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

The research, conducted at Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, followed 1,059 consecutive patients, both adults and children, who were referred for biopsy between 2010 and 2022 with clinical suspicion of a lymphoproliferative disease, an umbrella term covering lymphomas and related disorders of the lymphoid tissues. Every one of these patients underwent imaging-guided core needle biopsy as their first diagnostic procedure, and the results, published in CVIR Oncology, are striking. In 96.6 percent of all referred patients, the needle biopsy alone delivered a conclusive histological diagnosis without any need for follow-up surgery. Among the 882 patients ultimately confirmed to have lymphoma, 95.9 percent received a complete, actionable diagnosis from the needle procedure alone.

Those numbers matter because of what they replace. Traditional excisional biopsy requires surgical pre-assessment, anesthesia, an incision, and recovery time, and carries risks of infection, scarring, and bleeding. It can also introduce delays at exactly the moment when speed matters most, since different lymphoma subtypes demand radically different treatment strategies, and treatment often cannot begin until the subtype is pinned down. Core needle biopsy, by contrast, is a minimally invasive procedure performed through a tiny puncture, typically under local anesthesia, in an outpatient or short-stay setting. For frail patients, for those needing urgent therapy, and for anyone with a deep-seated lesion that surgery would struggle to reach safely, the difference is not merely one of convenience but of clinical feasibility.

The technical backbone of the procedure is the semiautomated Tru-cut needle, a spring-loaded device available in gauges ranging from 14 to 18 Gauge in routine practice, with 16 Gauge being the workhorse in the Milan series. The operator pulls back a mandrel to load the spring, advances the needle into the target tissue while continuously visualizing the needle tip, and then fires the outer cutting cannula over the stylet, capturing a slender cylindrical core of tissue. At this institution, at least three or four passes through the lymph node or lesion are typically made, and the median number of samples in the recorded data was four. The cores are fixed in formalin, embedded in paraffin, stained with hematoxylin and eosin, and then classified according to the World Health Organization criteria using morphology, immunohistochemistry, and, when needed, FISH and molecular testing.

Equally important is how the target is chosen and how the needle finds its way there. Ultrasound guided the large majority of the procedures, 891 of the 1,059, and remains the technique of choice for superficial lymph nodes, soft tissues, salivary glands, liver, and kidney, thanks to its real-time visualization, low cost, and wide availability, often complemented by color Doppler mapping of the lesion’s vascular structure. Computed tomography took over for deep anatomical sites, accounting for 168 procedures, particularly retroperitoneal and mediastinal lesions nestled near vessels and organs. For these, the team used a coaxial technique, placing a larger introducer through which the biopsy needle could be advanced repeatedly, allowing multiple samples from a single puncture while reducing the risks of bleeding and tumor seeding. Contrast-enhanced CT scans helped identify viable tissue and avoid sampling necrotic or liquefied areas, and the technique proved its worth: CT-guided biopsies actually achieved a slightly higher diagnostic yield, 97.1 percent, than ultrasound-guided ones, at 95.8 percent.

A particularly sophisticated element of the workflow was the use of positron emission tomography, or PET-CT, for target selection. In 42.5 percent of lymphoma cases, a PET-CT scan performed within 30 days before the biopsy was available to guide the choice of where to sample. Because fluorodeoxyglucose uptake correlates with the histological grade and proliferative activity of lymphoma cells, hot spots on a PET image mark the metabolically active, viable regions of a tumor, allowing operators to aim the needle at the most informative tissue and steer clear of dead or fibrotic zones. The study found that PET-CT availability did not measurably raise the overall binary diagnostic yield, but the authors argue that its true value is qualitative: distinguishing active disease from post-treatment fibrosis, and selecting the clinically most informative target in cases of suspected relapse or transformation. In one illustrative case, a retroperitoneal mass showed poor enhancement on contrast CT, yet PET imaging revealed intense uptake in the same region, and the needle was placed precisely where the PET signal was strongest, yielding a conclusive diagnosis that conventional imaging alone might have missed.

Safety was another standout finding. Not a single patient in the entire cohort suffered a biopsy-related complication of grade 2 or higher on the standard CTCAE v5 scale, meaning no severe bleeding, infection, or event requiring unplanned intervention. Minor local bleeding occurred in roughly 5 percent of cases, and no patient required hospitalization beyond the planned 24 hours after deep-tissue biopsies. Standard precautions, including blood counts and coagulation testing, stopping anticoagulation at least 24 hours before the procedure, and platelet transfusion for patients with counts below 50,000 per microliter, kept the risk profile firmly in check. Even the 22 pediatric patients in the cohort were managed successfully, underscoring that minimally invasive image-guided biopsy can be appropriate even in children when multidisciplinary teams weigh anesthetic risk, lesion location, and protocol requirements.

The study is honest about where the needle falls short. Thirty-six lymphoma patients, 4.1 percent of the cohort, still required a subsequent excisional biopsy, either because the needle sample was inadequate or because it was suggestive but not conclusive. Notably, certain subtypes were overrepresented in this surgical group: half of the patients with nodular lymphocyte-predominant Hodgkin lymphoma and 15 percent of those with peripheral T-cell lymphoma needed surgery to reach a final diagnosis, a pattern consistent with pathological guidance suggesting that these entities are best assessed when an entire lymph node’s architecture can be examined. Among the 36 surgical cases, the excisional diagnosis differed from the needle-based impression in 9 patients, confirmed it in 12, and provided a new conclusive answer in 15, all of whom ended up with a definitive histological result. The authors stress that these figures argue not against needle biopsy, but for prompt surgical follow-up whenever the needle result does not inspire confidence for treatment decisions, ideally after early multidisciplinary discussion among hematologists, radiologists, and pathologists.

The broader picture emerging from more than a decade of data is one of a diagnostic landscape in transition. The Lugano classification, the standard framework for lymphoma management, still reserves core needle biopsy for situations where surgery is not possible or for relapse. Yet this Milanese experience, one of the largest single-center intent-to-diagnose cohorts ever assembled, shows that with careful patient selection, meticulous imaging guidance, judicious needle gauge choice tailored to lesion location, multiple sampling, and PET-informed targeting, the needle succeeds where the scalpel was once thought indispensable. Follicular lymphoma, diffuse large B-cell lymphoma, and classical Hodgkin lymphoma, the three most common diagnoses in the cohort, were reliably captured by needle sampling, and 177 patients with suspected lymphoma actually turned out to have entirely different conditions, including metastatic carcinoma, sarcoma, neurogenic tumors, and retroperitoneal fibrosis, all of which the needle correctly identified. In an era when medicine increasingly prizes precision with minimal invasiveness, this study makes a compelling case that for most patients with suspected lymphoma, the first and often only diagnostic procedure needed is one that fits through a needle’s eye.

Subject of Research: Diagnostic yield and procedural techniques of imaging-guided core needle biopsy in patients with suspected lymphoproliferative disease

Article Title: Core needle biopsy in patients with suspected lymphoproliferative disease: diagnostic yield in a large single-center cohort and procedural techniques

Article References: Core needle biopsy in patients with suspected lymphoproliferative disease: diagnostic yield in a large single-center cohort and procedural techniques. (n.d.). https://doi.org/10.1007/s44343-026-00051-5

Image Credits: AI Generated

DOI: 10.1007/s44343-026-00051-5

Keywords: core needle biopsy, lymphoma, lymphoproliferative disease, excisional biopsy, ultrasound-guided biopsy, CT-guided biopsy, PET-CT, interventional radiology, diagnostic yield, hematologic malignancies, Tru-cut needle, minimally invasive diagnosis