Epidemiology

Around 1500 cases of Hodgkin’s disease are diagnosed every year in the UK and approximately 350 people die of this disease every year. Males are predominantly affected (male : female 1.8 : 1). There is bimodal peak of incidence with the first peak in those between 15 and 30 and the second peak between 50 and 60 years.

Aetiology

Pathology

The WHO classification of HD is shown in Table 21.1. Nodular sclerosis is the common subtype in young adults (more common in females), which presents with early stage supradiaphragmatic disease whereas mixed cellularity presents with generalized lymphadenopathy or extranodal disease with B symptoms. Lymphocyte depletion type presents with advanced stage disease with extranodal involvement and aggressive clinical course.

Table 21.1 WHO classification of Hodgkin’s lymphoma

LRCHL usually presents in young males with localized cervical node involvement with no B symptoms.

Histologically HD is characterized by the presence of Hodgkin and Reed–Sternberg (H-RS) cells in a background of non-neoplastic cells such as lymphocytes, histiocytes, neutrophils, eosinophils and monocytes. Classical HD is characterized by CD30 positive H-RS cells and the nodular lymphocyte predominant form of HL (LPHL) with CD20 positive lymphocytic and histiocytic (L and H) cells. In classical HD, RS cells stain positive for CD15 (80%) and CD30 (90%).

Clinical features

The most common presentation is lymphadenopathy in the cervical or supraclavicular region (60–70%). Almost two-thirds of patients with classical HL have mediastinal nodal disease producing symptoms: tight chest, cough, venous congestion, or dyspnoea. About 40% of patients present with ‘B-symptoms’ of fever >38°C, drenching night sweats, or weight loss >10% within the previous 6 months (not from other causes). Bone marrow involvement at presentation occurs in less than 10% of cases. Extranodal involvement commonly occurs in the lung.

Investigations and staging

Imaging

• Chest X-ray may show mediastinal widening (Figure 21.1), pleural effusion or pericardial effusion.

• CT of the neck, thorax, abdomen and pelvis will delineate lymphadenopathy as well as visceral involvement.

• Lung function tests, especially for those who may receive bleomycin as part of their treatment.

• PET scan – the role of FDG-PET is increasing. It is useful to define the extent of lymphadenopathy at diagnosis, as well in assessing post-treatment residual disease.

• MRI is useful to delineate disease in bone and the nervous system.

Figure 21.1 Mediastinal widening in Hodgkin’s disease.

Management

HD is a highly curable disease with long-term disease-free survival (DFS) exceeding 80%. Current efforts are to improve the chances of cure with the least long-term toxicity. Measures to preserve fertility should be discussed with all young patients prior to starting chemotherapy.

Patients with early stage disease (clinical stage I/II) are categorized as favourable and unfavourable group based on risk factors (Table 21.3). Prognosis of patients with advanced-stage (stage III and IV) disease is defined using the International Prognostic Score (IPS) (Box 21.1).

Table 21.3 EORTC risk grouping of early stage HD

Treatment group	Definition
Favourable	CS I–II without risk factors
Unfavourable	CS I–II with ≥ 1 risk factors
Risk factors	A large mediastinal mass (>10 cm/> thorax) B age ≥50 years C B symptoms or elevated ESR* D ≥4 involved regions

* Erythrocyte sedimentation rate (≥50 mm/h without or ≥30 mm/h with B-symptoms).

Classical HD

Early-stage favourable

The current standard treatment is combined modality treatment, consisting of two to four cycles of ABVD chemotherapy (Boxes 21.2 and 21.3), followed by 30–35 Gy in 15–20 fractions of involved field radiotherapy (IF-RT).

Box 21.2 Radiotherapy techniques in lymphoma

Definitions (see Figure 21.2 showing nodal regions)

• Involved field radiotherapy – involved lymph nodes with or without first echelon nodes.

• Extended field radiotherapy – involved lymph nodes with 1st and 2nd echelon nodes.

• Total nodal radiotherapy – all nodal regions.

Localization – based on CT scan or conventional definition of nodal regions.

Target volume definition – CTV depends on possible microscopic disease and PTV depends on site of treatment.

Dose

Hodgkin’s lymphoma

• Macroscopic disease: 30–36 Gy in 20 fractions.

• Prophylactic nodal areas: 30 Gy in 15–20 fractions.

• Postchemotherapy: 30–35 Gy in 15–20 fractions.

NHL

• RT alone: 40 Gy in 20 fractions.

• Postchemotherapy: 30–35 Gy in 15–20 fractions.

Total body electrons

• Whole skin to a depth of 3–5 mm (6 MeV).

• Dose 24 Gy in 8 fractions, 3 fractions per week.

Figure 21.2 Nodal regions: cervical (a-b), mediastinal (c), axillary (d-e), mesenteric (f), paraaortic (g), iliac (h-i) and inguinal (j-k).

Box 21.3 ABVD regime

• Doxorubicin 25 mg/m² IV D1 and D15

• Bleomycin 10 units/m² IV D1 and D15

• Vinblastine 6 mg/m² (max 10 mg) IV D1 and D15

• Dacarbazine 375 mg/m² IV D1 and D15

Cycles repeated every 4 weeks

Early-stage unfavourable

These patients are also treated with combined modality treatment; however, the optimal chemotherapy regime and radiotherapy fractionation are yet be determined. The current treatment is four courses of ABVD followed by involved field radiotherapy of 30–35 Gy in 15–20 fractions (Boxes 21.2 and 21.3). With this treatment 5% patients progress during or immediately after treatment and 15% relapse within 5 years.

Advanced stage

Combination chemotherapy with 6–8 cycles of ABVD is the current treatment of choice; although this regime is not as successful as in earlier stage disease. Various attempts are being made to modify the ABVD regime by adding newer drugs and increasing dose intensity.

The role of consolidation radiotherapy in advanced stage HD is also not clear. A meta-analysis of combined modality treatment showed equal tumour control but inferior overall survival compared with chemotherapy alone. An EORTC study suggested that involved field radiotherapy did not result in better outcomes in patients who achieve complete response after chemotherapy, but may be beneficial in patients with a partial response. Hence consolidation radiotherapy is considered in those with initial bulky disease and those who fail to achieve a complete response to chemotherapy.

Survival

With combined modality treatment patients in the early-favourable group achieve a disease free survival (DFS) of more than 90% and an overall survival of about 95% at five years. Patients in the early unfavourable group have a DFS of about 84% and an OS of 91%. In advanced stage combination chemotherapy results in 5-year failure free survival of 78% and overall survival of 90%. High-dose therapy and autologous stem cell transplantation results in DFS of 55% and the overall survival 71% at 5 years.

Follow-up

Two-thirds of relapses occur within 3 years of initial treatment and more than 90% occur within 5 years. Since a significant proportion of patients who relapse can be successfully salvaged, all patients need regular follow-up (Box 21.4). Follow-up is also helpful in identifying and managing long term side effects such as endocrine dysfunction.

Survivorship issues

The major causes of excess death in survivors of HD are second malignancies and ischaemic heart disease (p. 58).

One of the most common second malignancies is lung cancer which is attributed to mediastinal radiotherapy, chemotherapy and smoking. Patients who had thoracic radiotherapy are encouraged not to smoke. There is 20–50% risk of second breast cancer after mediastinal/axillary radiotherapy in young females and these patients should be screened for breast cancer. Common haematological neoplasms include acute myeloid leukaemia, myelodysplastic syndrome (develops within 3–5 years) and non-Hodgkin’s lymphoma (develops after 5–15 years).

Future perspectives

Future studies will address the issues of improving survival whilst minimizing the risk of long-term side effects. Newer imaging modalities such as functional imaging are already being incorporated into risk stratification to determine future treatments.

Introduction

Non-Hodgkin’s lymphomas are a group of lymphoid malignancies of varying subtypes with a range of clinical behaviours and treatment strategies. Around 8450 new cases are diagnosed per year in the UK and 65,980 cases in the USA. The median age is 65, although aggressive B-cell lymphomas are the predominant NHL in younger adults. Male : female ratio is 1.5 : 1. Almost of cases are due to two specific subtypes: diffuse large B-cell lymphoma and follicular lymphoma.

Pathology

The cell of origin is different for each subtype of lymphoma. Classification is by the updated WHO modification of the REAL (revised European and American lymphoma) classification system which is broadly divided into B-cell, T-cell/natural killer cell and Hodgkin’s disease (Table 21.4). Table 21.5 shows cytogenetic and molecular characteristics of NHL.

Table 21.4 Abridged WHO/REAL classification of NHL

B-cell neoplasms

• Precursor B-cell neoplasm • Peripheral B-cell neoplasms B-cell chronic lymphocytic leukaemia/small lymphocytic lymphoma Mantle cell lymphoma Follicular lymphoma Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphatic tissue (MALT) type Hairy cell leukaemia Plasmacytoma/plasma cell myeloma Diffuse large B-cell lymphoma Burkitt lymphoma

Imaging

CT scans of the neck, chest, abdomen and pelvis are carried out to assess lymphadenopathy and organ involvement (Figure 21.3).

Figure 21.3 CT scan in NHL. Figure shows massive para-aortic lymphadenopathy (A) and iliac and inguinal lymphadenopathy (B).

Other investigations

Staging

Staging is similar to Hodgkin’s disease (p. 299).

Follicular lymphoma

Follicular lymphoma accounts for approximately 20% of all lymphomas and has a variable clinical course. The median age at presentation is 50 years. Most patients present with advanced disease and median survival is 10–15 years from diagnosis. Spontaneous regression can occur and 40% of patients transform to an aggressive histologic type. Over 90% have rearrangement of the bcl-2 gene which inhibits apoptosis.