Reticuloendothelial Disorders: Lymphoma

Age

HL has a peak incidence in the 20–30 year age group, with a second peak in the elderly population. The incidence of NHL increases exponentially with age after 20 years. The subtypes of lymphoma encountered differ in frequency between adult and paediatric groups, with a strong bias towards precursor B- and T-lymphoblastic lymphoma and Burkitt lymphoma (BL) in childhood. Lymphomas with less typical age distribution include primary mediastinal large B-cell lymphoma (PMLCL), which has a peak incidence between 25 and 35 years, and lymphomas associated with immunodeficiency, which tend to occur in younger age groups.

Infectious Agents

Oncogenic lymphotrophic viruses have been implicated in many types of NHL. The single most important agent in this regard is Epstein-Barr virus (EBV). The EBV genome was first detected in cultured African BL cells and is present in over 90% of endemic cases. EBV is important as a trigger for lymphoproliferations/lymphomas occurring in patients with congenital immunodeficiencies, organ transplant recipients, HIV-positive patients and patients receiving combined immunosuppressive therapy for collagen disorders. EBV is also found in HL (mostly the mixed cellularity type); patients who have had infectious mononucleosis are at increased risk of HL. The retrovirus human lymphotropic virus type 1 (HTLV-1) is implicated in the causation of adult T-cell leukaemia/lymphoma, which is endemic in certain areas of East Africa, the Caribbean, southwest Japan and New Guinea. Human herpesvirus 8 (HHV-8) has been implicated as a cause of primary effusion lymphoma, a rare type of large cell lymphoma confined to serous-lined body cavities, which occurs with highest frequency in the HIV-positive population. Bacterial overgrowth can also promote lymphomagenesis. In gastric lymphoma of mucosa-associated lymphoid tissue (MALT) type, Helicobacter pylori infection has been shown to be necessary for the development and early proliferation of the lymphoma.

Immunosuppression

Certain subtypes of NHL are associated with pre-existing immunosuppression and autoimmune diseases. The degree of immunosuppression is important in determining the lymphoma subtype that may emerge. In organ-specific autoimmune diseases, such as Hashimoto's thyroiditis and Sjögren's syndrome, extranodal marginal zone lymphomas of MALT type can arise within the affected organ. In severe immunodeficiency states, such as the congenital immunodeficiencies, AIDS and post-organ transplantation, the lymphomas are often EBV-driven large B-cell lymphomas. Infection with human immunodeficiency virus (HIV) explains much of the massive increase in the incidence of NHL from the 1970s to the 1990s. In the setting of systemic collagen diseases, there is an increase in haematological malignancy, and patients receiving immunosuppressive therapy for these conditions are at still greater risk. The types of haematological malignancy that may arise are quite varied; they include HL and diffuse large B-cell lymphoma (DLBCL).

Genetic Factors

It is known that the risk of developing haematological malignancy is increased in patients with a family history of disease. This increased risk does not extend to the histological type or lineage of the tumours in question, such that one family member may have HL whereas a relative may have NHL or myeloid leukaemia.

Gender and Race

There is a slight predominance of NHL and HL in men (ranging from 1.1–1.4 to 1). The incidence of NHL and HL varies by race, with higher frequencies in whites than blacks or Asians. Certain NHL types cluster according to race: for example, the natural killer (NK) T-cell lymphomas are most frequently encountered in oriental Asian populations.

Hodgkin Lymphoma

HL is a true lymphoma, and the defining malignant cell of HL is the Reed-Sternberg cell, a large, binucleated blast cell. Mononuclear counterparts are called Hodgkin cells. The Reed-Sternberg cells and their variants form a minority population within an involved lymph node. The balance is made up of reactive non-neoplastic T cells, histiocytes, plasma cells, eosinophils and fibroblasts, varying in proportion according to the histological subtype. So-called classical HL (CHL) accounts for 95% of all HL and is subdivided into four histological types, indicated below with their relative frequencies in Western populations:

• Lymphocyte-rich—5%

• Mixed cellularity (MC)—15–20%

• Nodular sclerosing (NS)—75%

• Lymphocyte-depleted (LD)—less than 5%.

In the NS type, involved nodes contain cellular nodules separated by thick bands of collagen. It typically presents as a bulky anterior mediastinal mass and is the only form of HL lacking a male preponderance. Mixed cellularity HL is more common in developing countries and in patients with HIV infection, as is the rare LD HL. Both have an aggressive clinical course with advanced stage disease and systemic symptoms. All four classical subtypes share the same immunophenotype. A second distinct entity is nodular lymphocyte–predominant HL (NLPHL) which differs in morphology, immunophenotype, clinical behaviour and course; latent EBV infection is not a feature. It tends to occur in middle-aged men who present with early-stage peripheral adenopathy and has an indolent course with excellent overall survival.

Non-Hodgkin Lymphoma

Many of the difficulties that beset early taxonomists in the classification of NHL have been overcome with improved immunological and molecular methods of diagnosis. The Revised European–American Lymphoma (REAL) classification in 1994 depended on a triad of morphology, immunophenotype and molecular methods as well as clinical features for defining disease entities. The scheme forms the backbone of the World Health Organization (WHO) classification of tumours of haematopoietic and lymphoid tissues. A summary of the 2017 revised fourth edition of the WHO classification is given in Table 64.1 . This has drawn on findings from gene expression profiling to refine the classification. It stratifies neoplasms by lineage (myeloid, lymphoid and histiocytic/dendritic) into clinically distinct entities and is a real advance in the ability to identify disease accurately and consistently. The leukaemias are included, as they represent circulating phases of various neoplasms. For example chronic lymphatic leukaemia is the solid phase of small lymphocytic lymphoma. Further, it permits modification to improve patient management. For example, gene expression profiling in diffuse large B-cell lymphoma (DLBCL) enables recognition of two discrete subsets (germinal centre B-cell type and activated B-cell type), which have independent prognostic significance, and this has been included in the revised fourth edition of the classification. Other additions include paediatric-type follicular lymphoma, primary DLBCL of the central nervous system (PCNSL), and the so-called ‘grey zone’ lymphoma, B-cell lymphoma with features intermediate between DLBCL and CHL.

Hodgkin Lymphoma

Non-Hodgkin Lymphoma

Accurate diagnosis requires adequate tissue biopsy and an experienced histopathologist. Some lesions may be amenable to ultrasound (US) or CT-guided core-needle biopsy, which may safely yield adequate tissue for histological diagnosis and immunophenotyping. But, as with HL, an entire lymph node is preferable for diagnosis.

Imaging Nodal Disease

At present, size is the only criterion by which lymph nodes demonstrated on CT or MRI are considered to be involved, though clustering of multiple small lymph nodes—for example within the anterior mediastinum or the mesentery—is suggestive. A maximum short-axis diameter of 10 mm is taken to be the upper limit of normal, depending upon the exact site within the neck, thorax, abdomen, or pelvis. However, in the Lugano classification, a lymph node with a longest diameter greater than 1.5 cm is considered enlarged. For FDG-avid lymphomas, a node is considered positive if there is abnormal FDG uptake regardless of size. It should be noted that normal jugulodigastric nodes can measure up to 13 mm in short-axis diameter. Nodes in the gastrohepatic ligament and porta hepatis are considered abnormal if they measure more than 8 mm in diameter; retrocrural nodes greater than 6 mm are taken as enlarged. Lymph nodes at some sites, such as the splenic hilum, presacral and perirectal areas are not usually visualised on cross-sectional imaging and, when demonstrated, are likely to be abnormal.

Enlarged lymph nodes in both HL and NHL are usually homogeneous and of soft-tissue density on CT. Mild or moderate uniform enhancement occurs after intravenous injection of contrast medium. Calcification is uncommon but may be seen on post-treatment images. Necrosis is occasionally seen in large nodal masses in both HL (particularly NS HL) and aggressive NHL, more frequently after treatment. On MRI, involved lymph nodes have low-to-intermediate signal intensity on T ₁ weighted images; they may have very high signal intensity on fat-suppressed T ₂ weighted and short tau inversion recovery (STIR) sequences. Though the signal intensity of involved nodes and the presence of necrosis do not appear to have much prognostic significance, there is some evidence that within large lymphomatous masses, heterogeneous T ₂ signal at MRI, or heterogeneous enhancement at CT is associated with a worse outcome.

Choice of Imaging Technique

FDG PET/CT is now the preferred imaging technique for the staging and restaging of FDG-avid lymphomas and has superseded the use of CT in this group. FDG PET/CT is able to detect disease in normal-sized lymph nodes and can often differentiate between nodal enlargement secondary to lymphoma or reactive hyperplasia, unlike CT imaging.

Numerous studies have shown that FDG PET/CT is more accurate than CT in the depiction of nodal and extranodal disease. It results in clinically significant upstaging in up to 30% of patients compared with CT, which may result in changes in therapy, particularly in HL. Most NHLs are FDG-avid, although false-negative studies can occur with low-grade lymphomas such as chronic lymphocytic leukaemia/small lymphocytic lymphoma, mycosis fungoides and extranodal marginal zone NHL. For these subtypes, contrast-enhanced CT remains the standard of care. The development of FDG PET/CT with accurate co-registration means that both morphological and functional abnormalities can be assessed simultaneously, and this has revolutionised the staging of lymphoma. It is important to recognise that lymphomatous involvement of certain organs can be very difficult to recognise with FDG PET/CT because of physiological uptake—for example, in the stomach and CNS. Debate continues as to whether it is necessary to carry out full diagnostic CT imaging as part of the FDG PET/CT study; often a low-dose CT for the purposes of attenuation correction and anatomical correlation is sufficient, especially if a baseline CE-CT at diagnosis is non-contributory.

CT usually demonstrates the full extent of disease and enables localisation of the most appropriate lesion for percutaneous image-guided biopsy. US has no value in whole-body staging. Ultrasonographic appearances of lymphomatous nodal disease are non-specific, although the pattern of vascular perfusion as demonstrated by power Doppler interrogation may suggest the diagnosis, lymphomatous nodes having rich central and peripheral perfusion. The main value of US in lymphoma lies in confirming the nature of a palpable mass and assessing the major viscera.

The accuracy of MRI in detecting lymph node involvement is equal to that of CT (and is better in some areas, such as the supraclavicular fossa and within the pelvis), but it has no particular advantage over CT in this respect and its role is essentially adjunctive, to solve problems or monitor response to treatment. Recent advances in MRI technology (high-field-strength magnets and parallel imaging) have enabled MRI to be used for whole-body staging: the role of whole-body diffusion-weighted imaging in staging and response assessment is a field of active research. Major advantages in patients with HL in particular (who are often young) include the lack of ionising radiation.

Neck

Up to 80% of patients with HL present with cervical lymphadenopathy. The spread of the disease is most frequently to contiguous nodal groups, with involvement of the internal jugular chain and spread to other deep lymphatic chains in the neck. Patients with supraclavicular or bilateral neck adenopathy are at increased risk of infradiaphragmatic disease.

Cervical adenopathy is less common in NHL but frequently occurs in association with disease in Waldeyer's ring, which is counted as a lymph node for staging purposes. Approximately 40–60% of patients who present with head and neck involvement will have disseminated NHL. Involved nodal groups tend to be non-contiguous. Central necrosis within a lymph node is rarely seen compared with squamous cell carcinoma nodal metastases. Imaging with FDG PET/CT, contrast-enhanced CT or MRI has a useful role in evaluating the neck in patients with lymphoma, both in identification of impalpable enlarged nodes and in response assessment, particularly in patients treated with radiotherapy, where post-treatment fibrosis renders clinical assessment difficult.

Thorax

Intrathoracic nodes are involved at presentation in 60–85% of patients with HL and 25–40% of patients with NHL. Any intrathoracic group of nodes may be affected, but all the mediastinal sites other than paracardiac and posterior mediastinal nodes are more frequently involved in HL than NHL. Nearly all patients with NS HL have disease in the anterior mediastinum. The frequency of nodal involvement in HL is as follows: prevascular and paratracheal—84% ( Fig. 64.1 ); hilar—28% (see Fig. 64.1 ); subcarinal—22% (see Fig. 64.1 ); others—5% (aortopulmonary, anterior diaphragmatic, internal mammary) ( Fig. 64.2 ). In NHL, involvement of the hilar and subcarinal groups is rarer, occurring in 9% and 13%, respectively, whereas superior mediastinal nodes are involved in 35%.

The great majority of cases of HL show enlargement of two or more nodal groups, whereas only one nodal group is involved in up to half of the cases of NHL. Hilar nodal enlargement is rare without associated mediastinal involvement, particularly in HL. Although paracardiac and internal mammary nodes are rarely involved at presentation in HL, they may be involved in recurrent disease. In HL and NHL, large anterior mediastinal masses usually represent thymic infiltration as well as a nodal mass ( Fig. 64.3 ). A large anterior mediastinal mass in HL (>10 cm) is recognised as an adverse prognostic feature and, as such, defines the need for more aggressive initial therapy. FDG PET/CT or CT will demonstrate unsuspected mediastinal nodal involvement despite a normal chest radiograph in 10% of patients with HL. Impalpable axillary nodal enlargement is also frequently detected on CT in HL and NHL.

Abdomen and Pelvis

At presentation the retroperitoneal nodes are involved in 25–35% of patients with HL but up to 55% of patients with NHL. Mesenteric lymph nodes are involved in more than half the patients with NHL and less than 5% of patients with HL. Other sites, such as the porta hepatis and splenic hilum, are also less frequently involved in HL than NHL ( Fig. 64.4 ). In HL, nodal spread is predictably from one lymph node group to another through directly connected lymphatic pathways. Nodes are frequently of normal size or only minimally enlarged. Spread from the mediastinum occurs through the lymphatic vessels to the retrocrural nodes, coeliac axis and so on. Around the coeliac axis, multiple normal-sized nodes may be seen, which can be difficult to evaluate because involved, normal-sized nodes are frequent in HL ( Fig. 64.4 ). The coeliac axis, splenic hilar and porta hepatis nodes are involved in about 30% of patients and splenic hilar nodal involvement is almost always associated with diffuse splenic infiltration (see Fig. 64.4 ). The node of the foramen of Winslow (portacaval node), lying between the portal vein and the inferior vena cava is often overlooked and may be the only site of disease relapse. It has a triangular shape; its normal long-axis diameter is up to 3 cm and in the anteroposterior plane is approximately 1 cm.

In NHL, nodal involvement is frequently non-contiguous and bulky. Discrete mesenteric nodal enlargement or masses may be seen with or without retroperitoneal nodal enlargement. Large-volume nodal disease in both mesentery and retroperitoneum may give rise to the so-called ‘hamburger sign’, in which a loop of bowel is compressed between two large nodal masses ( Fig. 64.5 ). Multiple normal-sized mesenteric nodes should be regarded with suspicion for the diagnosis of lymphoma, and lymphoma is a recognised cause of the ‘misty mesentery’. Regional nodal involvement is frequently seen in patients with primary extranodal lymphoma involving an abdominal viscus. Involved nodes tend to enhance uniformly and the presence of multilocular enhancement should suggest an alternative diagnosis such as tuberculosis or atypical infection.

In the pelvis, any nodal group may be involved in both HL and NHL. Presentation with enlarged inguinal or femoral lymphadenopathy is seen in less than 20% of HL; its presence should prompt close scrutiny of the pelvic nodal groups. In patients with massive pelvic disease, MRI is helpful for delineating the full extent of tumour and the effect on the adjacent organs.

Thorax