Although molecular testing failed to reveal the presence of copy number alterations, a low-level somatic mutation was detected (Table 1). 

Table 1. Summary of molecular findings. 

Final diagnosis: Rosai-Dorfman-Destombes Disease

Discussion:

Rosai-Dorfman-Destombes disease (RDD) is a rare histiocytic disorder characterized by a clonal population of S100-positive histiocytes with variable emperipolesis. RDD can be seen in isolation or associated with inherited neoplastic or autoimmune conditions [1]. It commonly affects children, and young adults however can affect adults as well [2]. Affected patients may exhibit the classic systemic symptoms of painless cervical lymphadenopathy, fever and weight loss, as well as increased signs of intracranial pressure or focal neurological deficits depending on location of the mass or masses [3]. The disease predominantly affects the cervical lymph nodes; however, extranodal involvement is relatively frequent. Central nervous system involvement by RDD, whether primary or secondary, is distinctly uncommon and often presents as dural-based masses, either solitary or multiple, with rare intraparenchymal extension [4,5].

Histologically these tumors often exhibit collections of foamy histiocytes in diffuse sheets with vague nodularity and multinucleation. The neoplastic histiocytes tend to have relatively uniform round to oval nuclei, fine chromatin, inconspicuous nucleoli and moderate to abundant, pale eosinophilic cytoplasm. The background is composed of a mixed inflammatory infiltrate composed of numerous lymphocytes and plasma cells, with variable fibrosis. While emperipolesis, engulfment of intact lymphocytes, plasma cells, neutrophils, and occasionally eosinophils, is not pathognomic of RDD, it can be diagnostically useful. The neoplastic histiocytes are positive for CD11c, CD68, CD163, fascin, Oct2, S100 and cyclin D1 while negative for CD1a and CD207 (langerin) [6]. Other histiocytic disorders, including Erdheim-Chester disease, juvenile xanthogranuloma, Langerhans cell histiocytosis, histiocytic sarcoma and ALK-positive histiocytosis, can be distinguished from RDD using a combination of morphologic, immunohistochemical and molecular approaches (see table 2 for entities to be considered in the differential diagnosis).

Recent studies have found KRAS, NRAS, and rarely BRAF V600E mutations in RDD indicating that the lesion is neoplastic in nature and emphasizing the emerging potential of targeted therapeutic strategies [7-8]. Activation of the MAPK pathway in RDD has been shown to upregulate cyclin D1, emphasizing its diagnostic utility and association with increased signaling and proliferative activity [9]. Similar to our case, other studies have also shown an increase in IgG4-positive plasma cells as well as, obliterative phlebitis or storiform fibrosis in RDD which highlights it’s a potential overlap with IgG4-related disease (IgG4-RD), which can make the diagnosis of RDD on small biopsies challenging [10-12]. 

Table 2: Summary of various histocytic lesions with histopathologic features, immunohistochemical stains and unique molecular findings (table adapted from Patel and Pearce DSS, Case 1, 2023). 

References:

1. Cree IA. The WHO Classification of Haematolymphoid Tumours. Leukemia. Published online June 22, 2022. doi:https://doi.org/10.1038/s41375-022-01625-x
2. Sandoval-Sus JD, Sandoval-Leon AC, Chapman JR, et al. Rosai-Dorfman Disease of the Central Nervous System. Medicine. 2014;93(3):165-175. doi:https://doi.org/10.1097/md.0000000000000030
3. P. Purav, Ganapathy K, V.S. Mallikarjuna, et al. Rosai–Dorfman disease of the central nervous system. Journal of Clinical Neuroscience. 2005;12(6):656-659. doi:https://doi.org/10.1016/j.jocn.2005.06.003
4. Vaiselbuh SR, Bryceson YT, Allen CE, Whitlock JA, Abla O. Updates on histiocytic disorders. Pediatric Blood & Cancer. 2014;61(7):1329-1335. doi:https://doi.org/10.1002/pbc.25017
5. Abla O, Jacobsen E, Picarsic J, et al. Consensus recommendations for the diagnosis and clinical management of Rosai-Dorfman-Destombes disease. Blood. 2018;131(26):2877-2890. doi:https://doi.org/10.1182/blood-2018-03-839753
6. Parkhi M, Chatterjee D, Kashyap D, Aggarwal A, Radotra B. Primary Rosai‐Dorfman disease of the central nervous system: A clinical, histological, and molecular appraisal. Neuropathology. 2024;44(5):366-375. doi:https://doi.org/10.1111/neup.12972
7. Durham BH, Estibaliz Lopez Rodrigo, Picarsic J, et al. Activating mutations in CSF1R and additional receptor tyrosine kinases in histiocytic neoplasms. Nature Medicine. 2019;25(12):1839-1842. doi:https://doi.org/10.1038/s41591-019-0653-6
8. Diamond EL, Durham BH, Haroche J, et al. Diverse and Targetable Kinase Alterations Drive Histiocytic Neoplasms. Cancer Discovery. 2015;6(2):154-165. doi:https://doi.org/10.1158/2159-8290.cd-15-0913
9. Baraban E, Sadigh S, Rosenbaum J, et al. Cyclin D1 expression and novel mutational findings in Rosai‐Dorfman disease. British journal of haematology (Print). 2019;186(6):837-844. doi:https://doi.org/10.1111/bjh.16006
10. Tracht J, Reid MD, Xue Y, et al. Rosai-Dorfman Disease of the Pancreas Shows Significant Histologic Overlap With IgG4-related Disease. The American Journal of Surgical Pathology. 2019;43(11):1536-1546. doi:https://doi.org/10.1097/pas.0000000000001334
11. Kuo T, Chen T, Lee L, Lu P. IgG4‐positive plasma cells in cutaneous Rosai‐Dorfman disease: an additional immunohistochemical feature and possible relationship to IgG4‐related sclerosing disease. Journal of Cutaneous Pathology. 2009;36(10):1069-1073. doi:https://doi.org/10.1111/j.1600-0560.2008.01222.x
12. Gallo JR, Paira S, Hernández-Molina G, Mora JD la, Oca DMM de, Martín-Nares E. Immunoglobulin G4-Associated Rosai–Dorfman Disease: Report of 3 Cases. European Journal of Rheumatology. 2023;10(2):57-61. Doi:https://doi.org/10.5152/eurjrheum.2023.22064