Rare Castleman Disease Masquerading as Tuberculosis Finally Diagnosed as TAFRO Syndrome

A 21-year-old man who spent three years battling unexplained fevers, swollen lymph nodes, and dramatic weight loss has become the subject of a remarkable case report that sheds light on one of medicine’s most elusive diagnostic puzzles. Writing in Clinical Case Reports, physicians describe how the young patient, initially treated for tuberculosis without any benefit, was ultimately found to be suffering from idiopathic multicentric Castleman disease presenting as TAFRO syndrome, a rare and aggressive inflammatory disorder that can mimic infections, cancers, and autoimmune diseases all at once. The case, reported from India, underscores how easily this rare lymphoproliferative condition can hide behind far more common diagnoses, and how a delayed recognition can cost patients years of worsening illness before the correct therapy is finally started.

Castleman disease is a rare disorder of the lymphatic system in which lymph nodes become abnormally enlarged due to an overgrowth of lymphoid tissue. It exists along a spectrum: unicentric disease involves a single lymph node region and often behaves in a relatively benign fashion, while multicentric disease involves multiple lymph node stations and follows a far more aggressive, systemic course. Idiopathic multicentric Castleman disease, the subtype at the heart of this report, is characterized by widespread lymphadenopathy, systemic inflammation, and multiorgan involvement driven by dysregulated cytokine signaling, most notably interleukin-6. Because there is no single test for the condition, diagnosis requires a careful integration of clinical findings, laboratory data, imaging, and above all characteristic histopathology from an excised lymph node, together with the rigorous exclusion of diseases that can look strikingly similar.

The patient’s story began three years before admission, when he started experiencing intermittent low-grade fevers rising to around 100 degrees Fahrenheit, occurring in evening clusters without chills or night sweats. Two years later, painless swellings appeared on both sides of his neck and slowly enlarged. He received a course of empirical anti-tubercular therapy lasting nine months, a reasonable assumption in a tuberculosis-endemic region, yet his condition failed to improve. In the four weeks before hospitalization, his illness escalated dramatically: his abdomen swelled with accumulating fluid, his legs developed pitting edema, he lost roughly 15 kilograms, or 23 percent of his body weight, over six months, and he began coughing dryly with right-sided chest pain. By the time he reached the hospital, he was febrile, pale, and visibly wasted.

Examination revealed generalized lymphadenopathy, with firm, rubbery, non-tender nodes in the neck, armpits, and groin, the largest measuring up to three centimeters. His spleen was palpable four to five centimeters below the rib cage and his liver was enlarged, with shifting dullness on percussion indicating significant ascites. Reduced breath sounds over the right lung base pointed to a pleural effusion. Laboratory tests showed severe anemia with hemoglobin of 7.8 grams per deciliter, low white cell and platelet counts, and markedly elevated C-reactive protein at 43 milligrams per liter. Analysis of his ascitic fluid revealed a high serum-ascites albumin gradient with high protein content, a pattern suggesting portal hypertension, while adenosine deaminase levels were low, arguing against tuberculosis. Cytology of both ascitic and pleural fluid showed no malignancy.

The differential diagnosis was formidable. Disseminated tuberculosis, Epstein-Barr virus-associated lymphoproliferative disease, HIV, Hodgkin and non-Hodgkin lymphoma, leukemia, and systemic lupus erythematosus were all considered and systematically excluded through serology, imaging, bone marrow biopsy, and immunological testing. Contrast-enhanced CT of the abdomen confirmed massive ascites, hepatosplenomegaly, a dilated portal vein, and multiple small enhancing mesenteric lymph nodes. Fine-needle aspiration cytology of a cervical node proved inconclusive, a crucial teaching point of the case, since cytology frequently fails to capture the architectural features needed for a Castleman diagnosis. Only an excisional lymph node biopsy, the acknowledged diagnostic gold standard, could settle the question.

That biopsy delivered the answer. The excised lymph node displayed the classic histopathological signature of Castleman disease: atretic, involuting follicles, proliferation of small blood vessels in the interfollicular regions, and hyalinized vessels surrounded by concentric layers of mantle zone lymphocytes producing the so-called onion-skin appearance. Follow-up testing showed elevated serum interleukin-6 at 24 picograms per milliliter against a reference value below 7, negative Epstein-Barr virus and human herpesvirus-8 serologies, and negative LANA-1 staining, excluding the viral forms of multicentric disease and confirming the idiopathic subtype. A renal biopsy performed for persistent proteinuria revealed membranoproliferative glomerulonephritis, while a liver biopsy was nearly normal, leaving the portal hypertension partly unexplained but consistent with suspected secondary Budd-Chiari syndrome.

With these findings assembled, the patient fulfilled the diagnostic criteria for iMCD with the TAFRO phenotype, named for its five defining features: thrombocytopenia, anasarca, fever, reticulin fibrosis or renal dysfunction, and organomegaly. He met all the required histopathological criteria and at least three of the five major criteria, including platelets below 100,000 per microliter, massive fluid accumulation, CRP well above the diagnostic threshold, biopsy-confirmed renal involvement, and organomegaly. Interestingly, the authors note that while TAFRO syndrome is usually rapidly progressive and can become life-threatening within weeks, this patient’s prolonged constitutional phase preceded the emergence of the recognizable TAFRO constellation, complicating early recognition. Once the full phenotype appeared, he did not progress to the catastrophic organ failure seen in many reported cohorts, echoing evidence that TAFRO features do not invariably predict a uniformly fatal course.

Treatment began with systemic corticosteroids at one milligram per kilogram per day, which quickly improved his fever and inflammatory symptoms. Because the first-line therapies for iMCD, the anti-interleukin-6 antibodies siltuximab and tocilizumab, were not accessible in his setting, the team turned to rituximab, a B-cell-depleting antibody, given intravenously at 500 milligrams weekly for four weeks. This choice is explicitly permitted by Castleman Disease Collaborative Network and National Comprehensive Cancer Network guidelines when IL-6-targeted agents are unavailable, and registry data show roughly a quarter of patients respond to rituximab with or without steroids. Emerging evidence also suggests that B-cell dysregulation drives disease in a subset of TAFRO patients, particularly those with autoantibodies, providing a mechanistic rationale beyond simple cytokine blockade. The patient’s response was striking: fevers resolved completely, ascites and pleural effusion disappeared, lymphadenopathy regressed, and at six-month follow-up he had returned to work with prednisolone tapered to five milligrams on alternate days.

Beyond its clinical narrative, the case carries broader lessons for physicians and researchers alike. It highlights the diagnostic peril that rare cytokine-driven diseases face in regions where tuberculosis and lymphoma dominate the differential for chronic fever and lymphadenopathy, and it reinforces that fine-needle cytology is inadequate for diagnosing Castleman disease while excisional biopsy remains essential. It also illustrates the multisystem nature of iMCD-TAFRO, from cytokine-mediated glomerular injury thought to reflect chronic thrombotic microangiopathy, to transient autoimmune serology including antinuclear antibodies and anti-double-stranded DNA antibodies that can blur boundaries with lupus. The authors caution that a single case cannot establish rituximab’s efficacy relative to anti-IL-6 therapy, and they call for prospective studies to define its optimal role. Published data on iMCD-TAFRO from India remain sparse, making this report a valuable addition to a small but growing global literature on one of hematology’s most challenging mimics.

Subject of Research: Idiopathic multicentric Castleman disease presenting as TAFRO syndrome

Article Title: Rethinking Common Diagnoses: Idiopathic Multicentric Castleman Disease Presenting as TAFRO Syndrome: A Case Report

Article References: Rohatgi, D., Chakraborty, A., Kumar, S., & Rohatgi, A. (2026). Rethinking Common Diagnoses: Idiopathic Multicentric Castleman Disease Presenting as TAFRO Syndrome: A Case Report. Clinical Case Reports, 14(10), Article e73663. https://doi.org/10.1002/ccr3.73663

Image Credits: AI Generated

DOI: 10.1002/ccr3.73663

Keywords: Castleman disease, TAFRO syndrome, idiopathic multicentric Castleman disease, interleukin-6, rituximab, lymphadenopathy, excisional biopsy, membranoproliferative glomerulonephritis, misdiagnosis, tuberculosis, case report, rare disease