Haematology - Hodgkin's lymphoma

Prompt diagnosis and treatment is important, say Dr Lisa Lowry and Professor David Linch

CT-PET scan of bilateral ailary and mediastinal lymphadenopathy (Photograph: Centre Jean Perrin, ISM / Science Photo Library)
CT-PET scan of bilateral ailary and mediastinal lymphadenopathy (Photograph: Centre Jean Perrin, ISM / Science Photo Library)

Hodgkin's lymphoma (HL) was once considered a fatal disease but now 80-85 per cent of newly diagnosed patients should expect to be cured.

Classical HL is divided into four histological subtypes: nodular sclerosis, mixed cellularity, lymphocyte rich and lymphocyte depleted.1 These may have some prognostic significance but currently have little impact on management decisions. Nodular lymphocyte predominant HL is a separate disease with generally excellent outcomes.

Epidemiology and aetiology
HL is uncommon with approximately 1,600 cases diagnosed each year in the UK, accounting for 15 per cent of lymphomas and 0.5 per cent of all cancers.

However, it is relatively common in young adults and is the third most common cancer in 15-29 year-olds.

There is evidence of genetic susceptibility to HL, with a very modest increased risk for first-degree relatives of affected individuals and a 99-fold increased risk has been reported in monozygotic twins.2

HL incidence is increased in the immunosuppressed, particularly patients with HIV and organ transplant recipients.

Certain autoimmune conditions, such as rheumatoid arthritis, will increase the risk of developing HL and immunosuppressive therapy may further increase risk.

There is an association between HL incidence and socioeconomic indicators of affluence in childhood, such as small family size and high standard of maternal education. In addition, late exposure to a common infectious agent may be responsible. An increased risk of HL after a diagnosis of infectious mononucleosis has been reported.

However, Epstein-Barr virus antigens are identified in a minority of HL biopsies.3

Presentation, referral and diagnosis
The most common presenting symptom of HL is painless lymph node enlargement, most frequently affecting the cervical nodes.

The differential diagnosis includes a wide range of infections, including viral infections, toxoplasmosis and TB, and non-infective conditions including non-Hodgkin's lymphoma, non-haematological malignancies and sarcoidosis.

A thorough infectious and travel history should be sought, and the patient questioned about the presence of systemic symptoms including unexplained weight loss, night sweats, fever more or equal to 38Co (B symptoms) and fatigue and pruritus.

Alcohol-induced nodal pain occurs in less than 5 per cent of patients. However, when present, it is very strongly suggestive of the diagnosis.

Typical laboratory findings in HL include anaemia, elevated ESR, leucocytosis and/or eosinophilia; however, blood tests may not differentiate HL from other causes of systemic illness. A patient with HL may have entirely normal laboratory parameters. In those patients with clearly pathological nodes, referral for lymph node biopsy under the two week rule is appropriate.

However, for well patients with smaller nodes and possibly recent infective history, it is reasonable to reassess in a few weeks before you consider a referral.

While patients commonly present with palpable lymph nodes, disease may be largely mediastinal or, rarely, abdominal.

In this case the presentation may be with systemic, chest or abdominal symptoms.

A chest X-ray may reveal a widened mediastinum due to lymphadenopathy.

Extra-nodal presentation is uncommon in HL. Critical to making the diagnosis is an adequate biopsy, preferably an excision biopsy.

Fine needle aspirates are not suitable.

THE ANN-ARBOR STAGING SYSTEM
STAGE DESCRIPTION
I Disease confined to one lymph node region
II Disease in more than one lymph node region, but limited to
one side of the diaphragm
III Disease in lymph node regions on both sides of the
diaphragm
IV Extra-nodal involvement, for example liver, bone marrow

Management and prognosis
Staging

Once the diagnosis is confirmed, the disease is staged using a combination of CT, bone marrow biopsy, and, increasingly, PET scanning.

The Ann-Arbor staging system (see table) is widely used.

Patients with stage I or II disease and no adverse factors such as night sweats, weight loss, fever, or bulky disease, have 'limited stage' disease, while those with adverse risk factors or stage III/IV disease have 'advanced stage' disease, and the management approaches are different.

PET scanning utilises radioactive glucose, taken up by metabolically active tissue, including HL. It may refine staging, showing whether borderline enlarged lymph nodes contain active disease. It is of great use when restaging patients post-therapy.

CT abnormalities persist despite adequate therapy due to the presence of fibrous tissue.

Prognosis
The outcome for young patients with HL is favourable in contrast to older age groups. This dichotomy is due to increasing comorbidities and reduced tolerability of chemotherapy in older people. Although the cure rate is high, prolonged follow-up shows an increased risk of second malignancies, cardiac disease and pulmonary fibrosis.4,5

Treatment
ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) is the standard UK regimen, which does not contain an alkylating agent and is less likely to cause infertility or second cancers.

However, it carries late effect risks, particularly affecting the cardiorespiratory and peripheral nervous systems.

Limited stage
Combined modality therapy using abbreviated chemotherapy followed by involved-field radiotherapy gives a good chance of cure, while limiting the potential late effects.

Advanced stage
Standard therapy is six to eight cycles of ABVD, with or without consolidation radiotherapy and around 75 per cent of patients are cured with this approach. A further 10 per cent who are refractory to or relapse following ABVD can be cured with salvage regimens.

Relapse
Many young patients who do not achieve a lasting remission with first-line therapy can still be cured with subsequent lines of therapy.

The standard approach involves re-induction chemotherapy, followed by high-dose therapy with autologous stem cell rescue (autograft).

Conclusion
Although an uncommon malignancy, HL is relatively common in young people. Promptly diagnosed and treated, it is curable.

TEST YOUR KNOWLEDGE

1. A young man, previously weighing 80kg, presents with approximately 10 kg weight loss in the preceding six months, and mild chest discomfort. He is found to have extensive mediastinal lymphadenopathy and tissue obtained at mediastinoscopy confirms a diagnosis of Hodgkin’s lymphoma. His bone marrow biopsy is negative and PET/CT scanning shows, in addition to mediastinal lymphadenopathy, several 1-2cm supraclavicular and axillary nodes which strongly take up the FDG tracer. Bone marrow biopsy is negative. Using the Ann-Arbor system, what stage disease does he have?

2. The patient is finding it hard to come to terms with the diagnosis.  He is a smoker who has recently led a sedentary lifestyle. He wants to know what caused his lymphoma.  What would you tell him?

3. The patient embarks on a course of combination chemotherapy (ABVD).  What is the approximate probability that he will ultimately die of Hodgkin’s lymphoma?
 CLICK HERE TO SEE THE ANSWERS
  • Dr Lowry is a Lymphoma Research Trust clinical fellow and Professor Linch is a consultant haematologist at University College London Hospitals, and president of the Lymphoma Association

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References

1. Swerdlow SH, Campo E, Harris NL, et al. World Health Organisation Classification of tumours of haematopoietic and lymphoid Tissues, Fourth Edition (2008). WHO.

2. Goldin LR, Pfieffer RM, Gridley G, et al. Cancer 2004; 100(9): 1902-8.

3. Jarrett AF, Armstrong AA, Alexander E, et al. Ann Oncol 1996; 7: S5-S10.

4. Swerdlow AJ, Barber JA, Vaughan Hudson G, et al. J Clin Oncol 2000; 18: 498-509

5. Swerdlow A, Higgins CD, Smith P, et al. J Natl Cancer Inst 2007; 99: 206-14

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