Rosai–Dorfman disease (RDD) is a rare myeloproliferative disorder of histiocytes with a broad spectrum of clinical manifestations and peculiar morphologic features (accumulation of histiocytes with emperipolesis). Typically, the patient with RDD shows bilateral painless, massive cervical lymphadenopathy associated with B symptoms. Approximately 43% of patients presented with extranodal involvement. According to the 2016 revised histiocytosis classification, RDD belongs to the R group, including familial and sporadic form (classical nodal, extranodal, unclassified, or RDD associated with neoplasia or immune disease). Sporadic RDD is often self-limited. Most RDD needs only local therapies. Nevertheless, a small subpopulation of patients may be refractory to conventional therapy and die of the disease. Recent studies consider RDD a clonal neoplastic process, as approximately 1/3 of these patients harbor gene mutations involving the MAPK/ERK pathway, e.g., NRAS, KRAS, MAP2K1, and, rarely, the BRAF mutation. In addition to typical histiocytic markers (S100/fascin/CD68/CD163, etc.), recent studies show that the histiocytes in RDD also express BCL-1 and OCT2, which might be important in pathogenesis. Additionally, the heterozygous germline mutation involving the FAS gene TNFRSF6 is identified in some RDD patients with an autoimmune lymphoproliferative syndrome type Ia. SLC29A3 germline mutation is associated with familial or Faisalabad histiocytosis and H syndrome.

Hemophagocytic lymphohistiocytosis (HLH) is a rare but life-threatening hyperinflammatory/hypercytokinemia syndrome clinicopathologically manifested by fever, hepatosplenomegaly, cytopenias, liver dysfunction, and hemophagocytosis. We searched the medical literature for English-written articles and analyzed data regarding the diagnosis, pathoetiology, prognosis, and management of HLH. HLH can be subcategorized into primary/genetic (PHLH) or secondary/acquired (SHLH) according to etiology. PHLH, including familial HLH and inherited immune deficiency syndromes, typically occurs in children harboring underlying genetic defects, whereas SHLH frequently manifests in adults and is associated with infection, autoimmunity, immune suppression, or malignancy. The pathogenesis of HLH is still elusive. Its known mechanisms include somatic mutations in gene coding for proteins implicated in the cytotoxic pathways of cytotoxic T or natural killer cells. The impaired ability of these cells to kill target cells leads to an uncontrolled hypercytokinemia and hyperinflammatory process, triggering hemophagocytosis and multiorgan failure. Corticosteroids, chemotherapy, and immunotherapy are the mainstay therapeutic strategies. The consolidation with allogeneic hematopoietic stem cell transplantation is a potentially curative option for PHLH and refractory or relapsed SHLH. Understanding of the pathophysiology of HLH has improved in the last decade. The establishment of diagnostic and treatment guidelines for PHLH and SHLH has resulted in earlier diagnoses and the rapid initiation of therapy, both of which are associated with favorable outcomes.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with dismal clinical outcomes. Conventional chemotherapies such cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) and hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with high-dose cytarabine and methotrexate (CVAD) have been commonly used for the BPDCN treatment until a recent study showed promising outcomes in patients treated with SL-401 (Tagraxofusp). In this single-institution retrospective study, we identified a total of 49 consecutive BPDCN patients. Among 42 patients who received treatment, hyper-CVAD regimen was associated with higher complete response rate compared with CHOP-based regimens or SL-401 (91% vs 50% vs 50%), although the difference did not achieve statistical significance. Furthermore, there was no significant overall survival (OS) difference between patients treated with SL-401 vs other chemotherapies as their first-line treatment (hazard ratio = 1.597; 95% CI, 0.460-5.548; P = .431). Of note, patients who received allogeneic stem cell transplant (allo-SCT) had significantly longer OS (hazard ratio = 0.160; 95% CI, 0.0453-0.56; P = .041). Extent of disease (skin vs bone marrow vs both) or younger age (<60 years old) did not have significant prognostic impact on OS. Collectively, our study confirmed the survival benefit of allo-SCT and suggests that conventional and intensive chemotherapies such as CHOP and hyper-CVAD as well as SL-401 would be comparable first-line choice for the BPDCN patients.

Myelofibrosis (MF) is a bone marrow disorder characterized by clonal myeloproliferation, aberrant cytokine production, extramedullary hematopoiesis, and bone marrow fibrosis. Although somatic mutations in JAK2 , MPL , and CALR have been identified in the pathogenesis of these diseases, inhibitors of the Jak2 pathway have not demonstrated efficacy in ameliorating MF in patients. TGF-β family members are profibrotic cytokines and we observed significant TGF-β1 isoform overexpression in a large cohort of primary MF patient samples. Significant overexpression of TGF-β1 was also observed in murine clonal MPL ^W515L megakaryocytic cells. TGF-β1 stimulated the deposition of excessive collagen by mesenchymal stromal cells (MSCs) by activating the TGF-β receptor I kinase (ALK5)/Smad3 pathway. MSCs derived from MPL ^W515L mice demonstrated sustained overproduction of both collagen I and collagen III, effects that were abrogated by ALK5 inhibition in vitro and in vivo. Importantly, use of galunisertib, a clinically active ALK5 inhibitor, significantly improved MF in both MPL ^W515L and JAK2 ^V617F mouse models. These data demonstrate the role of malignant hematopoietic stem cell (HSC)/TGF-β/MSC axis in the pathogenesis of MF, and provide a preclinical rationale for ALK5 blockade as a therapeutic strategy in MF.

Malignant bone lymphoma can be classified as primary (PBL) or secondary (SBL) bone lymphoma. However, the clinico-pathological characteristics and prognostic factors of PBL versus SBL have not yet been well defined. Whether lymphoma with multifocal bone involvement should be considered as stage IV PBL or SBL still remain controversial throughout the literature. In this study, we retrospectively reviewed 127 patients with bone lymphoma diagnosed from1998 to 2013 at the Moffitt Cancer Center. Patients were classified as PBL (81 cases) and SBL (46 cases) using the 2013 WHO Classification of Bone/Soft Tissue Tumors and PBL patients were further subdivided into: 1) PBL with unifocal bone disease (uPBL, 46 cases), 2) PBL with multifocal bone involvement (mPBL, 35 cases). Patient characteristics, survival, and prognostic factors were analyzed. Diffuse large B-cell lymphoma (DLBCL) was the most common histological subtype in all three groups (37/46 of uPBL, 23/35 of mPBL, 23/46 of SBL). B symptoms, lymph node involvement, and bone marrow involvement were found to be more common in mPB-DLBCL and SB-DLBCL groups than in the uPB-DLBCL group. Femur was found to be the most common affected site in uPB-DLBCL patients, while spine was most commonly involved in the other two groups. Survival analysis indicated that uPBL-DLBCL patients had a significantly better progression-free survival (PFS) and overall survival (OS) than those in the other two groups (P < 0.05). We also found by univariate analysis that multifocality, and stage IV were significantly poor prognostic factors for both PFS and OS in PBL patients. Using multivariate analysis, multifocality remained an independent prognostic factor for both PFS and OS (P = 0.0117, RR: 3.789, 95% CI: 1.275-11.256). Overall, our results suggest that mPBL is more similar to SBL in characteristics and survival rather than uPBL, and thus should be better classified and treated as SBL.