What is triple positive lymphoma?

Triple Positive Lymphoma: Definition and Clinical Implications

Triple positive lymphoma, also known as triple-hit lymphoma (THL), is a rare and aggressive form of B-cell lymphoma characterized by concurrent genetic rearrangements of MYC, BCL2, and BCL6 genes, which is associated with poor prognosis and requires intensive treatment approaches. 1, 2

Definition and Pathophysiology

• Triple-hit lymphoma is defined by the presence of simultaneous chromosomal translocations or rearrangements involving three key genes: MYC, BCL2, and BCL6 2
• These lymphomas represent a subset of high-grade B-cell lymphomas that are more aggressive than the more common double-hit lymphomas (which have rearrangements of only two of these genes) 1, 3
• The genetic alterations can be detected using fluorescence in situ hybridization (FISH) or other cytogenetic techniques during the diagnostic workup 1

Epidemiology and Risk Factors

• Triple-hit lymphomas are extremely rare, accounting for less than 5% of all diffuse large B-cell lymphomas (DLBCL) 2
• They occur predominantly in males, with a median age of 64 years (range 45-80 years) 2
• Some patients have a history of antecedent or concurrent follicular lymphoma, suggesting potential transformation from indolent lymphoma 2
• Triple-hit lymphomas are more common in adolescent and young adult (AYA) patients than in the pediatric population 1

Clinical Presentation

• Patients typically present with advanced disease, B symptoms (fever, night sweats, weight loss), and elevated serum LDH levels 2
• Lymphadenopathy is common, often involving cervical, supraclavicular, and axillary regions 4
• Mediastinal masses may be present, particularly in T-cell variants, though triple-hit lymphomas are typically of B-cell origin 4
• Bone marrow involvement and extranodal disease are frequently observed 2

Diagnosis

Histopathology

• Histologically, triple-hit lymphomas may show features of:
  • B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma
  • Diffuse large B-cell lymphoma (DLBCL)
  • Occasionally, follicular lymphoma with transformation 2

Immunophenotyping

• Immunohistochemistry typically shows:
  • CD10 positivity (100% of cases)
  • BCL2 positivity (100% of cases)
  • High MYC expression (>90% of cases)
  • BCL6 positivity (approximately 73% of cases)
  • CD20 positivity (>90% of cases)
  • High Ki-67 proliferation index (70-100% in most cases) 2
• Most triple-hit lymphomas belong to the germinal center B-cell-like subgroup 2

Genetic Testing

• Cytogenetic or FISH studies are essential to confirm rearrangements of all three genes: MYC, BCL2, and BCL6 1
• The recommended diagnostic approach includes:
  • Excisional or incisional lymph node biopsy (FNA alone is insufficient)
  • Immunohistochemistry panel including CD20, CD3, CD5, CD10, CD45, BCL2, BCL6, Ki-67, IRF4/MUM1
  • FISH for MYC, BCL2, and BCL6 rearrangements 1

Staging and Workup

• Complete workup includes:
  • History and physical examination
  • Laboratory studies including complete blood count, comprehensive metabolic panel, LDH
  • Bilateral bone marrow aspiration and biopsy
  • Lumbar puncture (due to high risk of CNS involvement)
  • PET/CT or CT imaging of chest, abdomen, and pelvis 1
• The Lugano classification system is used for staging, incorporating PET/CT findings 5

Treatment

• Treatment of triple-hit lymphoma is challenging due to its aggressive nature and poor response to standard therapy 2
• The NCCN guidelines recommend treating triple-hit lymphomas in the pediatric population the same as other aggressive B-cell lymphomas (BL and DLBCL) 1
• For adults, more intensive regimens than standard R-CHOP are typically considered:
  • Dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab)
  • High-dose chemotherapy followed by stem cell transplantation in eligible patients 2
• CNS prophylaxis is recommended due to the high risk of CNS involvement 1
• Response rates to conventional chemotherapy are generally poor, with many patients showing partial or no response 2

Prognosis

• Triple-hit lymphomas generally have a poor prognosis with conventional therapy 2
• Most patients respond poorly to standard chemotherapy regimens 2
• However, a subset of patients may achieve complete remission with intensive chemotherapy followed by stem cell transplantation 2, 6
• Some rare cases have been reported with less aggressive behavior and better outcomes than typically expected 6

Follow-up and Surveillance

• Close monitoring for disease progression and treatment response is essential 5
• PET/CT is recommended for response assessment, though residual FDG-avid lesions should be confirmed by biopsy 1
• Long-term surveillance for late complications of therapy, including secondary malignancies, is necessary 5

Clinical Pitfalls and Considerations

• Triple-hit lymphomas may be misdiagnosed as standard DLBCL if comprehensive genetic testing is not performed 2
• The distinction between triple-hit lymphoma (genetic rearrangements) and triple-expressor lymphoma (protein overexpression without genetic rearrangements) is important but often overlooked 3
• Early consideration of stem cell transplantation in first remission may improve outcomes in eligible patients 2
• Patients should receive appropriate vaccinations due to the immunosuppressive nature of both the disease and its treatment 5