Castleman-Like Lymphadenopathy in a Patient with Mixed Connective Tissue Disease: A Case Report and Review of the Literature

Summary

Differentiating reactive lymphadenopathies in the context of autoimmune disease from Idiopathic Multicentric Castleman Disease (iMCD) poses a significant diagnostic challenge. Castleman-like histological features have been described in various autoimmune disorders, necessitating a strict and comprehensive integration of clinical and laboratory findings to reach the correct diagnosis. Although the Castleman Disease Collaborative Network (CDCN) consensus guidelines list several autoimmune conditions as exclusion criteria for an iMCD diagnosis, mixed connective tissue disease (MCTD) is not currently among them. We report the case of a  77-year-old woman presenting with fatigue, Raynaud’s phenomenon, sclerodactyly, mild generalized lymphadenopathy, in whom the lymph node biopsy revealed a Castleman-like histology. The absence of systemic inflammatory symptoms and the presence of high-titer anti-U1 -⁠ RNP antibodies were, however, inconsistent with iMCD, favouring the diagnosis of a reactive Castleman-like lymphadenitis secondary to MCTD. This report highlights that Castleman-like lymphadenopathy can occur in MCTD, closely mimicking iMCD. Therefore, in patients with autoimmune diseases not explicitly listed among the CDCN exclusion criteria, comprehensive clinicopathological integration is essential to avoid misdiagnosis and potentially inappropriate antiIL-6-based therapy.

Keywords:

autoimmune disease – mixed connective tissue disease – Castleman-like lymphadenopathy – Sclerodactyly – Raynaud’s phenomenon - anti-U1-RNP

Castleman disease (CD) represents a spectrum of disorders characterized by distinctive but not specific lymph node histopathology and clinical manifestations, including systemic inflammation, cytopenias, and, in severe cases, life-threatening multiorgan dysfunction (1-4). Significant advances in the understanding, diagnosis, and management of CD have been achieved by the Castleman Disease Collaborative Network (CDCN) consensus guidelines for diagnostic and therapeutic stratification (2, 5-7). According to these criteria, CD is subdivided into unicentric CD (UCD) and multicentric CD (MCD), that can be further categorized into three main subtypes (1, 2). Among these the idiopathic form is further divided into iMCD-TAFRO (defined by thrombocytopenia, acites (anasarca), bone-marrow reticulin fibrosis, renal impairment, and organomegaly), Idiopathic Plasmacytic Lymphadenopathy (IPL) (characterized by thrombocytosis, hypergammaglobulinemia, and a less severe clinical presentation), and iMCD not otherwise specified (8, 9). The etiology of iMCD remains incompletely understood, although excessive production of interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) are recognized as key pathogenic mediators (1). Patients with iMCD usually present with multiple enlarged lymph nodes and a vari

able constellation of systemic manifestations —fever, fatigue, weight loss, night sweats, serous effusions, and skin lesions (i.e. cherry angiomas) —⁠ accompanied by laboratory abnormalities such as anemia, thrombocytopenia or thrombocytosis, elevated ESR (Erythrocyte Sedimentation Rate) and CRP (C-Reactive Protein), polyclonal hypergammaglobulinemia, hypoalbuminemia, and renal dysfunction. The clinical course is often relapsing and remitting, requiring systemic therapy with anti-IL-6 agents (e.g., siltuximab) or anti-CD20 drugs (e.g. rituximab) (7, 10). From a histopathological standpoint, CD is classified into hyaline-vascular (in UCD) or hypervascular (in MCD) type (HVCD), plasma-cell type (P-CD), and mixed (mixed-CD) type, depending on the degree of follicular regression or hyperplasia and the extent of interfollicular vascular proliferation and plasmacytosis (2). Because CD-like histopathological and clinical features may also appear in other diseases, rigorous exclusion of alternative causes is essential before establishing an iMCD diagnosis (11-14). Among these mimicking conditions, the CDCN guidelines listed infections, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), adult-onset Still’s disease, juvenile idiopathic arthritis, autoimmune lymphoproliferative syndrome (ALPS), HIV-associated lymphadenopathy, and both Hodgkin and non-Hodgkin lymphomas. Other autoimmune diseases that may present with CD-like lymphadenopathy, such as mixed connective tissue disease (MCTD), are less well characterized and do not necessarily exclude a diagnosis of CD (13). MCTD is a rare systemic autoimmune disease characterized by the presence of anti-U1-ribonucleoprotein (RNP) antibodies, Raynaud phenomenon and signs/symptoms of at least 2 over lapping connective tissue diseases, including SLE, systemic sclerosis, polymyositis (15, 16). Given the anti-U1-RNP antibody is the hallmark of MCTD, it is believed that it plays a role in the pathogenesis of MCTD with two main proposed mechanisms. The first involves the direct binding to endothelial cells through U1 RNP peptides or recognition of nucleosome RNP fragments in endothelial cell apoptotic blebs (17, 18). This may lead to the vascular diseases (Raynaud phenomenon), skin sclerosis, and pulmonary hypertension. The second is through immune complex formation, which can activate the complement cascade and lead to tissue inflammation and damage, such as myositis, arthritis, and interstitial lung disease (17, 18). The inflammatory cascade induced by the anti-U1 RNP antibodies is also responsible for the elevated serum levels of IL-6, IL-1, TNF-alpha, and IFN-gamma observed in patients with MCTD (17, 19, 20). Herein we present the case of a patient with MCTD with CDlike lymphadenopathy, for which in accordance with CDCN recommendations, we employed a comprehensive, multidisciplinary evaluation integrating clinical, serological, radiologic, and pathological findings to assess the correct diagnosis (1, 5).

CASE REPORT

A  77-year-old female was referred to our hospital for evaluation of unexplained fatigue and mild generalized lymphadenopathy. She denied fever, weight loss, or night sweats. Clinical examination revealed non-tender lymph nodes in the supraclavicular region. Initial laboratory studies showed normal hematologic, hepatic, and renal parameters. Inflammatory markers (ESR, CRP) were within normal limits. Ultrasound and CT scans revealed multiple small lymph nodes  (<1.5 cm)

in both supradiaphragmatic and infradiaphragmatic stations, along with mild splenomegaly (maximal craniocaudal dimension of 13 cm). An excisional biopsy of a supraclavicular lymph node was performed. Histologically, the lymph node architecture was largely preserved, featuring patent sinuses and normal compartmentalization of the B -⁠ and T-cell areas (Figure 1). The B-cell zones displayed irregularly shaped lymphoid follicles whose germinal centres (GCs) showed variable degrees of regression (grade 2 according to the CDCN classification),  containing a lower number of GC cells (CD10+/-, BCL6+/-, BCL2 -⁠ ) and with moderate prominence of CD21+, CD23+ follicular dendritic cells (FDCs) (grade 2 according to the CDCN classification). Characteristically, some germinal centres were penetrated by radially oriented hyalinized capillaries, creating a “lollipop” appearance. These were surrounded by mantle-zone lymphocytes, occasionally concentrically arranged forming an “onion skin” pattern. The interfollicular areas contained a moderate proliferation of small blood vessels (grade 2 according to the CDCN classification), abundant reactive T cells, scattered immunoblasts, and a few polytypic plasma cells (grade 0 according to the CDCN classification) (Figure 1). Immunostaining for human herpes virus 8 (LANA-1) and in situ hybridization for EBER were both negative. The overall lymph node findings were interpreted as a reactive Castleman-like lymphadenitis, necessitating integration with clinical, radiological and laboratory data to differentiate HV-CD from an autoimmune or infectious etiology. Additional clinical investigations revealed sclerodactyly and a history of episodic Raynaud’s phenomenon. The patient did not report other systemic signs. Serologic tests demonstrated the presence of anti-nuclear (ANA) antibodies and high titers of anti-U1 RNP antibodies. Although the excised lymph node exhibited some morphological features reminiscent of Castleman disease—including regressed germinal centers, concentric mantle zones, and mildly increased vascular proliferation—the overall findings did not meet the established diagnostic criteria for iMCD. Specifically, the absence of systemic inflammatory symptoms and serological inflammatory markers, coupled with the presence of high-titer anti-U1 RNP antibodies and signs of connective tissue diseases, was more consistent with an underlying autoimmune process. Therefore, integrating the histopathological, serological, and clinical data, the lymphadenopathy was interpreted as a reactive Castleman-like lymphadenitis secondary to MCTD rather than an iMCD associated with MCTD.

DISCUSSION

The presence of regressed germinal centers, concentric mantle zones, marked vascular proliferation, and prominent interfollicular plasmacytosis can closely resemble the spectrum of histological lesions seen in iMCD. However, Castleman-like morphology alone does not establish a diagnosis of Castleman Disease (CD), as these findings may also occur in reactive conditions secondary to immune dysregulation or infection (11-14). According to the CDCN guidelines, a diagnosis of iMCD necessitates both characteristic histopathology and compatible systemic clinical and laboratory findings, as well as the exclusion of alternative conditions, including selected autoimmune and autoinflammatory diseases when the disease-specific clinical criteria are met (11, 13, 14). These criteria, however, do not specifically address less common overlap syndromes, such as MCTD. Indeed, CD-like histopathological changes have been described in a variety of established autoimmune diseases, such as SLE, RA, and ALPS (11-14), but are also reported—though less frequently—in MCTD (21-26). Several reports, summarized in Table 1, highlight cases of concomitant diagnosis of MCTD and CD (21-26). On the contrary, in our case we were unable to diagnose a MCD due to unmet diagnostic criteria. However, given that MCTD is also a multisystem autoimmune disorder with immune-mediated lymphoid activation, it remains uncertain whether its presence should be regarded as an exclusion criterion for iMCD or whether both conditions may genuinely coexist. This ambiguity has important implications for the interpretation of Castleman-like lymphadenopathy in patients with connective tissue diseases other than SLE or RA.

In MCTD the autoimmune background might provide a plausible mechanism for CD-like histological changes. Immune activation of the downstream inflammatory cascade driven by antiU1-RNP antibodies induces elevated serum levels of IL-6, IL-1alpha, TNF-alpha, and IFN-gamma, (17, 19, 20) which are responsible of the broad histologic heterogeneity observed in MCTD-associated lymphadenopathy. In Table 1 and 2, we summarize reported cases of MCTD with available lymph node histology. The lesions span a wide morphologic spectrum, including sarcoid-like granulomatous reactions (27), Kikuchi-like necrotizing lymphadenitis (28-33), non-specific reactive lymphadenitis (16, 34-39) and lymphadenitis with CD-like changes (21-26).

The distinction between iMCD and autoimmune-driven reactive conditions is clinically critical: misclassification as iMCD could lead to unnecessary anti-IL-6–based therapies, while correct recognition of an autoimmune-driven reactive process allows for appropriate immunomodulatory management. Recognition that Castleman-like morphology may represent a reactive pattern rather than a diagnostic entity prevents the overdiagnosis of iMCD and reinforces the need to interpret lymph node histopathology within the broader clinical and immunological context. In our case, the integration of clinical, serological, and pathological data strongly favoured the diagnosis of reactive Castleman-like lymphadenitis associated with MCTD, thus emphasizing the importance of a multidisciplinary, clinicopathological correlation when evaluating lymphadenopathy with Castleman-like features.

In conclusion, with the present case we highlighted that Castleman disease-like lymphadenopathies may occur as a histological pattern in the context of less characterized autoimmune diseases such as MCTD. A careful multidisciplinary assessment integrating clinical, serological, and pathological findings is therefore essential to distinguish reactive Castleman-like lymphadenitis from iMCD to avoid misdiagnosis and inappropriate treatment.