Eruptive naevi associated with encorafenib for metastatic colorectal cancer: two cases.

Encorafenib is a BRAF inhibitor increasingly used as a second-line treatment for metastatic melanoma and colorectal cancer. BRAF inhibitors have been reported to be associated with new and changing melanocytic lesions, including eruptive naevi. We describe two cases of eruptive naevi secondary to encorafenib used for the treatment of BRAF-mutant metastatic colorectal cancer.

Pleomorphic dermal sarcoma: Clinicopathological features and outcomes from a 5-year tertiary referral centre experience.

BACKGROUND: Pleomorphic dermal sarcoma (PDS) describes rare dermal-based malignant tumours that are morphologically similar to atypical fibroxanthoma (AFX). PDS may be differentiated from AFX by the presence of one or more of the following histologic features: subcutaneous invasion, tumour necrosis, lymphovascular invasion (LVI), and/or perineural infiltration (PNI). AIMS: To further define the clinicopathological features, surgical management, and outcomes of PDS primary tumours. METHODS AND RESULTS: This study was a retrospective observational case series using a database search from 2012 to 2017. Inclusion criteria required all cases to meet the histopathologic criteria for PDS as confirmed by a specialist soft-tissue histopathologist. A total of n = 17 cases were included with a median age of 78 years (range 66-85). All tumours were located on the head and neck, with 13/17 located on the scalp. Primary treatment was with wide local excision (WLE) in all cases. Median follow-up was 48 months. Local recurrence occurred in 4/17 cases (24%) and distant metastasis in 2/17 cases (12%). CONCLUSION: PDS behaves more aggressively than atypical fibroxanthoma with which it shares a biologic continuum. The optimal surgical management approach is yet to be determined.

Treatment of sebaceous gland hyperplasia: a review of the literature.

BACKGROUND: Sebaceous gland hyperplasia (SGH) is a benign cutaneous proliferation of the sebaceous glands that primarily affects the elderly group and frequently appears in individuals receiving long-term ciclosporin therapy such as organ transplant recipients. In the latter group, SGHs are usually multiple in number and occur predominantly on the face. Patients may find their appearance cosmetically undesirable and, in some cases, may result in significant negative psychological impact. There is, therefore, a demand for safe and effective treatment for SGH particularly in this patient group. A variety of treatment modalities have been previously described including electrodessication,surgery, cryotherapy, oral isotretinoin, lasers, and topical photodynamic therapy (PDT). METHODS: The objective of this paper is to review the various treatment modalities for SGH. We performed a systematic literature review using the National Library of Medicine's PubMed Database, whereby we included articles that met the following criteria: published in English, not focused on SGH in rhinophyma, studies with adult sample with SGH lesions, and studies with patients with SGH related to ciclosporin. RESULTS: Our findings show that the literature is categorized according to the treatment modalities ranging from conventional techniques such as oral isotretinoin and cryotherapy to more advanced topical PDT, lasers and a combination of both. We found that effectiveness does not depend on the technique itself but instead on the number of lesions, financial cost, psychological factors, skin phototype and age. CONCLUSIONS: Our work shows that SGH can be treated effectively by customizing the treatment modality according to different parameters, while effectively maintaining clearance of SGH lesions with best cosmetic outcome.

Sequential Treatment of Superficial Basal Cell Carcinomas With Topical Methyl Aminolevulinate Photodynamic Therapy and Imiquimod 5% Cream: A Retrospective Study of Clinical and Cosmetic Outcomes.

BACKGROUND: Topical photodynamic therapy (PDT) and imiquimod 5% (IMQ) cream are established treatments for superficial basal cell carcinoma (sBCC). Both have high initial response rates and recurrence rates of up to 37%. Recent studies demonstrate that PDT and imiquimod may act on sBCCs via synergistic immunomodulatory pathways. OBJECTIVE: To describe the sequential use of MAL-PDT and imiquimod 5% cream in the treatment of sBCCs and report treatment tolerability, cosmetic outcomes, and efficacy. MATERIALS AND METHODS: This is a retrospective case series of patients presenting over a 2-year period with primary sBCC who underwent 2 cycles of topical MAL-PDT, followed by 6 weeks of imiquimod 5% cream. Outcome measures were resolution of the index lesion at 3 months, side effects, cosmetic outcome, and long-term recurrence (LTR). RESULTS: A total of 17 consecutive patients (n = 17) with a combined 21 sBCCs (n = 21) were included. The median length of follow-up was 72 months (range 24-95 months). Long-term recurrence occurred in 2/21 lesions (10%). CONCLUSION: Sequential use of PDT and imiquimod was well tolerated with good cosmetic outcomes. The 10% LTR rate is at the lower end of the range reported for single modality treatment; however, larger samples are required to evaluate efficacy differences.

Combination Therapy of Ipilimumab and Nivolumab-associated Toxic Epidermal Necrolysis (TEN) in a Patient With Metastatic Melanoma: A Case Report and Literature Review.

Ipilimumab and nivolumab are immune checkpoint inhibitors used in the treatment of metastatic melanoma. The authors report the case of a 62-year-old white male individual with metastatic choroidal melanoma who had commenced adjuvant systemic treatment with combination checkpoint inhibitor therapy of intravenous ipilimumab (anti-cytotoxic T-lymphocyte antigen-4) and nivolumab (anti-programmed cell death-1) at 3-week cycle intervals. On day 4 after the second cycle, he developed an acute widespread rash. On examination there was confluent erythema with bullae and epidermal loss over 60% of the body surface area, with severe oral mucosal ulceration. A clinical diagnosis of toxic epidermal necrolysis (TEN) was made and he was transferred to the intensive care unit. Despite active treatment, he deteriorated systemically and died from multiorgan failure. This is the first reported case of TEN associated with nivolumab and ipilimumab dual therapy for metastatic uveal melanoma. Monotherapy improves survival in metastatic melanoma, but dual therapy has shown a greater mortality benefit at 3 years. Although the literature demonstrates case reports of Stevens-Johnson syndrome and TEN in association with nivolumab, ipilimumab has generally been regarded as a "safe" treatment with regard to severe cutaneous adverse reactions. With the increased use of immunotherapies, it is important to plan the management and early recognition of drug-related skin toxicity. This is of greatest concern during treatment initiation and with the higher risk associated with combination therapy. Reporting of adverse events and infrequently encountered complications with systemic biologic treatments will augment pharmacovigilance and improve the stratification of patients to treatments.

Multicentric visceral epithelioid hemangioendothelioma, with extremity dermal deposits, unusual late recurrence on the nasal bridge, and TFE3 gene rearrangement.

Epithelioid hemangioendothelioma (EHE) is a malignant neoplasm with vascular differentiation that most frequently occurs within soft tissues, bone, lung, and liver. It is histologically typified by epithelioid or spindle cells present singly or in cords or clusters, many with cytoplasmic vacuoles that can contain intraluminal erythrocytes (in keeping with primitive vascular differentiation), within myxohyaline or sclerotic matrix. Up to 50% present with synchronous lesions as multifocal disease. The WWTR1-CAMTA1 fusion has been demonstrated in EHEs at a variety of sites and is considered to represent its genetic hallmark. We describe a case of EHE in a patient who initially presented with multiple liver and pulmonary deposits, was found to have a soft tissue lesion in the foot, and then presented with further lesions on the nasal bridge and the arm approximately 6 years after initial presentation. Interestingly, the case showed diffuse CAMTA1 expression but negative TFE3 immunohistochemically, but in contrast showed TFE3 gene rearrangement with fluorescence in situ hybridization but no evidence of WWTR1-CAMTA1 translocation. The clinical behavior of EHE is unpredictable, and this case highlights unusual anatomic, immunohistochemical, and molecular cytogenetic findings. Characterization of the genetics of EHE is important because targeted therapies toward products of the specific WWTR1-CAMTA1 gene fusion may have an impact in the near future.

A Case of Hereditary Leiomyomatosis and Renal Cell Carcinoma.

A 49-year-old lady presented with multiple recurring painful lesions over her thighs, arms, and back. Past medical history included a left sided nephrectomy for renal cell carcinoma and a hysterectomy for multiple uterine fibroids (leiomyomas). Histopathological examination revealed changes consistent with pilar leiomyomas. Gene mutation analysis confirmed a diagnosis of hereditary leiomyomatosis and renal cell carcinoma. Hereditary leiomyomatosis and renal cell carcinoma is an uncommon autosomal dominant condition characterised by the concurrent presentation of cutaneous and uterine leiomyomas. Renal cell carcinoma associated with this condition is more aggressive and a significant cause of mortality. Due to this association with potentially fatal renal cell carcinoma we felt that it was important to highlight this case with an update on pathophysiology and management.

Atypical fibroxanthoma in an HIV-infected individual.

Atypical fibroxanthoma is a neoplasm primarily occurring in older patients, with a predilection for photo-damaged skin of the head and neck. Compared to the immunocompetent population, patients infected with HIV have a higher risk of certain malignancies including non-Hodgkin lymphoma, Kaposi's sarcoma and skin cancer. Although atypical fibroxanthoma has been reported in another immunocompromised group, namely organ transplant recipients, there are no previous reports in the published literature of this tumour arising in patients infected with HIV. We report a case of an atypical fibroxanthoma arising in a 71- year old HIV-positive male.

Reactive oxygen-mediated damage to a human DNA replication and repair protein.

Ultraviolet A (UVA) makes up more than 90% of incident terrestrial ultraviolet radiation. Unlike shorter wavelength UVB, which damages DNA directly, UVA is absorbed poorly by DNA and is therefore considered to be less hazardous. Organ transplant patients treated with the immunosuppressant azathioprine frequently develop skin cancer. Their DNA contains 6-thioguanine-a base analogue that generates DNA-damaging singlet oxygen ((1)O(2)) when exposed to UVA. Here, we show that this (1)O(2) damages proliferating cell nuclear antigen (PCNA), the homotrimeric DNA polymerase sliding clamp. It causes covalent oxidative crosslinking between the PCNA subunits through a histidine residue in the intersubunit domain. Crosslinking also occurs after treatment with higher-although still moderate-doses of UVA alone or with chemical oxidants. Chronic accumulation of oxidized proteins is linked to neurodegenerative disorders and ageing. Our findings identify oxidative damage to an important DNA replication and repair protein as a previously unrecognized hazard of acute oxidative stress.

Novel DNA lesions generated by the interaction between therapeutic thiopurines and UVA light.

The therapeutic effect of the thiopurines, 6-thioguanine (6-TG), 6-mercaptopurine, and its prodrug azathioprine, depends on the incorporation of 6-TG into cellular DNA. Unlike normal DNA bases, 6-TG absorbs UVA radiation, and UVA-mediated photochemical damage of DNA 6-TG has potentially harmful side effects. When free 6-TG is UVA irradiated in solution in the presence of molecular oxygen, reactive oxygen species are generated and 6-TG is oxidized to guanine-6-sulfonate (G(SO3)) and guanine-6-thioguanine in reactions involving singlet oxygen. This conversion is prevented by antioxidants, including the dietary vitamin ascorbate. DNA G(SO3) is also the major photoproduct of 6-TG in DNA and it can be selectively introduced into DNA or oligonucleotides in vitro by mild chemical oxidation. Thermal stability measurements indicate that G(SO3) does not form stable base pairs with any of the normal DNA bases in duplex oligonucleotides and is a powerful block for elongation by Klenow DNA polymerase in primer extension experiments. In cultured human cells, DNA damage produced by 6-TG and UVA treatment is associated with replication inhibition and provokes a p53-dependent DNA damage response.

Azathioprine and UVA light generate mutagenic oxidative DNA damage.

Oxidative stress and mutagenic DNA lesions formed by reactive oxygen species (ROS) are linked to human malignancy. Clinical treatments inducing chronic oxidative stress may therefore carry a risk of therapy-related cancer. We suggest that immunosuppression by azathioprine (Aza) may be one such treatment. Aza causes the accumulation of 6-thioguanine (6-TG) in patients' DNA. Here we demonstrate that biologically relevant doses of ultraviolet A (UVA) generate ROS in cultured cells with 6-TG-substituted DNA and that 6-TG and UVA are synergistically mutagenic. A replication-blocking DNA 6-TG photoproduct, guanine sulfonate, was bypassed by error-prone, Y-family DNA polymerases in vitro. A preliminary analysis revealed that in five of five cases, Aza treatment was associated with a selective UVA photosensitivity. These findings may partly explain the prevalence of skin cancer in long-term survivors of organ transplantation.