What malignancies can cause lymphopenia?

Malignancies That Cause Lymphopenia

Hematologic malignancies are the primary cancer types that directly cause lymphopenia, with T-cell and NK-cell lymphomas, acute leukemias, chronic lymphocytic leukemia, Hodgkin lymphoma, and non-Hodgkin lymphomas being the most common culprits. 1

Hematologic Malignancies

Lymphomas (Most Common)

• T-cell and NK-cell lymphomas are the most frequent malignancies causing lymphopenia, accounting for approximately 35% of malignancy-associated cases 1

  • Peripheral T-cell lymphomas (particularly subcutaneous panniculitis-like T-cell lymphoma) 1
  • Primary cutaneous γδ-T-cell lymphoma 1
  • Angioimmunoblastic T-cell lymphoma (AITL), with lymphopenia present in 47.5% of cases 2
  • Adult T-cell leukemia/lymphoma (ATLL), where lymphopenia independently predicts inferior survival (2-year OS of 15% vs 40% without lymphopenia) 2

• B-cell lymphomas account for 32% of malignancy-associated lymphopenia cases 1

  • Diffuse large B-cell lymphoma (DLBCL) is the predominant trigger in Western countries 1
  • Chronic lymphocytic leukemia 1

• Hodgkin lymphoma accounts for 6% of cases and commonly presents with secondary eosinophilia alongside lymphopenia 1

Leukemias

• Acute lymphocytic leukemia is the most common leukemia-malignancy association with lymphopenia 1
• Acute myelogenous leukemia 1
• Leukemias overall account for 6% of malignancy-associated lymphopenia 1

Other Hematologic Malignancies

• Multiple myeloma 1
• Primary cutaneous T-cell lymphoma (Sézary syndrome) 1

Solid Tumors

Solid tumors less commonly cause lymphopenia but can do so in advanced disease:

• Solid tumors account for only 3% of malignancy-associated lymphopenia cases 1
• Lymphopenia in solid tumors is generally limited to advanced stage disease with distant metastases 1
• The mechanism involves increased production of growth factors and eosinophilopoietic cytokines that suppress lymphocyte production 1

Clinical Context and Mechanisms

Direct Mechanisms

• Bone marrow infiltration by malignant cells directly suppresses lymphocyte production 3, 4
• Malignant cells secrete cytokines (interferon-γ, interleukin-6) that contribute to lymphocyte suppression 1

Age-Related Risk

• The likelihood of underlying malignancy increases with age in patients presenting with lymphopenia 1
  • 68% of patients >60 years with lymphopenia have lymphoma 1
  • 38% aged 30-59 years 1
  • 10% aged 15-29 years 1
  • 0% under 14 years 1

Treatment-Related Lymphopenia

While not directly caused by the malignancy itself, chemotherapy-induced lymphopenia is extremely common and prognostically significant:

• Occurs in 57% of patients with rectal cancer receiving chemoradiation 5
• 31.6% develop grade III/IV lymphopenia during treatment for gliomas 6
• Associated with significantly worse survival across multiple cancer types 7, 5, 6

Critical Pitfalls

• Do not assume lymphopenia is always treatment-related in cancer patients—it may indicate underlying hematologic malignancy requiring bone marrow evaluation 1, 4
• Lymphopenia at presentation (before treatment) carries independent prognostic significance and should prompt thorough hematologic workup 2, 8
• In patients with known solid tumors, new-onset lymphopenia may indicate disease progression to advanced stage rather than a separate hematologic process 1