Correspondence *First Department of Internal Medicine, Trial office GHSG: Herderstr. 52, University Hospital Cologne, 50924 Cologne, Germany

Email beate.klimm@biometrie.uni-koeln.de

The case

A 48-year-old man presented to his GP with an indolent swelling in his left axillary region, which had been growing slowly but constantly for at least 1 month. He had previously been in good health, except for some trauma fractures 12 years earlier. However, in the 2 weeks prior to visiting his GP, his physical condition deteriorated due to coughing, a feeling of thoracic pressure, fatigue and slight weight loss (5 kg; 6% of his body weight). In addition, he suffered from drenching night sweats and fever up to 38.5°C. On reporting to his GP, a physical examination and an ultrasound revealed an enlarged lymph node of approximately 4 cm in the left axillary region and several smaller lymph nodes of 1.5–2.0 cm in the left cervical region, ranging from the upper cervical to the infraclavicular region. Laboratory tests were unremarkable, except for an elevated erythrocyte sedimentation rate (ESR) of 77 mm/h. The patient was referred to a regional Hematologic Department in Germany.

A biopsy of the 4 cm lymph node revealed Hodgkin's lymphoma (HL). A lymphocyte-rich classical subtype was diagnosed by a lymphoma pathologist. Tumor staging was confirmed by chest X-ray, abdominal ultrasound, CT scans of the neck, chest, abdomen and pelvis, a bone marrow biopsy and skeletal radionuclide imaging. Collectively, these procedures showed nodal involvement of the left cervical and axillary region, the upper and lower mediastinum (as indicated by a bulky mass of 7 cm 3 cm), and the hilar regions of both lungs. There was no infradiaphragmatic disease, and no organ, bone or bone marrow involvement. Laboratory tests for differential blood count, coagulation, trans-aminases, alkaline phosphatase, -glutamyltransferase, lactate dehydrogenase, bilirubin, glucose, creatinine clearance, urea, uric acid, total protein, albumin, and thyroid stimulating hormone were performed to exclude infectious or other serious disease and to ensure adequate organ function, particularly of the liver and kidneys, prior to chemotherapy. Echocardiography and lung function tests showed no serious cardio-pulmonary impairment.

According to the criteria of the German Hodgkin Study Group (GHSG), the involvement of >2 lymph node areas and an elevated ESR (30 mm/h, when B-symptoms are present, otherwise 50 mm/h) are judged as risk factors. The patient was classified as clinical stage IIB with risk factors.

Discussion of diagnosis

Initial diagnosis

HL is usually diagnosed by a pathologist after analyzing samples extracted from the affected tissue by biopsy. Fine needle biopsy does not generally obtain sufficient material to specify the diagnosis; hence a complete lymph node biopsy is mandatory. 'Spacious debulking', i.e. extirpating more tumor mass than needed for diagnosis, does not improve the prognosis. Histologic subclassification of HL considers both the morphology and immunophenotype of Hodgkin and Reed–Sternberg cells and the composition of the cellular background. The WHO differentiates between the classical form of HL (cHL) and the nodular lymphocyte-predominant form of the disease.¹ The lymphocyte-rich classical subtype presented in this patient is rare and only diagnosed in 3–5% of cHL cases compared with the nodular sclerosing (60–70%) or mixed cellularity (20–30%) subtypes of cHL.

Unlike non-Hodgkin's lymphoma (NHL), histologic subtype in HL does not determine treatment choice, except in some nodular lymphocyte-predominant HL cases. HL patients are assigned to treatment groups according to their stage and risk factor pattern. Hence, accurate staging procedures and risk factor assessment are essential for adequate therapy. Disease stage is classified according to the cotswolds staging classification system² (Table 1) and HL patients are usually assigned to early-stage favorable (i.e. stage I or II without risk factors), early-stage unfavorable (i.e. intermediate; stage I or II with certain risk factors) or advanced-stage (i.e. stage III or IV) risk groups. The recognized stages and risk factors used to assign patients to treatment groups can differ slightly among study groups. In the GHSG, apart from the number of involved lymph node areas and an elevated ESR, two other risk factors qualify HL patients with stage I or IIA for the unfavorable group: a large mediastinal mass of 1/3 of the thoracic diameter and extranodal involvement. However, patients with stage IIB and one of the latter risk factors are already considered to have advanced stage disease. Other study groups also include age or certain histologic subtypes in their risk factor definition.³

Table 1 Table 1 Cotswolds staging classification² and designations applicable to any disease stage.

Full tableFigures & Tables indexDownload Power Point slide (224K)

In the case presented, diagnostic clues were the indolent and slowly-growing lymph node and appearance of B-symptoms (i.e. fever >38°C, drenching night-sweats and weight loss within the previous 6 months not attributed to other causes). In comparable cases with NHL patients, B-symptoms occur less frequently. In newly diagnosed HL patients, 60–70% have enlarged cervical or supraclavicular lymph nodes, 50–60% show radiographic evidence of intra-thoracic involvement and about 40% have B-symptoms. Patients may also suffer from a cough, a feeling of thoracic pressure, venous congestion, or dyspnea because of tracheal compression or pericardial or pleural effusions. Other symptoms include abdominal or bone pain, pruritus and fatigue. Neurologic or endocrinologic symptoms occur less frequently.

Treatment and management

The 'gold standard' treatment for early-stage unfavorable HL is a combined modality of 4–6 courses of chemotherapy, typically ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine), followed by 30 Gy of involved-field radiotherapy (IFRT). Clinical results from the GHSG are under analysis to determine whether patients with very localized lymphocyte-rich cHL have a more favorable outcome and should be treated less intensely than patients with other classical subtypes (A Shimabukuro-Vornhagen, personal communication). Currently, patients with all classical subtypes of HL are treated the same, according to stage and risk factor pattern. The ABVD regimen,⁵ introduced in 1975, has been shown to be equally effective and less toxic compared with other drug regimens previously used, which were mainly MOPP (mechlorethamine, vincristine, procarbazine, prednisone) or MOPP-like regimen. IFRT was introduced to minimize the risk of acute and long-term toxicities, particularly radiation-induced solid tumors, by reducing the field size. After effective chemotherapy, IFRT has demonstrated an equal outcome compared with extended-field radiotherapy, and IFRT has now replaced extended-field radiotherapy as a treatment option.⁶

Despite excellent results obtained by ABVD plus radiotherapy, about 15% of patients in early unfavorable stages relapse within 5 years and another 5% of patients suffer from primary progressive disease. Ongoing trials analyzing combined modality protocols are comparing ABVD with more intense novel regimens, previously established in the treatment of advanced stages (Table 2). The EORTC trial, H9U, and the recently closed GHSG trial, HD11, compared 4 cycles of ABVD with 4 cycles of BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone) baseline. The ECOG-2496 trial is evaluating the Stanford V regimen (mechlorethamine, doxorubicin, vinblastine, vincristine, bleomycin, etoposide and prednisone).⁷ In addition, the EORTC trials, H8U and H9U, are in progress to analyze whether 4 cycles of combined modality treatment are as effective as 6 cycles.⁸

Table 2 Table 2 Therapy regimen used in the treatment of Hodgkin's lymphoma.

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The patient in the case was enrolled in Arm A of the GHSG HD14 trial, an ongoing trial for patients with early-stage unfavorable HL. In this trial, patients receive 4 cycles of chemotherapy [either 4 ABVD (Arm A) or 2 BEACOPP escalated followed by 2 ABVD (Arm B)] and 30 Gy IFRT. The BEACOPP escalated regimen administered in Arm B was shown to be effective for the treatment of advanced stage HL patients.⁹ Interim restaging of the patient after chemotherapy showed a partial remission of the mediastinal/hilar and axillar nodes and complete remission of the smaller cervical nodes. At final restaging after IFRT, the patient had complete remission for all initially involved regions and a normal ESR rate. This result was confirmed by the first follow-up examination 3 months after the end of treatment and the remission state of the patient was classified as complete response.

Conclusion

HL is a rare but treatable tumor with an annual worldwide incidence of 2 to 3 per 100,000 persons. Typical symptoms include indolent lymph node enlargement and systemic symptoms. Diagnosis should be confirmed by excisional biopsy sent to an expert pathologist. Exact staging procedures and risk factor assessment are essential in order to determine an adequate risk-adapted treatment strategy. HL is very sensitive to chemotherapy and radiotherapy. Several generations of clinical trials over the past 3 decades have resulted in improved therapy and better outcome rates for patients in all stages. Recent trials at 5 years after random assignment revealed freedom from treatment failure for >90% of patients with early favorable stage disease and for 85% of patients with early unfavorable and advanced stages of the disease.^{6, 9, 10} Current strategies aim at both defining the best therapy for each treatment group by modifying the type of drugs, number of cycles, irradiation dose and/or field size, and reducing acute and long-term side effects, without compromising the efficacy of treatment.

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