PET/CT Exposes Occult Lymphoma After a False-Negative Marrow Biopsy
A 68-year-old woman’s prolonged fever, cytopenias, and unusual tongue pain began as a presumed infection, but the clinical course moved quickly toward a far more dangerous explanation: diffuse large B-cell lymphoma complicated by hemophagocytic lymphohistiocytosis. The case is a reminder that HLH can blur the diagnostic picture so completely that the underlying malignancy stays hidden even after an initial bone marrow biopsy. In this patient, the first tissue sample missed the diagnosis. A repeat biopsy, directed by functional imaging, finally revealed marrow-involved lymphoma and changed the direction of care.
Tongue pain is not the symptom clinicians usually expect to steer attention toward aggressive lymphoma. Here, it sat beside a persistent febrile syndrome that did not respond to broad-spectrum antimicrobial therapy, making infection less convincing as the sole explanation. As the illness progressed, the laboratory pattern became more alarming: worsening cytopenias, hyperferritinemia, hypofibrinogenemia, and elevated soluble interleukin-2 receptor levels met the HLH-2004 diagnostic criteria. That constellation points to immune overactivation, not a routine inflammatory reaction. Once macrophage-driven hyperinflammation takes hold, organ dysfunction can accelerate while the causal cancer remains clinically concealed.
Steroid Responsiveness Can Mislead When HLH Masks the Underlying Cancer
Corticosteroid therapy produced only transient improvement. Fever eased for a time, but the relapse after steroid withdrawal signaled that the biologic driver had not been removed. In HLH, temporary improvement after immunosuppression can create false reassurance, because steroids dampen the cytokine storm without answering the more important question of why the storm began. In this setting, the malignancy may still be active and continuing to seed the inflammatory cascade.
The first bone marrow biopsy was negative for malignancy. A single-site marrow sample can miss patchy infiltration, especially when lymphoma burden is unevenly distributed. Diffuse large B-cell lymphoma does not always occupy the marrow uniformly, and a biopsy that lands in a uninvolved area can return a misleadingly benign result. For a patient whose laboratory markers and systemic symptoms keep worsening, a negative marrow sample should not close the diagnostic process.
PET/CT Identified the Biological Target for Repeat Tissue Sampling
Positron emission tomography-computed tomography changed the case. Imaging demonstrated diffuse hypermetabolic activity in the spleen and bone marrow, pointing toward active reticuloendothelial involvement rather than isolated inflammatory disease. In practical terms, PET/CT identified where the disease signal was strongest, allowing tissue sampling to be redirected instead of repeated blindly. The repeat biopsy, guided by that imaging, confirmed non-germinal center B-cell-type DLBCL with marrow involvement.
This sequence matters because it reflects how lymphoma behaves in real patients: metabolically active disease often leaves a clearer footprint on PET/CT than on an initial random marrow core. Hypermetabolism in the spleen and marrow fits with a systemic lymphoproliferative process that can drive HLH through persistent immune activation. The imaging result did not merely add another data point; it supplied the anatomic map needed to find the malignancy that the first biopsy had missed.
One sentence captures the central diagnostic hazard: the marrow was involved, but not at the first biopsy site.
HLH Turns a Lymphoma Workup Into a Race Against Time
The pathophysiology explains why this case was so difficult. HLH creates a self-amplifying inflammatory state marked by fever, cytopenias, and biochemical evidence of immune activation. When lymphoma is the trigger, the cancer may be small in burden, scattered in distribution, or hidden behind overwhelming inflammatory findings. Clinicians can easily be drawn toward infection because fever is prominent and the patient is critically ill, yet persistent hyperferritinemia, falling fibrinogen, and high soluble interleukin-2 receptor levels should keep HLH high on the differential.
The tongue pain added another layer of diagnostic ambiguity. Extranodal symptoms outside the usual lymphoma presentation can delay recognition, especially when they are not dramatic enough to suggest an obvious mass lesion. Even so, atypical local pain in a patient with unexplained HLH should not be dismissed as incidental. It may be the earliest clue to extranodal disease or marrow involvement that has not yet declared itself radiographically.
Immunochemotherapy Achieved Remission After the Diagnosis Was Secured
After the diagnosis was established, the patient achieved clinical remission with immunochemotherapy. The therapeutic response supports the idea that the fever syndrome and cytopenias were downstream consequences of the lymphoma rather than a separate inflammatory disorder. Once the malignant driver is treated, the HLH loop can begin to collapse. Without identifying the cancer, however, treatment would have risked staying stuck in temporary immunosuppression and empiric anti-infective therapy.
This case argues for an earlier and more aggressive diagnostic strategy when HLH coexists with persistent systemic symptoms and an initial marrow biopsy is unrevealing. PET/CT can expose metabolically active disease that routine sampling misses, and it can guide the next biopsy to the most informative site. In critically ill patients, that approach may shorten the time to diagnosis and reduce the risk of therapeutic drift.
The lesson is concrete: a negative marrow biopsy does not exclude lymphoma when HLH is still unfolding.
Diagnostic Implications for Clinicians Facing Persistent Fever and Cytopenias
For clinicians, the case draws a clear boundary around when to escalate evaluation. Persistent fever despite antimicrobial therapy, progressive cytopenias, ferritin elevation, hypofibrinogenemia, and elevated soluble interleukin-2 receptor levels should trigger active consideration of HLH. If a first marrow biopsy is negative but the syndrome continues, PET/CT can identify hidden disease burden and help determine where to biopsy again. That sequence is particularly important in suspected lymphoma-associated HLH, where the mortality risk rises as diagnosis is delayed.
The report also shows how steroids can both help and obscure. Transient improvement after corticosteroids does not exclude occult lymphoma; it may simply suppress the inflammatory consequences long enough to delay the discovery of the cause. In a patient with unexplained HLH, especially one with an extranodal symptom such as tongue pain, imaging-guided repeat tissue sampling may be the difference between an elusive diagnosis and a treatable one.