Oxford Case Histories in Oncology

Case 26

Hodgkin lymphoma

Isabella Maund and Michael Williams

Case history

A 25-year-old woman presented with a painless lump on the left side of her neck. She was otherwise well. Biopsy performed under ultrasound guidance showed partial effacement of the lymph node architecture by scattered large cells. Immunohistochemistry showed that these large cells expressed CD30 and CD15 but were negative for CD45.

Questions

1. How do you interpret the histopathology results?

2. What other information would you require in order to fully stage the patient?

Answers

1. How do you interpret the histopathology results?

These cells have the characteristic immunophenotype of the Reed–Sternberg (RS) cell of classical Hodgkin lymphoma.

2. What other information would you require in order to fully stage the patient?

Clinical staging of Hodgkin lymphoma requires a full history, with particular focus on determining the presence of B symptoms (defined as fever ≥38°C, soaking night sweats, or weight loss ≥10% within 6 months), clinical examination, and laboratory workup.

FDG-PET is recommended as part of routine staging at initial diagnosis in conjunction with CT scan. PET-CT is more sensitive than other imaging modalities at detecting disease in unenlarged nodes. Bone marrow trephine biopsy is not indicated in routine staging of clinically localized (stage I–IIA) classical Hodgkin lymphoma, as the risk of bone marrow involvement is <1%.

The patient denied B symptoms and underwent staging including a FBC (Table 26.1) and PET-CT imaging (Fig. 26.1). Increased tracer uptake was seen within the left cervical (21mm), supraclavicular (8mm), high paratracheal (12mm), and bilateral axillary regions (largest 14mm). No extranodal disease was noted.

Table 26.1 Full blood count

WBC, white blood cells; ESR, erythrocyte sedimentation rate.

Fig. 26.1 Pre-treatment PET-CT shows activity in left cervical and bilateral axillary nodes (See also colour plate section)

Questions

3. What is the stage of this patient’s disease and her risk group?

4. What treatment would you recommend?

5. How would you modify chemotherapy in respect of cytopenias? Would you advise the use of growth factors?

If radiotherapy is included in your management plan:

6. Describe your intended radiation technique and dose.

7. What adverse effects of radiotherapy would you consent for?

Answers

3. What is the stage of this patient’s disease and her risk group?

The Ann Arbor staging classification (with Cotswold modifications) is widely used for the staging of Hodgkin lymphoma (Table 26.2). According to this system, the patient should be staged as IIA.

Patients are further classified according to the presence of clinical risk factors. These are broadly similar amongst the main cooperative groups; those used by the influential German Hodgkin Study Group are shown in Box 26.1. With involvement of four nodal areas above the diaphragm, this patient would be classified as having early unfavourable (non-bulky) Hodgkin lymphoma.

Table 26.2 Modified Ann Arbor staging system for Hodgkin lymphoma

Source: data from Lister TA et al, Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin’s disease: Cotswolds Meeting, Journal of Clinical Oncology, Volume 7, Number 11, pp. 1630–36, Copyright © 1989 with permission from the American Society of Clinical Oncology.

Box 26.1 Clinical risk factors in Hodgkin lymphoma

♦ Large mediastinal mass (at least one-third of the maximum thorax diameter)

♦ Extranodal disease

♦ Involvement of three or more nodal areas

♦ Elevated erythrocyte sedimentation rate (>50mm/h for stages IA, IIA and >30mm/h for stages IB, IIB)

Source: Data from Engert A et al., Reduced treatment intensity in patients with early stage Hodgkin’s lymphoma, New England Journal of Medicine, Volume 363, Issue 7, pp. 640–52, Copyright © 2010, Massachusetts Medical Society.

4. What treatment would you recommend?

The standard treatment for early unfavourable Hodgkin lymphoma is considered by most groups to be combined modality treatment with four cycles of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) (Box 26.2) and 30Gy involved-field radiotherapy.

Box 26.2 The ABVD regimen

♦ Adriamycin 25mg/m² intravenously (IV) on days 1 and 15

♦ Bleomycin 10U/m² IV on days 1 and 15

♦ Vinblastine 6mg/m² IV on days 1 and 15

♦ Dacarbazine 375mg/m² IV on days 1 and 15

♦ Cycle repeated every 28 days

5. How would you modify chemotherapy in respect of cytopenias? Would you advise the use of growth factors?

Treatment should continue unmodified despite low platelet or neutrophil counts, and routine granulocyte colony stimulating factor support is not required.

6. Describe your intended radiation technique and dose.

Radiotherapy should be planned using 3–5mm contiguous CT imaging with appropriate immobilization, including a customized head shell. Volumes should be defined using the ICRU concepts of GTV, CTV, and PTV. Involved-field radiotherapy limits radiotherapy to anatomical nodal regions involved with macroscopic lymphoma and has been adopted as the standard of care in recent trials. Information regarding the location and size of nodes on pre- and post-chemotherapy scans is essential and should be available at the time of planning. The initially involved sites and volumes should be used, tailoring the field borders to the post-chemotherapy volume in areas such as the mediastinum where regression of lymph nodes is readily detected on CT and the sparing of surrounding structures is critical.

For this patient, fields include the whole left neck (upper and lower cervical) including supra- and infraclavicular regions, bilateral axillary lymph node regions, and the upper mediastinal nodes (Fig. 26.2).

Involved-node radiotherapy, in which only the initially involved structures are irradiated, has been proposed. However, for this patient, extensive treatment would still be required; the technique remains unproven and is the subject of current trials.

The standard dose for treatment of macroscopic residual disease is 30Gy delivered over 15 fractions. This patient is not suitable for 20Gy over 10 fractions as she is in the unfavourable risk group.

7. What adverse effects of radiotherapy would you consent for?

Acute reactions are usually mild and transient, and include lethargy, nausea, dermatitis, dry cough, dysphagia, and mucositis. Transient radiation myelopathy characterized by Lhermitte’s sign can occur 6 weeks to 3 months following mantle field irradiation and settles spontaneously after a few months. Radiation myelopathy resulting in paresis has been reported following 30Gy radiotherapy given after standard chemotherapy.

Fig. 26.2 Diagram of suggested radiotherapy field using multileaf collimator (MLC) shaping. Normal structures including the heart (centre) and breasts (left and right) are displayed. (See also colour plate section)

Retrospective analyses of long-term survivors of Hodgkin lymphoma treated over the past three decades have shown elevated relative risks of developing most second malignancies, with breast being of particular concern. This is likely to reflect the long-term consequences of radiotherapy. Due to the involvement of multiple nodal regions the radiotherapy fields required for the patient would be of a size approaching that of a mantle field, and thus extrapolating risk from older trials of extended-field radiotherapy is not unreasonable. A woman treated at the age of 25 with typical mantle fields has an estimated risk of developing breast cancer of 29% by the age of 55; the incidence of other cancers, including those at distant sites, will also be elevated due to low-dose whole-body exposure.

The burden of non-malignant late effects is also significant. Mediastinal irradiation increases the risks of cardiovascular disorder, including myocardial infarction, congestive cardiac failure, and valvular dysfunction, by two- to seven-fold. Twenty-year follow-up of adults treated for Hodgkin lymphoma has also shown a 7% actuarial incidence of non-coronary atherosclerotic disease, such as ischaemic stroke.

After two cycles of ABVD the patient underwent re-staging with PET-CT. This showed no residual FDG uptake but there were persistent enlarged nodes within the cervical and axillary regions consistent with a partial response to treatment. She attends clinic to discuss on-going management but, after hearing about the adverse effects, she declines radiotherapy.

Questions

8. What course of action do you now recommend and how would you counsel the patient?

9. What is her prognosis?

Answers

8. What course of action do you now recommend and how would you counsel the patient?

The results of the Canadian HD6 trial support the use of chemotherapy alone in early stage Hodgkin lymphoma. Patients randomized to ABVD chemotherapy alone had significantly better OS at 12 year than patients whose treatment included subtotal nodal irradiation (94% versus 87%). This was attributed to excess mortality from causes other than lymphoma in the radiotherapy arm. Radiotherapy reduced the risk of relapse by 5%, and since the majority of patients with relapsed disease will be treated with salvage chemotherapy and autologous stem cell transplant, avoiding radiotherapy means accepting an increased risk of requiring more intensive salvage therapy.

This patient had a partial response to treatment after two cycles of ABVD and therefore should be treated with a total of six cycles of ABVD chemotherapy. She should be counselled regarding the increased risk of requiring salvage therapy, which carries significant additional acute and long-term risks, as well as the increased risk associated with the additional anthracycline dose.

9. What is her prognosis?

This patient has an excellent prognosis. The 12-year OS of patients with an unfavourable risk profile treated with ABVD alone in the HD6 trial was 92%, although 16% of patients relapsed over this time and required additional aggressive salvage therapy.

Further reading

Engert A, Plutschow A, Eich HT, et al. Reduced treatment intensity in patients with early stage

Hodgkin’s lymphoma. New England Journal of Medicine 2010; 363: 640–652.

Ferme C, Eghbali H, Meerwaldt JH, et al. Chemotherapy plus involved-field radiation in early-stage Hodgkin’s disease. New England Journal of Medicine 2007; 357: 1916–1927.

Girinsky T, van der Maazen R, Specht L, et al. Involved-node radiotherapy (INRT) in patients with early Hodgkin lymphoma: concepts and guidelines. Radiotherapy and Oncology 2006; 79: 270–277.

Nangalia J, Smith H, Wimperis J. Isolated neutropenia during ABVD chemotherapy for Hodgkin lymphoma does not require growth factor support. Leukemia and Lymphoma 2008; 49: 1530–1536.

Townsend W, Linch D. Hodgkin’s lymphoma in adults. The Lancet 2012; 380: 836–847.

Yahalom J, Mauch P. The involved field is back: issues in delineating the radiation field in Hodgkin’s disease. Annals of Oncology 2002; 13: 79–83.