Clinicohistopathological features and outcome of cutaneous and systemic plasmacytosis in 21 Chinese cases: A retrospective study

Introduction

Cutaneous and systemic plasmacytosis (CSP) is a rare disorder, predominantly reported in Japanese individuals.¹ Clinically, it presents as multiple red-brown patches and plaques on the trunk. Patients with systemic involvement often develop lymphadenopathy. Histologically, the dermis shows a polyclonal plasma cell infiltrate.^2,3 The exact pathogenesis remains unclear, though CSP shares features with multicentric Castleman disease, cutaneous marginal zone B-cell lymphoma (MZBCL), and IgG4-related disease.^4-6

Methods

We retrospectively analysed 21 patients diagnosed with CSP at the dermatology department of West China Hospital of Sichuan university (2012–2022). The diagnosis was established based on clinical, histopathological, immunohistochemical, and laboratory findings. CSP was diagnosed in patients presenting with diffuse or localised reddish-brown papules, nodules, or plaques on the trunk, face, or proximal extremities, with histopathological confirmation of dermal plasma cell infiltration without significant atypia. Immunohistochemistry confirmed polyclonal plasma cell proliferation (CD138⁺, polyclonal Igκ and Igλ expression). Malignant plasma cell disorders such as multiple myeloma and Castleman disease were excluded. Systemic involvement was determined based on the presence of systemic symptoms (fever, weight loss, night sweats), laboratory abnormalities (anemia, leukopenia, polyclonal hypergammaglobulinemia), or imaging findings (hepatosplenomegaly). Clinical and laboratory data were reviewed, including clinical parameters such as sex, age, disease duration, lesion location, lymphadenopathy, and extracutaneous involvement (anaemia, splenomegaly, hepatomegaly, and bone marrow involvement), as well as laboratory tests including serum immunoglobulin G4 (IgG4), interleukin 6 (IL-6), serum protein electrophoresis (SPEP), and immunofixation electrophoresis (IFE). Of the 21 patients, 17 had biopsy specimens available for comprehensive histopathological and immunohistochemical analysis, while four were diagnosed based on external pathology slides, without further staining due to unavailable paraffin blocks. These 17 samples were evaluated for histological features and stained for CD38, CD138, CD79a, CD20, CD3, CD21, BCL-2, BCL-6, CD10, Ki-67, IgG, IgG4, HHV8, and kappa (κ) and lambda (λ) light chains. Immunoglobulin gene rearrangement was assessed via BIOMED-2 polymerase chain reaction (PCR) and GeneScan assays. Epstein-Barr virus (EBV) was detected using EBER1/2 in situ hybridization.

The treatment response of CSP was categorised into five outcome classifications based on previously published criteria with minor modifications:⁶ complete remission (CR), partial remission (PR), stable disease (SD), progressive disease (PD), and relapse. CR was defined as the complete resolution of skin lesions and systemic symptoms with no clinical or laboratory evidence of disease activity. PR was characterised by a significant reduction in the number, size, or severity of skin lesions and/or systemic symptoms while retaining residual disease. SD refers to the absence of significant changes in disease extent or severity over a defined period, without meeting the criteria for remission or progression. PD was defined as the worsening of skin lesions and/or systemic symptoms, including the development of new lesions or systemic deterioration confirmed by clinical or laboratory findings. Relapse was identified as the recurrence of skin lesions and/or systemic symptoms, following a period of CR or PR.

Results

Clinical features

All patients developed multiple brown coloured pigmented lesions, including plaques [Figure 1a], patches [Figure 1b], nodules [Figure 1c], and papules [Figure 1d]. Lesions primarily affected the trunk (20/21, 95.2%), followed by the head/face/neck [13/21, 61.9%, Figure 1e], axillae [8/21, 38.1%, Figure 1f], extremities (6/21, 28.6%), and soles [Case 21, Figure 1g]. Twelve patients (12/21, 57.1%) displayed a characteristic Christmas tree-like distribution of skin lesions on the trunk [Figure 1h]. Most patients (18/21, 85.7%) were asymptomatic, while three (3/21, 14.3%) experienced pruritus, and one complained of mild pain. Lymphadenopathy occurred in seven (7/18, 38.9%). Bone marrow aspiration in all seven tested patients showed increased plasma cells. Additionally, three (3/18, 16.7%) had anaemia, three (3/18, 16.7%) had splenomegaly, and one (1/18, 5.6%) had hepatomegaly.

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Figure 1:

Cutaneous and systemic plasmacytosis. Clinical manifestations. (a) Case 5, multiple reddish-brown infiltrated plaques on the back, (b) Case 6, numerous dark brownish patches on the chest and abdomen, (c) Case 7, nodules and patches on the lower leg, (d) Case 16, diffuse light brownish papules on the abdomen, (e) Case 14, many reddish-brown patches on the face, (f) Case 17, reddish-brown patches on axilla, (g) Case 21, a plantar-involved case, (h) Case 13, the rash distributed in a “Christmas tree” pattern on the back

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Histopathologic features

Table 3 summarises the histopathologic findings. Most specimens exhibited epidermal hyperplasia [13/17, 76.5%, Figure 2a] and increased basal layer pigmentation [13/17, 76.5%, Figure 2a]. All specimens (17/17, 100%) showed a perivascular and peri-adnexal infiltrate of mature, non-atypical plasma cells in the dermis [Figures 2b and c]. Additionally, plasma cell infiltration extended to lymphoid follicles [11/17, 64.7%, Figure 2d], and to a lesser extent, the interstitium [7/17, 41.2%, Figure 2e]. Plasma cells also surrounded clusters of lymphocytes [Figure 2f]. The infiltrating lymphocytes were predominantly CD20⁺ B-cells [Figure 3a], while CD3⁺ T-cells [Figure 3b] were in the minority. Notably, the ratio of plasma cells to lymphocytes varied among cases, with plasma cells predominating in some (5/17, 29.4%) and lymphocytes predominating in others (12/17, 70.6%). Most specimens showed no κ or λ light chain restriction; however, monoclonal κ expression was detected in Case 6 [Figures 4a and b]. This case also exhibited an IgG4⁺ plasma cell proportion exceeding 40% [Figure 5a and b], meeting the histological criteria for IgG4-related disease, whereas other specimens had negligible IgG4⁺ cells. All samples were negative for HHV-8 and EBER1/2.

Table 3: Pathologic features and the results of immunoglobulin gene rearrangement studies

Case	Epidermal hyperplasia	Basal layer hyperpigmentation	Presence of lymphoid follicles	Lymphocytes	Plasma cells	Kappa/Lambda light chain restriction	IgG4%	HHV-8	EBER1/2	Skin IgH gene rearrangement
1	Y	N	Y	+++	+	N	N	N	N	M
2	Y	Y	Y	+	+++	N	5	N	N	P
3	Y	N	Y	+++	+	N	N	N	N	M
4	Y	Y	Y	+++	+	N	N	N	N	P
5	N	Y	Y	+	+++	N	30	N	N	NR
6	Y	Y	N	++	++	Y	55	N	N	M
7	Y	Y	Y	+	+	N	10	N	N	P
8	Y	Y	Y	++	+	N	N	N	N	P
9	Y	Y	Y	+++	++	N	5	N	N	NR
10	Y	Y	Y	+++	++	N	N	N	N	NR
11	N	Y	N	++	+	N	N	N	N	M
12	Y	Y	Y	++	+++	N	N	N	N	M
13	Y	Y	Y	+	+++	N	5	N	N	NR
14	N	N	N	+++	++	N	N	N	N	M
15	N	N	Y	+	++	N	N	N	N	P
16	Y	Y	N	++	+	N	N	N	N	NR
17	Y	N	N	++	+	N	5	N	N	ND

+: Mild, ++: Moderate, +++: Dense/prominent, M: Monoclonal, N: No or negative, ND: Not done, NR: No result due to the age of some of the samples, P: Polyclonal, Y: Yes.

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Figure 2a:

The histopathologic features of cutaneous plasmacytosis. Thickened epidermis with increased basal layer pigmentation (case 9). (Haematoxylin-eosin stain, 100×)

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Figure 2b:

The histopathologic features of cutaneous plasmacytosis. Presence of dermal perivascular and adnexal mixed cell infiltrate (case 4). (Haematoxylin-eosin stain, 40×)

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Figure 2c:

The histopathologic features of cutaneous plasmacytosis. Higher power shows the predominance of plasma cells without atypia (case 2). (Haematoxylin-eosin stain, 400×)

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Figure 2d:

The histopathologic features of cutaneous plasmacytosis. Plasma cells around a lymphoid follicle (case 2). (Haematoxylin-eosin stain, 200×)

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Figure 2e:

The histopathologic features of cutaneous plasmacytosis. Plasma cells infiltrate interstitially (case 14). (Haematoxylin-eosin stain, 200×)

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Figure 2f:

The histopathologic features of cutaneous plasmacytosis. Nodule of lymphocytes surrounded by clusters of plasma cells (case 1). (Haematoxylin-eosin stain, 200×)

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Figure 3a:

Infiltrating lymphocytes. CD20⁺ B cells (case 4). (Immunohistochemical staining, 200x).

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Figure 3b:

Infiltrating lymphocytes. CD3⁺ T-cells (case 4). (Immunohistochemical staining, 200x). .

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Figure 4a:

κ and λ expression. Monoclonal expression of κ light chain by plasma cells (case 6). (Immunohistochemical staining, 200x).

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Figure 4b:

κ and λ expression. Sporadic λ signal (case 6). (Immunohistochemical staining, 200x).

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Figure 5a:

IgG and IgG4 stain. IgG+ plasma cells (case 6). (Immunohistochemical staining, 200x).

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Figure 5b:

IgG and IgG4 stain. IgG4+ plasma cells accounted for over 40% of IgG+ plasma cells (case 6). (Immunohistochemical staining, 200x).

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Discussion

CSP is a rare chronic disease characterised by a cutaneous plasma cell infiltrate accompanied by polyclonal hypergammaglobulinemia.⁷ The disease is mainly reported in Asians, especially Japanese.⁸ This geographic pattern may be related to genetic factors. Polymorphisms in immunoregulatory genes, such as those encoding IL-6, have been proposed to influence susceptibility to CSP.⁸

Previous literature has reported a male-to-female ratio ranging from 1.2:1 to 2.8:1.^2,3,6,8,9 Consistent with these findings, our study demonstrated a male predominance. In most cases, the clinical presentation is characteristic, with multiple reddish-brown infiltrated macules, plaques, and flat tumours located mainly on the trunk. Notably, our report documents the first-ever reported incidence of plantar involvement. The most common extracutaneous manifestation is lymphadenopathy, observed in seven of 18 patients (38.9%).¹⁰ In addition, seven patients (Cases 3, 6, 9, 12, 16, 18, and 21) underwent bone marrow aspiration, showing varying degrees of increased plasma cell infiltration, a proportion higher than that reported in previous studies.⁶ According to follow-up data, four patients (Cases 6, 12, 16, and 21) developed progressive disease, one (Case 9) achieved partial remission with traditional Chinese medicine, and two (Cases 3 and 18) maintained stable disease. These findings reveal a wider range of clinical outcomes than previously reported. While earlier literature has associated bone marrow involvement in CSP with poor prognosis and systemic complications,² our observations suggest that such involvement does not uniformly predict an unfavourable disease course. Other complications seen with CSP include lymphoid interstitial pneumonia, renal failure, anemia, fever, hepatosplenomegaly, and mesangial proliferative glomerulonephritis.^1,3,11,12

Histopathologically, CSP skin lesions are characterised by dense dermal infiltrates of mature plasma cells without atypia. Immunohistochemistry typically reveals a polyclonal plasma cell population.⁷ However, six patients in our study (Cases 1, 3, 6, 11, 12, and 14) exhibited monoclonal immunoglobulin gene rearrangement. Among them, two were lost to follow-up, two had stable disease, and two experienced disease progression. These findings suggest a lack of association between the monoclonality of infiltrating plasma cells and disease prognosis.

Notably, the presence of monoclonal immunoglobulin gene rearrangement in CSP cases closely resembles cutaneous MZBCL. Borrelia burgdorferi has been detected in some cases of MZBCL;¹³ however, no evidence of infection has been found in CSP.¹² Clinically, MZBCL presents as localised red to violaceous papules, plaques, or nodules. Histologically, CSP and MZBCL share overlapping features, including deep dermal infiltrates with germinal centres admixed with small lymphocytes.¹⁴ This raises the question of whether CSP represents an early-stage lymphoproliferative disorder or a reactive process with occasional clonal evolution.

Additionally, CSP shares clinical and histopathological features with MCD, a reactive lymphadenopathy often associated with elevated serum IL-6.¹⁵ In our study, four CSP patients were later diagnosed with MCD, and five showed increased IL-6 levels. However, in most MCD cases, IL-6 is primarily produced by cells latently infected with HHV-8.¹⁵ Notably, immunohistological analysis did not detect HHV-8 in any of our CSP cases. EBV was likewise included in our aetiological evaluation due to its established role in B-cell transformation and lymphoproliferative disorders, but no evidence of EBV infection was found.

Furthermore, some cases of CSP exhibit elevated IgG4 levels and IgG4⁺ plasma cell infiltration, suggesting a potential link to IgG4-RD. Notably, previous studies have also reported an association between the two diseases, though the exact nature of this relationship remains unclear.¹⁶

Given the rarity of CSP, no standardised treatment guidelines exist. Topical or intralesional corticosteroids are commonly used but provide limited and transient benefits.^17,18 Other treatments, including tacrolimus, psoralen plus ultraviolet A (PUVA) therapy, photodynamic therapy, pulsed dye laser therapy, rituximab, and systemic immunosuppressants (e.g., cyclosporine, cyclophosphamide, azathioprine), have shown variable efficacy.^19-24 In this study, one patient achieved partial improvement with long-term thalidomide treatment, consistent with a prior report.²⁵ No adverse effects were reported in the literature following 3 months of thalidomide administration at 75 mg/day, nor in our patient, who has been taking thalidomide for 3 years at 200 mg/day. Thalidomide stimulates the cytotoxic functions of T-lymphocytes, thereby limiting the immunosuppressive function of regulatory T-cells and significantly altering the immunological profile by inhibiting the release of Tumour Necrosis Factor-α (TNFα) and Interleukin- 6 (IL-6).²⁶ We hypothesize that by reducing IL-6 secretions, thalidomide may inhibit plasma cell growth, which could be beneficial in treating CSP. Further studies are needed to evaluate its efficacy and safety in CSP.

Most CSP patients follow a chronic but benign course. In our cohort, disease duration ranged from 1 to 12 years, with progressive cutaneous lesions but no malignant transformations. However, rare cases of systemic involvement, including fatal outcomes from lymphoid interstitial pneumonia and renal failure, have been reported.² CSP has also been linked to T-cell lymphoma, non-Hodgkin lymphoma, and leukaemia.²⁷ Poor prognostic factors include IgG levels >5000 mg/dL and high bone marrow plasma cell counts, though no specific predictors were identified in this study.² Long-term monitoring for systemic complications remains essential.

Limitations

This study is a retrospective analysis of CSP in 21 Chinese patients, with a relatively small sample size limiting the ability to conduct robust statistical analyses. Additionally, the extended study period introduces variability in clinical and diagnostic practices, contributing to some heterogeneity in clinical, molecular, and histopathological assessments. Future studies with larger cohorts and standardised diagnostic protocols are needed to further elucidate the disease’s pathogenesis and improve diagnostic and therapeutic strategies.

Conclusion

CSP appears to have diverse underlying mechanisms, with both reactive polyclonal and monoclonal plasma cell proliferation observed. The condition may be associated with IgG4-RD and has the potential to progress to MCD. Given the risk of disease progression, including the potential development of lymphoma or leukaemia, long-term follow-up is warranted. To date, no standardised or consistently effective treatment has been established.