Chapter 29 Hematologic Malignancy

The Lymphomas

Sarah J. Vinnicombe, M.R.C.P., F.R.C.R. , Rodney H. Reznek, M.D. , Ama Rohatiner, M.D.

Introduction

The lymphomas are a diverse group of hematologic neoplasms arising primarily from lymph nodes. They vary widely in affected age group, clinical course, and prognosis. Hodgkin lymphoma (HL) was first described by Thomas Hodgkin in 1832, and since the early 1990s, advances in therapy have been so great that HL is now curable in most patients. The non-Hodgkin lymphomas (NHLs) are far more variable in their clinical course and may be rapidly fatal. As in HL, improvements in survival are largely attributable to advances in therapy, but modern cross-sectional and functional imaging studies have also had significant impact. The accurate delineation of disease extent and identification of risk factors both facilitate optimal, individualized, risk-adapted treatment with resultant survival benefits. Accurate imaging is crucial in choosing the most appropriate treatment at the time of diagnosis and staging, in monitoring response to therapy, and in the detection of recurrence.

The objectives of initial staging are twofold: to define the local extent of clinically overt disease and to seek for occult disease elsewhere, in the knowledge of the likely pattern of tumor spread. It should identify adverse prognostic features and factors that may influence delivery of therapy (e.g., central venous occlusion). Choice of the most appropriate imaging method requires an appreciation of the likelihood of particular sites being affected, the accuracy of specific tests chosen to investigate those sites, and the likely impact of a positive result on management.

Epidemiology

Incidence

In the United States, NHL annually accounts for 5% of new cancers in men and 4% of new cancers in women. It is estimated that there were 66,360 new cases of NHL and 19,320 deaths in 2011.¹ HL accounts for approximately 15% of all lymphomas. It is estimated that there will be 8830 new cases in 2011 and 1300 deaths.¹ Men are affected somewhat more than women: for HL, the male-to-female ratio is 1.4:1; for NHL, it is 1.1:1.

The incidence of HL has been stable for years, but that of NHL has risen by approximately 60% in the United States since 1960. This is evident for all age groups, but particularly for older persons. It occurs more often in men and in white ethnic groups, but has been observed in all geographic areas of the United States.² Geographically, the incidence of NHL varies 8- to 10-fold, being much more common in the West. The overall mortality for NHL has also risen over the last few decades, especially in older patients, despite the fact that survival rates for each subtype of NHL have improved, reflecting advances in treatment.

The reasons for the increasing incidence are only partly understood. Some may be artifactual, in that new lymphoma classifications have led to a diagnosis of NHL in patients who would previously have had other diagnoses,³ including HL in up to 15% of cases. Part of the increase from the late 1980s resulted from the increased incidence of lymphomas associated with immune deficiency, notably secondary to human immunodeficiency virus (HIV) infection. However, the occurrence of some HIV-associated NHLs has started to fall since the introduction of highly active antiretroviral therapies.⁴

HL has a bimodal peak distribution, one in the third decade of life and a second in patients older than 50 years. NHLs are diseases mainly of older persons with a median age at diagnosis of 65 years.

Key Points Incidence

• Incidence of NHL has increased by 60% since the 1960s in the United States and the United Kingdom.

• HL has a peak incidence between the ages of 20 and 40 years and also in those older than 50 years.

• NHLs are seen in children and in those older than 50 years.

• There is a link between Epstein-Barr virus (EBV) and lymphoma, especially Burkitt lymphoma (BL) and HL.

• Infective agents are also associated with NHLs.

Etiology

There is an association between EBV and HL, but the exact etiologic role of the virus is uncertain. Patients with HL have a higher antibody titer to EBV viral capsular antigen, and the risk of HL among patients who have had infectious mononucleosis is trebled. EBV can also be found in the malignant cells of HL. Other infective agents such as human herpesvirus-6 (HHV-6) and HIV-1, both associated with the mixed cellularity subtype of classic HL, may also have roles in development of this disease. Infective agents are also associated with the development of certain subtypes of NHL. EBV is found in virtually 100% of cases of endemic African BL; in the sporadic form, the incidence is 15% to 30%. The rare primary effusion lymphomas are associated with HHV-8. Helicobacter pylori infection is necessary for the development of gastric lymphoma of mucosa-associated lymphoid tissue (MALT) type. The human T-cell lymphotrophic virus (HTLV-1) retrovirus has a causal relationship with adult T-cell leukemia/lymphoma, seen in South Japan and the Caribbean. The disease is believed to represent clonal expansion of HTLV-1–infected T lymphocytes.

Genetic factors have limited importance in the etiology of HL, approximately 5% of cases being familial. This may relate to changes in the human leukocyte antigen (HLA) class 1 region of chromosome 6. Familial aggregation of NHL is well recognized. In NHL, immunosuppression is a very important etiologic factor. The incidence is greatly increased in patients with acquired immunodeficiency syndrome (AIDS) and in patients on long-term immunosuppressant therapy, for example, following renal transplantation. Up to 25% of patients with congenital immunodeficiency syndromes including ataxia-telangiectasia, Wiskott-Aldrich syndrome, and X-linked immunodeficiencies will develop malignancies, of which lymphoproliferative disorders account for over 50%. Organ-specific autoimmune diseases predispose to the development of lymphomas of MALT type within the affected organs (e.g., the thyroid and salivary glands). Finally, occupational exposure to certain chemicals such as pesticides and organic solvents may be a risk factor for the development of NHL.

Pathology

There have been several pathologic classifications of lymphoma in the past; however, the functional anatomy of the lymph node is key to understanding the pathologic classification of lymphomas (Figure 29-1).

Figure 29-1 The functional anatomy of the lymph node.

Non-Hodgkin Lymphoma

Over 90% of NHLs in the Western world are of B-cell origin. In general, those arising at stages of development within the germinal center of the node have a follicular or nodular architecture, whereas those arising outside the germinal center have a diffuse pattern. New insights into the pathogenesis of NHL, in terms of cellular and immunologic origins, have resulted in the introduction of the Revised European American Classification of Lymphoid Neoplasms (REAL) classification in 1994. This, in turn, led to the adoption of the definitive World Health Organization (WHO) Classification of Tumors of Hematopoietic and Lymphoid Tissues in 1995,⁵ which is an updated version of the REAL classification (Table 29-1).

Table 29-1 Summary of the World Health Organization Classification of Tumors of Lymphoid Tissue

Precursor B-Cell Neoplasms	Precursor T-Cell Neoplasms
B lymphoblastic leukemia/lymphomas	T lymphoblastic leukemia/lymphoma
Mature B-Cell Neoplasms	Mature T-Cell and Natural Killer Neoplasms
CLL/small lymphocytic lymphoma B-cell prolymphocytic leukemia Splenic B-cell marginal zone lymphoma Hairy cell leukemia Lymphoplasmacytic lymphoma Waldenström’s macroglobulinemia Heavy chain diseases Alpha heavy chain disease Gamma heavy chain disease Mu heavy chain disease Plasma cell myeloma Solitary plasmacytoma of bone Extraosseous plasmacytoma Extranodal marginal zone B-cell lymphoma of MALT Nodal maginal zone lymphoma Follicular lymphoma Primary cutaneous follicle center lymphoma Mantle cell lymphoma DLBCL, NOS T-cell/histiocyte-rich LBCL Primary DLBCL of the CNS Primary cutaneous DLBCL, leg type DLBCL associated with chronic inflammation Lymphomatoid granulomatosis Primary mediastinal (thymic) LBCL Intravascular LBCL ALK-positive LBCL Plasmablastic lymphoma LBCL arising in HHV-8–associated multicentric Castleman’s disease Primary effusion lymphoma BL B-cell lymphoma, unclassifiable, intermediate between DLBCL and BL B-cell lymphoma, unclassifiable, intermediate between DLBCL and classical HL	T-cell prolymphocytic leukemia T-cell large granular lymphocytic leukemia Aggressive NK cell leukemia Systemic EBV-positive T-cell lymphoproliferative disease of childhood Adult T-cell leukemia/lymphoma Extranodal NK/T-cell lymphoma, nasal type Enteropathy-type T-cell lymphoma Hepatosplenic T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Mycosis fungoides Sézary syndrome Primary cutaneous CD30-positive T-cell lymphoproliferative disorders Lymphoid papulosis Primary cutaneous anaplastic large cell lymphoma Primary cutaneous gamma-delta T-cell lymphoma Peripheral T-cell lymphoma, NOS Angioimmunoblastic T-cell lymphoma Anaplastic large cell lymphoma
Histiocytic and Dendritic Cell Neoplasms	Hodgkin’s Lymphoma
Histiocytic sarcoma Langerhans cell histiocytosis Langerhans cell sarcoma Interdigitating dendritic cell sarcoma Follicular dendritic cell sarcoma Fibroblastic reticular cell tumor Indeterminate dendritic cell tumor	Nodular lymphocyte predominant HL Classical HL Nodular sclerosis classical HL Lymphocyte-rich classical HL Mixed cellularity classical HL Lymphocyte-depleted classical HL
Posttransplant Lymphoproliferative Disorders
Early lesions Plasmacytic hyperplasia Infectious mononucleosis–like PTLD Polymorphic PTLD Monomorphic PTLD (B and T/NK cell types) Classic HL-type PTLD

ALK, anaplastic lymphoma kinase; BL, Burkitt lymphoma; CNS, central nervous system; CLL, chronic lymphocytic leukemia; DLBCL, diffuse large B-cell lymphoma; EBV, Ebstein-Barr virus; HHV-8, human herpesvirus-8; HL, Hodgkin lymphoma; LBCL, large B-cell lymphoma; MALT, mucosa-associated lymphoid tissue; NK, natural killer; NOS, not otherwise specified; PTLD, posttransplant lymphoproliferative disorder.

The WHO classification is a list of distinct disease entities defined by a combination of morphology, immunophenotype, and genetic and clinical features. It stratifies neoplasms according to myeloid, lymphoid, and histiocytic/dendritic cell lineages and recognizes three major categories of lymphoid neoplasms: B cell, T cell, and natural killer (NK) cell; and separately, HL. Precursor neoplasms, corresponding to the early stages of differentiation and including lymphoblastic leukemias and lymphomas, are separated from the more mature or peripheral neoplasms. Conversely, chronic lymphocytic leukemia (CLL) is the circulating form of small lymphocytic lymphoma, a mature B-cell neoplasm, and is classified as such. Histologic grade may influence therapeutic decision-making. For example, follicular lymphoma (FL) is graded according to the number of centroblasts per high-power field.

This comprehensive approach has significantly improved the consistency of classification of lymphoma, such that, if given sufficient material, expert hematopathologists agree on classification of entities in over 95% of cases.⁶ Further refinements may facilitate appropriate patient management.⁷ For example, gene expression profiling for diffuse large B-cell lymphoma (DLBCL) enables recognition of discrete subsets (germinal center B-cell type and activated B-cell type) that have independent prognostic significance.^8,⁹ Other recent additions to the classification include pediatric FL, primary DLBCL of the central nervous system (PCNSL), and two so-called gray zone lymphomas: B-cell lymphoma with features intermediate between DLBCL and classic HL, and B-cell lymphoma with features intermediate between DLBCL and BL.

Hodgkin Lymphoma

Investigators have demonstrated that HL is a true lymphoma; hence, the term Hodgkin lymphoma is preferred to Hodgkin disease. Indeed, the distinction between HL and NHL is not always straightforward, and composite cases occur. Diagnosis depends upon the demonstration of malignant Reed-Sternberg and Hodgkin cells against a background of non-neoplastic inflammatory cells. The WHO classification recognizes two distinct entities that differ in clinical features, behavior, morphology, and immunophenotype: classical Hodgkin lymphoma (CHL, 95%) and nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL, 5%). CHL is, in turn, divided into four subgroups, based on the proportion of lymphocytes in relation to the number of malignant cells and on the connective tissue background (Table 29-2).¹⁰ All share the same immunophenotype, with expression of CD30 by the malignant cells.

Table 29-2 Rye Classification of Classical Hodgkin Lymphoma and Approximate Frequency

HISTOLOGY	FREQUENCY (%)
Lymphocyte rich	5
Nodular sclerosis	65
Mixed cellularity	25
Lymphocyte depletion	5

From Harris NL, Jaffe ES, Diebold J, et al. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting—Airlie House, Virginia, November 1997. J Clin Oncol. 1999;17:3835-3849.

In nodular sclerosing HL, nodules of lymphoid tissue are separated by dense bands of collagen. It accounts for approximately 70% of CHL and is the only form of HL without a male preponderance. Anterior mediastinal disease occurs in 80% of cases and bulky disease in approximately 50%. Mixed cellularity HL accounts for 20% to 25% of CHL and is more common in patients with HIV infection and in developing countries. Advanced-stage disease is common. EBV positivity is frequent. Lymphocyte-rich classic HL accounts for 5% of all HL; 70% of cases are male, with a higher median age. Stage I or II peripheral nodal disease is typical. Lymphocyte-depleted CHL is the rarest subtype, accounting for less than 5% of cases; the median age at presentation is 35 to 40 years. It is associated with HIV infection and in developing countries. Advanced-stage disease at presentation is common (70%), with frequent involvement of abdominal organs, retroperitoneal nodes, and bone marrow. Most cases of NLPHL were probably misclassified as lymphocyte-rich HL in the past. The malignant cells (called popcorn cells because of their striking nuclear convolutions) express CD20, not CD30. Affected patients are mostly male, aged 30 to 50 years, presenting with peripheral adenopathy affecting one or two nodal groups (axillary, cervical, or inguinal).

Key Points Classification of lymphomas

• HL comprises two distinct entities: NLPHL (5%) and CHL (95%).

• CHL consists of four subtypes: nodular sclerosing (70%), mixed cellularity (20-25%), lymphocyte-rich (5%), and lymphocyte-depleted (<5%).

• WHO classification stratifies lymphoma according to myeloid, lymphoid, and histiocytic/dendritic lineage and provides distinction between disease entities.

Clinical Features

Both HL and NHL are predominantly diseases of lymph nodes, which may present as a localized process involving a single nodal group or organ or as widely disseminated disease. However, there are recognizable differences in the clinical presentation of the two diseases (Table 29-3).

Table 29-3 Key Differences between the Clinical Features of Hodgkin Lymphoma and Non-Hodgkin Lymphoma

Hodgkin Lymphoma

Most patients with HL present with painless asymmetrical lymph node enlargement, which may be accompanied by sweats, fever, weight loss (“B” symptoms), and pruritus in approximately 40% of patients. B symptoms are more common in advanced-stage disease and thus in the mixed cellularity and lymphocyte-depleted subtypes of CHL. Alcohol-induced pain is rare.

The cervical lymph nodes are affected in 60% to 80% of patients; the axillary nodes in 6% to 20%, and the inguinal/femoral nodes in 6% to 15%. Exclusive infradiaphragmatic lymphadenopathy occurs in less than 10% of patients at diagnosis. Splenomegaly is found on clinical examination in about 30% of patients. Eighty percent of patients present with early-stage disease and the incidence of splenic or bone marrow involvement is low, although these vary with the histologic subtype.

Non-Hodgkin Lymphomas

Although most patients with NHL present with nodal enlargement, extranodal disease is far more frequent than in HL, as is bone marrow involvement, with over 80% of patients having advanced-stage disease at diagnosis. Despite this, “B” symptoms are less frequent at diagnosis compared with HL, occurring in approximately 20% of patients.

So-called indolent lymphomas account for up to 35% of NHL and lymphadenopathy may be intermittent. FL is typically indolent, accounting for 25% to 30% of all newly diagnosed NHL. It is usually diagnosed in the sixth decade. Conversely, grade 3b FL behaves more like DLBCL, which is termed aggressive, but generally responds well to therapy. DLBCL accounts for 35% of all NHL and is the most common B-cell NHL, usually presenting with rapidly enlarging lymph nodes.

The most aggressive subtypes include BL and lymphoblastic lymphoma; these are histologically characterized by very high proliferation fractions, and patients often exhibit rapidly progressive systemic disease that requires urgent treatment.

Key Points Clinical

• Most patients with HL and NHL present with painless enlargement of a group of lymph nodes.

• In HL, most patients present with stage I or II disease; in NHL most patients have stage III or IV disease at diagnosis.

• Systemic symptoms are twice as common in HL as in NHL.

Staging Systems and Prognostication

Because lymphomas are primarily neoplasms of lymphoid tissues (whether nodal or extranodal), the tumor-node-metastasis (TNM) staging system is not appropriate. The Ann Arbor staging system for HL was introduced in 1970 and took into account the extent of nodal disease and the presence of extranodal extension. Increasing recognition of the influence of tumor bulk as an independent prognostic indicator within each stage and the routine application of computed tomography (CT) in the 1980s led to a modification of the classification in 1989, the Cotswolds classification.¹¹ This system is similar to the original Ann Arbor classification, but stage III is subdivided and an additional qualifier “X” denotes bulky disease (Table 29-4). The prognosis of HL depends upon a number of factors, including

Table 29-4 Staging of Lymphoma (Cotswolds Classification)

STAGE	AREA OF INVOLVEMENT
I	One lymph node region or extralymphatic site
II	Two or more lymph node regions on the same side of the diaphragm
III	Involvement of lymph node regions or structures on both sides of the diaphragm subdivided: 1. With involvement of spleen and/or splenic hilar, celiac, and portal nodes 2. With pararaortic, iliac, or mesenteric nodes
IV	Extranodal sites beyond those designated “E”
Additional qualifiers	A	No symptoms
	B	Fever, sweats, weight loss (to 10% body weight)
	E	Involvement of a single extranodal site, contiguous in proximity to a known nodal site
	X	Bulky disease. Mass >10 cm maximum dimension
	CS	Clinical stage
	CE1	Pathologic stage. Denoted by a subscript at a given site (M, marrow; H, liver; L, lung; O, bone; P, pleural; D, skin; S, spleen)

From Lister TA, Crowther D, Sutcliffe SB, et al. Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin’s disease: Cotswolds meeting. J Clin Oncol. 1989;7:1630-1636.

These adverse prognostic features, together with stage, enable risk stratification, which, in turn, directs treatment.

The modified Ann Arbor classification is also currently applied to NHL, but is less useful, because the prognosis in NHL is more dependent on the histologic subtype, tumor bulk, and specific organ involvement, as well as stage. In NHL, the critical questions are whether or not disease is limited, the effect of the disease on end organs such as bone marrow, and symptomatology. Because NHL spreads more randomly than HL, the Ann Arbor staging system is less helpful in defining prognostic subgroups. Therefore, considerable effort has been applied to the development of robust prognostic indices that are accurate, simple, and discriminant. Such indices not only aid in the management of the individual patient but also facilitate meaningful comparison of results from clinical trials. The International Prognostic Index (IPI) was developed by an international collaborative group.¹² For DLBCL, five factors have prognostic significance: age older than 60 years, elevated serum lactate dehydrogenase (LDH), Eastern Cooperative Oncology Group (ECOG) performance status greater than 1 (i.e., nonambulatory), advanced stage (III or IV) disease, and more than one extranodal site of disease.

Four risk groups are recognized depending on the number of adverse prognostic features that are present. Such a stratification enables choice of more intensive therapies for those at higher risk. Prior to the monoclonal antibody era, patients in the low risk group (no or one prognostic factor present) had a 5-year survival greater than 70%, whereas patients in the high risk group (four or five factors present) had only a 25% 5-year survival. More recently, the prognostic importance of gene expression profiling within individual subtypes of NHL has become evident, as described previously for DLBCL,⁸ where the better prognosis of the germinal center–like subtype compared with the activated B-cell subtype is independent of the IPI. A similar prognostic index has been developed for FL,¹³ where the important factors are age older than 60, elevated serum LDH, hemoglobin less than 12 g/dL, stage 3 or 4 disease, and more than four nodal sites of disease.

For the purposes of this index, nine nodal sites are recognized (right and left cervical; right and left axillary; mediastinal; para-aortic; mesenteric; and right and left inguinal). A recent modification (FLIPI 2) includes elevated serum beta-2 microglobulin and the presence of a lymph node over 6 cm in diameter. Histologic factors are also important; grades I, II, and IIIa FL are treated similarly; however, grade 3b FL is now treated as DLBCL. Recent work also suggests that gene expression profiling yields significant prognostic information in FL, although the cells within the tumor microenvironment rather than the tumor cells themselves carry prognostic significance. In other NHL subtypes, other prognostic factors are important. In mantle cell lymphoma (MCL), which has a dismal prognosis, the Ki-67 proliferation index has greater predictive value than any other histologic or clinical criterion.

The clinical spectrum of childhood lymphoma differs somewhat from adult lymphoma with more frequent extranodal involvement, especially of the gastrointestinal tract, solid viscera including the kidneys and pancreas, and extranodal sites in the head and neck.¹⁴ In these situations, the St. Jude or Murphy’s staging classification is applied, because it takes into account the increased frequency of extranodal disease (Table 29-5).

Table 29-5 Murphy’s Staging System for Childhood Non-Hodgkin Lymphoma

STAGE	CRITERIA FOR EXTENT OF DISEASE
I	A single tumor (extranodal) or single nodal region except in the mediastinum or abdomen
II	A single tumor (extranodal) with regional nodal involvement Two or more nodal areas on the same side of the diaphragm Two single (extranodal) tumors with or without regional node involvement on the same side of the diaphragm A primary GI tract tumor, usually ileocecal, with or without involvement of associated mesenteric nodes only, grossly completely resected
III	Two single tumors (extranodal) on opposite sides of the diaphragm Two or more nodal areas above and below the diaphragm ALL primary intrathoracic tumors (mediastinal, pleural, thymic) ALL extensive primary intra-abdominal disease, unresected ALL paraspinal or epidural tumors, regardless of other tumor site(s)
IV	Any of the above with initial CNS and/or bone marrow involvement