Non-Hodgkin Lymphoma (NHL)
A heterogeneous group of lymphoproliferative malignancies, NHL usually originates in lymphoid tissue. Historically, uniform treatment of patients with NHL was hampered by the lack of a uniform classification system. In 1982, the Working Formulation (WF) was developed to unify different classification systems into one. The WF divided NHL into low-, intermediate-, and high-grade, with subgroups based on histologic cell type. Since our understanding of NHL has improved, the diagnosis has become more sophisticated and includes the incorporation of new immunophenotyping and genetic techniques. As a result, the WF has become outdated.
European and American pathologists proposed a new classification, the Revised European American Lymphoma (REAL) Classification, and an updated version of the REAL system, the new World Health Organization (WHO) classification. The WHO/REAL classification recognizes three major categories of lymphoid malignancies based on morphology and cell lineage: B-cell neoplasms, T-cell/natural killer (NK)-cell neoplasms, and Hodgkin lymphoma.
Within the B-cell and T-cell categories, two subdivisions are recognized: precursor neoplasms, which correspond to the earliest stages of differentiation, and more mature differentiated neoplasms.
Updated Revised European American Lymphoma (REAL)/ World Health Organization (WHO) Classification
- Precursor B-cell neoplasm: precursor B-acute lymphoblastic leukemia/lymphoblastic lymphoma (LBL),
- Peripheral B-cell neoplasms:
- B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma,
- B-cell prolymphocytic leukemia,
- Lymphoplasmacytic lymphoma/immunocytoma,
- Mantle cell lymphoma (MCL),
- Follicular lymphoma (FL),
- Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphatic tissue (MALT) type,
- Nodal marginal zone B-cell lymphoma (+/- monocytoid B-cells),
- Splenic marginal zone lymphoma (+/- villous lymphocytes),
- Hairy-cell leukemia,
- Plasmacytoma/plasma cell myeloma,
- Diffuse large B-cell lymphoma,
- Burkitt lymphoma.
T-Cell and Putative Natural Killer (NK) Cell Neoplasms
- Precursor T-cell neoplasm: precursor T-acute lymphoblastic leukemia/LBL,
- Peripheral T-cell (PTCL) and NK-cell neoplasms:
- T-cell chronic lymphocytic leukemia/prolymphocytic leukemia,
- T-cell granular lymphocytic leukemia,
- Mycosis fungoides/Sézary syndrome,
- Peripheral T-cell lymphoma, not otherwise characterized,
- Hepatosplenic gamma/delta T-cell lymphoma,
- Subcutaneous panniculitis-like T-cell lymphoma,
- Angioimmunoblastic T-cell lymphoma,
- Extranodal T-/NK-cell lymphoma, nasal type,
- Enteropathy-type intestinal T-cell lymphoma,
- Adult T-cell lymphoma/leukemia (human T-lymphotrophic virus [HTLV] 1+),
- Anaplastic large cell lymphoma, primary systemic type,
- Anaplastic large cell lymphoma, primary cutaneous type,
- Aggressive NK-cell leukemia.
In the United States, B-cell lymphomas represent 80%–85% of cases of NHL, and T-cell lymphomas represent 15%–20%. NK lymphomas are relatively rare.
The International Lymphoma Classification Project identified the most common NHL subtypes as follows:
- diffuse large B-cell lymphoma (DLBCL) 31%,
- follicular lymphoma (FL) 22%,
- small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL) 6%,
- mantle cell lymphoma (MCL) 6%, peripheral T-cell lymphoma (PTCL) 6%,
- marginal zone B-cell lymphoma/mucosa-associated lymphoid tissue (MALT) lymphoma 5%.
All other subtypes each represent less than 2% of cases of NHL.
Several subtypes of NHL have emerged with the REAL/WHO classification with unique clinical and biologic features, and they will be addressed separately throughout the policy, when necessary (specifically MCL and PTCL).
In general, the NHL can be divided into two prognostic groups, indolent and aggressive. Indolent NHL has a relatively good prognosis, with a median survival of 10 years; however, it is not curable in advanced clinical stages. Early-stage indolent NHL (stage one or two) may be effectively treated with radiation alone. Although indolent NHL is responsive to radiation and chemotherapy, a continuous rate of relapse is seen in advanced stages. These patients can often be re-treated, if their disease remains of the indolent type. Indolent NHL may transform into a more aggressive form, which is generally treated with regimens that are used for aggressive, recurrent NHL. Histologic transformation to higher grade lymphoma occurs in up to 70% of patients with low-grade lymphoma, and median survival with conventional chemotherapy is one year or less. FL is the most common indolent NHL (70%–80% of cases), and often the terms indolent lymphoma and FL are used synonymously. Also included in the indolent NHL are SLL/CLL, lymphoplasmacytoid lymphoma, marginal zone lymphomas, and cutaneous T-cell lymphoma.
Aggressive NHL has a shorter natural history; however, and 30%–60% of these patients can be cured with intensive combination chemotherapy regimens. Aggressive lymphomas include DLBCL, MCL, PTCL, anaplastic large cell lymphoma, and Burkitt’s lymphoma.
Oncologists developed a clinical tool to aid in predicting the prognosis of patients with aggressive NHL (specifically DLBCL), referred to as the International Prognostic Index (IPI). Prior to the development of IPI in 1993, prognosis was predominantly based on disease stage.
Based on the number of risk factors present and adjusted for patient age, the IPI defines four risk groups: low, low intermediate, high intermediate and high risk, based on five significant risk factors prognostic of overall survival (OS):
- Age older than 60 years,
- Elevated serum lactate dehydrogenase (LDH) level,
- Ann Arbor stage III or IV disease,
- Eastern Cooperative Oncology Group (ECOG) performance status of 2, 3, or 4, and
- Involvement of more than 1 extranodal site.
Risk groups are stratified according to the number of adverse factors as follows: zero or one is low risk, two is low intermediate risk, three is high intermediate risk, and four or five are high risk.
Patients with two or more risk factors have a less than 50% chance of relapse-free survival and OS at five years. Age-adjusted (aaIPI) and stage-adjusted modifications of this IPI are used for younger patients with localized disease.
Adverse risk factors for age-adjusted IPI include stage III or IV disease, elevated LDH and ECOG performance status greater than two, and can be calculated as follows: : zero is low risk, one is low intermediate risk, two is high intermediate risk, and three is high risk.
With the success of the IPI, a separate prognostic index was developed for FL, which has multiple independent risk factors for relapse after a first CR. The proposed and validated Follicular Lymphoma International Prognostic Index (FLIPI) contains five adverse prognostic factors:
- Age older than 60 years,
- Ann Arbor stage III-IV,
- Hemoglobin level less than 12.0 g/dL,
- More than four lymph node areas involved.
- Elevated serum lactate dehydrogenase (LDH) level.
These five factors are used to stratify patients into three categories of risk: low (zero to one risk factor), intermediate (two risk factors), or poor (more than three risk factors).
Mantle Cell Lymphoma (MCL)
Mantle cell lymphoma (MCL) comprises approximately 6%-8% of NHL, and has been recognized within the past 15 years as a unique lymphoma subtype with a particularly aggressive course. MCL is characterized by a chromosomal translocation “t”, and the term mantle cell lymphoma was proposed in 1992 by Banks et al. The number of therapeutic trials are not as numerous for MCL as for other NHL as it was not widely recognized until the REAL classification. MCL shows a strong predilection for elderly men, and the majority of cases (70%) present with disseminated (stage four) disease and extranodal involvement is common. Localized MCL is quite rare. MCL has a median survival of approximately two to four years, and although most patients achieve remission with first-line therapy, relapse inevitably occurs, often within 12–18 months. MCL is rarely, if ever, cured with conventional therapy, and no standardized therapeutic approach to MCL is used.
There had been no generally established prognostic index for patients with MCL. Application of the IPI or FLIPI system to patients with MCL showed serious limitations, which included no separation of some important risk groups. In addition, some of the individual IPI and FLIPI risk factors, including number of extranodal sites and number of involved nodal areas showed no prognostic relevance, and hemoglobin showed no independent prognostic relevance in patients with MCL. Therefore, a new prognostic index for patients with MCL was developed, and should prove useful in comparing clinical trial results for MCL.
MCL international prognostic index (MIPI):
- ECOG (Eastern Cooperative Oncology Group) performance status,
- Serum LDH, (lactate dehydrogenase) calculated as a ratio of LDH to a laboratory’s upper limit of normal,
- White blood cell count (WBC):
- Zero points each are assigned for age younger than 50 years, ECOG performance 0-1, LDH ratio less than 0.67, WBC less than 6,700,
- One point each for age 50–59 years, LDH ratio 0.67–0.99, WBC 6,700–9,999,
- Two points each for age 60–69 years, ECOG 2–4, LDH ratio 1.00–1.49, WBC 10,000–14,999,
- Three points each for age 70 years or older, LDH ratio 1.5 or greater, WBC 15,000 or more.
MIPI allows separation of three groups with significantly different prognoses:
- 0–3 points = low risk, 44% of patients, median overall survival (OS) not reached and a five year OS rate of 60%,
- 4–5 points = intermediate risk, 35% of patients, median OS 51 months,
- 6–11 points = high risk, 21% of patients, median OS 29 months.
Peripheral T-Cell Lymphoma (PTCL)
Immature T-cell lymphomas are generally treated on leukemia protocols, whereas mature (peripheral) T-cell lymphomas are usually treated with chemotherapy regimens similar to those used in DLBCL.
PTCLs are less responsive to standard chemotherapy than DLBCLs (diffuse large B-cell lymphoma) and therefore carry a worse prognosis. The poor results with conventional chemotherapy have prompted exploration of the role of HDC/SCT as first-line consolidation therapy.
The Ann Arbor staging classification is commonly used for the staging of lymphomas and is the scheme defined in the AJCC (American Joint Committee on Cancer) Manual for Staging Cancer. Originally developed for Hodgkin's disease, this staging scheme was later expanded to include non-Hodgkin lymphoma.
Involvement of a single lymph node region (I) or of a single extralymphatic organ or site (IE).
Involvement of two or more lymph node regions on the same side of the diaphragm (II) or localized involvement of extralymphatic organ or site and of one or more lymph node regions on the same side of the diaphragm (IIE).
Involvement of lymph node regions on both sides of the diaphragm (III) which may also be accompanied by localized involvement of extralymphatic organ or site (IIIE) or by involvement of the spleen (IIIS) or both (IIISE).
Diffuse or disseminated involvement of one or more extralymphatic organs or tissues with or without associated lymph node enlargement.