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

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).

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    

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).

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).

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

CNS, central nervous system; GI, gastrointestinal.

For primary extranodal lymphoma (see later), a modified Ann Arbor staging classification may be used, with isolated involvement of one extranodal site generally being regarded as stage IE disease. Concomitant involvement of locoregional lymph nodes is stage IIE.

Patterns of Tumor Spread

HL tends to spread predictably in a contiguous fashion from one lymph node group or region to the next adjacent group via lymphatic pathways. Thus, clinical involvement of the cervical lymph nodes should prompt careful scrutiny of the anterior and middle mediastinal nodal groups at staging CT. Similarly, in the presence of bulky mediastinal disease, attention should be paid to the upper retroperitoneal, celiac, portal, and splenic hilar nodal stations. Lymph node involvement is usually the only manifestation of disease. Primary extranodal HL is exceptionally rare and is a diagnosis of exclusion, although it is not uncommon for nodal HL to affect contiguous organs. For example, bulky anterior mediastinal disease can involve the adjacent lung parenchyma or the chest wall, but in itself, this does not affect the disease stage or prognosis and would be designated “E” at staging. By contrast, the presence of peripheral subpleural pulmonary nodules not in contiguity with the mediastinal mass would indicate hematogenous spread and disseminated disease, which would be designated stage IV. With disease progression or relapse, visceral involvement occurs and tumoral deposits may be seen in the liver, spleen, lungs, and bones.

NHL is generally a disseminated disease involving lymph node groups through hematogenous spread, and multiple organs may be involved as well as the bone marrow. Thus, nodal enlargement might be seen at CT in the neck and pelvis, with no abnormality in the chest or abdomen, whereas this distribution would be most unusual for HL. This unpredictability makes a whole body staging technique imperative. However, individual subtypes of NHL are associated with certain patterns of disease. Marked splenomegaly is a feature of splenic marginal zone lymphoma and MCL, the latter often in association with bowel involvement. The constellation of a large anterior mediastinal mass with central venous obstruction and disease in the liver, kidneys, or adrenal glands but little or no nodal disease makes primary mediastinal large B-cell lymphoma (PMBL) the most likely diagnosis, whereas widespread peritoneal disease at presentation, with involvement of the viscera and female genital tract, suggests BL. Certain types of NHL are strongly associated with central nervous system (CNS) or meningeal disease, especially testicular and head and neck lymphoma, and this association may warrant screening of the craniospinal axis or prophylactic intrathecal therapy. With disease progression, nodal lymphoma may spread to involve adjacent structures. In the retroperitoneum, this can affect the paravertebral and paraspinal structures with resultant neural compression. In the mesentery, spread into adjacent bowel loops is common, causing displacement, encasement, or compression. As disease advances, peritoneal involvement can occur, radiologically indistinguishable from peritoneal carcinomatosis.

Often, the pattern of disease at CT may suggest the diagnosis. Thus, involvement of cervical lymph nodes and the tissues of Waldeyer’s ring suggests NHL rather than HL. Nodal enlargement in the anterior and middle mediastinum suggests HL, whereas disease in the mesentery, with or without concomitant bowel involvement, strongly favors NHL (see Table 29-3).

Imaging Techniques