Recurrent Nonmelanoma Skin Cancer Research Articles

High Prevalence of Beta-Human Papilloma Virus in Patients with Concurrent Chronic Lymphocytic Leukemia and Non-Melanoma Skin Cancer

Introduction Patients with chronic lymphocytic leukemia (CLL) are at least twice as likely to develop a second malignancy as their age-matched peers, which is likely secondary chronic CLL-related immunosuppression (Royle 2011). Non-melanoma skin cancers (NMSC) are the most common type of second cancer and those with CLL are seven times more likely to have recurrent NMSC than those without CLL (Mehrany 2005). The etiology of NMSC is likely multifactorial, but we hypothesized that viral load of beta-subtype of human papillomavirus (B-HPV) is correlated with likelihood of NMSC in patients with CLL. Virtually all of the currently available commercial HPV testing targets alpha-subtypes of HPV, but B-HPV has recently been associated with NMSC's (Rollison 2021). The prevalence and viral load of B-HPV in patients with CLL has not been studied. Methods We collected blood samples from patients with CLL and non-CLL controls (patients with solid malignancies) through the ORIEN AVATAR program and performed whole exome sequencing. We used Kraken2 metagenomic software to identify co-purifying HPV DNA using a custom-built viral database composed of unique sequences from alpha and beta HPV reference genomes. Comparison of viral load between patients with and without CLL, and CLL patients with and without NMSC was performed by a 2 sample t-test. Statistic significance was set as p<0.05. Results We measured B-HPV viral loads in the peripheral blood of 333 CLL patients and 69 non-CLL control patients. We determined that the average B-HPV viral load in the peripheral blood of CLL patients was double the load in our non-CLL controls (2724.9 versus 1315.0 viral counts; p<0.001). When we classified the B-HPV subtypes, we found higher viral loads of the subtypes 8, 15, 110, 143, 150 in CLL patients than non-CLL controls (p<0.001 for all CLL vs control comparisons). B-HPV subtype 8 (B-HPV8) was the subtype with the highest viral load as determined by exact matches to our Kraken2 HPV database. We identified 29 CLL patients with known diagnosis of NMSC. In this population, the viral load of B-HPV8 was >6-fold higher than that found in the non-CLL control patients (1009.8 vs 149.6 viral sequences; p<0.001; 2-sample t-test). Conclusions These preliminary data support our hypothesis that B-HPV infection is associated with NMSC in CLL patients. At minimum, it may serve as a biomarker for level of immunosuppression, which predisposes to NMSC. We are currently enrolling a prospective clinical trial for CLL patients with recurrent NMSC (NCT04844528). We plan to sequence both the peripheral blood and the skin cancer samples from these patients to determine whether there is a correlation between B-HPV subtype and NMSC occurrence. We will also evaluate components of the immune system such as T-cell function in an attempt to quantify and correlate immune dysfunction in these patients.

A More Severe Non-melanoma Skin Cancer Phenotype Is Seen in Patients with Inflammatory Bowel Disease on Tumor Necrosis Factor-α Antagonists

Limited data suggest that non-melanoma skin cancer (NMSC) risk is higher in patients with inflammatory bowel disease (IBD) particularly in those on a tumor necrosis factor-α antagonist (TNF antagonist). It remains unknown whether TNF antagonist exposure alters the clinical course of NMSC in patients with IBD or if this therapy should be discontinued. To assess the impact of TNF antagonist exposure on NMSC severity, recurrence and need for ancillary treatments. Patients with IBD seen at London Health Sciences Centre, London, Canada were assessed for a history of NMSC and pre-diagnosis TNF antagonist exposure. NMSC severity (low risk and high risk), ancillary NMSC therapies, including chemo or radiotherapy, and changes to IBD therapy were assessed. Eleven of 472 patients with IBD reviewed were diagnosed with NMSC. Sixty-four percent (7/11) were on a TNF antagonist at the time of NMSC diagnosis. All patients with TNF antagonist exposure, (7/7) presented with a high-risk lesion based on National Comprehensive Cancer Network (NCCN) clinical practice guidelines. The incidence of positive margins was 42.9% (3/7) and 14.3% (1/7) required ancillary therapy. No metastatic disease was seen. TNF antagonist therapy was discontinued in a single patient due to NMSC diagnosis. Recurrent NMSC lesions were not seen in any of the TNF antagonist exposed patients. In this case series, TNF antagonist exposure may be associated with a severe NMSC clinical course. Larger studies are needed to confirm whether TNF antagonist discontinuation should be considered in the setting of NMSC diagnosis in IBD.

Mohs Micrographic Surgery: Past, Present, and Future

Mohs micrographic surgery (MMS) is a frequently used technique that provides total margin visualization for treatment of skin neoplasms. To provide a comprehensive review of MMS literature, focusing on its origins, evidence behind present-day uses of MMS, and future directions. A literature search was conducted using PubMed to identify articles pertaining to MMS. The fresh frozen technique led to widespread use of MMS in the 1970s. One randomized controlled trial and several large prospective studies have demonstrated low recurrence rates for treatment of nonmelanoma skin cancer (NMSC). MMS, when compared with surgical excision, also achieved a statistically significant higher cure rate for treatment of recurrent NMSC. Studies have demonstrated low recurrence for the treatment of melanoma and melanoma in situ with MMS. MMS has also been shown to effectively treat several rare cutaneous neoplasms. The future of MMS is likely to include the adoption of noninvasive imaging, immunostaining, and digital technology. Mohs micrographic surgery is an effective treatment modality for numerous cutaneous neoplasms. It has achieved statistically significant superiority to surgical excision for the treatment of recurrent and high-risk NMSC. The future is likely to see increased use of noninvasive imaging, immunostaining, and digital technology.

Laboratory errors leading to nonmelanoma skin cancer recurrence after Mohs micrographic surgery.

Compared with standard surgical excision, Mohs micrographic surgery (MMS) provides superior cure rates for nonmelanoma skin cancer (NMSC). Although cure rates of NMSC approach 99% with MMS, local recurrences occasionally occur. The authors sought to identify histological features during frozen section examination that were associated with local recurrence of NMSC after MMS. A retrospective chart review was performed of patients undergoing a second MMS procedure to treat locally recurrent NMSC over a 20-month period. Histological slides were reviewed to assess for possible causes of local recurrence. Of 3,169 NMSCs treated, 22 were locally recurrent. Possible causes of recurrence identified after MMS included dense inflammation in the final margin at sites affected by tumor in prior slides (27%), visible remaining tumor (23%), missing epidermal or dermal tissue (23%), and actinic keratosis (4%). One recurrence was possibly explained by incorrect mapping. No abnormality could be detected in 18% of cases. Possible limitations include the small sample size, retrospective design, and the possibility that some patients may have been lost to follow-up. Local recurrences after MMS are extremely rare. When recurrences do occur, they can be attributed to errors in histological interpretation or tumor mapping.

Comments on: "Clinical implementation of a new electronic brachytherapy system for skin brachytherapy".

To the Editor: We have read with an interest the article of Olga Pons-Llanas et al. [1] published in the Journal about the use of electronic brachytherapy (EBT) in non-melanoma skin cancer (NMSC). However, we noticed the exclusion criteria for the following tumors: lesions with a diameter greater than 20 mm, invasion of more than 4 mm, irregular anatomic areas. Besides, there are limits linked to the use of circular collimators and the daily set-up position. NMSC often have irregular shapes and diameter longer than 2 cm; besides, in most cases, NMSC are recurrent and located in periorbital area (i.e. inner canthus). In these instances, both EBT and brachytherapy are difficult and/or inadequate to treat safely most of patients. Among the new technologies, stereotactic ablative radiation therapy could be a valid therapeutic option treating “difficult NMSC”. In a recent paper [2], we reported our experience with Stereotactic Body Radiation Therapy (SBRT) in a patient with recurrent and complicated NMSC using Cyberknife System (CKS). In fact, the CKS is a possible alternative to surgery and brachytherapy in patients with recurrent NMSC located in irregular anatomical areas close to critical organs (i.e. eyes). The SBRT with image guided exceeds the limits of the set-up for relocation; the inverse planning allows to cover irregular volumes greater than 20 mm. The use of the photons X-6 MV permits to treat the lesions with invasion more than 4 mm. Do Olga Pons-Llanas et al. have experience and/or data on the use of brachytherapy in “difficult areas”? In fact, in daily clinical practice many patients have “irregular and difficult” NMSC and it is important that Radiation Oncologists have more therapeutic options in these instances. We think that it is important for the authors to comment on these issues and perhaps reply within the context of this journal.

Mohs moat: Peripheral cutaneous margin clearance in a collaborative approach for aggressive and deeply invasive basal cell carcinoma

Although Mohs micrographic surgery is the standard of care for large, aggressive or recurrent non-melanoma skin cancers of the head and neck, tumours that involve deep underlying structures (including bone, parotid gland and named nerves) are impractical for extirpation under local anaesthesia. Such cases are often referred to a head and neck surgeon, who typically relies on intraoperative frozen section analysis of the peripheral cutaneous margin. Here we describe the use of the Mohs moat technique as part of a collaborative approach for the treatment of aggressive and deeply invasive basal cell carcinoma that allows an analysis of the complete peripheral cutaneous margin and results in decreased operating room and general anaesthesia time.

Randomized Controlled Trial of Sirolimus for Renal Transplant Recipients at High Risk for Nonmelanoma Skin Cancer

Sirolimus has antineoplastic effects and may reduce skin cancer rates in kidney transplant patients. This prospective, multicenter, randomized, open-label, controlled trial randomized 86 kidney transplant recipients (≥1 year posttransplant) with history of nonmelanoma skin cancer (NMSC) to continue calcineurin inhibitor (CNI) or convert to sirolimus. Patients were stratified by number of NMSC lesions (0-5, 6-20) in previous year. Primary end point was number of biopsy-confirmed new NMSC lesions per patient-year. Yearly NMSC rate was significantly lower with sirolimus (1.31 vs. 2.48 lesions/patient-year; p = 0.022). Squamous cell carcinoma occurred at a lower rate in the sirolimus versus CNI group (p = 0.038); basal cell carcinoma rate was similar in both. A lower proportion of patients receiving sirolimus developed new or recurrent NMSC (56.4% vs. 80.9%; p = 0.015) or new squamous cell carcinoma (41.0% vs. 70.2%; p = 0.006). No sirolimus patients and one CNI continuation patient experienced acute rejection. Incidence of treatment-emergent adverse events was similar between groups; however, discontinuation rates related to adverse events were significantly higher with sirolimus (46.2% vs. 0%; p < 0.001). In kidney transplant recipients with history of NMSC, conversion from CNI to sirolimus reduced rates of NMSC, without increasing acute rejection risk.

Recurrent Non-melanoma Skin Cancer: Remission of Field Cancerization after Conversion from Calcineurin Inhibitor- to Proliferation Signal Inhibitor-based Immunosuppression in a Cardiac Transplant Recipient

Non-melanoma skin cancers (NMSCs) are the most common malignancies after solid organ transplantation. Their incidence increases with time after transplantation. Calcineurin-inhibitors (CNIs) and azathioprine are known as skin neoplasia-initiating and -enhancing immunosuppressants. In contrast, increasing clinical experience suggests a relevant antiproliferative effect of mammalian target of rapamycin inhibitors, also named proliferation signal inhibitors (PSIs). We report the case of a cardiac allograft recipient with an impressive and consolidated reduction of recurrent NMSC, observed after conversion from CNI-therapy to a PSI-based protocol.

Monitoring immunosuppression with measures of NFAT decreases cancer incidence

Long-term immunosuppression causes a significantly increased risk for the development of malignancies in transplanted patients. A link between immunosuppression and incidence of cancer is well documented and involves the effect of immunosuppression on anti-tumor surveillance and antiviral adaptive immune responses. We present a 67-year-old patient with a history of recurrent non-melanoma skin cancer. After adjustment of immunosuppressive therapy under close pharmacodynamic control, the development of new malignant lesions could be prevented. The availability of a quantitative, quick laboratory test for an assessment of the individual functional activity of immunocompetent cells that are crucial for transplant rejection, defense against viral infection, and tumor surveillance along with the ability to adjust doses of immunosuppressive agents such that patients are largely protected against malignant disease and/or viral infection are important. NFAT-regulated gene expression measured in peripheral blood allowed us to predict "safe" immunosuppression. Thus patients could maintain a stable allograft function. This represents a breakthrough in transplantation medicine and advances our attempts to individualize treatment in transplanted patients.

Treatment of Multiple Relapsing Non-Melanoma Skin Cancers in a Patient with Severe Hemophilia A

Although non-melanoma skin cancers are the most predominant malignancies in the Caucasian population and hemophilia A is one of the most frequent hereditary bleeding disorders, medical literature data about the management of non-melanoma skin cancers in patients with hemophilia are surprisingly scarce. In this case report we describe the treatment of a patient with multiple recurrent non-melanoma skin cancers and severe hemophilia A. The management of such patients could be very challenging, with possible significant bleeding complications, and requires a multidisciplinary approach.

Variation in Care for Recurrent Nonmelanoma Skin Cancer in a University-Based Practice and a Veterans Affairs Clinic

To learn if treatment of recurrent nonmelanoma skin cancer (NMSC) varied in different practice settings. Prospective cohort study of consecutive patients with recurrent NMSC. A university-based dermatology practice and the dermatology clinic at the affiliated Veterans Affairs Medical Center (VAMC). Conventional therapies for NMSC were available at both sites. Patients All 191 patients diagnosed as having recurrent NMSC in 1999 and 2000 were included in the study. Data were collected from medical record review and surveys mailed to patients. Main Outcome Measure Performance of Mohs micrographic surgery (Mohs). Patients at the VAMC were older, less educated, poorer, and had more comorbid illnesses, but their tumors were similar to those of patients at the university-based practice. Treatment choices differed at the 2 sites: the proportions of tumors treated in the VAMC and university sites were 60% and 14%, respectively, for excisional surgery; and 24% and 61%, respectively, for Mohs (P < .001). In multivariate analyses adjusting for patient, tumor, and physician features that may have affected treatment choice, tumors treated at the university-based site remained significantly more likely to be treated with Mohs (odds ratio, 8.68 [95% confidence interval, 3.66-20.55]; P < .001). Substantial variation existed in the treatment of recurrent NMSC in different practice settings. This variation was not explained by measured clinical characteristics of the patients or the tumors.

Advanced and recurrent nonmelanoma skin cancer: Luce E. Clin Plast Surg 24:731, 1997

Advanced and recurrent nonmelanoma skin cancer: Luce E. Clin Plast Surg 24:731, 1997

Advanced and Recurrent Nonmelanoma Skin Cancer

Advanced skin cancer presents a substantial challenge to the surgeon, who must incorporate sound oncologic principles and carefully considered reconstruction into the treatment plan. Using an anatomical format, this article discusses the treatment plans for advanced skin cancer and outlines various pitfalls. The appropriateness and advisability of other modalities are also discussed.

RECURRENT NONMELANOMA SKIN CANCER IN SOUTHERN AUSTRALIA

In retrospective studies of non-melanoma skin cancers, the recurrence rates were relatively high. This study had as its aim to determine the recurrence rate of nonmelanoma skin cancer (NMSC) and prospectively, risk factors for recurrence in southern Australia. This is a prospective study of outpatients with histologically confirmed NMSC. All patients seen by a dermatologist between November 1988 and November 1989 were entered into the study and followed for at least 3 years. Any recurrent NMSCS were removed and recorded. Four hundred and eighty-one patients were entered and 420 followed for at least 3 years. A recurrent NMSC developed in 8% (adjusted for losses). A multivariate analysis determined that the main risk factor for recurrence within the first 3 years of follow-up was the number of NMSC a patient had when entering into the study. Those with 3 to nine NMSC were five times more likely to develop a recurrence than those with less than three NMSC. Those with 10 or more NMSC were 25 times more likely to develop a recurrence. Age, sex, and types of skin cancers removed were not risk factors within the first 3 years of follow-up. Patients who have had multiple skin cancers require careful follow-up because of the risk of developing recurrences.

Photodynamic Therapy for the Treatment of Basal Cell Carcinoma

Photodynamic therapy is an investigational method for the treatment of a variety of solid tumors. The purpose of this study was to determine the optimum factors and illustrate the effectiveness of photodynamic therapy in the treatment of basal cell carcinomas. This was a prospective study in which patients presenting with primary or recurrent basal cell tumors, particularly but not exclusively widespread tumors or large single tumors, were offered the option of photodynamic therapy in their treatment regimen. Patients were administered 1 mg/kg of a photosensitizer (Photofrin II). Light doses (630 nm) ranged from 72 to 288 J/cm2. A total of 37 patients with 151 sites were treated in this study. A complete response rate of 88% was achieved with one application. Morbidity was low; the most significant side effects were moderate pain and edema. Photodynamic therapy is a modality that offers localized treatment of primary or recurrent nonmelanoma skin cancer. By applying reciprocal doses of photosensitizer and light, the efficacy of photodynamic therapy in the treatment of skin lesions is demonstrated achieving significant light penetration into tissue with a high complete response rate of the lesions and acceptable normal tissue response.