The upcoming 5th edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours is part of an effort to hierarchically catalogue human cancers arising in various organ systems within a single relational database. This paper summarizes the new WHO classification scheme for myeloid and histiocytic/dendritic neoplasms and provides an overview of the principles and rationale underpinning changes from the prior edition. The definition and diagnosis of disease types continues to be based on multiple clinicopathologic parameters, but with refinement of diagnostic criteria and emphasis on therapeutically and/or prognostically actionable biomarkers. While a genetic basis for defining diseases is sought where possible, the classification strives to keep practical worldwide applicability in perspective. The result is an enhanced, contemporary, evidence-based classification of myeloid and histiocytic/dendritic neoplasms, rooted in molecular biology and an organizational structure that permits future scalability as new discoveries continue to inexorably inform future editions.

Background Chilblains ("COVID toes") are being seen with increasing frequency in children and young adults during the COVID‐19 pandemic. Detailed histopathological descriptions of COVID‐19 chilblains have not been reported, and causality of SARS‐CoV‐2 has not been established yet. Objective To describe histopathological features of Covid‐19 chilblains and explore the presence of SARS‐CoV‐2 in the tissue. Methods We examined skin biopsies from 7 paediatric patients presenting with chilblains during the COVID‐19 pandemic. Immunohistochemistry for SARS‐CoV‐2 was performed in all cases and electron microscopy in one. Results Histopathology showed variable degrees of lymphocytic vasculitis ranging from endothelial swelling and endothelialitis to fibrinoid necrosis and thrombosis. Purpura, superficial and deep perivascular lymphocytic inflammation with perieccrine accentuation, oedema, and mild vacuolar interface damage were also seen. SARS‐CoV‐2 immunohistochemistry was positive in endothelial cells and epithelial cells of eccrine glands. Coronavirus particles were found in the cytoplasm of endothelial cells on electron microscopy. Conclusions Although the clinical and histopathological features were similar to other forms of chilblains, the presence of viral particles in the endothelium and the histological evidence of vascular damage, support a causal relation of the lesions with SARS‐CoV‐2. Endothelial damage induced by the virus could be the key mechanism in the pathogenesis of COVID‐19 chilblains and perhaps also in a group of patients severely affected by COVID‐19 presenting with features of microangiopathic damage.

Generalized lymphatic anomaly (GLA) is a vascular disorder characterized by diffuse or multifocal lymphatic malformations (LMs). The etiology of GLA is poorly understood. We identified four distinct somatic PIK3CA variants (Glu542Lys, Gln546Lys, His1047Arg, and His1047Leu) in tissue samples from five out of nine patients with GLA. These same PIK3CA variants occur in PIK3CA-related overgrowth spectrum and cause hyperactivation of the PI3K–AKT–mTOR pathway. We found that the mTOR inhibitor, rapamycin, prevented lymphatic hyperplasia and dysfunction in mice that expressed an active form of PIK3CA (His1047Arg) in their lymphatics. We also found that rapamycin reduced pain in patients with GLA. In conclusion, we report that somatic activating PIK3CA mutations can cause GLA, and we provide preclinical and clinical evidence to support the use of rapamycin for the treatment of this disabling and deadly disease.

Standard treatment for osteosarcoma patients consists of a combination of cisplatin, adriamycin, and methotrexate before surgical resection of the primary tumour, followed by postoperative chemotherapy including vincristine and cyclophosphamide. Unfortunately, many patients still relapse or suffer adverse events. We examined whether common germline polymorphisms in chemotherapeutic transporter and metabolic pathway genes of the drugs used in standard osteosarcoma treatment may predict treatment response. In this study we screened 102 osteosarcoma patients for 346 Single Nucleotide Polymorphisms (SNPs) and 2 Copy Number Variants (CNVs) in 24 genes involved in the metabolism or transport of cisplatin, adriamycin, methotrexate, vincristine, and cyclophosphamide. We studied the association of the genotypes with tumour response and overall survival. We found that four SNPs in two ATP-binding cassette genes were significantly associated with overall survival: rs4148416 in ABCC3 (per-allele HR = 8.14, 95%CI = 2.73-20.2, p-value = 5.1×10⁻⁵), and three SNPs in ABCB1, rs4148737 (per-allele HR = 3.66, 95%CI = 1.85–6.11, p-value = 6.9×10⁻⁵), rs1128503 and rs10276036 (r² = 1, per-allele HR = 0.24, 95%CI = 0.11–0.47 p-value = 7.9×10⁻⁵). Associations with these SNPs remained statistically significant after correction for multiple testing (all corrected p-values [permutation test] ≤0.03). Our findings suggest that these polymorphisms may affect osteosarcoma treatment efficacy. If these associations are independently validated, these variants could be used as genetic predictors of clinical outcome in the treatment of osteosarcoma, helping in the design of individualized therapy.

Background: Wilms tumor 1 (WT1) protein is expressed during angiogenesis and malignant transformation of endothelial cells and can be helpful to distinguish between proliferative and malformative vascular lesions. Methods: We evaluated retrospectively 117 vascular neoplasms and 50 vascular malformations. Vascular neoplasms included infantile hemangioma (n = 87), noninvoluting congenital hemangioma (n = 5), rapidly involuting congenital hemangioma (n = 3), tufted angioma (n = 8), pyogenic granuloma (n = 13), and spindle cell hemangioma (n = 1). Vascular malformations were lymphatic malformations (n = 28), venous malformations (n = 16), capillary malformation (n = 1), and stage II arteriovenous malformations (n = 5). Immunohistochemical stains for WT1 and GLUT1 were performed in all lesions. Results: All 117 vascular neoplasms showed positive expression of WT1, whereas all vascular malformations in our study were completely negative for WT1 except in arteriovenous malformations, where WT1 expression was positive. Conclusions: The comparison between vascular neoplasms and vascular malformations showed that GLUT1 expression is positive only in infantile hemangiomas, whereas WT1 positivity is found in all vascular neoplasms and in arteriovenous malformations. WT1 antibody is an ancillary test that can be helpful to differentiate vascular neoplasms from most vascular malformations.

Our knowledge in vascular anomalies has grown tremendously in the past decade with the identification of key molecular pathways and genetic mutations that drive the development of vascular tumors and vascular malformations. This has led us to better understand the pathogenesis of vascular lesions, refine their diagnosis and update their classification while also exploring the opportunity for a targeted molecular treatment. This paper aims to provide an overview of venous malformations (VM) in childhood. Specific entities include common VMs, cutaneo-mucosal VM, blue rubber bleb nevus syndrome or Bean syndrome, glomuvenous malformation, cerebral cavernous malformation, familial intraosseous vascular malformation and verrucous venous malformation. The clinicopathological features and the molecular basis of each entity are reviewed.