Part of the malignant histiocytosis group, HS is a hematolymphoid neoplasm classified as primary (in the skin, lymph nodes, digestive system, central nervous system, and disseminated) or secondary to a hematological neoplasm (follicular lymphoma, acute lymphocytic leukemia, or hairy cell leukemia), according to its location. It may also be subclassified according to the tumor’s cellular origin (histiocytic, interdigitating dendritic, Langerhans or indeterminate cells, or of unspecified origin) [3]. Due to the possible common cellular origin and clinical similarities of histiocytoses, primary malignant histiocytoses may be properly diagnosed by first ruling out other tumors showing negativity for keratin, EMA, Melan-A, HMB45, T and B lymphocyte markers, and follicular dendritic cell markers; and second, by expressing at least two of the following dendritic cell and/or histiocyte markers: CD68, CD163, CD4, and lysozyme. Cell subtype identification among malignant histiocytoses relies on stains such as S100, CD1a, and CD207 [3]. According to the WHO, the microscopic morphology of HS is characterized by diffuse proliferation of large and pleomorphic cells; neoplastic cells are round to oval with spindle-shaped areas; and the nucleus is large, round to oval or irregular, and frequently peripheral, with mild to severe atypia and vesicular chromatin. The cytoplasm is abundant and eosinophilic with fine vacuoles, and hemophagocytosis may be present [4]. Our patient’s morphology, microscopy, and immunohistochemistry results meet the diagnostic criteria for HS.
HS is not necessarily associated with a B-cell neoplasm, since these mutations have been observed in sporadic or primary cases of HS, despite the presence of clonal immunoglobulin rearrangements or translocations [5]. C. Egan et al. performed a genomic study of 21 primary histiocytic sarcoma (PHS) cases that has helped to shed light on the differentiation of primary from secondary HS, showing that the RAS/MAPK pathway had the most frequent mutations in 19/21 cases; the most commonly altered genes were NF1 and MAP2K1, with five cases each; and four of the five cases with NF1 mutation involved the gastrointestinal tract. It should be noted that no primary splenic case was included [5].
Our patient’s NGS study reported FLT3 and NOTCH2 gene mutations, MSS, and a TMB of 2 mut/Mb. The MSS status and TMB data suggested that he probably would not benefit from immunotherapy and were concordant with those described by Goyal et al. through his prospective study of genomic biomarkers in 16 histiocytic neoplasms, which included a case of HS of the nasal cavity [6]. The fms-related receptor tyrosine kinase-3 (FLT3) is a type III tyrosine kinase that functions as a hematopoietic progenitor of cell proliferation, survival, and differentiation [7]. Studies have shown that FLT3 activation is involved in leukemogenesis through serine/threonine kinase AKT phosphorylation or activation, which occurs in one-third of acute myeloid leukemia cases and confers a worse prognosis [7]. Presumably, FLT3 ligands can activate the RAS/MAPK pathway, and MAP kinase activation is needed for mitogenic signaling of FLT3 [8]. Despite the clear association between FLT3 and acute myeloid leukemia, we were unable to find any mention of a possible association between FLT3 and HS in our search of medical literature. Experiments in mice demonstrated that FLT3 is one of the regulators of dendritic cell progenitors in the bone marrow and peripheral dendritic cells; it is also essential in regulating homeostasis in splenic dendritic cell development [9]. Despite the important role of FLT3 in vivo, no overexpression of this gene was found in Langerhans cell histiocytosis (LCH) [10]. Bao et al. describe an unusual case of myeloid sarcoma (MS) of the vaginal wall having a morphological and immunohistochemical overlap with HS. NGS demonstrated FLT3 mutation, but no medical literature was found that associates these two neoplasms. The findings in our case may suggest genomic links between MS and HS [11].
Notch signaling pathway gain-of-function mutations are well-known oncogenic drivers, especially for neoplasms such as T-cell lymphoblastic leukemia, chronic lymphocytic leukemia, diffuse B-cell lymphoma, mantle lymphoma, breast cancer, and lung cancer [12]. NOTCH2 plays a specific immunological role in splenic marginal zone cells and dendritic cells. Inadequate signaling of this pathway has been shown to play an oncogenic role in B-cell and myeloid neoplasms [13]. The specific NGS-identified mutations of our patient have not been previously described in direct relation to PSHS, but C. Egan et al. described four cases of HS with Notch signaling pathway mutations including NOTCH2, demonstrating the possible relationship of this pathway with B-cell lymphomas and, in particular, HS [5].
In addition to the mentioned mutations, the variants of unknown significance (VUS) ATM,LRKK2,MYO18A,SETBP1,NOD1,TSC1,NTRK1,CBL,NOTCH1, and KMT2 were described in our patient's tumor. These mutations had not been described at the time of the report (March 2020) and in light of their genomic context, their significance is not clear. Interestingly, C. Egan et al. describe mutations in cell cycle regulators, which include the ATM kinase. They also mention epigenetic modifier gene mutations and/or transcription factors in eight HS (KMT2D) cases [5]. Epigenetic dysregulation in cancer manifests as global DNA hypomethylation, causing genomic instability and tumor suppressor gene and microRNA silencing through hypermethylation [14]. The VUS KMT2A/MLL1 was found in our patient . Mixed leukemia lineage (MLL) is a family of proteins whose function is histone-H3K4 methylation to regulate active gene transcription [15]. It is known that the KMT2A gene is necessary to generate an adequate number of hematopoietic progenitors [16]. Mutation of this gene is found in 5%–10% of adult acute myeloid and lymphocytic leukemias; such cases are characterized by poor prognosis and refractory to treatment [14]. Bao et al. [11] highlight the importance of KMT2A mutations and rearrangements found in MS with HS-like morphology, leading us to consider the relationship that these two neoplasms may have in addition to their common oncogenic pathway. We have so far found no literature describing the possibility of transdifferentiation from HS to MS [11]. Other authors have reported molecular similarities with variants like those of our patient (NTRK1 in LCH), pointing to the possible importance of these mutations in histiocytosis and other hematological neoplasms [17].
Our case is exceptional in that it is, to our knowledge, only the second reported case of PSHS with no macroscopic splenic nodules [18] and constitutes an unusual presentation of HLH associated with a primary splenic tumor, which has been scantly described in the literature [19,20,21]. Horny et al. described the association between HS and HLH in 1988, but the difficulty of differentiating the specific cause of HLH persists, because it can result from primary causes (hereditary Mendelian diseases) or secondary causes (infections, hematological neoplasms, solid tumors, and autoimmune diseases) [20,4].
Despite the paucity of reported PSHS cases, neoplastic cells and reactive histiocytes have been shown to present phagocytosis in one or all hematological cell lines, including proteins such as immunoglobulins and albumin [22], and PSHS may thus be a secondary cause of HLH [19]. Despite the possibility for neoplastic HS cells to produce hemophagocytosis, there is no information regarding the cause nor the consequence for reactive histiocytes to lose their physiological activity and start acting like neoplastic cells; we hypothesize that PSHS can be the responsible for the aberrant activity of histiocytic cells, which can range from normal to reactive, and finally neoplastic. [21,22]. Furthermore, fulfillment of the Histiocyte Society HLH-2004 diagnostic criteria [23] has not been described in PSHS, possibly due to the extreme rarity of this neoplasm.
Our patient met the criteria for HLH (fever, splenomegaly, and platelets: 10 x 109/L; fibrinogen: 49.3 mg/dl; triglycerides: 2271 mg/dl; ferritin: 5196 mg/dl; and splenic hemophagocytosis) secondary to PSHS during his first hospitalization. During his second hospital stay, he presented positive CMV IgM serology, indicating an opportunistic CMV infection. Epstein-Barr virus serology was negative. The patient’s distal axonal sensorimotor polyneuropathy is likely to have been of paraneoplastic etiology, due to its presentation from the first hospitalization and prior to any treatment.