What are the differential diagnoses for painful lymphadenopathy with pancytopenia?

Differential Diagnoses for Painful Lymphadenopathy with Pancytopenia

The combination of painful lymphadenopathy and pancytopenia most commonly suggests infection-related hemophagocytic lymphohistiocytosis (HLH), overwhelming bacterial/viral infection with cytokine-mediated marrow suppression, or tuberculosis-associated HLH, though hematologic malignancies and autoimmune conditions must be systematically excluded. 1, 2, 3

Primary Infectious Etiologies

Hemophagocytic Lymphohistiocytosis (HLH)

• HLH presents with pancytopenia, fever, hepatosplenomegaly, hypertriglyceridemia (>229 mg/dL), hypofibrinogenemia, and markedly elevated ferritin (often >1,420 ng/mL). 1, 3, 4
• Tuberculosis-associated HLH manifests with weight loss, malaise, prolonged fever, generalized lymphadenopathy, and pancytopenia, requiring early bone marrow biopsy showing hemophagocytosis and PCR confirmation of Mycobacterium tuberculosis. 3
• Kikuchi's disease-associated HLH presents with fever, seizures, cervical lymphadenopathy, pancytopenia, and elevated transaminases, LDH, triglycerides, and ferritin, with lymph node biopsy showing necrotizing lymphadenitis. 4
• HLH requires prompt immunosuppressive treatment with dexamethasone and intravenous immunoglobulin, with less aggressive clinical course when associated with Kikuchi's disease in childhood. 1, 3, 4

Overwhelming Bacterial/Viral Infection

• Severe pharyngitis with painful cervical lymphadenopathy can cause transient severe pancytopenia through markedly elevated TNF-alpha levels, presenting with fever, sore throat, neck pain, and hypocellular bone marrow. 2
• EBV-associated lymphadenitis with systemic lupus erythematosus presents with recurrent fever, sore throat, general lymph node swelling, liver enlargement, pancytopenia with neutropenic fever, and 2 × 10⁶/ml EBV gene copies in blood. 5
• Treatment with antibiotics and G-CSF successfully ameliorates inflammatory lesions and restores hematopoiesis when TNF-alpha-mediated suppression is the mechanism. 2

Nontuberculous Mycobacterial Infections

• Disseminated MAC in HIV-infected patients presents with fever of unknown origin, but suppurative lymphadenopathy with swollen and painful cervical, axillary, or inguinal nodes typically represents immune reconstitution syndrome after antiretroviral therapy initiation, not classic disseminated disease. 6
• MAC cervical adenitis in children aged 1-5 years affects submandibular, submaxillary, cervical, or preauricular lymph nodes, but rarely causes pancytopenia unless disseminated in immunocompromised hosts. 6

Hematologic Malignancies

Lymphoproliferative Disorders

• Non-Hodgkin's lymphoma requires excisional or incisional lymph node biopsy with immunophenotyping and cytogenetic analysis, as FNA alone is insufficient for initial diagnosis despite painful lymphadenopathy presentation. 6
• Autoimmune lymphoproliferative syndrome (ALPS) presents with childhood-onset chronic lymphadenopathy, splenomegaly, multilineage cytopenias from sequestration and autoimmune destruction, requiring FAS mutation testing. 6
• Chronic lymphocytic leukemia with massive (≥10 cm) or progressive or symptomatic lymphadenopathy meets treatment criteria, though painful nodes are atypical for CLL. 6

Histiocytic Disorders

• Classic nodal Rosai-Dorfman-Destombes disease typically presents with bilateral, massive, and painless cervical lymphadenopathy, making painful presentation unusual, though intermittent fevers, night sweats, and weight loss may occur. 6
• Extranodal RDD affects 43% of cases with multisystem involvement in 19%, requiring S100-positive, CD68-positive, CD1a-negative histiocytes with emperipolesis on biopsy. 6

Autoimmune and Nutritional Causes

Systemic Lupus Erythematosus

• SLE with EBV co-infection causes pancytopenia through autoantibodies against all three blood cell compartments, requiring low-dose corticosteroid immunosuppression despite recurrent infections, resulting in normalization of blood counts and negative antibody/EBV genome levels. 5

Megaloblastic Anemia

• Vitamin B12 deficiency presents with pancytopenia, macrocytosis, hypersegmented neutrophils, teardrop cells, elevated LDH, indirect hyperbilirubinemia, and markedly low serum B12, responding to B12 supplementation without invasive procedures. 1, 7
• Lymphadenopathy is not a typical feature of isolated B12 deficiency, making this diagnosis less likely when prominent painful nodes are present. 7

Diagnostic Algorithm

Immediate Laboratory Assessment

• Obtain CBC with differential, peripheral smear (assess for blasts, dysplasia, hypersegmented neutrophils), reticulocyte count, LDH, ferritin, triglycerides, fibrinogen, and liver function tests. 1, 8, 3, 4
• Measure vitamin B12, folate, HIV, HCV, and HBV serologies in all adult patients with pancytopenia. 1, 8
• Check ANA and anti-dsDNA when systemic symptoms suggest autoimmune disease. 8, 5

Tissue Diagnosis Requirements

• Perform excisional lymph node biopsy with histopathology, immunohistochemistry, flow cytometry, and culture (including mycobacterial and fungal) for painful lymphadenopathy with pancytopenia. 6, 3
• Bone marrow aspiration and biopsy with cytogenetic analysis is mandatory when age >60 years, systemic symptoms present, abnormal physical findings exist, or diagnosis remains unclear after initial workup. 1, 8, 9
• PCR testing of bone marrow and lymph node specimens for Mycobacterium tuberculosis and EBV should be performed when HLH is suspected. 5, 3

Specific Diagnostic Thresholds

• Ferritin >1,420 ng/mL with triglycerides >229 mg/dL strongly suggests HLH, requiring immediate hematology consultation and consideration of HLH-2004 diagnostic criteria. 1, 3, 4
• TNF-alpha levels should be measured when overwhelming infection with hypocellular marrow is present without identified pathogen. 2

Critical Pitfalls to Avoid

• Do not assume isolated ITP based on thrombocytopenia and petechiae when WBC is also decreased (3,800/μL), as this represents pancytopenia requiring bone marrow examination for aplastic anemia or other marrow failure syndromes. 9
• Do not delay bone marrow examination in patients with painful lymphadenopathy and pancytopenia, as this combination requires exclusion of infiltrative processes, HLH, and tuberculosis. 1, 8, 3
• Do not rely on FNA alone for lymph node diagnosis in pancytopenia cases, as excisional biopsy with architecture preservation is essential for diagnosing histiocytic disorders and lymphomas. 6
• Do not overlook EBV and tuberculosis PCR testing when HLH is suspected, as these infections are treatable causes requiring specific antimicrobial therapy in addition to immunosuppression. 5, 3
• Do not assume painless lymphadenopathy is required for RDD, as clinical presentations vary and painful nodes may occur with superimposed infection or inflammation. 6