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Simple Summary: Conjunctival melanoma (Co-M) is a rare and aggressive eye surface cancer. It is often misdiagnosed or overlooked, leading to late diagnosis. Co-M can cause sight loss and even eye loss, impacting quality-of-life. The numbers of new cases globally are rising at alarming rates. There is no standard treatment for Co-M and management varies between eye cancer centres. In ~25% of cases the cancer spreads elsewhere in the body, which can lead to death. The aim of this review is to concisely present what is currently known about Co-M presentation, its development and progression, clinical management and outcomes, and finally summarise future directions for research into novel therapies. Conjunctival melanoma (Co-M) is an aggressive, invasive eye and eyelid cancer. Its global incidence of ~1 in a million is increasing at a rate ratio of ~1.4, but this rises sharply in over 65-year-olds. Although rare, Co-M has a devastating impact on the lives of those who develop it. Co-M is often misdiagnosed or overlooked, leading to vision loss either from the destructive effects of the tumour or side effects of therapy, facial disfigurement from radical surgery, and death from metastases. Due to its rarity, there is limited evidence for diagnosis and management; hence, there is no standardised treatment and not all cases are referred to a specialised ocular oncology centre. Recent progress in cancer immunology and genetics have revolutionised the treatment of cutaneous melanomas, which share some similarities to Co-M. Importantly, a better understanding of Co-M and its precursor lesions is urgently needed to lead to the development of novel targeted and immunotherapies both for local tumour control and disseminated disease. This review aims to provide a comprehensive clinical overview of the current knowledge regarding Co-M, its epidemiology, pathogenesis, presentation, diagnosis and recent changes in the classification of its precursor lesions, management, and recent advances in novel biological therapies for personalised treatment of this disease. [ABSTRACT FROM AUTHOR]

Simple Summary: Sortilin is a protein with tumour-suppressor activity. Among other functions, sortilin moves around other proteins in the cell and also out of it by leading them to small vesicles termed exosomes. The aim of this study was to establish the degree of abnormal expression of the gene in non-small cell lung cancer. We show here that the alternative forms of the gene are affected both qualitatively and quantitatively. In addition, the ratio of their expression changes. We demonstrate that expression changes of the SORT1 form are due to DNA methylation of its regulatory region. As sortilin is involved in trafficking EGFR, a known target of current drugs, it is possible that these alterations, beyond their involvement in cancer development, may be predictive of the response to these therapies. Sortilin is an important regulator with potential tumour-suppressor function by limiting EGFR signalling. In this study, we undertook a comprehensive expression analysis of sortilin transcript variants and the DNA methylation status of their corresponding promoters in human non-small cell carcinomas (NSCLCs). RNA/DNA was extracted from 81 NSCLC samples and paired normal tissue. mRNA expression was measured by qPCR and DNA methylation determined by pyrosequencing. BigDye-terminator sequencing was used to confirm exon-8 alternative splicing. Results demonstrated that both SORT1A and SORT1B variants were downregulated in lung tumours. The SORT1A/SORT1B expression ratio was higher in tumours compared to normal tissue. SORT1B promoter hypermethylation was detected in lung tumours compared to normal lung (median difference 14%, Mann–Whitney test p = 10−6). Interestingly, SORT1B is hypermethylated in white blood cells, but a small and very consistent drop in methylation (6%, p = 10−15) was observed in the lung cancer cases compared to control subjects. We demonstrate that the SORT1B exon-8 splice variation, reported in sequence databases, is also a feature of SORT1A. The significantly altered quantitative and qualitative characteristics of sortilin mRNA in NSCLC indicate a significant involvement in tumour pathogenesis and may have significant impact for its utility as a predictive marker in lung cancer management. [ABSTRACT FROM AUTHOR]

Simple Summary: Choroidal melanomas are treated in the hope of preventing metastatic death; however, such treatment often causes severe visual loss. There is debate as to whether the treatment of small tumors can be deferred until tumor growth is observed. Using the Liverpool Uveal Melanoma Prognosticator Online v.3 (LUMPO3), this study provides an indication of change in the 15-year absolute risk of metastatic death, according to whether the tumor is treated immediately or after 4 or 12 months, when growth is observed. It considers tumor growth rate, dimensions, laboratory indicators of metastasis risk, prevalence of monosomy 3, patient's age, and sex. Our study suggests that deferring treatment until growth is observed is associated with minimal, if any, increase in the risk of metastatic death with usual tumor growth rates of up to 40% per year. It would seem reasonable to delay treatment until tumor growth is documented, especially if this is likely to cause visual loss. Background: We estimated metastatic-death risk when the treatment of small choroidal melanomas is deferred until growth is observed. Methods: In 24 patients with choroidal melanoma (median diameter 5.85 mm), the exponential growth rate estimated by a mixed-effects model was 4.3% per year. Using the Liverpool Uveal Melanoma Prognosticator Online v.3 (LUMPO3), we measured changes in 15-year metastatic and non-metastatic death risks according to whether the tumor is treated immediately or after observing growth 4 or 12 months later, considering age, sex, and metastasis predictors. Results: In 40-year-old females with 10 mm, disomy 3 and monosomy 3 choroidal melanomas (prevalence 16%), the 15-year absolute risks of metastatic death are 4.2% and 76.6%, respectively, increasing after a 4-month delay by 0.0% and 0.2% and by 3.0% and 2.3% with tumor growth rates of 5.0% and 20.0%, respectively. With 12-month delays, these risks increase by 0.0% and 0.5% and by 1.0% and 7.1%, respectively. Increases in metastatic-death risk are less with smaller tumors and with a higher risk of non-metastatic death. Conclusions: Deferring treatment of choroidal melanomas until documentation of growth may delay iatrogenic visual loss by months or years and is associated with minimal increase in metastatic mortality, at least with small tumors with usual growth rates of up to 40% per year. [ABSTRACT FROM AUTHOR]

The fifth edition of the World Health Organization Classification of Haematolymphoid Tumours (WHO‐HAEM5) is the product of an evidence‐based evolution of the revised fourth edition with wide multidisciplinary consultation. Nonetheless, while every classification incorporates scientific advances and aims to improve upon the prior version, medical knowledge remains incomplete and individual neoplasms may not be easily subclassified in a given scheme. Thus, optimal classification requires ongoing study, and there are certain aspects of some entities and subtypes that require further refinements. In this review, we highlight a selection of these challenging areas to prompt more research investigations. These include (1) a 'placeholder term' of splenic B‐cell lymphoma/leukaemia with prominent nucleoli (SBLPN) to accommodate many of the splenic lymphomas previously classified as hairy cell leukaemia variant and B‐prolymphocytic leukaemia, a clear new start to define their pathobiology; (2) how best to classify BCL2 rearrangement negative follicular lymphoma including those with BCL6 rearrangement, integrating the emerging new knowledge on various germinal centre B‐cell subsets; (3) what is the spectrum of non‐IG gene partners of MYC translocation in diffuse large B‐cell lymphoma/high‐grade B‐cell lymphoma and how they impact MYC expression and clinical outcome; how best to investigate this in a routine clinical setting; and (4) how best to define high‐grade B‐cell lymphoma not otherwise specified and high‐grade B‐cell lymphoma with 11q aberrations to distinguish them from their mimics and characterise their molecular pathogenetic mechanism. Addressing these questions would provide more robust evidence to better define these entities/subtypes, improve their diagnosis and/or prognostic stratification, leading to better patient care. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Kimura disease (KD) is a rare, chronic, inflammatory condition, predominantly found in male patients of Asian ethnicity. It typically presents between 50–60 years of age and usually with bilateral disease. Angiolymphoid hyperplasia with eosinophilia (ALHE) remains the main differential diagnosis, although histological analysis is essential in differentiating from other similarly presenting pathologies. In this case, we present an atypical case of unilateral orbital KD in a middle-aged, Caucasian, male gentleman and no evidence of regional lymphadenopathy along with a literature review of orbital KD and the differential diagnoses, histological features and management modalities available, adding to the sparse literature on the topic. At present, no recognised diagnostic criteria for KD are available, with histopathological analysis through incisional or excisional biopsy being the primary diagnostic method. Complete surgical excision with or without corticosteroid management remains the most common treatment modality although management is shifting to steroid-sparing immunomodulatory therapy. To the best of our knowledge, this is the first case to describe maintenance therapy of KD using mycophenolate mofetil. [ABSTRACT FROM AUTHOR]