Idiopathic Plasmacytic Lymphadenopathy Forms an Independent Subtype of Idiopathic Multicentric Castleman Disease

Idiopathic multicentric Castleman disease (iMCD) is a type of Castleman disease that is not related to KSHV/HHV8 infection. Currently, iMCD is classified into iMCD-TAFRO (thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly) and iMCD-NOS (not otherwise specified). The former has been established as a relatively homogeneous disease unit that has been recently re-defined, while the latter is considered to be a heterogeneous disease that could be further divided into several subtypes. In 1980, Mori et al. proposed the concept of idiopathic plasmacytic lymphadenopathy (IPL), a disease presenting with polyclonal hypergammaglobulinemia and a sheet-like proliferation of mature plasma cells in the lymph nodes. Some researchers consider IPL to be a part of iMCD-NOS, although it has not been clearly defined to date. This is the first paper to analyze iMCD-NOS clinicopathologically, to examine whether IPL forms a uniform disease unit in iMCD. Histologically, the IPL group showed prominent plasmacytosis and the hyperplasia of germinal centers, while the non-IPL group showed prominent vascularity. Clinically, the IPL group showed significant thrombocytosis and elevated serum IgG levels compared to the non-IPL group (p = 0.007, p < 0.001, respectively). Pleural effusion and ascites were less common in the IPL group (p < 0.001). The IPL group was more likely to have an indolent clinical course and a good response to the anti-IL-6 receptor antibody, while the non-IPL counterpart frequently required more aggressive medical interventions. Thus, the IPL group is a clinicopathologically uniform entity that forms an independent subtype of iMCD.


Introduction
Castleman disease (CD) is a rare lymphoproliferative disorder described by Castleman et al. in 1956 [1]. CD is clinically classified into unicentric and multicentric types. Unicentric CD (UCD) is characterized by a localized lymphadenopathy with or without minimal systemic symptoms, and the resection of the affected lymph node is often curative [2]. In contrast, multicentric CD (MCD) shows a generalized lymphadenopathy with systemic inflammatory symptoms, such as generalized weakness and fever [3]. The infection status of Kaposi sarcoma-associated herpesvirus/Human herpesvirus type 8 (KSHV/HHV8) defines the etiology of MCD [4]. Idiopathic MCD (iMCD) is defined as Int. J. Mol. Sci. 2022, 23, 10301 2 of 10 a group of KSHV/HHV8-negative MCD without POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-proteins, and skin changes) [5]. Clinically, iMCD is classified into iMCD-TAFRO (thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly) [6][7][8] and iMCD-NOS (not otherwise specified). Histologically, there are two main pathological variants in iMCD: plasma cell (PC) and hypervascular (HyperV) types [5,9,10]. The mixed type shows the features of both the PC and HyperV variants, but no clear pathological definition [11,12]. Commonly, iMCD-TAFRO is histologically associated with the HyperV type, and iMCD-NOS frequently has PC morphology [5]. As the name suggests, iMCD-NOS is a heterogenous entity. Previous studies have suggested that iMCD-NOS could include atypical and undiagnosed autoimmune diseases [13]. Moreover, it could potentially be further classified into several subtypes with research efforts, including clinicopathological analyses and genomic sequencing [14,15]. One potential candidate that is to be separated from the current iMCD-NOS is idiopathic plasmacytic lymphadenopathy (IPL). IPL was initially proposed in 1980 by Mori et al., characterized by polyclonal hypergammaglobulinemia and a sheet-like proliferation of mature plasma cells in the lymph nodes, as well as the exclusion of known diseases associated with hypergammaglobulinemias such as infections, collagen diseases, hyperthyroidism, allergic diseases, hepatitis, liver cirrhosis, and lymphoma [16]. In the clinical course, IPL was indolent, and all the cases achieved the remission of disease activity [13,16]. The concept of IPL was proposed before the establishment of MCD, and IPL was later considered as a part of iMCD-NOS, given the clinicopathological similarity [11,16]. However, there has been no study to validate whether or not IPL has distinct clinicopathologic features compared to other iMCD-NOS. In this study, we perform a comprehensive clinicopathological analysis of iMCD-NOS, with a focus on IPL or others (non-IPL) to examine if IPL needs to be defined as an independent iMCD subtype.

Treatment and Clinical Course
Outpatient follow-up data were available for 23/34 cases in the IPL group and for 5/8 cases in the non-IPL group, with a median follow-up period of 65.5 months (Table 3). Treatment information was available for 23 cases of the IPL group and 5 cases of the non-IPL group. PR, partial remission; mPSL, methylprednisolone; PSL, prednisolone. "Outcome" represents the clinical condition of the patient at the last visit. "Partial remission" represents improvement in some laboratory data or subjective symptoms. "Complete remission" represents improvement in all laboratory data, objective symptoms, and radiographic findings. "No response" represents all clinical findings and subjective symptoms unchanged. "No change" represents no worsening nor improving of the disease during follow-up. "Progression" represents a worsening of laboratory findings, subjective symptoms, or radiographic findings. † Case 4: Lost to follow-up. ‡ Cases 11 and 15 achieved PR, but expired from non-iMCD disease (lung cancer) and post-surgical bleeding, respectively.
For the first-line treatment, corticosteroids were used in 13/23 (56.5%) cases in the IPL group and 4/5 (80%) cases in the non-IPL group. One patient in the non-IPL group (Case 1) received corticosteroid and tocilizumab. Among those treated with corticosteroids, corticosteroids were successfully tapered in 3/13 (23.1%) patients in the IPL group and 1/4 (25.0%) patients in the non-IPL group. One case in the IPL group (Case 11) expired during the follow-up period with corticosteroid monotherapy, likely due to lung cancer.
Overall, 14/23 (60.9%) patients in the IPL group and 1/5 (20.0%) patients in the non-IPL group received tocilizumab during the follow-up period. Those in the IPL group who received tocilizumab achieved an improvement in disease activity. One patient in the IPL group treated with tocilizumab expired due to post-surgical bleeding that was unrelated to IPL (Case 15). In contrast, the non-IPL case treated with tocilizumab had a progressive disease and required rituximab as a second-line therapy to achieve a partial remission of disease activity.

Discussion
iMCD is a rare lymphoproliferative disorder that is characterized by multiple lymphadenopathies with unknown etiology [17]. In particular, iMCD-NOS is a heterogenous entity, likely including undefined disease [11,[18][19][20][21]. The present results show that IPL is likely to be a separate subtype of iMCD, along with iMCD-TAFRO and iMCD-NOS, given its unique clinicopathological characteristics.
Our results show that the IPL group had distinct clinicopathological features compared to the non-IPL iMCD-NOS cases. Pathologically, the IPL group had less significant vascularity, as well as more prominent plasmacytosis and hyperplastic GCs than the non-IPL group. By contrast, the non-IPL group showed marked hypervascularization both in GCs and in interfollicular areas. Clinically, the IPL group had higher platelet counts and serum IgG levels, and fewer signs of fluid retention in third space such as pleural effusions and/or ascites, than the non-IPL group.
In 2008, before the current iMCD criteria were proposed, Kojima et al. reported that iMCD had at least two clinical subtypes, IPL and non-IPL, with the latter showing more thrombocytopenia, fluid retention, positive autoantibodies, and relatively aggressive clinical symptoms [13]. They also suggested that non-IPL may be associated with autoimmune diseases. In addition, Frizzera et al. reported multiple lesions of CD, which led to the term MCD being established [3,22]. Some of their MCD cases included those with clinical and laboratory findings characteristic of systemic lupus erythematosus (SLE), Sjögren's syndrome, or both [3]. Currently, such cases may be considered ill-defined autoimmune diseases [23][24][25]. Moreover, SLE cases with MCD-like histology [24,26] and iMCD cases with various autoantibodies [23] have been reported. Although no significant differences were observed for disease-specific autoantibodies in the present results, this may be due to a lack of power to detect the difference, given the small number of non-IPL cases. Combined with the context and the present results, it may be crucial to closely follow-up with non-IPL patients on an outpatient basis to find clinical signs of autoimmune diseases. The two groups also had different clinical courses and treatment responses. There were a few patients who were treated with tocilizumab (an anti-IL-6 receptor monoclonal antibody approved in Japan for the treatment of iMCD [27]), and all patients with IPL who received tocilizumab achieved a remission of disease activity. In contrast, the non-IPL case that had a poor response to tocilizumab also required rituximab. Despite the second-line non-IL-6 therapy, the patient still had progressive disease during the follow-up period. The results concur with previous studies suggesting that IPL may have an indolent clinical course compared to the non-IPL group, with a superior response to anti-IL-6 agents. In recent studies, the PI3K/Akt/mTOR pathway, JAK/STAT3 pathway, and type I IFN have focused on the treatment targets in iMCD cases refractory to IL-6-targeted therapy [28][29][30][31]. While non-IPL iMCD-NOS cases could be heterogenous, as discussed, efforts to identify a primary etiology (for example, possible autoimmune disease) by molecular analysis and targeted therapies for the cellular signals may need to be considered.
In conclusion, the present results suggest that IPL is clinicopathologically a uniform disease entity, and may be an independent subtype of iMCD. Future studies are warranted