When Two Rare Immune Diseases Look Alike: A Diagnostic Puzzle Unraveled

A 46-year-old man with no significant medical history walked into his primary care provider’s office with a three-month history of painless swelling in the lymph nodes of his neck and beneath his jaw. He had no fever, no malaise, and no weight changes. What followed was a months-long diagnostic odyssey that ultimately revealed one of the most confounding overlaps in modern immunology: the striking similarity between IgG4-related disease and idiopathic multicentric Castleman disease, two rare immune-mediated disorders that can mimic each other so closely that even tissue biopsies may point clinicians down the wrong path. A recently published case report details how the patient was initially treated for one condition, failed to respond, and was eventually rediagnosed with the other — a sequence with important lessons for how rare inflammatory diseases are distinguished in clinical practice.

IgG4-related disease is an immune-mediated inflammatory disorder capable of involving multiple organs at once. Its clinical spectrum is remarkably broad, ranging from localized enlargement of the salivary glands to renal failure caused by widespread retroperitoneal fibrosis that obstructs urinary outflow. Under the microscope, the disease is defined by a dense lymphoplasmacytic infiltrate dominated by IgG4-positive plasma cells, along with two other hallmark features: storiform fibrosis, a whorled pattern of scar tissue, and obliterative phlebitis, in which inflammatory cells invade and shut down small veins. Corticosteroids are considered first-line treatment, but long-term use carries toxicities. Steroid-sparing maintenance options include B cell-depleting agents such as rituximab and inebilizumab, as well as conventional disease-modifying drugs like azathioprine or mycophenolate mofetil.

Castleman disease, meanwhile, is an immune-mediated lymphoproliferative disorder that can also affect multiple organ systems. It is divided into unicentric and multicentric subtypes depending on regional lymph node involvement. Multicentric disease tends to present with nonspecific constitutional symptoms — fever, night sweats, and weight loss. By etiology, it is subdivided into variants associated with human herpesvirus 8, with POEMS syndrome, and idiopathic cases with no identifiable driver. Histologically, two primary subtypes dominate: the plasma cell variant, marked by sheet-like interfollicular plasmacytosis with normal to hyperplastic germinal centers, and the hyaline vascular variant, characterized by prominent vascular proliferation and often atrophic germinal centers. Treatment targets the interleukin-6 signaling axis, using agents such as siltuximab and tocilizumab.

The patient’s workup began with computed tomography of the neck, which identified asymmetric enlargement of the left lacrimal gland, partial effacement of the right vallecula, bilateral axillary lymphadenopathy, and borderline cervical lymphadenopathy. Five months after symptom onset, while traveling in his home country, he underwent fine needle aspiration of a left cervical lymph node, which showed only nonspecific chronic inflammatory changes and lymphocytes. Six months in, after returning to the United States, repeat imaging redemonstrated the cervical lymphadenopathy and revealed slight enlargement of the lacrimal glands, with no evidence of necrosis or infection. Fine needle aspiration of three right-sided cervical lymph nodes again demonstrated nonspecific reactive lymphoid tissue, and flow cytometry revealed no malignancy.

With repeated nonspecific aspiration results, the clinical team proceeded to an excisional biopsy of a right cervical lymph node — and the tissue finally spoke. Pathology revealed increased follicles with variably sized germinal centers showing hyalinization and concentric rings of small lymphocytes in the mantle zones, imparting the classic onion-skinning appearance. There was also a dense lymphoplasmacytic infiltrate with a predominance of plasma cells, of which more than 95 percent stained positively for IgG4. Critically, however, no storiform fibrosis or obliterative phlebitis was observed. The findings were deemed compatible with the plasma cell variant of Castleman disease. Subsequent positron emission tomography identified widespread hypermetabolic lymphadenopathy above and below the diaphragm, with avid nodes in the mediastinal, axillary, paravertebral, retroperitoneal, and inguinal regions, plus moderate uptake in the enlarged parotid, sublingual, and submandibular glands.

Serology added further complexity. The patient had an elevated erythrocyte sedimentation rate of 98 millimeters per hour but a normal C-reactive protein, along with mild anemia, hypoalbuminemia, and markedly elevated IgG of 5396 milligrams per deciliter. His IL-6 level was not elevated, and tests for HHV-8 and HIV were negative. Based on the available information, his presentation was judged most consistent with idiopathic multicentric Castleman disease with abundant IgG4 plasma cells, and he received first-line treatment with siltuximab. After four cycles, he showed no clinical improvement. Interval testing revealed persistently elevated sedimentation rate, persistent anemia, new thrombocytopenia, and worsened renal function. His measured IL-6 level was newly elevated, and both the thrombocytopenia and the increased IL-6 were attributed to the siltuximab itself, since measured IL-6 can rise following IL-6 blockade. Imaging highlighted persistent extensive lymphadenopathy and new extranodal involvement, including bilateral perirenal and periureteric soft tissue that could account for the renal changes, along with new esophageal and tracheal thickening.

Referred to rheumatology for reconsideration, the patient by this time reported sicca symptoms and increasing nasal, sinus, and ear pressures. His examination revealed multiple firm, nontender lymph nodes in the cervical, submandibular, and inguinal regions, with nodes measuring up to four centimeters. Given concern for IgG4-related disease, he was started on high-dose corticosteroids — and within six days of beginning prednisone, he noted improvement in his sicca symptoms and sinus congestion. He then began rituximab, and his laboratory derangements improved throughout the treatment course: IgG fell from over 6500 to under 2000 milligrams per deciliter, hemoglobin recovered, and platelets normalized. After four weekly rituximab infusions, imaging showed remarkable resolution of all his lymphadenopathy. He was ultimately diagnosed with IgG4-related disease based on clinical features, laboratory findings, and treatment response, despite the absence of classic histopathologic evidence, and he subsequently tapered off corticosteroids while continuing to feel well.

The case illustrates why these two disorders are so easily confused — and which features can pull them apart. Generalized lymphadenopathy occurs in both. Constitutional symptoms such as fevers, chills, and night sweats are observed in roughly half of all idiopathic multicentric Castleman disease patients, whereas fevers are not seen in IgG4-related disease. Lacrimal and salivary gland involvement is common in IgG4-related disease and would be atypical of Castleman disease. Serologically, persistently elevated C-reactive protein favors multicentric Castleman disease, while anemia, thrombocytopenia, hypoalbuminemia, and elevated IL-6 are laboratory findings characteristic of it. The patient’s low baseline IL-6 and normal C-reactive protein were not typical of the inflammatory phenotype of Castleman disease. Histologically, the picture was equally treacherous: the classic IgG4-related disease triad includes dense lymphoplasmacytic infiltrate, storiform fibrosis, and obliterative phlebitis, but the patient had only the first. Notably, prior observations indicate that approximately 36 percent of small biopsies in presumed IgG4-related disease patients lack both storiform fibrosis and obliterative phlebitis.

At presentation, the patient’s clinical and histopathologic findings fulfilled the 2017 international consensus criteria for idiopathic multicentric Castleman disease, meeting both major criteria and seven of the 11 minor criteria, and his disease resembled the idiopathic plasmacytic lymphadenopathy subtype. Yet the clinical phenotype of Castleman disease significantly overlaps with other hematologic and rheumatologic conditions, and the hyaline vascular and onion-skinning lymph node patterns may occur as reactive phenomena to other systemic inflammatory conditions. Achieving a Castleman diagnosis requires extensive exclusion of other diseases, and therapeutic response patterns add further ambiguity: while improvement with anti-IL-6 therapy lends support to the diagnosis, nonresponse does not exclude it, since only about two-thirds of patients benefit. The authors emphasize that a reliance on histopathology alone can lead to misdiagnosis and delayed care, and that the absence of classic findings should not preclude the diagnosis of either disorder. Their conclusion is a warning against anchoring bias, even when diagnostic criteria appear satisfied: integrating clinical symptoms, laboratory results, imaging, and tissue analysis — with ongoing reassessment as treatment responses unfold — remains the surest route to diagnostic accuracy in diseases that wear each other’s masks.

Subject of Research: A case report describing how IgG4-related disease mimicked idiopathic multicentric Castleman disease, leading to initial misdiagnosis and delayed treatment before rituximab therapy resolved the patient's lymphadenopathy.

Article Title: Lumps, Bumps, and Diagnostic Stumps: A Case Report of IgG4‐Related Disease

Article References: Miller, M., Strouse, J., Yu, N., Holman, C., & Moy, L. (2026). Lumps, Bumps, and Diagnostic Stumps: A Case Report of IgG4 ‐Related Disease. Clinical Case Reports, 14(11), Article e73793. https://doi.org/10.1002/ccr3.73793

Image Credits: AI Generated

DOI: 10.1002/ccr3.73793

Keywords: IgG4-related disease, Castleman disease, idiopathic multicentric Castleman disease, rituximab, siltuximab, lymphadenopathy, histopathology, interleukin-6, plasma cells, diagnostic overlap, case report, immunology