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Children with Langerhnans cell histiocytosis (LCH) develop granulomatous lesions with characteristic clonal CD207+ dendritic cells that can arise as single lesions or life-threatening disseminated disease. Despite the wide range of clinical presentations, LCH lesions are histologically indistinguishable based on severity of disease, and uncertain classification as an immune versus neoplastic disorder has historically challenged the development of optimal clinical strategies for patients with LCH. Recently, activating somatic mutations in MAPK pathway genes, most notably BRAFV600E, have been discovered in almost all cases of LCH. Further, the stage of myeloid differentiation in which the mutation arises defines the extent of disease and risk of developing LCH-associated neurodegeneration. MAPK activation in LCH precursor cells drives myeloid differentiation, inhibits migration, and inhibits apoptosis, resulting in accumulation of resilient pathologic dendritic cells that recruit and activate T cells. Recurrent somatic mutations in MAPK pathway genes have also been identified in related histiocytic disorders: juvenile xanthogranuloma, Erdheim-Chester disease, and Rosai-Dorfman disease. New insights into pathogenesis support reclassification of these conditions as a myeloid neoplastic disorders. Continued research will uncover opportunities to identify novel targets and inform personalized therapeutic strategies based on cell of origin, somatic mutation, inherited risk factors, and residual disease., (© 2021 John Wiley & Sons Ltd.)

Background: The BRAF(V600E) mutation is the most common diagnostic/prognostic marker in papillary thyroid carcinoma (PTC). Its evaluation is typically performed with DNA-based techniques; nonetheless, a few articles have recently proposed the morphological prediction of BRAF(V600E) in histological PTCs. We investigated this morphological parameter in our cytological series., Methods: We re-analyzed all 72 cytohistological samples diagnosed as positive for malignancy (favoring PTC) on fine-needle aspiration cytology from January 2012 to December 2013. We included 22 male patients and 50 female patients. The cytological cases were processed with liquid-based cytology. We performed molecular analysis and immunocytochemistry for the VE1 BRAF(V600E) antibody., Results: We reported 47 mutated cases and 25 wild-type (WT) cases with 100% cytohistological concordance. The cytological evaluations revealed plump cells (abundant eosinophilic cytoplasm and PTC nuclei) in all 47 mutated cases, with only 6 having a focal plump cell component (≤20% cells). Furthermore, 5 of the 25 WT cases showed focal plump cells. A distinctive sickle nuclear shape was found only in the mutated cases. VE1 yielded 100% positivity for all 24 mutated cases that were tested, including 3 cases with focal plump cells., Conclusions: We demonstrated that the BRAF(V600E) mutation might be predicted in cytological samples on the basis of some specific morphological features. Although the detection of plump cells (mainly focal) was also observed in WT cases, the detection of sickle-shaped nuclei provided the highest specificity and sensitivity as a predictive mutational parameter. These morphological features might be a valid tool for selecting cases for molecular analysis., (© 2014 American Cancer Society.)