Checkpoint inhibitor-associated bullous cutaneous immune-related adverse events: a multicentre observational study.

BACKGROUND: Checkpoint inhibitor (CPI) therapy has significantly improved overall survival in several cancers including metastatic melanoma (MM) and in the adjuvant setting. Cutaneous immune-related adverse events (irAEs) secondary to CPIs are commonly observed; however, autoimmune blistering disorders such as bullous pemphigoid (BP) are rare. OBJECTIVES: To review the prevalence, incidence risk, clinicopathological features and management of toxicity in bullous cutaneous irAEs associated with CPI therapy. METHODS: A multicentre, retrospective, observational study of CPI-associated bullous irAEs in adults with all cancers across four UK specialist centres between 2006 and 2019. RESULTS: In total, 7391 patients were identified. CPI-associated bullous irAEs including BP (n = 16) occurred in 0·3% (n = 22). The median age of onset was 76 years, and there was a male predominance. Most patients had cutaneous melanoma (73%, n = 16), of which 81% (13 of 16) were BRAF wildtype. Grade 1, 2, 3 and 4 skin toxicity occurred in 9%, 45%, 41% and 5%, respectively. The mucosae were involved in 27%, and 25% of confirmed cases of BP did not present with bullae. The median time to onset of bullous irAEs was 12 months, with a median total symptom duration of 6 months. Single PD-1/PD-L1 agents had a longer time to onset of symptoms than combination therapy (median 12 vs. 7 months, respectively). Overall, 91%, 64% and 9% of patients required one, two or three lines of treatment, respectively. Two cases occurred after completion of CPIs (1 and 3 months). Of the 20 cases that presented while on CPIs this was permanently discontinued in 55% (11 of 20) and temporarily held in 20% (four of 20). In the four held cases of CPI, bullous eruption reflared in 50%. CONCLUSIONS: CPI-associated bullous skin toxicity is a rare cutaneous irAE occurring in approximately 0·3% of cases over 13 years of treated patients in this series. Not all cases are diagnostic of BP, but management remains the same. There is a prolonged latency of onset compared with other cutaneous irAEs, with a median time of 12 months, and they can occur after cessation of therapy. Discontinuation of CPIs may be required. Recognizing bullous irAEs promptly and referral to dermatology are essential to optimize management and improve patient outcomes and tumour responses. What is already known about this topic? Checkpoint inhibitor (CPI)-associated bullous pemphigoid is a rare dermatological immune-related adverse event (irAE) that has been reported in small case series and reports. What does this study add? This is the largest multicentre, observational study conducted in the UK over the longest period of 13 years, which demonstrates an overall incidence of bullous cutaneous irAEs secondary to CPIs of 0·3%. Clinical presentation is variable, with one-quarter of patients with bullous pemphigoid presenting without bullae, and mucosal involvement was noted in 27%. Prolonged pruritus is frequently a prodromal symptom. The median time to diagnosis is 12 months and irAEs rarely present after cessation of treatment. Time to onset of symptoms is longer with a single CPI, but with a shorter duration of symptoms compared with combination CPI therapy. Most patients had cutaneous melanoma, of which 81% were BRAF wildtype.

Cutaneous toxicities occurring during palbociclib (CDK4/6 inhibitor) and endocrine therapy in patients with advanced breast cancer: a single-centre experience.

PURPOSE: Treatment with Palbociclib, a cyclin-dependent kinase 4/6 inhibitor, has demonstrated significantly improved progression-free survival in patients with hormone receptor-positive, HER2-negative, advanced breast cancer, when used in combination with letrozole or fulvestrant endocrine therapies. However, limited information exists on its cutaneous adverse effects (AE). Hence, we conducted a retrospective cohort study to investigate the prevalence and management of cutaneous AE during palbociclib and endocrine therapy. METHOD: We included 324 adult patients with advanced breast cancer who received palbociclib between March 2016 and August 2020 within a tertiary comprehensive cancer centre. Patient demographics, details of previous and concurrent treatments, as well as treatment-related cutaneous AE were recorded from electronic records. RESULTS: The incidence of treatment-related cutaneous AE was 14.2% (46 from a total of 324 patients). The most frequent cutaneous reactions included maculopapular rash (41%), asteatosis (37%), pruritus and urticaria (20%), and bullous dermatitis reactions (9%). We identified two patients with treatment-induced subacute cutaneous lupus erythematosus, one case of bullous pemphigoid, and a single erythema multiforme. Patients received an average of 9 cycles of treatment, completing an average of 6 cycles before developing cutaneous AE, which persisted for a median of 43 days. Only 15% (n = 7) of affected patients required temporary suspension, and 4% (n = 2) required discontinuation. The majority were managed with potent topical steroids, with oral corticosteroids being required in 3 patients, and one patient required hydroxychloroquine. CONCLUSION: Our study describes both the spectrum of cutaneous AE of palbociclib and endocrine therapy, and approaches to management. Prompt management may limit the negative impact on patients, facilitating beneficial continuation of palbociclib and endocrine therapy.

Annular atrophic lichen planus induced by anti-HER2 antibodies.

Pertuzumab and trastuzumab are monoclonal antibody inhibitors targeting human epidermal growth factor receptor 2 (HER-2) and are increasingly being utilised in the management of HER2-positive breast cancer, having been demonstrated to improve progression-free survival in conjunction with docetaxel. We present a rare presentation of a lichenoid drug eruption, in an annular atrophic variant, in a 35-year-old woman after initiation of HER2-inhibitor (pertuzumab and trastuzumab) therapy for metastatic breast cancer.

Dermatoscopic findings of penile intraepithelial neoplasia: Bowenoid papulosis, Bowen disease and erythroplasia of Queyrat.

BACKGROUND/OBJECTIVES: The clinical diagnosis of penile intraepithelial neoplasia is challenging. No specific dermoscopic criteria for penile intraepithelial neoplasia have been described in the literature. This study aimed to describe and evaluate the dermoscopic features of penile intraepithelial neoplasia. METHODS: Clinical and dermoscopic images of 11 patients with histopathologically confirmed penile intraepithelial neoplasia were recorded and evaluated. RESULTS: The most frequent dermoscopic features were the presence of structureless areas (100%, structureless pink 72.7%) and vascular structures (81.8%), particularly dotted vessels (72.7%). Other findings included the absence of a pigment network (100%); scale (45.5%); scar-like areas (45.5%); erosions (27.3%); and pigmentation consisting of brown-grey dots and globules (27.3%). CONCLUSIONS: The dermoscopic features that characterise penile intraepithelial neoplasia are structureless pink areas and a prominent vascular pattern (mainly clustered dotted vessels). Dermoscopy is a useful tool that can aid in the diagnosis and surveillance of penile intraepithelial neoplasia.

Neonatal lupus syndrome associated with ribonucleoprotein antibodies.

Neonatal lupus erythematosus (NLE) is a rare acquired autoimmune disease caused by transplacental transfer of maternal immunoglobulin G antibodies to the fetus. NLE has well-recognized cutaneous features and may also manifest in other organs. The majority of cases are associated with Ro/SSA and La/SSB antibodies. Neonatal lupus due to antiribonucleoprotein (RNP) antibodies has rarely been reported. On rare occasions RNP has been found in association with other antibodies. We report a case of NLE occurring solely due to RNP antibodies presenting as varicelliform lesions at birth. We recorded the features in our case and 14 additional cases identified in the literature. It is important to recognize that maternal transfer of RNP antibodies may produce the classic cutaneous features of neonatal lupus. The limited case reports of this condition suggest that manifestations are limited to the skin; specifically, there are no reports of cardiac involvement. The long-term outcome remains unknown. RNP-positive, Ro/La-negative NLE seems to represent a different clinical subset of NLE. The recognition of RNP antibody NLE as a benign condition limited to the skin is helpful in planning antenatal care for subsequent pregnancies.

Characterization of sebaceous and non-sebaceous cutaneous manifestations in patients with lynch syndrome: a systematic review.

A subset of patients with Lynch Syndrome demonstrates cutaneous manifestations of the disorder. Characterization of these Lynch-related skin lesions could help in early recognition of patients with Lynch Syndrome. A broad search of the literature on OVID Medline and Embase was carried out to capture papers reporting cutaneous manifestations in Lynch Syndrome patients. The results were uploaded into Mendeley reference management software. The PRISMA workflow was used in the literature selection process. In this systematic review, data were collected from 961 cases from 413 studies, including 380 molecularly confirmed Lynch Syndrome cases. The main skin lesions were: Sebaceous adenomas (43%), sebaceous carcinomas (27%), keratoacanthomas (16%), sebaceomas (13%), squamous cell carcinomas (23%), and basal cell carcinomas (10%). MSH2 variants were the most common underlying genotype (72%). Assessment of mismatch repair by immunohistochemistry, microsatellite instability analysis, or both were performed on 328 skin lesions from 220 (58%) molecularly confirmed cases. In those skin lesions, 95% of Immunohistochemistry and 90% of the microsatellite instability test results were concordant with the underlying genotype. Sebaceous skin lesions are well-recognised phenotypic features of Lynch Syndrome. Our results show that squamous and basal cell carcinomas are relatively common in patients with Lynch syndrome; however, available evidence cannot confirm that Lynch syndrome is causal. Immunohistochemistry and/or microsatellite instability testing of skin tumours in patients with a family history of Lynch Syndrome-associated cancers may be a useful approach in identifying patients requiring referral to Clinical Genetics and/or consideration of germline genetic testing for Lynch Syndrome.

Panton-Valentine leukocidin-producing Staphylococcal aureus: report of four siblings.

Panton-Valentine leukocidin (PVL)-producing Staphylococcus aureus results in leukocyte destruction and tissue necrosis (Pediatric Dermatology 2007;24:401). It can be associated with a spectrum of clinical manifestations that range from localized staphylococcal skin infections to sometimes severe necrotizing pneumonia (Clin Infect Dis 1999;29:1128). We report a case of four siblings, three brothers whose atopic dermatitis was complicated by cutaneous lesions and furunculosis, while their 21-month-old sister had a fatal PVL positive staphylococcal pneumonia.

Uterine leiomyomatosis in adolescents and young adults (AYAs) may represent a narrow phenotypic variant of FH tumour predisposition syndrome.

FH Tumour Predisposition Syndrome, also known as Hereditary Leiomyomatosis and renal cell cancer (HLRCC), or Reed Syndrome, is an autosomal dominant condition clinically characterized by multiple cutaneous leiomyomas, multiple early-onset uterine leiomyomas and early-onset renal cell cancer. Here we report a young female with FH Tumour Predisposition Syndrome with no clinical features except early-onset uterine leiomyomas. Whilst there is a significant history of uterine leiomyomas in her family, there is no history of cutaneous leiomyomas or renal cell cancer (RCC). Uterine leiomyomatosis in young adults may represent a narrow phenotypic variant of FH Tumour Predisposition Syndrome. It is important that young women who present with multiple leiomyomata or leiomyomata with atypical features are referred for molecular genetic testing.

Checkpoint Inhibitor-associated Cutaneous Small Vessel Vasculitis: A Review of the Literature.

Checkpoint inhibitor therapy is an established cancer treatment option often complicated by the development of immune-related adverse events. Vasculitis has been reported with a broad spectrum of both cutaneous and systemic manifestations and can be complicated by delayed diagnosis. The authors report 2 histologically proven cases of cutaneous leucocytoclastic vasculitis induced by programmed cell-death 1 inhibitor inhibitor nivolumab. As physicians, including medical oncologists and dermatologists, we need to be aware of this clinical entity and the importance of clinicopathological confirmation in this setting to confirm the diagnosis to help guide the management of these complex patients.

Factors Affecting Sentinel Node Metastasis in Thin (T1) Cutaneous Melanomas: Development and External Validation of a Predictive Nomogram.

PURPOSE: Thin melanomas (T1; ≤ 1 mm) constitute 70% of newly diagnosed cutaneous melanomas. Regional node metastasis determined by sentinel node biopsy (SNB) is an important prognostic factor for T1 melanoma. However, current melanoma guidelines do not provide clear indications on when to perform SNB in T1 disease and stress an individualized approach to SNB that considers all clinicopathologic risk factors. We aimed to identify determinants of sentinel node (SN) status for incorporation into an externally validated nomogram to better select patients with T1 disease for SNB. PATIENTS AND METHODS: The development cohort comprised 3,666 patients with T1 disease consecutively treated at the Istituto Nazionale Tumori (Milan, Italy) between 2001 and 2018; 4,227 patients with T1 disease treated at 13 other European centers over the same period formed the validation cohort. A random forest procedure was applied to the development data set to select characteristics associated with SN status for inclusion in a multiple binary logistic model from which a nomogram was elaborated. Decision curve analyses assessed the clinical utility of the nomogram. RESULTS: Of patients in the development cohort, 1,635 underwent SNB; 108 patients (6.6%) were SN positive. By univariable analysis, age, growth phase, Breslow thickness, ulceration, mitotic rate, regression, and lymphovascular invasion were significantly associated with SN status. The random forest procedure selected 6 variables (not growth phase) for inclusion in the logistic model and nomogram. The nomogram proved well calibrated and had good discriminative ability in both cohorts. Decision curve analyses revealed the superior net benefit of the nomogram compared with each individual variable included in it as well as with variables suggested by current guidelines. CONCLUSION: We propose the nomogram as a decision aid in all patients with T1 melanoma being considered for SNB.

Symptomatic dermatographism treated with narrowband UVB phototherapy.

Dermatographism occurs when there is an exaggerated response to physical stimulus. There are both simple and symptomatic forms. Symptomatic dermatographsim can be exceedingly difficult to treat. Treatment modalities include H1 and H2 antagonists, leukotriene antagonists, cyclosporine and oral steroids. In a few small case series and studies, phototherapy has been used. We report a further two patients who were treated successfully with TL01 UVB narrowband (NB) phototherapy.

Pemphigus herpetiformis: a case series and review of the literature.

BACKGROUND: Pemphigus herpetiformis (PH) is a rare subtype of pemphigus that presents challenges in diagnosis. OBJECTIVE: To review the presentation, diagnosis, and management of PH. METHODS: We reviewed the charts of all patients diagnosed and treated for PH in an immunobullous referral center between September 2007 and June 2013. RESULTS: Eight patients were identified with a diagnosis of PH. All presented initially with pruritus. Clinical disease was manifest as either urticated erythematous plaques or a vesiculobullous eruption. Histological evaluation demonstrated eosinophilic spongiosis in all patients with acantholysis in half of cases (n = 4/8). Peripheral eosinophilia was noted in three of eight (37.5%) patients. In all cases, direct immunofluorescence showed intercellular deposition of immunoglobulin G in the epidermis. All patients required high-dose corticosteroid initially. All patients treated with dapsone or sulfasalazine (n = 4) achieved at least partial control. Other effective treatments included intravenous immunoglobulin (n = 2), azathioprine (n = 2), and leflunomide (n = 1). Rituximab was ineffective in two patients. CONCLUSION: The clinical and histological features of PH develop over time and with treatment, making distinction between pemphigus subtypes challenging and delay in diagnosis common. Diagnosis of PH requires a high index of suspicion and is made on clinical grounds (urticated erythema) in the context of compatible histology and immunofluorescence findings. Treatment may be challenging, although efficacy of sulfonamide derivatives appears to offer a therapeutic effect.

Cost and Resource Use of Pemphigus and Pemphigoid Disorders Pre- and Post-Rituximab.

BACKGROUND: Rituximab (RTX) is increasingly used for the treatment of pemphigus and pemphigoid disorders. The high cost of RTX frequently limits its use and access. OBJECTIVE: To determine the health system resources and costs associated with RTX treatment of pemphigus and pemphigoid. METHODS: Health system resources and costs attributed to a convenience sample of 89 patients with either pemphigus or pemphigoid were identified, quantified, and valued 6 months prior to and following RTX initiation between May 2006 and August 2012. Overall cohort costs and costs per patient were calculated (2013 Can$). RESULTS: The overall cohort cost for 6 months pre-RTX was $3.8 million and for 6 months post-RTX was $2.6 million. The average cost per patient decreased from $42,231 to $29,423 (30.3% decrease). The main cost driver was intravenous immunoglobulin. CONCLUSIONS: Our findings suggest that RTX is effective in reducing health system resources and the costs associated with the treatment of pemphigus and pemphigoid.