Diffuse Large B Cell Lymphoma

DIFFUSE LARGE B CELL LYMPHOMA(DLBCL) 

• It is the most common form of NHL(Non-Hodgkin’s Lymphoma).
• The most common variant of Non-Hodgkin’s Lymphoma in India is Diffuse Large B cell Lymphoma.
• Diffuse Large B cell Lymphoma is also the most common variant of Non-Hodgkin’s Lymphoma in the United States.
  
• It is a tumour of the mature B cells.
• It is rapidly fatal if untreated.

IMMUNOPHENOTYPE

• They will demonstrate markers of mature B lymphocytes as well as germinal centre markers- CD 19- CD 20 – CD 10- BCL-6- slg- BCL-2 (see in 10% to 20% associated with t(14:18)).

CLINICAL FEATURES OF DIFFUSE LARGE B CELL LYMPHOMA

• Incidence of this lymphoma is more common in males(male-to-female disease incidence ratio of 1.3:1).
• DLBCL typically affects patients in their sixth decade, except for primary mediastinal DLBCL variant, which affects mostly females in their late 20s or early 30s.
• These tumors have a rapid growth rate and present as masses, causing symptoms when they infiltrate tissues or obstruct organs.
• Two thirds NHLS present with nontender nodal enlargement.
• Two thirds of NHLS arise at extranodal sites which are skin, stomach or brain.
• As with other types of non-Hodgkin lymphoma (NHL), diffuse large cell lymphomas can present with B-symptoms, including fever, drenching night sweats, and weight loss.
• Most common extranodal site for non – hodkin’s lymphoma is Stomach.
• 60-80% of intestinal lymphomas are B cell lymphomas, mostly diffuse large B cell type of Non Hodgkin’s lymphoma of the distal small intestine and especially in the ileo-cecal region
• Most common ocular lymphoma is B Cell Non Hodgkin’s Lymphoma.Most common Lymphoma of Thyroid are of Non-Hodgkin’s B Cell Type.
• B cell lymphoma, Burkit lymphoma, Non Hodgkin’s lymphoma, mantle cell lymphoma are common in orbit.
• The paraneoplastic hypercalcemia in lymphoma is due to ectopic production of 1,25 dihydroxyvitamin D.
• 5 year survival rate of Diffuse large B cell lymphoma is 46%.

CYTOGENIC ABNORMALITIES AND ONCOGENE ASSOCIATED WITH DIFFUSE LARGE B CELL LYMPHOMA 

• Cytogenic Abnormality associated with Diffuse Large B Cell Lymphoma is t(3;-)(q27;-)t(17;-)(p13;-).

Oncogene associated with Large B Cell Lymphoma is BCL-6,p53.

• Disease    Cytogenetic Abnormality Oncogene
• Mantle cell lymphoma   t(11;14)(q13;q32) BCL-1, IgH
• Follicular lymphoma  t(14;18)(q32;q21) BCL-2, IgH
• Diffuse large cell lymphoma t(3;-)(q27;-)t(17;-)(p13;-) BCL-6,p53
• Burkitt’s lymphoma,Burkitt’s leukemia t(8;-)(q24;-) C-MYC
• CD30+ Anaplastic large cell lymphoma t(2;5)(p23;q35) ALK
• Lymphoplasmacytoid lymphoma  t(9;14)(p13;q32) PAX5, IgH

CLASSIFICATION OF NHL
Working formulation in staging of non-hodgkins lymphoma is based on Morphology of Cells.:

• Low grade:Small lymphocytic,Follicular, predominantly small cleaved cell ,Follicular, mixed, small cleaved and large cell.

1. Follicular cell lymphoma falls under the low grade non-Hodgbkins lymphoma .
2.  Lymphomas with a follicular histological pattern have a longer survival than those of diffuse pattern.
   

• Intermediate grade:Follicular predominantly large cell ,Diffuse small cleaved cell,Diffuse mixed small and large cell,Diffuse large cell.

1. Diffuse small, mixed , as well as large cell Lymphoma falls in the Intermediate form of Non-Hodgkin’s Lymphoma.

• High grade:Large cell immunoblastic,Lymphoblastic,Small non cleaved cell.

 The classification proposed by the International Lymphoma Study Group for non-Hodgkin’s lymphoma is known as REAL Classification(‘Revised European-American Classification of Lymphoid Neoplasms (REAL).)

• In addition to morphologic descriptions, this schema includes immunologic, cytogenetic, and molecular information to define distinct lymphoma entities
• WHO has now reviewed and updated the real classification:WHO Classification / Modified ‘REAL’ Classification..
• Currently, diffuse large B-cell lymphoma is designated under the REAL classification as classic diffuse large cell lymphoma of B-cell origin .

INTERNATIONAL PROGNOSTIC INDEX(IPI) FOR NHL:

• The IPI score system is calculated by the sum of the presence or absence of 5 variables :age ≥ 65 y, performance status ≥ 2, elevated lactate dehydrogenase (LDH), Ann Arbor stage III or IV, and ≥2 extranodal sites of disease.
• Based on the total score, DLBCL patients are assigned into 4 risk category groups (low, low-intermediate, high-intermediate, and high).

DIAGNOSIS

• The diagnosis of diffuse large cell lymphoma is usually confirmed after positive findings are obtained from a lymph node biopsy specimen
• Distinction between a poorly differentiated carcinoma and a lymphoma can be made by immunoperoxidase staining of the tumour tissue with antibodies directed against Cytokeratin.
• Immunohistochemical stains is used for the diagnosis of lymphomas is CD45 (leucocyte common antigen).
• Routine CT scanning of the neck, chest, abdomen, and pelvis is the standard imaging study for patients with lymphoma.
• Gallium-67 (67 Ga) scans are valuable in the staging of diffuse large cell lymphomas.
• Currently the Ann Arbor staging system is the preferred staging system for DLBCL.

1. Stage I – Involvement of a single lymph node region (I) or localized involvement of a single extralymphatic organ or site (I E)
2. Stage II – Involvement of 2 or more lymph node regions on the same side of the diaphragm (II) or localized involvement of a single associated extralymphatic organ or site and its regional lymph nodes, with or without involvement of other lymph node regions on the same side of the diaphragm (II E)
3. Stage III – Involvement of lymph node regions on both sides of the diaphragm (III), which may also be accompanied by localized involvement of an associated extralymphatic organ or site (III E ), by involvement of the spleen (III s), or by both (III E+S)
4. Stage IV – Disseminated (multifocal) involvement of one or more extra lymphatic organs, with or without associated lymph node involvement, or isolated extralymphatic organ involvement with distant (nonregional) nodal involvement

• A – No systemic symptoms present
• B – Unexplained fever ≥ 38 o C; drenching night sweats; weight loss ≥ 10% body weight. 

TREATMENT

• In general, the role of surgery in the treatment of diffuse large cell lymphomas is limited.
• Treatment of these tumors is primarily with cytotoxic agents, with or without radiation therapy.
• The treatment of diffuse large B-cell lymphoma (DLBCL) should include the use of rituximab- and anthracycline-based-multiagent chemotherapy.
• Rituximab is a targeted antibody against cell surface molecule CD-20.
• It is used in :B-cell lymphomas: Low grade lymphomas, mantle cell lymphomas, relapsed aggressive B cell lymphomas, CLL;SLE and Rheumatoid Arthritis.