Global and mitosis-specific interobserver variation in mitotic count scoring and implications for malignant melanoma staging

AIMS Staging is the gold standard for predicting malignant melanoma outcome but changes in its criteria over time indicate ongoing evolution. One notable recent change from the 8 edition of the AJCC staging manual was removal of mitotic count. We explore the extent that this feature is limited by interobserver error in order to find ways to improve its fitness for use should it be revisited in future staging versions. METHODS AND RESULTS In a cohort of 476 patients with melanoma ≤ 1.0 mm, a mitotic count of 0 vs 1 was significant for metastasis-free survival, but not melanoma-specific or overall survival. In 10 melanomas that were 0.9 to 1.0 mm thick, the mitotic count intra-class correlation coefficient for histopathologists was 0.58 (moderate agreement). Uniquely, we also assessed agreement for specific putative mitotic figures, identifying precise reasons why specific mitotic figures qualified for scoring or elimination. A kappa score was 0.54 (moderate agreement). We also gathered data on other staging features. Breslow thickness had an intraclass correlation coefficient of 0.41 (moderate agreement) and there was a systematic difference between histopathologists across cases (p = 0.04). Every case had a range that crossed the AJCC8 0.8 mm pT1a/pT1b staging boundary. Ulceration was only identified in 2 out the 10 cases. For ulceration, kappa agreement score was 0.31 (fair). CONCLUSION This study supports the removal of mitotic count from staging but shows that its scoring is substantially affected by interobserver variation, suggesting that more prescriptive guidelines might have a beneficial impact on its prognostic value

Anetodermic pilomatrixomas: A case series

Abstract Pilomatrixoma is a benign hair follicle tumour. Anetodermic changes overlying pilomatrixoma are rare. The aim of this study is to evaluate a case series of patients with a clinical diagnosis of anetodermic pilomatrixoma presenting to our Dermatology Department over a 5‐year period. Eight cases were identified. The median age of onset was 21 years. All cases presented on the upper limbs and trunk with a solitary rapidly evolving tumour, tender on palpation. They had an erythematous protuberant appearance with a wrinkled and atrophic surface. Underlying pilomatrixomas were firm measuring 1–5 cm. Simple excision was carried out in seven cases without postoperative complications. In conclusion, anetodermic pilomatrixoma is a rare variant of this tumour, occurring more frequently on the upper body. It presents with identifiable features and should be differentiated from other skin tumours. Surgical removal is usually the gold standard treatment

Anetodermic pilomatrixomas: A case series

Funder: This article received no specific grant from any funding agency in the public, commercial, or not‐for‐profit sectorsPilomatrixoma is a benign hair follicle tumour. Anetodermic changes overlying pilomatrixoma are rare. The aim of this study is to evaluate a case series of patients with a clinical diagnosis of anetodermic pilomatrixoma presenting to our Dermatology Department over a 5‐year period. Eight cases were identified. The median age of onset was 21 years. All cases presented on the upper limbs and trunk with a solitary rapidly evolving tumour, tender on palpation. They had an erythematous protuberant appearance with a wrinkled and atrophic surface. Underlying pilomatrixomas were firm measuring 1–5 cm. Simple excision was carried out in seven cases without postoperative complications. In conclusion, anetodermic pilomatrixoma is a rare variant of this tumour, occurring more frequently on the upper body. It presents with identifiable features and should be differentiated from other skin tumours. Surgical removal is usually the gold standard treatment

Malta (MYH9 Associated Elastin Aggregation) Syndrome: Germline Variants in MYH9 Cause Rare Sweat Duct Proliferations and Irregular Elastin Aggregations.

To the Editor. Sweat duct proliferations and related cutaneous tumours pose a challenge for diagnosis and treatment due to the presence of multiple overlapping histopathological features (Schaller et al. 2010). In 1961 Nicolau and Balus described individuals with benign cutaneous lesions including atrophodermia vermiculata, multiple syringomata and milia which become known as Nicolau-Balus syndrome and was characterised by irregular distribution of elastin fibres (Nicolau and Balus 1961). A similar phenotype was later described as Rombo syndrome by Michaelsson et al (Michaelsson et al. 1981), with elastin distribution in these cases appearing like “swathes of steel wool” in some areas of the dermis (Van Steensel et al. 2001). In 2010, Schaller et al described several cases with the same abnormal elastin distribution, with the additional feature of sweat duct proliferations that appear morphologically similar to those found in microcystic adnexal carcinoma (MAC) patients, but (unlike MAC) were not invasive and did not require surgical resection (Schaller et al. 2010). In this study we describe five families with clinical and histopathological features that show similarities to Nicolau-Balus and Rombo syndromes with some cases also showing MAC-like ductal proliferations (figure S1). We provide evidence that these syndromes are caused by germline pathogenic variants in MYH9. Accordingly, we propose the term MALTA (MYH9 Associated eLasTin Aggregation) syndrome to reflect the common underlying genetic basis of this disease

The DILfrequency study is an adaptive trial to identify optimal IL-2 dosing in patients with type 1 diabetes.

BACKGROUND: Type 1 diabetes (T1D) results from loss of immune regulation, leading to the development of autoimmunity to pancreatic β cells, involving autoreactive T effector cells (Teffs). Tregs, which prevent autoimmunity, require IL-2 for maintenance of immunosuppressive functions. Using a response-adaptive design, we aimed to determine the optimal regimen of aldesleukin (recombinant human IL-2) to physiologically enhance Tregs while limiting expansion of Teffs. METHODS: DILfrequency is a nonrandomized, open-label, response-adaptive study of participants, aged 18-70 years, with T1D. The initial learning phase allocated 12 participants to 6 different predefined regimens. Then, 3 cohorts of 8 participants were sequentially allocated dose frequencies, based on repeated interim analyses of all accumulated trial data. The coprimary endpoints were percentage change in Tregs and Teffs and CD25 (α subunit of the IL-2 receptor) expression by Tregs, from baseline to steady state. RESULTS: Thirty-eight participants were enrolled, with thirty-six completing treatment. The optimal regimen to maintain a steady-state increase in Tregs of 30% and CD25 expression of 25% without Teff expansion is 0.26 × 106 IU/m2 (95% CI -0.007 to 0.485) every 3 days. Tregs and CD25 were dose-frequency responsive, Teffs were not. The commonest adverse event was injection site reaction (464 of 694 events). CONCLUSIONS: Using a response-adaptive design, aldesleukin treatment can be optimized. Our methodology can generally be employed to immediately access proof of mechanism, thereby leading to more efficient and safe drug development. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number Register, ISRCTN40319192; ClinicalTrials.gov, NCT02265809. FUNDING: Sir Jules Thorn Trust, the Swiss National Science Foundation, Wellcome, JDRF, and NIHR Cambridge Biomedical Research Centre.Sir Jules Thorn Trust Swiss National Science Foundation, Wellcome Trust JDRF, NIHR Cambridge Biomedical Research Centre