Cutaneous and systemic plasmacytosis is a rare disorder observed mainly in Japanese that features an infiltration of mature plasma cells in various organ systems. In addition to the skin, lymph nodes and bone marrow are regularly affected. Laboratory tests show a polyclonal hypergammaglobulinemia. The cutaneous morphology is characterized by red to dark brown macules, papules and plaques a few centimeters in diameter, usually distributed symmetrically on the face, neck and back. Etiology and pathogenesis are not known. It is speculated that a reactive dysfunction of plasma cells may be triggered by various stimuli, such as interleukin 6. Treatment of cutaneous and systemic plasmacytosis is difficult. A standardized treatment concept does not yet exist. Topical corticosteroids and calcineurin inhibitors are mainly used.
The disease, first reported first in 1976 by Yashiro under the title “A kind of plasmocytosis”, and later termed cutaneous plasmocytosis by Kitamura et al., manifests clinically in the form of red-brown macules, papules and plaques which microscopically show a dermal infiltration of mature plasma cells [1, 2]. Together with the dermatological findings, a polyclonal hypergammaglobulinemia is found in serum electrophoresis. The cause of increased numbers of plasma cells in cutaneous plasmocytosis is unknown; other diseases characterized by plasma cell infiltrations, such as myeloproliferative neoplasias or inflammatory dermatoses must be excluded.
In 1986 Watanabe et al. described five cases of cutaneous plasmocytosis with involvement of further organ systems and defined the term systemic plasmocytosis as infiltration of mature plasma cells in two or more organ systems, such as skin, lymph nodes or lungs . The differentiation between cutaneous and systemic plasmocytosis in the individual case appears problematic, as the detection of systemic manifestations is the rule and not the exception and further even in a patient classified first as cutaneous plasmocytosis, an occult systemic manifestation can be present. This fact has in recent years led increasingly more authors to favor the diagnosis cutaneous and systemic plasmocytosis (CSP) [4-8].
CSP is a rare disease that to date has primarily been presented in the form of case reports. On the basis of literature research, Uhara et al. found 41 cases up to 1994 and Leonard et al. about 50 cases up to 2007 [5, 9]. In a subsequent literature search 17 further cases were found since 2008 [10-16]. To date CSP has been observed in most cases in Asians and here almost exclusively in Japanese. All 41 patients reported by Uhara et al. were Japanese . Further, very isolated cases have been reported in Chinese, Koreans and Thais [5, 6, 10, 17, 18]. On a worldwide basis CSP has to date only been reported in about 10 white patients . Typically, middle-aged patients are affected. The majority develop CSP between the third and fifth decade of life [9, 18]. Rare cases have presented in childhood [10, 12, 15]. With respect to the gender distribution, the studies of Uhara et al. and Shimizu et al. demonstrated a dominance of male patients by a ratio of 1 : 0.6 or 1.2 : 1 [9, 18].
The clinical morphology of CSP is characterized by round or oval, red-brown to dark brown poorly circumscribed macules, papules and plaques [8, 18, 19]. Individual lesions can demonstrate a zone-like appearance with an elevated center and a flat border. Older lesions may be hyperpigmented [6, 20]. Scaling, crusts or erosions are not found. Typical sites for CSP are the face, nape, trunk (especially posterior thorax), and axilla (Figures 1-4). The limbs are rarely involved, while the palms and soles are spared [7, 11, 12, 16, 18, 21]. The numerous lesions are distributed symmetrically and follow the skin lines, especially on the lateral aspects of the trunk [5, 9, 11, 16, 20]. Up to 40% of affected patients compliance of pruritus [9, 11, 20], which in the majority of cases is only moderate and sporadic [9, 11, 20]. CSP is usually chronic, with spontaneous regression rare [5, 6].
Besides the obligatory cutaneous manifestation, polyclonal hypergammaglobulinemia is the most frequent symptom of CSP seen in 88–93% [9, 18]. Most proliferations are IgG and IgA, IgM is distinctly rarer and less pronounced [3, 16, 21]. The level of the hypergammaglobulinemia was viewed as a prognostic factor by Uhara et al. Extracutaneous involvement and systemic signs and symptoms are more common in patients with IgG levels over 5,000 mg/dl . Monoclonal paraproteinemias are not seen. Lymphadenopathy was detected clinically, sonographically or with computed tomography in 44–62% of analyzed cases [8, 18]. Both peripheral and central lymph nodes can be affected . The lack of detection of lymphadenopathy, clinically or with imaging procedures, does not exclude a plasma cell infiltration of the lymph nodes. Often a biopsy is required to document involvement [8, 18]. Besides the skin and the lymph nodes, the bone marrow is the third regularly-involved organ system in CSP. Here too microscopic examination of a bone marrow aspirate or biopsy is required. Shimizu et al performed bone marrow examinations in 20 of the 26 cases and found involvement in 8 patients, corresponding to a frequency of 40% . A concentration of plasma cells of more than 7% is, just like an IgG value of over 5,000 mg/dl, viewed as a prognostic indication of a more severe disease course of CSP . Both other systemic involvement and organ complications seem more common [8, 9, 18]. Most other suspected systemic involvement has rarely been confirmed by biopsy, such as in hepatosplenomegaly, interstitial pneumonia and nephropathies. While hepatosplenomegaly is common, biopsies have rarely been reported and were negative [3, 16, 18, 22]. The interstitial pneumonia reported in CSP is characterized by lymphocytic and plasma cell infiltrates [3, 14, 16, 18, 23]. The interstitial pneumonia with dysproteinemia is classified in the group of benign plasma cell proliferations, so that a direct connection with CSP appears possible . In further individual cases, manifestations of CSP in the breast, the retroperitoneum and the kidneys have been described, in the latter case in the form of a mesangioproliferative glomerulonephritis or a plasma cell infiltration [16, 22, 24, 25]. The general symptoms of CSP are unspecific and include fatigue, weight loss, fever and dyspnea [3, 9, 23].
Histology reveals a characteristic picture with a moderately dense, superficial and deep perivascular and –adnexal infiltrate of mature plasma cells without atypia (Figure 5) [9, 18, 20]. Often the infiltrate is also found perineurally and occasionally plasma cells are found in the nerve fascicles (Figure 6) . The plasma cells are polyclonal, which can easily be demonstrated immunohistologically. The epidermis can be slightly thickened with increased basal layer pigmentation. Honda et al. recently reported in one of 6 patients with an otherwise typical presentation a cutaneous plasmocytosis with a monoclonal plasma cell infiltrate and classified the case as “borderline” cutaneous plasmocytosis/ marginal zone lymphoma . In another patient from this case series besides the plasma cells a histiocytic component was found. This was more distinct in the lymph node than in the skin. In about one-third of cases, accompanying small reactive germinal centers are found . Iliac crest biopsy revealed normocellular bone marrow and an increase of polyclonal plasma cells that were physiologically distributed in a perivascular fashion (Figure 7).
Etiology and pathogenesis
Secure knowledge on etiology and pathogenesis of CSP does not exist. The geographic distribution of disease cases with the focal point in Japan led to different presumptions that CSP might be the result of environmental factors, genetic -disposition or infectious etiology. Mutations of individual signal molecules in plasma cell regulation are likely suspects, but no such mutation has been detected to date [5, 11]. The plasma cell infiltrate itself might be an indication of an infectious agent as cause of CSP with particularly syphilis or a Borrelia infection being considered. Serological and molecular genetic studies have not, however, found evidence for such an infection in numerous patients [3, 5, 9, 11, 16, 26]. On the basis of comparable clinical and laboratory chemical findings, some authors suspect that CSP is a variant of multicentric Castleman disease, in which a plasma cell-rich lymphadenopathy, hepatosplenomegaly, disturbances of general well-being and hypergammaglobulinemia may be present [27-31]. Typical for multicentric Castleman disease is an elevated serum concentration of IL-6, a cytokine of plasma cell differentiation, and the detection of human herpes virus type 8 (HHV-8) [25, 31]. While an elevation of IL-6 is usually found in CSP, HHV-8 has not been detected, so it appears unlikely as a possible cause of CSP [7, 20, 30, 32]. Other, particularly viral, pathogens, also have not been identified [16, 30]. Haque et al. recently formulated a hypothesis on the pathogenesis of CSP similar to that generally accepted for marginal zone lymphoma . Here it is suspected that persistent antigens or infectious agents can be responsible for the plasma cell differentiation. The geographic variability of humans or the genetic polymorphism of immunoregulatory genes, such as those of IL-6, might possibly explain the frequency of CSP in individual regions, especially in Japan. Further, Haque et al. stress the importance of the IL-6 elevation for the pathogenesis of CSP. According to the authors, CSP may be attributed to a continuing IL-6 stimulation having its origin in the dermal structures or in the associated lymph nodes. This postulate is supported by the fact that IL-6 mRNA is detected only in lesional skin, not in clinically normal skin. The observation that plasma cells express IL-6 might indicate that there is a cellular defect in the plasma cells themselves that might lead to an autocrine-paracrine stimulation of the cells . Along this line CSP might represent a reactive dysregulation of the plasma cells triggered by different causes [5, 8, 33].
Recently a possible role of IgG4 antibodies in the -pathogenesis of CSP has been suggested. IgG4 antibodies are found in numerous inflammatory dermatoses, such as pemphigus foliaceus, where their binding to desmoglein leads to blistering . Miyagawa-Hayashino et al. were able to detect a high share of IgG4-positive plasma cells in 3 patients with CSP. In all cases this staining pattern could also be detected in extracutaneous locations (lymph nodes, lung and bone marrow) . Genetic factors, bacterial infections or autoimmune mechanisms have all been incriminated as possible causes of IgG4-mediated diseases [14, 35].
Clinically and histopathologically, various differential diagnoses must be considered in CSP. Involvement of the back has been repeatedly misinterpreted as acne or as lichen planus, on the face as rosacea or lupus erythematosus [6, 11, 20, 21, 28]. Among other clinical differential diagnoses are lymphoma, mastocytoses, parapsoriasis en plaques and pityriasis rosea [11, 20, 28]. Occasionally CSP has also been classified as post-inflammatory pigmentation [11, 20]. Histopathologically, CSP must be differentiated from other dermatoses that are typically or occasionally characterized by plasma cell infiltrations. These include malignant monoclonal proliferations, such as marginal zone lymphoma, cutaneous plasmocytoma and leukemia cutis in plasma cell leukemia [17, 19, 20]. Further histopathological differential diagnoses with a polyclonal infiltration pattern are the B-cell pseudolymphomas and multicentric Castleman disease as well as syphilis and borreliosis. Collagen vascular diseases, particularly morphea and less often lupus erythematosus, must also occasionally be considered [5, 10, 11, 19, 20].
CSP versus cutaneous plasmocytosis
With respect to the differential diagnoses, occasionally the question arises if CSP or cutaneous plasmocytosis is present. When clinical or sonographic evidence of lymphadenopathy is lacking, numerous authors have classified the cases they observed as cutaneous plasmocytosis [9-11, 20]. Normal imaging procedures do not exclude plasma cell infiltration in the lymph nodes. Often interfollicular plasma cell infiltrations are identified on biopsy without lymphadenopathy being detected clinically or with imaging [8, 18]. Tada et al. reported a patient in whom they had first diagnosed cutaneous plasmocytosis. The patient simultaneously had stomach cancer, so that a gastrectomy with regional lymph node dissection had to be performed. Even though computed tomography and abdominal sonography revealed no pathologic lymph nodes, all 36 excised abdominal lymph nodes showed plasma cell infiltration. They found 30 patients in the literature who had no palpable lymph nodes. Despite this, biopsies or punctures of the lymph nodes were performed in 4 patients. In all 4 cases plasma cell infiltrations were found histopathologically . In other patients, in whom the diagnosis of a cutaneous plasmocytosis was made, no further testing to detect lymphadenopathy was performed or the general well-being of the patients was considered an indication for a lack of systemic manifestations [12, 15, 20]. The detection or the exclusion of lymph node involvement can in the end result only be made histopathologically. A comparable situation also exists for the manifestation of plasmocytosis in the bone marrow. In the majority of published cases, bone marrow biopsy was waived. In an individual case, the diagnosis or CSP or cutaneous plasmocytosis may be dependent on at what time point in the disease diagnostic measures are performed and how aggressively they are pursued. Thus it remains unclear if a pure cutaneous plasmocytosis exists along with CSP .
In the majority of published cases of CSP, treatment was -limited to the dermatological findings. Most frequently topical or intralesional therapy was performed with corticosteroids with no, slight or an only transient improvement [10-12, 20, 31]. Systemic prednisolone 30–40 mg daily over a time period of up to 8 weeks also was ineffective [3, 10, 28]. On occasion, even when a lesion improved, the histopathological findings remained largely unchanged [10, 28]. Both tacrolimus as well as pimecrolimus have repeatedly been employed in the treatment of CSP, usually also with only slight benefit [6, 12, 36]. In one case pimecrolimus did produce almost complete clearing of both the clinical and histopathologic findings . In other patients the pruritus stopped, a phenomenon that we have also observed with pimecrolimus, which is much appreciated by patients. Further topical and in part effective treatment measures for CSP include topical PUVA therapy , radiotherapy , PDT  as well as the use of the pulsed dye laser . In individual cases with severe findings, unusual manifestations or complications of CSP, thalidomide, rituximab and an experimental anti-IL-6 antibody have been employed but without great benefit [4, 38]. Melphalan and the combination of prednisolone, immunoglobulins and cyclophosphamide proved effective in single cases [22, 39].