Langerhans Cell Histiocytosis, Non-Langerhans histiocytosis and concurrent Papillary Thyroid Carcinoma with BRAF V600E mutations: A case report and literature review

Abstract

Langerhans Cell Histiocytosis (LCH) and the non-LCH, Erdheim Chester Disease, are rare histiocytic neoplasms with distinctive clinical and immunophenotypic features, but with several overlapping molecular features. LCH is a neoplasm of Langerin-positive, CD1a-positive, S100-positive dendritic cells (DCs), once thought to arise from the epidermal or mucosal-derived Langerhans Cell (LC) due to the morphologic, immunophenotypic, and ultrastructural similarities between neoplastic LCH cell and the physiologic LC [5,6]. However, gene expression profiling studies of LCH cells have shown that these cells are not derived from terminally differentiated LCs as originally thought, but rather share a closer kinship with dendritic cells of the bone marrow than with LCs of the skin [5-7]. LCH presents most often as a solitary lesion involving the bone, lymph node, skin or lung, but may also present with multifocal lesions or multisystemic disease, additionally involving the liver, spleen and bone marrow. Although LCH displays a broad spectrum of clinical presentations, histologically, all lesions include prototypic LCH cells in an inflammatory background, often with admixed eosinophils and T-cells, leading those who originally studied the disease to question the neoplastic versus the reactive or inflammatory nature of the lesion [8]. One of the most common non-LCH histiocytoses, Erdheim Chester Disease (ECD), is a rare multisystem neoplasm of adults diagnosed via a combination of clinical, radiological and pathological findings, with consensus diagnostic criteria requiring detection of the typical neoplastic cells and nearly constant skeletal involvement [9-11]. The neoplastic cells are foamy histiocytes that express CD14, CD68 and CD163, rarely S100, and are negative for CD1a and Langerin and are often admixed with Touton giant cells and other reactive cells [12]. ECD may also involve multiple sites, similar to LCH. ECD patients commonly present with retroperitoneal, renal and/or cardiac involvement, and have a historically poor overall survival (median 3 years), often with progressive neurodegenerative disorders [10]. Molecular studies have detected recurrent BRAF and MAPK pathway-activating mutations in both of these neoplasms, with BRAF mutations present in up to 69% of LCH and in 82% of ECD [4]. These findings have led researchers to believe that LCH and ECD may be clonally related disorders, and may theoretically arise from a primitive common progenitor, supported by the fact that these neoplasms occasionally co-occur. Approximately 20% of patients with LCH also present with non-LCH either subsequently or simultaneously, even within the same biopsy site, a phenomenon known as “mixed histiocytosis” (MH) [2-4]. LCH and non-LCH may also co-occur with non-hematopoietic neoplasms, including Papillary Thyroid Carcinoma (PTC), approximately half of which have activating BRAF mutations [13-32]. Although rare cases of concurrent histiocytosis and PTC exist, most reports have not documented the BRAF status of the lesions. Herein we present a case of a 39-year-old female with LCH and non-LCH involving a left neck soft tissue mass, as detected in two biopsy specimens, along with a separate, but concurrent, Papillary Thyroid Carcinoma, all harboring the canonical BRAF V600E mutation. We discuss this unique case to illustrate the relationship between LCH and non-LCH lesions and explore their connections with tumors of different cellular origins. We also review the literature to document the prevalence of these lesions and their mutations, and to gain insight into the role that molecular drivers like BRAF play in histologically diverse tumors.