First INCTR Multidisciplinary Conference

Management of a Patient With Hodgkin Lymphoma With Mediastinal Involvement
Presented at the INCTR Annual Meeting, 2004

INTRODUCTION

Dr. AZIZA SHAD: Multidisciplinary conferences are a standard feature of patient management in major cancer centers. The aim of such meetings, in which a team of medical experts discusses the optimal management of a particular patient, is to confirm the diagnosis, ascribe stage, where appropriate, review all investigations and reach a consensus on the best possible treatment for the patient. Thus, multidisciplinary conferences may be held to discuss newly diagnosed cases, relapsed cases, or any patient in which a therapeutic decision needs to be made. In addition, such conferences foster good relationships among the members of the medical team, and an educational experience for all.

PARTICIPANTS

Session Chair: Dr. Aziza Shad, Pe-diatric Oncologist, Lombardi Cancer Center, Washington DC, USA.

Moderators: Dr. Corina Gonzalez, Pediatric Oncologist, Lombardi CancerCenter, Washington DC, USA, and Dr. Henning Bredenfeld, Medical Oncologist, University of Cologne, Germany.

Participants: Prof. Nadia Mokhtar, Pathologist, NCI Cairo, Egypt; Dr. Ali Khan, Radiologist, North Manchester General Hospital, UK; Prof. Mahmoud El-Gantiry, Radiation Oncologist, NCI Cairo, Egypt, and the audience of the 2004 annual INCTR meeting.

PRESENTATION OF CASE

Dr. GONZALEZ: An 11-year-old Caucasian female living in the USA was admitted to the hospital because of progressive cervical lymphadenopathy, mediastinal mass and constitutional symptoms. Eight weeks earlier, the patient had noticed several tender swellings on the left side of her neck, which enlarged over time. A month prior to admission, intermittent fevers up to 38.5° C, non-productive cough and bilateral knee pain developed. Three days prior to hospitalization the patient developed drenching night sweats. On the day of admission the patient was seen by her primary physician. There was no history of shortness of breath, weight loss, fatigue or difficulty in swallowing and no significant past or family history. A chest radiograph (CXR) and a blood cell count were ordered, and oral cephalexin was prescribed for presumptive lymphadenitis. The CXR revealed a mediastinal mass (Figure 1) and the patient was admitted to hospital for additional diagnostic tests.

Physical examination revealed bilaterally enlarged lymph nodes in anterior cervical, occipital and preauricular areas, which were 1.5 - 2 cm in size, non-tender, firm and rubbery. The left supraclavicular nodes were hard and matted, forming a lobulated mass measuring about 5 cm in diameter. Physical examination was otherwise unremarkable. On the second hospital day the patient underwent computerized tomography (CT) scans of the neck, chest, abdomen and pelvis and a biopsy of the most prominent cervical node. Extensive laboratory tests revealed no abnormalities except increased WBC (17.800/mm3), ESR (79 mm/hr), and LDH (265 IU/L).

DIAGNOSIS

Histopathology

Prof. MOKHTAR: Histopathological examination (Figure 2) revealed nodules of lymphocytes separated by fibrous tissue. Numerous Reed-Sternberg (RS) cells are seen in the nodules as well as a background infiltrate of inflammatory cells composed mostly of small lymphocytes and eosinophils. These findings are consistent with the nodular sclerosis type of Hodgkin lymphoma.

Dr. GONZALEZ: What problems may be encountered in making a diagnosis of Hodgkin lymphoma?

Prof. MOKHTAR: The type of specimen obtained is important. An excisional biopsy of a suspicious node is the preferred diagnostic procedure, as it permits the evaluation of the architectural as well as cellular features characteristic of the specific histological types. By contrast, a fine needle aspirate of a suspicious node is often not diagnostic because of the limited numbers of malignant cells in the affected tissue. Specimens should, ideally, be received directly from the surgeon or the oncologist in normal saline or tissue culture medium rather than formalin in order that flow cytometry and molecular studies can be performed or a piece of tissue frozen for subsequent studies. Sections of the specimen should be fixed in formalin and also in B5, if available, since the latter can be more rapidly processed. In spite of optimal processing, classical, diagnostic RS cells may be lacking, particularly in the nodular lymphocyte predominant Hodgkin lymphoma. In such cases, immunophenotyping is helpful in distinguishing Hodgkin lymphoma from Non-Hodgkin lymphomas, in particular diffuse large B cell lymphoma, and in separating nodular lymphocyte predominant Hodgkin disease from classical Hodgkin lymphoma. In the former, atypical RS cells, often called “lacunae” or “popcorn” cells, express CD45+, B-cell associated antigens (CD19, CD20, CD22, DC79a) and epithelial membrane antigen (EMA) and are negative for CD30 and CD15. In contrast, classical Hodgkin lymphoma is defined by the presence of typical RS cells, which express CD30+, CD15+, and are negative for B or T cell markers, with architectural and cellular features consistent with nodular sclerosis, mixed cellularity, or lymphocyte predominant Hodgkin lymphoma.

Dr. GONZALEZ: Do the different histological subtypes of Hodgkin lymphoma carry any prognostic value?

Prof. MOKHTAR: Historically, a better prognosis was linked to a higher ratio of lymphocytes to abnormal cells, no matter which histopathology classification for Hodgkin lymphoma was used. However, since the development of highly curative treatment regimens, all histological subtypes of classical Hodgkin lymphoma are equally responsive to treatment.

Figure 1. Chest X-ray showing a large mediastinal mass in a patient with Hodgkin Lymphoma.

Lymphocyte predominant	Nodular sclerosis
Mixed cellularity	Lymphocyte depleted
Figure 2. Appearances of the four histological types of classical Hodgkin’s disease. (Hematoxylin and eosin stain): lymphocyte predominant, mixed cellularity, lymphocyte depleted (magnification x 20) and nodular sclerosis (magnification x 40).

Imaging studies

Dr. KHAN: The CXR, posterior-anterior and lateral views reveal a large, lobulated anterior mediastinal mass which exerts mild mass effect on the trachea, causing it to deviate to the right. The lungs are well aerated with no infiltrates, nodules, pleural effusion, or pneumothorax. The bony thorax is unremarkable. The cardiac silhouette is within normal limits. The larger tumor diameter is more than a third of the diameter of the thorax when measured at the level of the dome of the diaphragm, thus is defined as bulky disease. The CT scan of the neck and chest shows lymphadenopathy in virtually all lymph node groups in the neck, measuring, on average, about 1.5 cm. The most prominent region of lymphadenopathy is in the left supraclavicular region, which most likely represents a confluence of lymph nodes, measuring approximately 1.5 by 4.5 cm in transaxial dimensions. The CT scan of the chest shows a left upper mediastinal mass measuring approximately 3.4 by 5.1 cm, which is contiguous with the left supraclavicular mass. CT scans of the abdomen and pelvis show no abnormalities. 67Gallium scan showed intense uptake in the left lower neck, left paramediastinum and right hilar and parahilar areas.

Dr. GONZALEZ: Dr. Khan, do we absolutely need CT scans for the radiographic staging of Hodgkin lymphoma?

Dr. KHAN: No, we do not need CT scans; CXR – anterior, posterior and lateral views – and ultrasound of the abdomen should be sufficient for the assessment of Hodgkin lymphoma. The neck and axillary areas can be evaluated by physical exam; any cervical or axillary node >1.5 cm in longest transverse diameter, any cluster of matted nodes, or any enlarged supraclavicular nodes should be considered Hodgkin lymphoma positive nodes, provided they are not obviously caused by infection. 67Gallium or FDG-PET scans can be performed when the results of other conventional diagnostic methods are not conclusive in identifying disease above the diaphragm. PET scan can be of real value when investigating abdominal involvement of Hodgkin lymphoma.

Dr. BREDENFELD: Dr. Khan, what is the value of 67Gallium and FDG-PET scans?

Dr. KHAN: Both FDG-PET and 67Gallium scans are studies that provide whole-body images and give a comprehensive assessment of disease extent. Recent reports suggest that the greatest value of FDG-PET scan lies in its positive predictive value for relapse in patients with residual masses. Positive uptake on FDG-PET scan signifies functional metabolic status, suggesting active areas of disease. Persistently positive PET scans at the end of therapy warrant close follow-up and additional diagnostic procedures. Conversely, a negative PET scan at the end of therapy provides very favorable prognostic information.

AUDIENCE: In my country we do not have FDG-PET scans. How useful is a 67Gallium scan in predicting relapse in Hodgkin lymphoma?

Dr. BREDENFELD: The positive and negative predictive values of 67gallium scans in predicting relapse of Hodgkin lymphoma are lower than those for FDG-PET scans, which are close to 100% – at best, 80 to 85% of the predictive value of FDG-PET scans. When there is an uncertainty, or suspicious findings, histopathological verification is strongly recommended.

STAGING

Dr. GONZALEZ: Based on the history and investigations detailed by Dr. Khan and Professor Mokhtar, this patient has nodular sclerosis Hodgkin lymphoma involving more than two node regions on one side of the diaphragm, bulky mediastinal disease, and B symptoms. In addition to the investigations described, the patient underwent bilateral bone marrow biopsies that were negative for disease. Her stage, therefore, is IIB-X.

Accurate staging of Hodgkin lymphoma is of paramount importance in defining therapy (Table 1). Currently, modern treatment strategies for Hodgkin lymphoma are evolving towards a risk-adapted approach. The strategy is to give more intensive treatment to patients with more advanced disease with the goal of maintaining high overall survival rates in all stages of disease. Advanced disease would be an unfavorable prognostic factor in an unselected group of patients treated identically. The predictive value is lost, however, when patients with advanced disease are treated with a more effective regimen, as demonstrated by recent studies in which survival curves for previously identified “risk categories” of Hodgkin lymphoma are essentially superimposable. Such risk factors include the direct measurement of tumor burden by stage, size of masses and splenic involvement, and indirect measurements such as hemoglobin, serum albumin, B symptoms and sedimentation rate. Today, most pediatric study groups divide Hodgkin lymphoma into three risk categories: early, intermediate and advanced, using these criteria.

TREATMENT

Dr. GONZALEZ: The treatment of childhood Hodgkin lymphoma consists of a combined modality approach, using chemotherapy plus or minus radiotherapy. Chemotherapy consists of a combination of several agents active against Hodgkin lymphoma which generally have a different mechanism of action. Prof. El-Gantiry will give us an overview or radiotherapy for Hodgkin lymphoma.

MEDICAL HISTORY with attention to presence or absence of systemic symptoms, such as unexplained recurrent fevers >38° C, unexplained weight loss >10%, and drenching night sweats. PHYSICAL EXAM emphasizing node chains, Waldeyer’s ring, and size of liver and spleen. CHEST RADIOGRAPH with measurement of the mass-thoracic ratio. CT-SCANS: Neck, Chest, abdomen and pelvis. RADIOISOTOPIC EVALUATION with 67Gallium or FDG-PET scans, when the results of the other diagnostic procedures are not diagnostic. BILATERAL BONE MARROW BIOPSIES of the posterior iliac crest in patients with stage IIB-IV. EXCISIONAL BIOPSY OF A NODAL MASS. CYTOLOGIC EXAMINATION of any effusion. NEEDLE OR SURGICAL BIOPSY of suspicious extranodal disease. Table 1. Recommended Staging Procedures for Hodgkin’s disease. (FDG-PET: fluorodeoxyglucose-Positron emission tomography)

Radiation Therapy

Prof. El-GANTIRY: Radiotherapy is a very effective locoregional treatment modality in Hodgkin lymphoma and was the first therapy to produce a significant fraction of cures. The rationale for its use in addition to chemotherapy stems from the observation that disease progression after chemotherapy alone often occurs in sites of prior involvement. However, the long-term morbidity associated with radiation therapy has been significant – particularly with respect to second malignancies such as breast cancer, which correlate with the dose and volume of radiation. When combined modality therapy is used, radiation can be given at reduced dose to involved sites only.

The mantle field is the most complex and important treatment field used in the management of Hodgkin lymphoma. It includes the submandibular, submental, cervical, axillary, mediastinal and pulmonary hilar lymph nodes. The inverted Y field includes paraaortic, pelvic and inguinal nodes. Prophylactic pelvic irradiation is rarely used in modern treatment for supradiaphragmatic disease; subtotal nodal irradiation including mantle and paraaortic fields is preferred. Pelvic irradiation continues to be used for patients who present with infradiafragmatic disease with protection of the ovaries in female patients if appropriate.

The usual radiotherapy dose for adults is 40-45 Gy when used alone and 30-36 Gy when used in combination with chemotherapy. For pediatric patients, the dose is 15-25 Gy in 14 fractions, confined to involved fields. Radiotherapy alone for pediatric patients is not recommended any longer because of the high incidence of associated late effects.

Dr. SHAD: I’d like to add a word about radiation therapy in children. In some developing countries, there is limited or even no access to radiation, and given the high incidence of late effects, some investigators have not used radiation in children at all, while others have conducted clinical studies to examine this question. In part, the answer with respect to disease-free survival depends upon whether or not additional chemotherapy is given in place of radiation, but overall survival is similar whether or not radiation is given. Patients with bulky disease, such as those with large mediastinal masses, may benefit with respect to local disease control from radiation, but chest irradiation in young women also increases the risk for breast cancer later in life.

Dr. BREDENFELD: In recently performed trials in adults with HD, even patients with large mediastinal masses achieved high remission rates without additional radiotherapy, providing that early shrinking of the initial tumor mass after sufficient chemotherapy was observed. Careful monitoring of radiotherapy plans by an expert panel (which checked all restaging images) resulted in 50% less radiation being given compared to standard treatment.

Dr. GONZALEZ: Is there any role for radiotherapy upfront in cases of large mediastinal mass with secondary upper airway compression and respiratory distress?

Dr. El-GANTIRY: An initial course of mediastinal irradiation in a symptomatic patient with extensive mediastinal disease often relieves respiratory distress promptly and enables the continuation of staging evaluation.

Dr. BREDENFELD: Alternatively, in this situation one can also use upfront steroids prior to definitive chemotherapy to provide a quick tumor response, with a smaller radiation field being used for consolidation.

THERAPY    DRUGS LATE EFFECT APPROACH ALKYLATING AGENTS Procarbazine Methchlorethamine Dacarbazine    Gonadal: 50% of males are sterile after 3 cycles - Almost all after 6 cycles Secondary leukemia: up to 1% per year after MOPP + radiotherapy    ELIMINATE METHCHLORETHAMINE AND DACARBAZINE ELIMINATE PROCARBAZINE OR LIMIT TO 3 CYCLES ANTITUMOR ANTIBIOTICS Bleomycin Pulmonary fibrosis - Grade 3 - 10% after 6 cycles of ABVD Cardiac toxicity LIMIT OR ELIMINATE CONSIDER USE OF DEXRAZOXANE LIMIT DOSE (< 300-350 MG/M2) LIMIT OR ELIMINATE RADIOTHERAPY CONSIDER USE OF DEXRAZOXANE EPIPODO- PHYLLOTOXIN Doxorubicin ANLL incidence data not yet available in children LIMIT DOSE LIMIT DURATION RADIOTHERAPY Etoposide Hypothyroidism, hypoplasia, valvular and atherosclerotic heart disease Secondary cancers: breast, sarcoma, melanoma, lung, thyroid, salivary gland Reduce dose and field or Eliminate Table 2. Modification of Pediatric Hodgkin Lymphoma Therapy to Decrease Late Effects.

Chemotherapy

Dr. GONZALEZ: The classic chemotherapy regimens combine usually four non-cross resistant agents (MOPP or ABVD) and are outpatient regimens with easily manageable acute toxicities but potentially significant long-term toxicities (Table 2). Alternating or hybrid regimens (MOPP with ABVD or COPP with ABVD) are regimens designed to avoid reaching the cumulative doses associated with significant toxicity for any of the drugs and have been widely used in both adult and pediatric Hodgkin lymphoma trials. Other regimens that do not include alkylating agents, in order to limit long-term effects, have been studied and shown to give good results in early stage disease in children but not for advanced stage disease. Most effective regimens for adults and children with advanced stages combine non-cross resistant agents in a dose intensive fashion, for example, in ABVE-PC, BEACOPP, or escalated BEACOPP. Instead of further dose escalation, the dose intensity approach allows doxorubicin and etoposide doses to be limited, and in the case of ABVE-PC, the elimination of procarbazine. Whether those with early response can be treated with fewer cycles is currently being investigated. In summary, the current treatment strategy for Hodgkin lymphoma, which this patient will receive, is risk-adapted, response-based, and dose/time intensive therapy. With the use of this therapeutic modality and involved field radiation, nearly 90% of patients with Hodgkin’s disease are cured with initial therapy. The challenge remains to minimize the late effects of treatment.

SUGGESTED READING

1. Thomas AB, Wallace WHB. Treatment of pediatric Hodgkin’s disease: a balance of risks. Eur J Cancer 2002, 38;468-477
   
2. Nachman JB, Sposto R, Herzog P, et al. Randomized comparison on low dose involved field radiotherapy and no radiotherapy for children with Hodgkin’s disease who achieve a complete response to chemotherapy. J Clin Oncol 2002, 20: 3765-3671.
   
3. Donaldson SS, Hudson MM, Lamborn KR, et al. VAMP and low dose, involved-field radiation for children and adolescents with favorable, early stage Hodgkin’s disease: results of a prospective clinical trial. J Clin Oncol 2002, 20:3081-3087.
   
4. Dieckman K, Potter R, Wagner W, et al. Upfront centralized data review and individualized treatment proposals in a multicenter pediatric Hodgkin’s disease trial with 71 participating hospitals: the experience of the German-Austrian pediatric multicenter trial DAL-HD-90. Radiother Oncol 2002, 62:191-200.
   
5. Sieber M, Tesch H, Pfistner B, et al. Treatment of advanced Hodgkin’s disease with COPP/ABV/IMEP versus COPP/ABVD and consolidating radiotherapy: final results of the German Hodgkin’s Lymphoma Study Group HD6 trial. Ann Oncol. 2004;15:276-82.
   
6. Josting A, Diehl V. Current treatment strategies in early stage Hodgkin’s disease. Curr Treat Options Oncol. 2003; 4:297-305.
   
7. Engert A, Schiller P, Josting A, et al. Involved-field radiotherapy is equally effective and less toxic compared with extended-field radiotherapy after four cycles of chemotherapy in patients with early-stage unfavorable Hodgkin’s lymphoma: results of the HD8 trial of the German Hodgkin’s Lymphoma Study Group. J Clin Oncol. 2003;21:3601-3608.
   
   Diehl V, Franklin J, Pfreundschuh M, et al. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin’s disease. N Engl J Med. 2003;348:2386-2395.