Roel E. Genders

The Presence of Betapapillomavirus Antibodies around Transplantation Predicts the Development of Keratinocyte Carcinoma in Organ Transplant Recipients: A Cohort Study

Organ transplant recipients (OTRs) have an increased risk of developing keratinocyte carcinomas (KCs). The aim of this study was to correlate infection with human papillomaviruses (HPVs) belonging to the beta genus (Beta-papillomavirus (Beta-PV)) at transplantation with later development of KCs. In a cohort study, sera collected between 1 year before and 1 year after transplantation of OTRs transplanted between 1990 and 2006 were tested for antibody responses against the L1 capsid antigen of Beta-PV and other HPV genera (Gamma-, Mu-, Nu-, and Alpha-PV) using multiplex serology. The OTRs were followed for a maximum of 22 years. Cox regression models with KC, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC) as outcome variables were used. Out of 445 OTRs, 60 had developed KC: 14 developed only SCC, 24 only BCC, and 22 both types of KC. The time-dependent hazard ratio (HR) to develop either or both types of KC, adjusted for age, sex, and transplanted organ, in tested Beta-PV-seropositive OTR around the time of transplantation compared with Beta-PV-seronegative OTR was 2.9 (95% confidence interval (CI) 1.3-6.4). The HR for SCC was 2.9 (95% CI 0.99-8.5) and for BCC it was 3.1 (95% CI 1.2-8.0). There was also an association between Mu-PV seropositivity and KC, but there were no significant associations between other HPV genera tested and KC. A positive seroresponse for Beta-PV around transplantation significantly predicted the development of KC in OTRs up to 22 years later, providing additional evidence that infection with Beta-PV has a role in KC carcinogenesis.

Pain Identifies Squamous Cell Carcinoma in Organ Transplant Recipients: The SCOPE-ITSCC PAIN Study

Organ transplant recipients (OTR) are at high risk for cutaneous squamous cell carcinomas (SCC). We aimed to define clinically meaningful patient‐reported warning signals predicting the presence of invasive SCC. Patient‐reported signs and symptoms of 812 consecutively biopsied skin lesions from 410 OTR were determined by questionnaire and physical examination and related to the subsequent biopsy‐proven diagnoses. Receiver‐operating characteristic (ROC) curve analyses were used as a measure of distinction between the predictive values of patient‐reported warning signals and the occurrence of SCC. Pain was an independent predictive patient‐reported warning signal for a biopsy‐proven invasive SCC. The odds ratio from the fully adjusted model predicting SCC was 4.4 (95% confidence interval: 2.4–8.2). Higher scores on the visual analog scale (VAS) for pain were associated with a greater likelihood for the presence of SCC compared to none or mild pain. The for scores on the VAS from 1 to 3, 4 to 6 and 7 to 10 were 4.9 (2.2–10.5), 2.3 (0.96–5.5) and 16.5 (3.6–75.8), respectively. Pain is the most powerful patient‐reported warning signal for invasive cutaneous SCC in OTR. Empowerment of patients by education could accelerate diagnosis and treatment of cutaneous SCC.

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 patients 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.

Human papillomavirus and posttransplantation cutaneous squamous cell carcinoma: A multicenter, prospective cohort study

Organ transplant recipients (OTRs) have a 100‐fold increased risk of cutaneous squamous cell carcinoma (cSCC). We prospectively evaluated the association between β genus human papillomaviruses (βPV) and keratinocyte carcinoma in OTRs. Two OTR cohorts without cSCC were assembled: cohort 1 was transplanted in 2003‐2006 (n = 274) and cohort 2 was transplanted in 1986‐2002 (n = 352). Participants were followed until death or cessation of follow‐up in 2016. βPV infection was assessed in eyebrow hair by using polymerase chain reaction–based methods. βPV IgG seroresponses were determined with multiplex serology. A competing risk model with delayed entry was used to estimate cumulative incidence of histologically proven cSCC and the effect of βPV by using a multivariable Cox regression model. Results are reported as adjusted hazard ratios (HRs). OTRs with 5 or more different βPV types in eyebrow hair had 1.7 times the risk of cSCC vs OTRs with 0 to 4 different types (HR 1.7, 95% confidence interval 1.1‐2.6). A similar risk was seen with high βPV loads (HR 1.8, 95% confidence interval 1.2‐2.8). No significant associations were seen between serum antibodies and cSCC or between βPV and basal cell carcinoma. The diversity and load of βPV types in eyebrow hair are associated with cSCC risk in OTRs, providing evidence that βPV is associated with cSCC carcinogenesis and may present a target for future preventive strategies.

Update on Our Understanding of HPV as a Risk Factor for Cutaneous Squamous Cell Carcinoma in Organ Transplant Recipients

Keratinocyte carcinomas are by far the most common malignancies seen in organ transplant recipients (OTR). Life-long immunosuppressive therapy is the most important risk factor for developing squamous cell carcinoma (SCC) in OTR. In the years after transplantation, OTR develop numerous warts and wart-like lesions followed by the development of SCC, which resembles the clinical picture of epidermodysplasia verruciformis patients in which human papillomavirus (HPV) infection was linked with skin cancer for the first time. HPV can be divided into genera and cause several distinct benign and (pre-) malignant diseases.There is evidence linking beta HPV infection with the development of SCC in OTR. However, the role of beta HPV in cutaneous SCC carcinogenesis is still enigmatic. Beta HPV is not integrated in the human cellular DNA and is not necessary for the maintenance of the malignant phenotype of cutaneous SCC. Whether different beta HPV types have different effects on cellular mechanisms and a combination of these HPV types may further increase the risk of cutaneous SCC is unknown. The carcinogenic effect, if present, is subtle and probably exerted early in carcinogenesis.

p16 immunostaining in keratinocytic neoplasia in organ transplant recipients: Bowen's disease shows a characteristic pattern. “R1”

For selecting therapy, it is important to distinguish different types of keratinocytic neoplasia. It is sometimes difficult to make histopathologic diagnosis, especially in organ transplant recipients (OTR) who develop numerous lesions.

Metastasis Risk of Cutaneous Squamous Cell Carcinoma in Organ Transplant Recipients and Immunocompetent Patients

Organ transplant recipients (OTRs) have a high incidence of cutaneous squamous cell carcinoma (cSCC), and immunosuppression has been reported to be an important risk factor for metastasis. The aim of this study was to identify the metastasis risk over a 10-year period for 593 patients with cSCC, of whom 134 were OTR and 459 were immunocompetent. Metastasis incidence rate was 1,046 (95% confidence interval (95% CI) 524-2,096) per 100,000 person years in OTR and 656 (95% CI; 388-1,107) in immunocompetent patients, yielding an incidence rate ratio of 1.6 (95% CI 0.67-3.81). In OTRs head/neck location, older age at transplantation and older age at diagnosis of first cSCC were associated with metastatic risk, and 7 out of 8 metastasized tumours were smaller than 2 cm. In immunocompetent patients tumour size and tumour depth were associated with metastasis. In conclusion, we were not able to demonstrate an increased incidence rate of metastasis in OTRs compared with immunocompetent patients. However, OTRs and immunocompetent patients differed with regard to risk factors for metastasis.

The wingman flap: Bilateral closure of a supra-tip defect of the nose

SOLUTION Newlove et al recently described a case series with a solution for this type of defect with a bilateral Dufourmentel rhomboid flap. We show a modification of this flap resulting in a shortened scar toward the nasal root and diminished elevation of the tip. We modified the technique into a bilateral rhomboid transposition flap from both lateral sidewalls with an M-shaped dog-ear correction (Fig 2, A). The bilateral wings are flapped into the defect resulting in a somewhat bat-shaped scar. The skin on the sidewalls of the nose with similar texture provides closure in a vertical direction without too much tension. However the size of this type of repair is limited to the size of the lateral sidewall.

Prostaglandin E2, Tumor Necrosis Factor α, and Pro-opiomelanocortin Genes as Potential Mediators of Cancer Pain in Cutaneous Squamous Cell Carcinoma of Organ Transplant Recipients

6. International Organization for Standards. ISO 24444:2010. Cosmetics—sun protection test methods—in vivo determination of the sun protection factor (SPF). http://www.iso.org/iso/catalogue_detail.htm?csnumber=46523. Accessed October 12, 2016. Prostaglandin E2, Tumor Necrosis Factor α, and Pro-opiomelanocortin Genes as Potential Mediators of Cancer Pain in Cutaneous Squamous Cell Carcinoma of Organ Transplant Recipients Pain is a frequently reported symptom in keratinocyte cancer.1,2 In particular, squamous cell carcinoma (SCC) is associated with spontaneous pain or pain evoked by touching the lesion. The association of pain with SCC has been reported in the general population as well as in organ transplant recipients (OTRs).1,3,4 The recent SCOPE ITSCC PAIN study3 reported that pain as a symptom predicts a histological diagnosis of SCC in the high-risk group of OTRs in 75% of biopsy specimens. In addition, the presence of pain separated SCC well from other skin lesions, like basal cell carcinoma, seborrheic keratosis, SCC in situ (Bowen disease), and actinic keratosis.3 Thus, the aim of our study was to identify possible mediators of pain in SCC to elucidate potential mechanism of SCCassociated pain in OTRs.