Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive neoplasm derived from plasmacytoid dendritic cells (pDCs). In this study, we investigated by immunohistochemical analysis the expression of E-cadherin (EC) on pDCs in reactive lymph nodes and tonsils, bone marrow, and in BPDCN. We compared the expression of EC in BPDCN to that in leukemia cutis (LC) and cutaneous lupus erythematosus (CLE), the latter typically featuring pDC activation. In BPDCN, we also assessed the immunomodulatory activity of malignant pDCs through the expression of several type I interferon (IFN-I) signaling effectors and downstream targets, PD-L1/CD274, and determined the extent of tumor infiltration by CD8-expressing T cells. In reactive lymph nodes and tonsils, pDCs expressed EC, whereas no reactivity was observed in bone marrow pDCs. BPDCN showed EC expression in the malignant pDCs in the vast majority of cutaneous (31/33 cases, 94%), nodal, and spleen localizations (3/3 cases, 100%), whereas it was more variable in the bone marrow (5/13, 38,5%), where tumor cells expressed EC similarly to the skin counterpart in 4 cases and differently in other 4. Notably, EC was undetectable in LC (n=30) and in juxta-epidermal pDCs in CLE (n=31). Contrary to CLE showing robust expression of IFN-I-induced proteins MX1 and ISG5 in 20/23 cases (87%), and STAT1 phosphorylation, BPDCN biopsies showed inconsistent levels of these proteins in most cases (85%). Expression of IFN-I-induced genes, IFI27, IFIT1, ISG15, RSAD2, and SIGLEC1, was also significantly (P<0.05) lower in BPDCN as compared with CLE. In BPDCN, a significantly blunted IFN-I response correlated with a poor CD8⁺T-cell infiltration and the lack of PD-L1/CD274 expression by the tumor cells. This study identifies EC as a novel pDC marker of diagnostic relevance in BPDCN. The results propose a scenario whereby malignant pDCs through EC-driven signaling promote the blunting of IFN-I signaling and, thereby, the establishment of a poorly immunogenic tumor microenvironment.

Doxorubicin represents the mainstay in the upfront treatment of diffuse large B-cell lymphoma (DLBCL) patients. However, its administration is sometimes hampered by the coexistence of former comorbidities/cardiac issues, especially in the elderly population. Liposome encapsulated drug delivery systems have been adopted to reduce the exposure of normal tissues to the drug, both in solid cancers and lymphomas. Despite claims for lower toxicity, the efficacy of non-pegylated liposome doxorubicin (NPLD) in DLBCL, as compared to standard doxorubicin, has never been established. We systematically reviewed relevant literature of NPLD in lymphoma treatment. Adjusting for age/comorbidities, our metanalysis revealed that the use of combinations including NPLD (R-COMP) were non-inferior in terms of response, overall and progression-free survival to the standard of care (R-CHOP) in overlapping series of DLBCL patients. R-COMP may represent a safe and active option for elderly patients with DLBCL, or for those with some extent of cardiac impairment at baseline.

Bone marrow mastocytosis (BMM) represents a provisional, indolent subvariant of systemic mastocytosis (SM). Utilizing WHO criteria, BMM requires bone marrow (BM) involvement and the absence of mastocytosis skin lesions. BMM is characterized by male sex prevalence, a slight increase of serum tryptase levels, low BM mast cells (MC) burden, and an indolent clinical course. BMM shows a strong correlation with severe anaphylaxis, mainly due to an IgE-mediated allergy to bee or wasp venom and, less frequently, to unexplained (idiopathic) anaphylaxis. Furthermore, BMM is often associated with osteoporosis which could be the only presenting symptom of the disease. BMM is an undervalued disease as serum tryptase levels are not routinely measured in the presence of unexplained osteoporosis or anaphylaxis. Moreover, BMM patients are often symptom-free except for severe allergic reactions. These factors, along with typical low BM MCs infiltration, may contribute to physicians overlooking BMM diagnosis, especially in medical centers that lack appropriately sensitive diagnostic techniques. This review highlights the need for a correct diagnostic pathway to diagnose BMM in patients with suspected symptoms but lacking typical skin lesions, even in the case of normal serum tryptase levels. Early diagnosis may prevent potential life-threatening anaphylaxis or severe skeletal complications.

Patients with mantle cell lymphoma (MCL) who experience first relapse/refractoriness can be categorized into early or late progression-of-disease (POD) groups, with a threshold of 24 months from MCL diagnosis. Bruton tyrosine kinase inhibitors (BTKi) are the established standard treatment at first relapse, but their effectiveness compared with chemoimmunotherapy (CIT) in late-POD patients remains unknown. In this international, observational cohort study, we evaluated outcomes among patients at first, late POD beyond 24 months. The primary objective was progression-free survival from the time of second-line therapy (PFS-2) of BTKi vs CIT. Overall, 385 late-POD patients were included from 10 countries. Their median age was 59 years (range, 19-70), and 77% were male. Median follow-up from the time of second-line therapy was 53 months (range, 12-144). Overall, 114 patients had second-line BTKi, whereas 271 had CIT, consisting of rituximab-bendamustine (R-B; n = 101), R-B and cytarabine (R-BAC; n = 70), or other regimens (mostly cyclophosphamide-hydroxydaunorubicin-vincristine-prednisone]- or platinum-based; n = 100). The 2 groups were balanced in clinicopathological features and median time to first relapse. Overall, BTKi was associated with significantly prolonged median PFS-2 than CIT (not reached [NR] vs 26 months, respectively; P = .0003) and overall survival (NR and 56 months, respectively; P = .03). Multivariate analyses showed that BTKi was associated with lower risk of death than R-B and other regimens (hazard ratio, 0.41 for R-B and 0.46 for others), but similar to R-BAC. These results may establish BTKi as the preferable second-line approach in patients with BTKi-naïve MCL.

Classical Hodgkin lymphoma (cHL) is a unique neoplastic ecosystem characterized by a heterogeneous immune infiltrate surrounding the rare malignant Hodgkin Reed-Sternberg cells. Though less abundant than T-cells, tumor-infiltrating macrophages play a pivotal role in supporting HRS survival through cell-to-cell and paracrine interactions. Traditional immunohistochemistry based upon the M1-M2 dichotomy yielded controversial results about the composition, functional role and prognostic impact of macrophages in cHL. More recent studies exploiting single-cell technologies and image analyses have highlighted the heterogeneity and the peculiar spatial arrangement of the macrophagic infiltrate, with the most immunosuppressive subpopulations lying in close proximity of HRS cells and the most tumor-hostile subsets kept far away from the neoplastic niches. High-throughput analysis of peripheral blood mononuclear cells in cHL patients have also identified a novel, potentially cytotoxic, subpopulation predicting better response to PD-1 blockade. This review examines the phenotypic profile, spatial localization and clinical impact of tumor-infiltrating macrophages and circulating monocytes in cHL, providing an up-do-date portrait of these innate immune cells with possible translational applications.