Cutaneous Plasmacytosis (CP), a rare disorder predominantly affecting Asian populations, is characterized by violaceous plaques with histopathological features of polyclonal mature plasma cell infiltration.1 Emerging data suggest systemic involvement in CP, though its incidence and treatments remain incompletely characterized.2 Therefore, we conducted a systematic reviews and meta-analyses (PRISMA) ‒ compliant systematic review across PubMed, Embase, Scopus and Cochrane databases (search strategy: “cutaneous or skin” and “plasmacytosis”) to clarify systemic involvement patterns and therapeutic approaches in CP.

Case reports, series and retrospective studies written in English or Chinese published before November 13, 2024, describing CP cases were included. All required pathologically confirmed prominent mature plasma cell infiltration with polyclonality, verified by κ/λ immunostaining or gene rearrangement analysis. Cases primarily involving mucosal and lymphoplasmacytic plaque in children were excluded, as they are considered separate disease entities.3,4 We also excluded cases with possible infection-induced plasmacytosis, including active syphilis, Human Herpesvirus-8 (HHV-8), or ehrlichiosis.

Seventy-nine articles reporting 109 CP cases were identified (Fig. 1). Patients were stratified by systemic involvement: localized CP (no evidence of extracutaneous infiltration) or systemic CP (pathologically confirmed extracutaneous polyclonal plasma cell infiltration). Among 109 patients (mean age 51.0 ± 14.6 years; M:F ratio 1.6:1; 84.5% Asian), systemic involvement occurred in 37 (33.9%), primarily affecting lymph nodes (n = 23, 21.1%), bone marrow (n = 21, 19.3%), kidney (n = 4, 3.7%), lungs (n = 2, 1.8%), and ectopic masses (n = 2, 1.8%, ureteral/breast lesions), with 12 patients (11.0%) having more than one organ involved.

Figure 1.

Study selection flow diagram.

We analyzed clinical characteristics, laboratory parameters, imaging findings, and pathological features documented in ≥ 40 cases to identify factors associated with systemic involvement, and compared treatment patterns and outcomes between localized and systemic CP (Table 1). Leukocytosis, polyclonal hypergammaglobulinemia, and histologically confirmed Germinal Center (GC) formation showed significant associations with systemic involvement (p < 0.05). Stronger correlations emerged for imaging detection of lymphadenopathy or hepatosplenomegaly, constitutional symptoms, anemia, and Interleukin-6 (IL-6) elevation (p < 0.001). To isolate early pathogenic drivers rather than systemic consequences, multivariate analysis focused on IL-6 and GC formation. After adjusting for demographics, duration, and GC status, IL-6 elevation emerged as the sole independent predictor (adjusted OR = 18.4, 95% CI = 2.6‒128.7, p = 0.003).

Treatment data existed for 76 patients (69.7%), with outcomes evaluable in 66 (60.5%) (Table 2). We assigned patients receiving sequential therapies to separate treatment groups based on clinical responses, excluding therapeutic approaches documented in ≤ 2 patients. Topical therapies were corticosteroids (Overall Response Rate [ORR] = 50%) and calcineurin inhibitors (ORR = 60%), primarily for localized CP. Systemic corticosteroids served as the mainstay for both localized CP (n = 8, ORR = 75%) and systemic CP (n = 8, ORR = 100%), though most achieved only partial response with potential relapse after tapering. Immunosuppressant add-ons provided no ORR improvement. The CHOP chemotherapy regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone) showed efficacy in 3 refractory cases (ORR = 100%). PUVA (psoralen-UVA therapy) and NB-UVB (narrowband-ultraviolet B) were primarily used in patients with localized CP, and demonstrated ORR of 50% and 40%, respectively. Six patients received IL-6 pathway-targeting inhibitors. One localized CP patient on unspecified anti-IL-6 antibody showed no response, 2 systemic CP patients on siltuximab demonstrated no efficacy, and the outcome was unreported for each patient, respectively.5–7 Notably, 3 tocilizumab-treated systemic CP patients achieved 100% ORR (1 with partial improvement, 2 with significant rash reduction).8–10 Conversely, all 3 rituximab (CD20 inhibitor)-treated systemic CP patients exhibited no therapeutic effects.

Follow-up data existed for 36 patients (33.0%), including outcomes for 33 (30.3%). Median follow-up was 27.0 ± 48.0 months. Adverse outcomes occurred in 6/19 (31.6%) localized CP patients: progressive disease, fatal respiratory and cardiac failure, T-cell lymphoma, and Castleman disease. Among 14 systemic CP patients, 4 (28.6%) had adverse outcomes: progressive disease with elevated IL-6, sudden death, acute myeloid leukemia M2, and gastric adenocarcinoma. Two tocilizumab-treated patients maintained complete remission at 10- and 18-months.9,10

IL-6, a pleiotropic cytokine driving plasma cell differentiation and inflammatory cascades, is identified as a primary biomarker of systemic progression in CP, supporting its utility for early risk stratification. Although our study showed no prognostic difference between localized and systemic CP, this may be obscured by the retrospective study design, limited sample size, and incomplete patient assessment and biomarker documentation. Tocilizumab, an IL-6 receptor blocker, demonstrates superior efficacy to direct IL-6 inhibitors, representing a promising therapeutic candidate. Future multicenter prospective studies employing standardized diagnostic frameworks and biomarker-driven stratification are needed to validate these findings and establish evidence-based guidelines.