Monitoring immunE DysregulAtion foLLowing Immune checkpOint-inhibitioN (MEDALLION): protocol for an observational cancer immunotherapy cohort study.

BACKGROUND: Checkpoint inhibitors (CPIs) are widely used in cancer treatment, with transformative impacts on survival. They nonetheless carry a significant risk of toxicity in the form of immune-related adverse events (IrAEs), which may be sustained and life-altering. IrAEs may require high-dose and/or prolonged steroid use and represent a significant healthcare burden. They mimic immune-mediated inflammatory diseases (IMIDs) but understanding of their pathogenesis is limited. The MEDALLION project aims to determine targetable mechanisms of immune dysregulation in IrAE development, employing an immune monitoring approach to determine changes in circulating and tissue resident cells of CPI recipients who do/do not develop them and assessing the contribution of the microbiome in parallel. METHODS: MEDALLION is a non-randomised longitudinal cohort study aiming to recruit 66 cancer patient recipients of anti-PD1/PD-L1, anti-CTLA-4 or combination therapy. Eligible participants include those with malignant melanoma in the adjuvant or metastatic setting, mesothelioma and non-small cell lung carcinoma (NSCLC) treated in the metastatic setting. Comprehensive clinical evaluation is carried out alongside blood, skin swab and stool sampling at the time of CPI initiation (baseline) and during subsequent routine hospital visits on 6 occasions over a 10-month follow-up period. It is conservatively anticipated that one third of enrolled patients will experience a "significant IrAE" (SirAE), defined according to pre-determined criteria specific to the affected tissue/organ system. Those developing such toxicity may optionally undergo a biopsy of affected tissue where appropriate, otherwise being managed according to standard of care. Peripheral blood mononuclear cells will be analysed using multi-parameter flow cytometry to investigate immune subsets, their activation status and cytokine profiles. Stool samples and skin swabs will undergo DNA extraction for 16 S ribosomal RNA (rRNA) sequencing and internal transcribed spacer (ITS) gene sequencing to determine bacterial and fungal microbiome diversity, respectively, including species associated with toxicity. Stored tissue biopsies will be available for in situ and single-cell transcriptomic evaluation. Analysis will focus on the identification of biological predictors and precursors of SirAEs. DISCUSSION: The pathogenesis of IrAEs will be assessed through the MEDALLION cohort, with the potential to develop tools for their prediction and/or strategies for targeted prevention or treatment. TRIAL REGISTRATION: The study was registered on 18/09/2023 in the ISRCTN registry (43,419,676).

National epidemiology of digital papillary adenocarcinoma in England 2013-2020: a population-based registry study.

BACKGROUND: Digital papillary adenocarcinoma (DPA), formerly known as aggressive DPA, is a rare adnexal cancer of sweat gland differentiation with metastatic potential. DPA epidemiology and patient outcome data are a prerequisite to develop diagnostic and therapeutic guidance, which is lacking for this rare cancer. OBJECTIVES: To report the incidence, patient demographics and treatment of patients with DPA in England from 1 January 2013 to 31 December 2020 using national cancer registry data. METHODS: DPA diagnoses in England during 2013-2020 were identified from the National Cancer Registration Dataset using morphology and behaviour codes. These were registered from routinely collected pathology reports and cancer outcomes and services datasets. The 2013 European age-standardised incidence rates (EASRs) were calculated. RESULTS: In total, 36 DPA (7 in females and 29 in males) were diagnosed. The median age at diagnosis for the cohort was 54 years (interquartile range 46-64). The most frequently affected sites were upper limbs (81%). All patients in the cohort received surgical excisions. The European age-standardised incidence rate (EASRs) was 0.10 [95% confidence interval (CI) 0.07-0.14] per 1,000,000 person-years (PY)]. CONCLUSION: This study reports the incidence and variation of DPA in England between 2013 and 2020. DPA was more common in older men and predominantly affected the upper limbs. This supports the need to develop a national policy for the reporting and management of DPA as well as clinical guideline development.

'Get Data Out' Skin: national cancer registry incidence and survival rates for all registered skin tumour groups for 2013-2019 in England.

BACKGROUND: Providing detailed skin cancer statistics, including incidence and survival, by tumour type and patient characteristics is important for up-to-date epidemiological information. OBJECTIVES: To create a new clinically relevant consensus-based classification for registered skin tumours using tumour type and patient characteristics and to describe its application to all registered tumours in England between 2013 and 2019. METHODS: Tumours with skin topographical codes (ICD-10) and morphology and behaviour (ICD-O3) were grouped together in an iterative process creating a hierarchical tree structure. The primary-level grouping partitioned skin tumours into skin cancer, melanoma in situ, extramammary Paget disease (EMPD) and tumours of uncertain malignant potential. Second-level groups split skin cancer into keratinocyte cancer (KC), melanoma and rare cancers. The third-level group split KC into basal cell carcinoma (BCC) and squamous cell carcinoma (cSCC). Further groups were split into genital or non-genital, first or subsequent tumour, age, gender, stage, or National Health Service (NHS) region. Incidence counts, Kaplan-Meier and net survival estimates and referral routes [two-week wait (TWW), general practitioner (GP), outpatient] categorisations were calculated for each grouping across all years. RESULTS: A total of 1 445 377 skin cancers and 49 123 precancerous lesions and undefined entities were registered in England between 2013 and 2019. Skin tumours and skin cancer incidence rates are increasing for most tumour types. The most common type of skin cancer was BCC with an incidence rate of 282.36 per 100 000 person-years (PYs) [n = 158 934, 95% confidence interval (CI) 280.98-283.76] in 2019, followed by cSCC with an incidence rate of 85.24 per 100 000 PYs (n = 47 977, 95% CI 84.48-86.00) and melanoma with 27.24 (n = 15 332, 95% CI 26.81-27.67) per 100 000 PYs. Each year approximately 1800 rare skin cancers, 1500 genital cSCCs and 100 cases of EMPD are registered. Of 15 000 melanoma cases, 120 cases of melanoma occur in individuals aged < 25 years annually. One-year and five-year overall net survival varies by tumour type. cSCC 5-year net survival (89.8%, 95% CI 88.8-90.9) was comparable to the net survival of all melanomas (89.6%, 95% CI 88.7-90.6). BCC had excellent survival (overall net survival > 100%). Patients with late-stage melanoma, Merkel cell carcinoma and genital cSCC have a 5-year net survival < 60%. Older patients received fewer TWW referrals than their younger counterparts with the same tumour type at the same location. Patients with acral lentiginous melanoma had fewer TWW referrals and more standard GP referrals than patients with common melanomas. CONCLUSIONS: 'Get Data Out' Skin provides detailed and up-to-date statistics on all registrable skin tumours in England, including for the first time precancerous lesions and rare subtypes of common cancers. These data can be used by clinicians, researchers and commissioners to better understand skin cancer and improve resource allocation.

Comparison of clinicopathologic features, survival, and demographics in sebaceous carcinoma patients with and without Muir-Torre syndrome.

BACKGROUND: Visceral malignancies in patients with Lynch syndrome behave less aggressively than in those without Lynch syndrome. The behavior of sebaceous carcinoma (SC) in Muir-Torre syndrome (MTS), a variant of Lynch syndrome, is incompletely investigated. OBJECTIVE: To investigate features and survival of SC patients with and without MTS. METHODS: Retrospective cohort study in the Surveillance, Epidemiology, and End Results 17 database from 2000 to 2019 of patients with SC. Patients were classified as MTS or non-MTS cases based on a threshold score of 2 on the Mayo MTS risk score. RESULTS: We identified 105 (2.8%) MTS cases and 3677 (97.2%) non-MTS cases. On univariate analysis, MTS patients were younger, had a higher proportion of tumors outside the head/neck, and had fewer high-grade tumors. On Kaplan-Meier analysis, MTS patients trended toward having better SC-specific survival. On multivariate Cox proportional hazards analysis adjusting for other covariates, MTS status was an independent predictor of worse overall survival. However, there was no association between MTS status and SC-specific survival. LIMITATIONS: Given relatively high disease-specific survival in SC, our study may have been underpowered to detect a difference on Kaplan-Meier analysis. CONCLUSIONS: Our study suggests SC does not behave more aggressively in patients with MTS.

Sebaceous carcinoma epidemiology, associated malignancies and Lynch/Muir-Torre syndrome screening in England from 2008 to 2018.

BACKGROUND: Sebaceous carcinomas (SC) may be associated with the cancer predisposition syndrome Muir-Torre/Lynch syndrome (MTS/LS), identifiable by SC mismatch repair (MMR) screening; however, there is limited data on MMR status of SC. OBJECTIVE: To describe the epidemiology of SC, copresentation of other cancers, and population level frequency of MMR screening in SC. METHODS: A population-based retrospective cohort study of SC patients in the National Cancer Registration and Analysis Service in England. RESULTS: This study included 1077 SC cases (739 extraocular, 338 periocular). Age-standardized incidence rates (ASIR) were higher in men compared with women, 2.74 (95% CI, 2.52-9.69) per 1,000,000 person-years for men versus 1.47 person-years (95% CI, 1.4-1.62) for women. Of the patients, 19% (210/1077) developed at least one MTS/LS-associated malignancy. MMR immunohistochemical screening was performed in only 20% (220/1077) of SC tumors; of these, 32% (70/219) of tumors were MMR deficient. LIMITATIONS: Retrospective design. CONCLUSIONS: Incorporation of MMR screening into clinical practice guidelines for the management of SC will increase the opportunity for MTS/LS diagnoses, with implications for cancer surveillance, chemoprevention with aspirin, and immunotherapy treatment targeted to MTS/LS cancers.

Epidemiology of porocarcinoma in England 2013-2018: a population-based registry study.

BACKGROUND: Porocarcinoma (PC) is a cutaneous malignancy that differentiates towards (possibly arises from) the sweat ducts and glands. Lack of histological diagnostic markers makes clinical and pathological diagnosis complex. The limited data available suggest the incidence is increasing; however, this remains to be established in national epidemiological studies. OBJECTIVES: To report the incidence, treatment and survival of patients with PC in England from 1 January 2013 to 31 December 2018 using national cancer registry data. METHODS: PC diagnoses in England during 2013-2018 were identified from the National Disease Registration Service using morphology and behaviour codes. These were registered from routinely collected pathology reports and cancer outcomes and services datasets. The 2013 European age standardized incidence rates (EASRs), Kaplan-Meier all-cause survival and log-rank test were calculated. RESULTS: In total, 738 tumours (396 in males and 342 in females) were diagnosed. The median age at diagnosis was 82 years old (interquartile range 74-88). The most frequently affected site were lower limbs (35.4%), followed by the face (16%). The majority of the cohort received surgical excision (73.0%). The Kaplan-Meier all-cause survival was 45.4% at 5 years, which was lower than in previous studies. The EASR for the whole population was 0.25 [95% confidence interval (CI) 0.23-0.27] per 100 000 person-years (PY)]. PC incidence rates in the East of England (EASR of 0.54, 95% CI 0.47-0.63 per 100 000 PY) were three times higher than the South West (EASR of 0.14, 95% CI 0.10-0.19 per 100 000 PY) where the regional rates were the lowest. CONCLUSIONS: This study shows that there is large variation in the EASRs of PC across England. This may reflect differences in how PC is diagnosed and registered in different regions in England. These data support national assessment of the management of PC, which will inform future studies and guideline development.

Clinical Outcomes in Sebaceous Carcinoma: A Retrospective Two-Center Cohort Study.

BACKGROUND: Sebaceous carcinoma (SC) is a rare, potentially recurrent, and life-threatening cutaneous malignancy that can be associated with Muir-Torre syndrome (MTS), a DNA mismatch repair-driven genodermatosis. Earlier studies examining factors associated with recurrence have focused on periocular tumors only. OBJECTIVE: Examine outcomes of SC and identify factors associated with recurrence. MATERIALS AND METHODS: Retrospective study from 2 tertiary care centers. RESULTS: Sixty-seven cases from 63 patients were identified, including 7 cases of MTS and 13 arising in the context of immunosuppression. Fifty-five cases (82.1%) were treated with complete circumferential peripheral and deep margin assessment (CCPDMA) methods. Five recurrences developed during the postoperative period. On univariate analysis, periocular location (odds ratio [OR] 7.6, p = .0410), and lesion size ≥2 cm (OR 9.6, p = .005) were associated with recurrence, whereas CCPDMA (OR 0.052, p = .0006) was inversely associated with recurrence. On multivariate analysis, only lesion size ≥2 cm (OR 9.6, p = .0233) and CCPDMA approaches (OR 0.052, p = .007) were significant. CONCLUSION: Non-complete circumferential peripheral and deep margin assessment methods and large lesion size were independent risk factors predicting recurrence, whereas anatomic subtype and MTS status were not. These findings can assist in identifying SC cases that may benefit from more aggressive treatment and closer surveillance.

Huriez syndrome: Additional pathogenic variants supporting allelism to SMARCAD syndrome.

Huriez syndrome (HRZ, OMIM181600) is a rare genodermatosis characterized by scleroatrophic hands and feet, hypoplastic nails, palmoplantar keratoderma, and predisposition to cutaneous squamous cell carcinoma (cSCC). We report herein three HRZ families from Croatia, the Netherlands, and Germany. Deep sequencing followed by Sanger validation, confirmed the presence of germline causative SMARCAD1 heterozygous pathogenic variants. All seven HRZ patients displayed hypohidrosis, adermatoglyphia, and one patient developed cSCC at 32 years of age. Two novel monoallelic germline mutations were identified which are predicted to disrupt the first exon-intron boundary of the skin-specific SMARCAD1 isoform. On the basis of phenotypic and genotypic convergence with Adermatoglyphia (OMIM136000) and Basan syndrome (OMIM129200), our results lend credence to the notion that these three Mendelian disorders are allelic. We propose adding Huriez syndrome to the previously suggested SMARCAD syndrome designation, which was originally invoked to describe the spectrum of monogenic disorders between Adermatoglyphia and Basan syndrome.

Porocarcinoma: a review.

From the first report in 1969 to the present day, diagnosis of eccrine porocarcinoma, also known simply as porocarcinoma (PC), remains a challenge. This review presents a concise update of the history, pathogenesis, epidemiology, diagnosis, management and prognosis of this rare sweat gland neoplasm. PC differentiates towards the intraepidermal spiral ducts in the eccrine gland, is more common in people aged > 60 years and often affects the head, neck and legs. PC presents as a dome-shaped papule, plaque or nodule growing over weeks to months. The exact incidence of PC is unknown but appears to be rising. Diagnosis is difficult because of variable presentations and similar clinical and histological features to cutaneous squamous cell carcinoma. Management involves removal of the tumour, usually using wide local excision or Mohs micrographic surgery. Prognosis is poor, with PC recurring after surgery in 35% of cases. Given the lack of standardized protocols and risk profiles, further studies would help improve the understanding of PC.

TRAF3 and NBR1 both influence the effect of the disease-causing CYLD(Arg936X) mutation on NF-κB activity.

Recently described Hungarian and Anglo-Saxon pedigrees that are affected by CYLD cutaneous syndrome (syn: Brooke-Spiegler syndrome (BSS)) carry the same disease-causing mutation (c.2806C>T, p.Arg936X) of the cylindromatosis (CYLD) gene but exhibit striking phenotypic differences. Using whole exome sequencing, missense genetic variants of the TRAF3 and NBR1 genes were identified in the affected family members of the Hungarian pedigree that are not present in the Anglo-Saxon pedigree. This suggested that the affected proteins (TRAF3 and NBR1) are putative phenotype-modifying factors. An in vitro experimental system was set up to clarify how wild type and mutant TRAF3 and NBR1 modify the effect of CYLD on the NF-κB signal transduction pathway. Our study revealed that the combined expression of mutant CYLD(Arg936X) with TRAF3 and NBR1 caused increased NF-κB activity, regardless of the presence or absence of mutations in TRAF3 and NBR1. We concluded that increased expression levels of these proteins further strengthen the effect of the CYLD(Arg936X) mutation on NF-κB activity in HEK293 cells and may explain the phenotype-modifying effect of these genes in CYLD cutaneous syndrome. These results raise the potential that detecting the levels of TRAF3 and NBR1 might help explaining phenotypic differences and prognosis of CCS.

CYLD is a causative gene for frontotemporal dementia - amyotrophic lateral sclerosis.

Frontotemporal dementia and amyotrophic lateral sclerosis are clinically and pathologically overlapping disorders with shared genetic causes. We previously identified a disease locus on chromosome 16p12.1-q12.2 with genome-wide significant linkage in a large European Australian family with autosomal dominant inheritance of frontotemporal dementia and amyotrophic lateral sclerosis and no mutation in known amyotrophic lateral sclerosis or dementia genes. Here we demonstrate the segregation of a novel missense variant in CYLD (c.2155A>G, p.M719V) within the linkage region as the genetic cause of disease in this family. Immunohistochemical analysis of brain tissue from two CYLD p.M719V mutation carriers showed widespread glial CYLD immunoreactivity. Primary mouse neurons transfected with CYLDM719V exhibited increased cytoplasmic localization of TDP-43 and shortened axons. CYLD encodes a lysine 63 deubiquitinase and CYLD cutaneous syndrome, a skin tumour disorder, is caused by mutations that lead to reduced deubiquitinase activity. In contrast with CYLD cutaneous syndrome-causative mutations, CYLDM719V exhibited significantly increased lysine 63 deubiquitinase activity relative to the wild-type enzyme (paired Wilcoxon signed-rank test P = 0.005). Overexpression of CYLDM719V in HEK293 cells led to more potent inhibition of the cell signalling molecule NF-κB and impairment of autophagosome fusion to lysosomes, a key process in autophagy. Although CYLD mutations appear to be rare, CYLD's interaction with at least three other proteins encoded by frontotemporal dementia and/or amyotrophic lateral sclerosis genes (TBK1, OPTN and SQSTM1) suggests that it may play a central role in the pathogenesis of these disorders. Mutations in several frontotemporal dementia and amyotrophic lateral sclerosis genes, including TBK1, OPTN and SQSTM1, result in a loss of autophagy function. We show here that increased CYLD activity also reduces autophagy function, highlighting the importance of autophagy regulation in the pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis.

Identification of putative phenotype-modifying genetic factors associated with phenotypic diversity in Brooke-Spiegler syndrome.

Brooke-Spiegler syndrome (BSS, OMIM 605041) is a rare monogenic skin disease characterized by the development of skin appendage tumors caused by mutations in the cylindromatosis gene. We recently investigated a Hungarian and an Anglo-Saxon pedigrees affected by Brooke-Spiegler syndrome. Despite carrying the same disease-causing mutation (c.2806C>T, p.Arg936X) of the cylindromatosis (CYLD) gene, the affected family members of the two pedigrees exhibit striking differences in their phenotypes. To identify phenotype-modifying genetic factors, whole exome sequencing was performed and the data from the Hungarian and Anglo-Saxon BSS patients were compared. Three putative phenotype-modifying genetic variants were identified: the rs1053023 SNP of the signal transducer and activator of transcription 3 (STAT3) gene, the rs1131877 SNP of the tumor necrosis factor receptor-associated factor 3 (TRAF3) gene and the rs202122812 SNP of the neighbour of BRCA1 gene 1 (NBR1) gene. Our study contributes to the accumulating evidence for the clinical importance of phenotype-modifying genetic factors, which are potentially important for the elucidation of disease prognosis.

Diverse presentations of cutaneous mosaicism occur in CYLD cutaneous syndrome and may result in parent-to-child transmission.

BACKGROUND: Clusters of rare cylindroma or spiradenoma tumors are a recurrent clinical presentation, yet conventional genetic testing results in individuals with these tumors are frequently normal. OBJECTIVE: To determine if genetic mosaicism accounts for such cases. METHODS: A study of 6 cases from a series of 55 patients who met criteria for diagnostic gene testing for pathogenic CYLD variants over a 5-year period (2012-2017) was performed. A novel genetic assay was used to study DNA from peripheral blood leukocytes and, where possible, matched skin and tumor tissue. RESULTS: Two patients had mosaic pathogenic CYLD variants in both the blood and skin. One of these patients transmitted a pathogenic variant to her daughter, and we report the novel phenotype of a contiguous gene deletion syndrome involving CYLD. Two patients had recurrent pathogenic variants in skin tumors from a single cluster but none detectable in the blood. LIMITATIONS: The remaining 2 patients had clinical features of mosaicism, but these cases were not solved with the assays used because of a lack of access of fresh tumor tissue. CONCLUSION: Genetic mosaicism should be considered in patients presenting with clustered cylindromas, because this may inform genetic testing and counseling of these patients.

p63 and smooth muscle actin expression in low-grade spiradenocarcinomas in a case of CYLD cutaneous syndrome.

Low-grade spiradenocarcinoma is a rare skin tumor, with fewer than six reported cases, arising in the context of CYLD cutaneous syndrome (CCS; syn: Brooke-Spiegler syndrome [BSS]). We report two independent cases of spiradenocarcinoma arising in a 50-year-old man with CCS. The tumors grew rapidly, prompting clinical excision. The histologic features in our cases corresponded to the salivary gland type basal cell adenocarcinoma-like pattern, low grade (BCAC-LG), that has been previously recognized as a recurrent finding in CCS. We performed genetic testing of the patient and found a novel mutation in CYLD. Recognition of low-grade spiradenocarcinoma can be difficult for the pathologist as the features can be subtle, especially in those cases where the transition from benign to malignant tumor is gradual. We examined p63 and smooth muscle actin (SMA) expression patterns in BCAC-LG and compared it with the expression pattern in the precursor spiradenoma. Our report provides information on two rare tumors in the context of CCS and suggests that the pattern of p63 and SMA staining may aid pathological detection of the BCAC-LG subtype of spiradenocarcinoma.