Idiopathic multicentric Castleman disease (iMCD) is a rare inflammatory lymphoproliferative disorder with protean manifestations (1, 2). There are three distinct subtypes of iMCD: thrombocytopenia, anasarca, fever, renal dysfunction, organomegaly (iMCD-TAFRO), idiopathic plasmacytic lymphadenopathy (iMCD-IPL), and not otherwise specified (iMCD-NOS) (3–6). The iMCD-IPL subtype is characterized by lymphadenopathy, systemic inflammation, and polyclonal hypergammaglobulinemia, often with elevated serum IgG4 levels and increased IgG4+ plasma cells, along with other Castleman-like histology in the lymph nodes (4, 5, 7). Historically, patients with idiopathic plasmacytic lymphadenopathy (IPL) have diagnostic conundrums, particularly in the Western Hemisphere. Nearly all the extant literature is from East Asia, particularly Japan and China. The classification of IPL as a subtype of IgG4-related disease, Castleman disease, or a distinct entity has been a long- standing debate (8, 9). However, over the past three years, consensus has emerged that IPL is indeed a third subtype of iMCD, and that these patients benefit from iMCD-directed therapy (5, 10).

With the recognition of IPL as a subtype of Castleman disease in North America, patients with previously undiagnosed syndromes of lymphadenopathy and inflammation are now being identified as iMCD-IPL. Here, we present two of the first cases of iMCD-IPL diagnosed in British Columbia, Canada. Both patients were young Asian women who had a > 1 year history of lymphadenopathy and inflammation, both requiring review by Hematologists and Pathologists with expertise in Castleman disease to arrive at a clinicopathological diagnosis of iMCD-IPL. Strikingly, both patients had normolipemic xanthelasma palpebrum, which, to our knowledge, has not been previously reported in association with iMCD-IPL. Both patients provided written consent for publication.

A 42-year-old Chinese woman presented with a 12-year history of chronic anemia, hypoalbuminemia, and inflammation, and a 5-year history of diffuse, asymptomatic, small-volume lymphadenopathy in the supraclavicular, thoracic, and intra-abdominal lymph nodes on computed tomography (CT) scan. She had undergone a left axillary lymph node biopsy 4-years prior to the current assessments which revealed non-specific reactive changes with polyclonal plasmacytosis. Her medical history was significant for an episode of cutaneous vasculitis, thought to be Henoch-Schönlein purpura, at age 21, and lymphocytic interstitial pneumonitis (LIP) diagnosed on surgical lung biopsy at age 38; she had been treated with corticosteroids, mycophenolate mofetil, and rituximab with no appreciable improvement.

On physical examination, she was noted to have yellow plaques and papules on the medial and lateral aspects of both upper eyelids (Figure 1). The lesions had been present for 10 years and had slowly increased in size and number over that time. She did not have palpable lymphadenopathy or organomegaly, and no other xanthomas were noted.

Positron emission tomography (PET) CT revealed lymphadenopathy up to 1.7 cm in the short axis, demonstrating mild ¹⁸FDG avidity (SUV max 5.0) along with mild diffuse ¹⁸FDG avidity in both the submandibular and parotid glands. Laboratory investigations (Table 1) revealed severe inflammation with elevated C-reactive protein (CRP) and polyclonal hypergammaglobulinemia consisting of elevated immunoglobulins, particularly IgG1. ANA was weakly positive 1.5 (ratio <0.7), and extractable nuclear antibody was negative. The patient’s serum lipid profile was normal. Her fasting lipid profile showed decreased HDL cholesterol 1.10 mmol/L (ref. > 1.29) but was otherwise normal, fasting glucose was normal at 5.3 mmol/L, and her thyroid stimulating hormone (TSH), free T4, liver enzymes and INR were normal. She did not have any clinical submandibular or parotid symptoms or physical exam abnormalities so these organs were not biopsied.

Upon review of her previous excisional lymph node biopsy as well as the lung specimen with associated lymph nodes, scattered reactive secondary lymphoid follicles with sheets of mature plasma cells expanding the interfollicular area were observed. Immunohistochemical stains for IgG4 and IgG showed greater than 100 IgG4-positive plasma cells per high-power field, with an IgG4:IgG ratio of less than 40%. No stromal fibrosis or storiform fibrosis was seen. With respect of iMCD histological features, there were few regressed germinal centers (1/3), negligible follicular dendritic cell predominance (0/3), moderately increased vascularity (2/3), many hyperplastic germinal centers (2/3), and very increased/”sheet-like” plasmacytosis (3/3) (7). (Supplementary Figure) Immunohistochemistry for Latency-Associated Nuclear Antigen (LANA) in the lymph node, and serum human herpesvirus-8 (HHV-8) viral load were both negative. Importantly, these findings are not specific in isolation, but in the correct clinical context, as in this case, the patient was diagnosed with iMCD-IPL with IgG4 enriched plasmacytic histology.

She underwent a left upper eyelid biopsy, which revealed common xanthelasma palpebrum (Figure 2). With the diagnosis of iMCD-IPL, she was started on siltuximab 11 mg/kg IV every three weeks with partial biochemical response. After 6 months of treatment, her hemoglobin was 107 g/L (from baseline 93 g/L), CRP was 16.5 mg/L (from baseline 94.3 mg/L), and IgG was 45.2 g/L (from baseline 63.2 g/L). Her xanthelasmas were unchanged.

A 40-year-old Filipino woman was referred for chronic lymphadenopathy, anemia, and inflammation. Two years prior to the current assessment, she had presented with right lower quadrant abdominal pain due to appendicitis. During laparoscopic appendectomy, she was incidentally found to have a 3.7 x 2.6 x 4.7 cm soft tissue mass in the left lower quadrant as well as additional lymphadenopathy in the small bowel mesentery and retroperitoneum.

On physical examination, she had yellow plaques and papules on the medial and lateral upper eyelids (Figure 1) and small subcentimeter bilateral palpable inguinal lymph nodes. Laboratory investigations revealed anemia, inflammation (CRP 161 mg/L), and polyclonal hypergammaglobulinemia with elevated IgG4 4.96 g/L. She had a normal serum lipid profile, fasting glucose, TSH, free T4, liver enzymes and INR. A PET CT scan confirmed multiple ¹⁸FDG avid lymph nodes in the left common iliac (3.2 x 3.9 cm, SUV-max 12.6), left psoas, and mesenteric regions. Laparoscopically obtained excisional biopsy of the pelvic retroperitoneal lymph node revealed increased plasma cells, with some areas of IgG4 positive plasma cells greater than 100 per high-power field IgG4-IgG ratio > 40% (Figure 3). There was no stromal fibrosis or storiform fibrosis. Immunohistochemistry for Latency-Associated Nuclear Antigen (LANA) in the lymph node, and serum human herpesvirus-8 (HHV-8) viral load were both negative.

Taken together, these findings were suspicious for iMCD-IPL; therefore, her lymph node biopsy was reviewed by a pathologist with expertise in Castleman disease. The lymph node showed negligible regressed germinal centers (0/3), negligible follicular dendritic cell predominance (0/3), moderately increased vascularity (2/3), mostly hyperplastic germinal centers (3/3), and moderately increased plasmacytosis (2/3) (7). Overall, this was considered consistent with the plasmacytic variant of Castleman disease (Figure 3). Eyelid biopsy revealed common xanthelasma palpebrum (Figure 2). She was treated with siltuximab 11 mg/kg IV every three weeks with a partial response in her biochemical parameters: hemoglobin 127 g/L (from 89), CRP 13 mg/L (from 161) and IgG 25.6 g/L (from 33.3), but no change in the xanthelasmas.

Clinicopathological correlation is crucial for the diagnosis of idiopathic multicentric Castleman disease (iMCD) as histological findings alone, such as regressed germinal centers, hypervascularity, and polyclonal plasmacytosis, are often non-specific. In both cases described here, the patients had pre-existing biopsy specimens that were initially read as reactive or non-diagnostic. For iMCD-IPL in particular, clinicopathological correlation is crucial, as there is substantial overlap with other entities, such as IgG4-RD and eosinophilic granulomatosis with polyangiitis; improved awareness of iMCD-IPL among clinicians and pathologists in the western hemisphere is needed. The cases described herein are two of the first cases of iMCD-IPL diagnosed in Canada.

The increased IgG4+ plasma cells and PHGG with elevated serum IgG4 raised suspicion for IgG4-related disease (IgG4-RD), but the anemia, markedly elevated CRP, and lack of other typical IgG4-RD manifestations (such as retroperitoneal fibrosis, lacrimal or salivary gland swelling, or pancreatic involvement) made this diagnosis unlikely (11, 12). The lymph node histology was reviewed in the context of clinical and laboratory features suspicious for Castleman disease. Although lymphadenopathy in IgG4-related disease can often be non-specific, there were no other features present in the lymph such as stromal fibrosis or storiform fibrosis to suggest IgG4-RD. Thus, in combination with the other clinical and laboratory findings, a diagnosis of iMCD-IPL with plasmacytic histology was made in both cases, based on the diagnostic criteria proposed by Gao et al. (5):

Xanthomas are cutaneous lesions that are histologically characterized by lipid-laden macrophages. Historically, xanthomas have been associated with hyperlipidemia, although recent studies have drawn this association into question (13). Xanthomas, particularly xanthelasma palpebrum, are important physical examination findings in patients suspected of having a hematological disorder, primarily due to their association with histiocyte disorders (14). Histiocytoses, particularly the group “L” (Langerhans Cell Histiocytosis and Erdheim-Chester disease), often present with xanthomas (15). In histiocyte disorders, xanthelasmas are histologically characterized by foamy histiocytes and Touton giant cells (16).

We searched PubMed and interrogated the Castleman Disease Collaborative Network’s ACCELERATE database for other cases of Castleman disease with xanthomas or xanthelasmas. No cases were found in the ACCELERATE database, which may reflect a lack of attention paid to this physical examination finding in CD patients (17). Three other cases of Castleman disease with xanthoma or xanthelasma have been identified in the literature and are summarized in Supplementary Table 1.

The first was a 22-year old Afghan woman who presented with fatigue, weight loss, and generalized plane xanthomas of the peri-orbital regions, anterior neck, upper arms, and upper back (18). She had anemia, inflammation, thrombocytosis, alkaline phosphatase (ALP) 1700 IU/L (<300 IU/L), and polyclonal hypergammaglobulinemia. Her HDL cholesterol level was slightly low 0.61 mmol/L (0.6-2.69) but the remainder of her lipid and complement levels were normal. Imaging revealed hepatomegaly, and liver biopsy showed sinusoid dilatation with peliotic (vascular) cysts and polyclonal plasmacytosis. She had a 6 cm retroperitoneal mass that was excised. The histology was consistent with the plasmacytic variant of Castleman disease. After excision of the lymph node mass, the patient gained 5 kg, her hepatomegaly resolved, the xanthomas regressed, and her PHGG improved (IgG 19.3 g/L). In retrospect, this appears to be unicentric Castleman disease with paraneoplastic systemic and hepatic inflammation and xanthelasmas. More recent studies have shown that UCD can cause systemic inflammation and paraneoplastic phenomena, such as pemphigus and bronchiolitis obliterans (19, 20).

The second describes a 23 year-old male who presented with hepatic sinusoidal dilatation and normolipemic periorbital plane xanthomas (21). He had severe wasting, celiac disease, polyclonal hypergammaglobulinemia, anemia, inflammation, elevated ALP 955 (<160 IU/L), and hypoalbuminemia (24 g/L). Complement levels were not reported. The patient was found to have a large retroperitoneal mass which was completely resected. Histology showed hyaline vascular Castleman disease; his liver abnormalities, wasting, inflammation, and anemia resolved with resection, as did the plane xanthomas. Overall, this case seems consistent with UCD, which causes paraneoplastic inflammation and hepatic congestion.

The third was a 49-year old female patient with fever, fatigue, and hepatosplenomegaly with bilateral xanthelasma palpebrum (22). She was anemic, with marked polyclonal hypergammaglobulinemia and a normal serum lipid profile. Complements were normal. She had an 8.5 x 7 cm mass near the right ovary. Resection of the mass, which upon histology was UCD, resulted in improvement of xanthelasma lesions, anemia, inflammation, polyclonal hypergammaglobulinemia, and organomegaly.

Common xanthomas are traditionally thought to be related to hyperlipidemia and atherosclerosis. High serum levels of atherogenic low-density lipoproteins and upregulation of T-cells, macrophages, and inflammatory mediators are thought to contribute to their formation (23, 24). Subtle metabolic disturbance of lipid metabolism have been described in polyneuropathy, organomegaly, endocrinopathy, monoclonal paraprotein, skin changes (POEMS) syndrome, and Castleman disease (25). Although both patients presented here had normal serum lipid profiles, this does not exclude more subtle disturbances of lipid metabolism from their iMCD-IPL contributing. The biochemical mechanism of xanthelasmas in relation to iMCD-IPL is unclear and we seek to present these cases to prompt further investigation. Both patients were treated with prolonged release (PR), and it is possible controlled release (CR) dosage may result in xanthelasma remission, but this is speculative.

Patients with monoclonal proteins in necrobiotic xanthogranuloma (NXG) can develop xanthelasmas with normal serum lipid levels. The monoclonal immunoglobulin (Mlg) was IgG in 80% of presented cases, with myeloma diagnosed in 35% of these cases (26). While NXG is related to monoclonal proteins rather than polyclonal hypergammaglobulinemia, increased immunoglobulins in iMCD-IPL may also play a role. A key feature of iMCD-IPL is profound polyclonal hypergammaglobulinemia, which raises the question of whether these immune globulins play a role in xanthoma formation.

These two cases of iMCD-IPL demonstrated the importance of clinicopathological correlations in CD. Both patients presented with xanthelasmas, which have not been previously reported in iMCD-IPL. The xanthelasmas in these two cases did not improve with siltuximab therapy. However, we also identified three cases of UCD associated with xanthomas, inflammation, and polyclonal hypergammaglobulinemia, all of which improved with resection of the UCD. This suggests a potential immune or inflammatory mechanism behind xanthomas in Castleman disease, which warrants further investigation.