Etiology

Adult T-cell lymphoma/leukemia (ATLL) associated with human T-cell lymphotropic virus (HTLV-1) occurs in areas endemic with HTLV-1 in southern Japan and the Caribbean. Burkitt’s lymphoma in Africa is associated with malaria and EBV infection. Carriers of HIV have a higher risk of developing aggressive types of NHL, particularly primary central nervous system lymphoma. The cumulative incidence of NHL among the HIV-infected population is now 5% to 10% over a decade. Molecular genetics studies indicate that more than one pathogenic mechanism is operative in HIV-associated NHL. The presence of the bacteria Helicobacter pylori has been closely associated with the development of mucosa-associated lymphoid tissue lymphoma of the stomach, and in some cases, eradication of H. pylori by antibiotic treatment may result in lymphoma regression.

Several epidemiologic studies have shown that agricultural workers have a high incidence of the disease. Some researchers have attributed this to pesticide exposure. There is also evidence that suggests that hair dyes may play a role in the etiology of lymphoma. Ionizing radiation alone has little or no effect on risk of NHL, but patients with Hodgkin’s lymphoma treated with radiation therapy and/or chemotherapy have an increased risk of developing secondary large-cell lymphoma.

Classification

Over the last decades, lymphoma classification has changed multiple times. In the 1980s, the International Working Formulation (IWF) classified NHL into three major categories—low, intermediate, and high grade—based on the morphology and natural history. The Revised European-American Classification of Lymphoid neoplasm (REAL) was developed in 1994. It classified NHL based on the cell of origin (B, T, or NK) and included morphology, immunophenotype, and genetic and clinical features. The currently accepted World Health Organization (WHO) classification is a refinement of the REAL classification.²

The REAL/WHO classification of NHL includes several additional, newly identified entities not recognized by the IWF.² After consideration of cell of origin (B, T, or NK) the classification subdivides lymphomas into those derived from precursor lymphocytes versus those derived from mature lymphocytes. The classification is further refined based on immunophenotype and genetic features. These considerations have aided in defining active treatment for specific subtypes of lymphoma.

Currently, a comprehensive description of the natural history and clinical features of all NHL diagnoses recognized by the WHO classification does not exist. However, the International Lymphoma Classification Project evaluated 1403 lymphoma cases and identified the 13 most common histologic types responsible for about 90% of cases of NHL in the United States.³ The findings were as follows: diffuse large B-cell (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%; and marginal zone B-cell lymphoma (MZL), mucosa-associated lymphoid tissue (MALT) lymphoma, 5%. The remaining subtypes each occurred in less than 2% of cases. Composite lymphomas were not included in these distribution figures. Importantly, in the United States more than 50% of cases of lymphoma are either DLBCL or FL. In a study performed by the International T-cell Lymphoma Project, PTCL–not otherwise specified (PTCL-NOS) was the most common subtype of PTCL (29.3%).⁴

Cytogenetics and Molecular Biology

Several lymphomas are associated with nonrandom chromosomal abnormalities.⁵ These abnormalities often correlate with the histologic type, immunophenotype, and clinical behavior. For example, translocation t(14:18) (q32;q21) occurs commonly in follicular lymphoma. It results in the transposition of the bcl-2 oncogene of chromosome 18 to become adjacent to the heavy chain immunoglobulin gene on chromosome 14. The bcl-2 oncogene is essential for apoptosis or programmed cell death. The t(14:18) translocation interferes with normal senescence and death of the follicular center cell and is possibly engaged in its malignant transformation. Most patients with Burkitt’s lymphoma have translocation t(8:14) or one of its variants, and c-myc is the relevant translocated oncogene. The c-myc product is an important transcription factor, and its dysregulation is probably involved in the proliferative process. Translocation t(11:14) involving bcl-1 is characteristic for recognition of mantle cell lymphoma. The gene product of bcl-1, cyclin D, is directly involved in the regulation of cell division. Rearrangement of bcl-6 has been reported in a third of patients with diffuse large-cell lymphoma. In 25% to 40% of patients with MALT lymphoma, t(11:18) has been detected and indicates an unlikely response of MALT lymphoma of the stomach to antibiotic therapy of an associated H. pylori infection.

Pathologic Diagnosis

In consideration of the clinical and histologic diversity of the lymphoid malignancies grouped together under the generic title non-Hodgkin’s lymphoma, it is crucial to obtain clear and detailed pathologic information about the biopsy specimen. An adequately processed pathologic specimen should be analyzed by a hematopathologist who is well versed in interpreting modern immunohistopathologic and molecular genetics techniques required for modern diagnosis and classification of NHL.

In Table 61-1, the more common histologies are listed by WHO classification and grouped as low grade (indolent), intermediate grade (aggressive), or high-grade (highly aggressive), a terminology that is still in clinical use.

Table 61-1 Abridged Version of the WHO Lymphoma Classification Organized by Clinical Groups

Staging and Prognostic Factors

Although histology is the predominant determinant of prognosis in this diverse group of lymphoid malignancies, stage remains important for selection of treatment strategy and predicting prognosis in each histologic category. The Ann Arbor Staging Classification system, developed originally for Hodgkin’s disease, has also been used for NHL. The staging system is described in Chapter 60, Hodgkin’s Disease, and reflects the number of sites of involvement and their relation to the diaphragm, existence of B symptoms, and the presence of extranodal disease. In NHL, most patients are assigned to a stage based on physical examination, imaging studies, and bone marrow biopsy. The Ann Arbor staging system is considered by many to be inadequate for NHL, a shortfall that has led to the incorporation of other prognostic factors to define initial therapy.

The International Prognostic Index

In addition to stage, other important prognostic factors have been identified in patients with NHL.⁶ They frequently include patient parameters such as age, performance status, and tumor burden indicators such as bulk, number of involved sites, presence of extranodal disease, and lactate dehydrogenase (LDH) level.

An international team developed a prognostic model to predict outcomes of patients with aggressive NHL ⁶ (Table 61-2). The International Prognostic Index (IPI) identified five significant risk factors predictive of overall survival: age (<60 years versus >60 years), serum LDH (normal versus elevated), performance status (0 or 1 versus 2 to 4), stage (I or II versus III or IV), and number of extranodal sites involved (0 or 1 versus 2 to 4). These features were incorporated into a model that identified four groups of patients with significantly different outcomes following treatment. Risk groups were determined by the sum of adverse risk factors: low (0 to 1 factor), low-intermediate (2 factors), high-intermediate (3 factors), and high (4 to 5 factors). The predicted 5-year survival rates for these groups were 73%, 51%, 43%, and 26%, respectively. When only patients younger than 60 were evaluated, stage, performance status, and LDH levels remained significant for poor prognosis (age-adjusted IPI).

Table 61-2 International Prognostic Index for Aggressive NHL

All Patients

Age > 60 years

Serum LDH above normal

ECOG performance status > 2

Ann Arbor clinical stage III or IV

Number of involved extranodal sites > 1

	IPI Score	5-Year Survival (%)
Low-risk	0-1	73
Low-intermediate	2	51
High-intermediate	3	43
High-risk	4-5	26
Patients ≤ 60 years
Serum LDH above normal
ECOG performance > 2
Ann Arbor stage III or IV

	Age-Adjusted IPI Score	5-Year Survival (%)
Low-risk	0	83
Low-intermediate	1	69
High-intermediate	2	46
High-risk	3	32

Patients With Early-Stage (I-II) Disease
Age > 60
Serum LDH above normal
Stage II disease
ECOG performance status ≤2

Modified IPI Score	10-Year Survival (%)
0	90
1-2	56
3	48

After validation by several centers, the major cooperative groups have accepted this index for the design of new protocols. The model is simple to apply, reproducible, and predicts outcome even after patients have achieved complete response. Although originally designed for patients with untreated aggressive lymphomas, it has been shown to be predictive after relapse for patients undergoing salvage therapy with or without high-dose therapy and stem cell support.

For follicular lymphoma, the Follicular Lymphoma International Prognostic Index (FLIPI) has been shown to be a valuable prognostic tool.⁷ It is depicted in Table 61-3.

Table 61-3 The International Prognostic Index for Follicular Lymphoma⁴

Age	≤60 years
Ann Arbor stage	III-IV
Hemoglobin level	<12 g/dL
Serum LDH level	>ULN (upper limit of normal)
Number of nodal sites	>5
Risk Group According to FLIPI Chart	Number of Factors
Low	0-1
Intermediate	2
High	≤3