformation of CULP to SCC.     

Detection of human papillomavirus type 56 in Bowen's disease involving the nail matrix

Background As Bowen’s disease of the nail apparatus is quite rare, there have been only a few reports on the prevalence of human papillomavirus (HPV) infection in this condition. Objectives The purpose of this study was to clarify the association of HPV with this disease involving the nail apparatus. Methods Five patients with Bowen’s disease of the nail apparatus were investigated clinically, virologically and histologically. Total DNAs extracted from excised skin lesions were analysed using polymerase chain reaction (PCR) for the presence of HPV DNA and the amplified products were subjected to DNA sequence analyses. Histological localization of HPV DNA was examined by in situ hybridization. Results In three of five patients, HPV was detected by PCR amplification, and subsequent sequence analyses of the PCR products showed the sequences of HPV type 56. A common clinical feature of the three HPV‐positive patients was longitudinal melanonychia. In contrast, the two HPV‐negative patients presented with a convex nail deformity and a periungual ulcerative lesion. In two of three positive cases, there was a silent point mutation in the L1 gene of each HPV. In the remaining one case, the nucleotide sequence was consistent with the consensus sequence of HPV 56. Sequence analyses of the E6 gene revealed the infection of different variants of HPV 56 among the three cases. The viral genomes were located in keratinocyte nuclei upon in situ hybridization. Conclusions HPV 56 may be involved in the carcinogenesis of Bowen’s disease affecting the nail matrix with longitudinal pigmentation.     

MMP‐10 (Stromelysin‐2) and MMP‐21 in human and murine squamous cell cancer

Abstract: The squamous cell cancers (SCC) of renal transplant recipients are more aggressive and metastasize earlier than those of the non‐immunocompromised population. Matrix metalloproteinases (MMPs) have a central role in tumor initiation, invasion and metastasis. Our aim was to compare the expression of MMPs‐10, ‐12 and ‐21 in SCCs from immunosuppressed (IS) and control patients and the contribution of MMPs‐10 and ‐21 to SCC development in the FVB/N‐Tg(KRT5‐Nfkbia)3Rto mouse line. Immunohistochemical analysis of 25 matched pairs of SCCs, nine of Bowen’s disease and timed back skin biopsies of mice with selective inhibition of Rel/NF‐κB signalling were performed. Semiquantitatively assessed stromal MMP‐10 expression was higher (P = 0.009) in the control group when compared with IS patients. Tumor cell‐derived MMP‐10, ‐12 and ‐21 expression did not differ between the groups but stromal fibroblasts of the control SCCs tended to express MMP‐21 more abundantly. MMP‐10 expression was observed already in Bowen’s disease while MMP‐21 was absent. MMP‐10 and ‐21 were present in inflammatory or stromal cells in ageing mice while dysplastic keratinocytes and invasive cancer were negative. Our results suggest that MMP‐10 may be important in the initial stages of SCC progression and induced in the stroma relating to the general host‐response reaction to skin cancer. MMP‐21 does not associate with invasion of SCC but may be involved in keratinocyte differentiation.     

Human papillomavirus type 26 infection causing multiple invasive squamous cell carcinomas of the fingernails in an AIDS patient under highly active antiretroviral therapy

Squamous cell carcinoma (SCC) of the nail unit is a rare disorder. An association with high-risk genital human papillomavirus (HPV) infection has been reported. We report a 28-year-old human immunodeficiency virus (HIV)-infected bisexual man who had multiple invasive SCC of the fingers, infected with the rare type HPV 26. Classification of HPV 26 as high- or intermediate-risk type has been uncertain, due to its rare presence in cervical cancer. Despite successful treatment with highly active antiretroviral therapy (HAART), the patient developed extensive hyperkeratotic nailbed proliferations of all fingers. Tumours were refractory to treatment and invaded into adjacent tissues. X-rays of the hands demonstrated bone invasion, necessitating amputation of distal phalanges of several fingers. Histologically, highly differentiated preinvasive and invasive verrucous SCCs were identified. Molecular DNA typing identified HPV 26 in the SCCs and in some premalignant lesions. By in situ hybridization HPV 26 DNA was detected in numerous tumour cells, indicating productive infection with high-level amplification of the viral genome. In the remaining proliferations, high-risk HPV type 58, cutaneous HPVs and a putative new HPV type were identified. HPV 26 infection appears to be causally involved in the development of SCC of the nail unit in this immunosuppressed patient. Timely evaluation of chronic verrucous nailbed tumours is recommended, especially in immunocompromised patients. Identification of HPV 26, besides known high-risk HPV types, may identify patients at risk for developing SCC of the nailbed and possibly at other locations.     

Seropositivity for human papillomavirus and incidence of subsequent squamous cell and basal cell carcinomas of the skin in patients with a previous nonmelanoma skin cancer

Background Infection with human papillomaviruses (HPVs) is a risk factor for several epithelial cancers, but its relationship with keratinocyte tumours has not yet been established. Objective In this prospective study we investigated the possible role of different HPVs in the incidence of a subsequent nonmelanoma skin cancer (NMSC). Methods One hundred and fifty‐three patients with squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) enrolled in a previous case–control study were re‐contacted, and a follow‐up visit was offered. Demographic and clinical data, date of first NMSC presentation, Fitzpatrick skin type and history of NMSC during the follow‐up period were ascertained. Recurrences and new second cancers were considered together as ‘outcomes’ in time‐to‐event analyses and in Cox proportional hazard models. Results Clinical data were obtained in 107 patients. HPV seropositivity at baseline was strongly associated with the risk of developing a second SCC after 5 years for a number of beta and gamma HPV types. For example, HPV‐24‐seropositive patients with an SCC at baseline had a 4‐fold increased risk of developing a subsequent SCC (hazard ratio 4·35, 95% confidence interval 1·2–15·6, P = 0·024). No association between serological status for any HPV type tested and an increased risk of BCC was found. Conclusions We observed a consistent pattern of a positive association between seropositivity for beta and gamma HPV types and the risk of a subsequent SCC in patients with a previous SCC. Our data corroborate the results of previous case–control studies and may spur further prospective studies on the causal role of HPVs in NMSC.     

Effects of Coccoloba uvifera L. on UV‐stimulated melanocytes

Background: Exposure to ultraviolet (UV) radiation induces generation of reactive oxygen species, production of proinflammatory cytokines and melanocyte‐stimulating hormone (MSH) as well as increase in tyrosinase activity. The potential photoprotective effects of Coccoloba uvifera extract (CUE) were evaluated in UV‐stimulated melanocytes. Methods: Human epidermal melanocytes were used as an in vitro model to evaluate the effects of CUE on the production interleukin‐1α (IL‐1α), tumor necrosis factor α (TNF‐α), and α‐MSH under basal and UV‐stimulated conditions. Antioxidant and anti‐tyrosinase activities were also evaluated in membrane lipid peroxidation and mushroom tyrosinase assay, respectively. Results: Coccoloba uvifera L. showed antioxidant and anti‐tyrosinase activities and also inhibited the production of IL‐1α, TNF‐α and α‐MSH in melanocytes subjected to UV radiation (P<0.01). Moreover, CUE inhibited the activity of tyrosine kinase in cell culture under basal and UV radiation conditions (P<0.001), corroborating the findings of the mushroom tyrosinase assay. Conclusion: This study supports the photoprotective potential of CUE.     

Multiple‐digit periungual Bowen's disease: a novel treatment approach with radiotherapy

Multiple periungual Bowen disease [BD; also known as squamous cell carcinoma (SCC) in situ] is rare. The pathogenesis of the disease is linked to human papilloma virus, and in some instances to chronic immunosuppression. The usual management of periungual BD is by local excision, Mohs micrographic surgery or distal phalanx amputation. Our patient was offered radiotherapy in the hope of maximizing residual function and minimizing morbidity from treatment. A good response was seen at 2 months post‐radiotherapy, but this was followed by relapses at 4 and 6 months post‐radiotherapy. Persistent anonychia resulted in improved access to the involved skin, making topical therapy possible. Radiotherapy can be a valuable management approach for periungual SCC/BD in locations where amputation could result in substantial disability.     

Lichen sclerosus is frequently present in penile squamous cell carcinomas but is not always associated with oncogenic human papillomavirus

BACKGROUND: Penile squamous cell carcinoma (SCC) may occur on pre-existing lesions of lichen sclerosus (LS). However, the prevalence of histological changes of LS in penile SCC is not well established. Moreover, mucosal oncogenic human papillomaviruses (HPVs) are sometimes detected in penile SCC, but have not been systematically sought in LS-associated penile SCC. OBJECTIVES: To establish the prevalence of LS histological changes and of mucosal oncogenic HPV in a series of patients with penile SCC. METHODS: Consecutive cases of histologically proven penile SCC from a single university hospital over a 14-year period were retrospectively selected and reviewed. Histological signs of LS were systematically sought. HPV was detected by polymerase chain reaction (PCR) amplification of DNA from paraffin-embedded skin samples using general primers GP5+/GP6+ (allowing detection of mucosal HPV) and oncogenic type 16-, 18-, 31- and 33-specific primers. RESULTS: Eighteen cases of penile SCC were found. The mean +/- SD age of patients at diagnosis was 67.3 (14.5 years). In eight of 18 (44%) cases, SCC was associated with histological features of LS. Seventeen skin biopsy specimens of SCC (nine without and eight with LS histology) were subjected to PCR amplification for HPV. Mucosal HPV was detected in six of them (35%). Five of nine SCCs without histological features of LS were positive for mucosal HPV: three with HPV type 16 and two with only general primers. In contrast, all eight SCCs associated with LS were negative for oncogenic HPV types, although one was positive with general primers. CONCLUSIONS: Penile SCC seems to be frequently associated with LS histological changes. As with vulval SCC, we found that non-LS-associated penile SCC tended to be frequently associated with oncogenic HPV infection, whereas LS-associated penile SCC was not. Larger series are needed to confirm this association.     

Betapapillomavirus in multiple non‐melanoma skin cancers of Netherton syndrome: Case report and published work review

Netherton syndrome (NS) is a rare genetic disease presenting with ichthyosiform erythroderma, hair alterations and atopy. NS is due to SPINK5 gene mutations, which cause absent or decreased expression of the encoded protein lymphoepithelial Kazal‐type‐related inhibitor (LEKTI) in all stratified epithelia. We report a 43‐year‐old man affected with NS, who developed several squamous and basal cell carcinomas on the face, ears and scalp and papillomatous lesions of hips, groin and genitoanal area. Molecular analysis of the SPINK5 gene revealed homozygosity for the recurrent mutation c.238dupG. Human papillomavirus (HPV) DNA detection and genotyping on patient skin carcinomas and hyperplastic lesions found betapapillomavirus DNA in 10 of 12 (83%) carcinomas and in a hip papilloma, with multiple betapapillomavirus types being identified. Immunohistochemistry showed upregulated expression of p16^INK4a protein in nine of 12 (75%) patient carcinomas, in line with findings reported in HPV‐related cancers. LEKTI and filaggrin immunostaining was strongly decreased in patient skin. A published work search for NS cases with skin cancers and HPV infection identified 15 NS patients, five of them showing mucosal or cutaneous HPV infection. Overall, our results confirm the increased susceptibility to skin carcinomas of some NS patients and provide further evidence of an association between HPV and non‐melanoma skin cancers in NS. The highly impaired skin barrier function, hallmark of NS, could facilitate HPV infection, in turn increasing the risk for cancer development.     

Matrix metalloproteinase‐7 activates heparin‐binding epidermal growth factor‐like growth factor in cutaneous squamous cell carcinoma

Background Tumour‐specific expression of matrix metalloproteinase (MMP)‐7 has been noted in cutaneous squamous cell carcinomas (SCCs) in patients with recessive dystrophic epidermolysis bullosa (RDEB). Objectives To examine the potential role of MMP‐7 in shedding of heparin‐binding epidermal growth factor‐like growth factor (HB‐EGF) in RDEB‐associated and sporadic SCCs. Methods Tissue microarrays of RDEB‐associated SCC (n = 20), non‐EB SCC (n = 60) and Bowen disease (n = 28) were immunostained for MMP‐7, CD44 variant 3 (CD44v3) and HB‐EGF. Shedding of HB‐EGF was studied in vitro using two cutaneous SCC cell lines. Results Immunohistochemical analysis showed that HB‐EGF was absent in tumour cells when MMP‐7 and CD44v3 colocalized, and that the absence of HB‐EGF was more pronounced in RDEB‐associated SCCs than in non‐EB SCCs. The loss of HB‐EGF in MMP‐7–CD44v3 double‐positive areas was interpreted to indicate shedding and activation of HB‐EGF; this was also detected in Bowen disease indicating its importance in the early phase of SCC development. Specific knockdown of MMP‐7 expression in human cutaneous SCC cells by small interfering RNA inhibited shedding of HB‐EGF and resulted in diminished activation of the EGF receptor (EGFR) and ERK1/2, and in reduced proliferation of SCC cells. Conclusions These findings provide evidence for the role of MMP‐7 in promoting the growth of cutaneous SCCs by shedding HB‐EGF, and identify EGFR signalling as a potential therapeutic target in RDEB‐associated SCC and unresectable sporadic cutaneous SCC.