Lymphoproliferative Disorders Presenting as Mediastinal Neoplasms

Lymphoproliferative Disorders Presenting as Mediastinal Neoplasms Stephen H Petersdoifand Douglas E. Wood Lymphoproliferative disorders may present in any organ of the body. The mediastinum is an uncommon location for presentation of these heterogenous disorders, but involvement of the mediastinum may be the sole site of disease for several aggressive lymphomas. Both Hodgkin's disease and non-Hodgkin's lymphoma may present in the mediastinum. The most common types of non-Hodgkin's lymphoma involving the mediastinum include lymphoblastic lymphoma and mediastinal large cell lymphoma. These lymphomas most commonly develop in the anterior mediastinum but may be seen in the middle and posterior mediastinum. Symptoms associated with a mediastinal presentation of a Iymphoproliferative disorder are often attributable to compression of mediastinal structures (eg, superior vena cava syndrome) or invasion of thoracic structures such as the pericardium or pleura. Although staging can be performed with routine imaging studies, surgical intervention is often required to ensure accurate histologic diagnosis of these lymphomas. Once a diagnosis has been established, therapeutic modalities usually include chemotherapy and/or radiotherapy. Copyright © 2000 by WB. Saunders Company Key words: Mediastinum, Hodgkin's disease, non-Hodgkin's lymphoma, biopsy.

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ymphoproliferative disorders, including nonHodgkin's lymphoma and Hodgkin's disease, may involve any organ of the body. Lymphomatous involvement of the mediastinum may be seen in patients with advanced widespread disease or, less commonly, may occur with disease limited to the mediastinum alone. When patients present with symptoms attributable to mediastinal involvement, they typically have a large tumor mass that causes complaints such as dyspnea, cough, or chest pain. Hodgkin's disease has long been associated with mediastinal involvement, and in recent years, the recognition of high-grade non-Hodgkin's lymphoma limited to the mediastinum has become increasingly common, particularly in young women. Primary mediastinal lymphomas are relatively uncommon in adults, but in children, malignant lymphoma is among the most common of malignant mediastinal neoplasms. The majority of mediastinal lymphomas occur in the anterior or middle mediastinal compo-

From the Department if Medical Oncolof!JI and the Section if General Thoracic Surger;', University if Washington, Seattle, WA. Address reprint requests to Stephen H Petersdorf, MD, Box 356043, University if Washington Medical Center, University if Washington, Seattle, WA 98195. COjJyright © 2000 b;' W.B. Saunders Compay!y 1043-0679/00/1201:-0003$10.00/0 doi:10.1053/stcs.2000.16736

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nents. Lymphomas of the mediastinum usually arise in the lymph nodes, but rarely, other tissues such as the thymus or thyroid gland may be the site of the primary disease. The differential diagnosis of malignant processes in this location includes thymoma, germ cell tumors, and thyroid neoplasms. The most common lymphoproliferative disorders with mediastinal presentation are Hodgkin's disease, lymphoblastic lymphoma, and mediastinal large cell lymphoma. Therefore, it is essential to have an adequate tissue diagnosis not only to confirm the diagnosis of lymphoma but also to distinguish these different histologic entities that are very curable but are treated with very different chemotherapy protocols.

Presentation Lymphoma is among the more common mediastinal neoplasms. Most frequently, lymphoproliferative disorders affect the mediastinum as part of a generalized process, but they may present as a primary mediastinal mass without other adenopathy. Although Hodgkin's disease and non-Hodgkin's lymphoma share some features, they are distinct clinical entities. Hodgkin's disease, which accounts for approximately 20% of lymphomas, is more likely to have involvement of the mediastinum than nonHodgkin's lymphoma: 50% to 70% of patients with Hodgkin's disease have such involvement. l Women

Seminars in Thoracic and Cardiovascular Surgery, Vol 12, No 4 (October), 2000: pp 290-300

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account for 70% of Hodgkin's disease patients with mediastinal disease. 2 Mediastinal involvement with non-Hodgkin's lymphoma may be seen in 20% of patients with this diagnosis. In patients with a mediastinal component of generalized non-Hodgkin's lymphoma, this will mostly be seen in mediastinal and hilar lymph nodes and may occur with nearly all histologic subtypes of non-Hodgkin's lymphoma. However, the 2 most common histologic subtypes that present with localized mediastinal involvement, mediastinal large cell lymphoma and lymphoblastic lymphoma, appear to arise from thymic tissue. 3,4 Patients with mediastinal lymphoma usually present with symptoms related to mediastinal disease if there is bulky adenopathy. Patients often have symptoms that are a consequence of impingement of the lymphoma on structures within the mediastinum, usually in the anterior or middle compartments. Several vital structures may be compressed by or involved with malignant lymphoma, including the trachea, heart, great vessels including the superior vena cava, esophagus, and thyroid gland. Patients with bulky adenopathy are more likely to present with symptoms attributable to compression of one or more of these vital structures. Superior vena cava syndrome (SVC syndrome) is common in both Hodgkin's disease and mediastinal large cell nonHodgkin's lymphoma. Presenting symptoms associated with SVC syndrome may include upper extremity and facial edema, venous engorgement, and shortness of breath. The differential diagnosis of patients presenting with SVC syndrome includes lymphoma, thymoma, lung cancer, germ cell tumor, and breast cancer. Other presenting complaints associated with mediastinal lymphoma may include shortness of breath due to direct tracheal compression, hoarseness due to recurrent laryngeal nerve involvement, dysphagia due to esophageal compression, and chest pain due to pericardial, pleural, or chest wall invasion. Fevers, night sweats, and weight loss are common systemic complaints that are frequently seen in patients with lymphoproliferative disorders. Patients may show evidence of supraclavicular adenopathy or of diffuse adenopathy. Pleural and pericardial effusions may also be present. Furthermore, patients with a histologically high-grade tumor (ie, lymphoblastic lymphoma) may present with a rapid onset of symptoms over a period of hours or days, because the tumor may reach a critical mass within a short period of time.

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Diagnosis When patients present with complications attributable to a mediastinal mass, definitive histologic confirmation of a lymphoproliferative process is essential to determine an appropriate treatment plan. Because a number of mediastinal neoplasms such as thymoma and germ cell tumor may present with mass lesions in an identical location, adequate tissue diagnosis is important to confirm the presence of lymphoma and to identify its histologic subtype. Initial evaluation typically includes a chest roentgenogram and a computed tomography (CT) scan of the chest, abdomen, and pelvis. CT examination is critical in defining the true extent of tumor, other related masses or adenopathy, and compression or invasion of adjacent structures and for assessing characteristics of heterogeneity, tumor margins, and invasiveness for making a presumptive radiologic diagnosis. CT imaging also provides the best assessment of the optimal site and approach for tissue diagnosis. Magnetic resonance imaging (MRI) scans also may be used to evaluate the mediastinum, particularly in those patients who cannot receive iodinated contrast. MRI is also superior to CT imaging for defining lesions in the posterior mediastinum that may extend into the spinal canal. MRI has the advantages of multiplanar reconstruction and provides the best assessment of vascular invasion. However, CT imaging remains superior in determining pathologic calcification as well as spatial planes,5 and MRI rarely adds enough significant diagnostic information to warrant its routine use. Once the extent of mediastinal involvement has been determined, histologic diagnosis must be pursued. If there is peripheral adenopathy, such as a supraclavicular or axillary lymph node, an excisional biopsy under local anesthesia provides an adequate volume of tissue with intact nodal architecture for histologic diagnosis and subtyping. However, in many instances of mediastinal lymphoma, the disease is localized to the mediastinum, and more invasive procedures are required. Several techniques may be considered to confirm the histologic diagnosis (Table 1). Fine needle aspiration (FNA) of a mediastinal mass is never adequate to obtain sufficient tissue to establish an adequate histologic diagnosis of lymphoma. This technique may confirm an epidermoid neoplasm or infection but does not provide adequate sample to establish the diagnosis of lymphoma.

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Table 1. Biopsy Techniques to Obtain Adequate Histologic Diagnosis of Mediastinal Lymphoma Core needle biopsy Anterior mediastinotomy Mediastinoscopy Median sternotomy Thoracotomy

Although a FNA may establish malignancy and suggest lymphoma, treatment depends on distinguishing Hodgkin's disease from non-Hodgkin's lymphoma as well as the subtypes of non-Hodgkin's lymphoma, and unfortunately, an FNA is not adequate to determine the type or subtypes of lymphoma. Alternatively, transthoracic cutting needle biopsy usually can be performed with CT, fluoroscopic, or ultrasounographic guidance for anterior mediastinal lesions. The contraindications to such a procedure include the presence of a hydatid cyst, a bleeding disorder, a suspected vascular lesion, or a resectable primary mediastinal tumor such as a thymoma or teratoma. Relative contraindications to a transthoracic core-needle biopsy are advanced emphysema and pulmonary hypertension. One of the potential inadequacies of this technique is the inability to obtain a sufficient biopsy sample to make an accurate evaluation of the type or subtypes of lymphoma. However, core-needle biopsy may be a useful technique if adequate tissue samples are obtained. Zinzani et al 6 were able to diagnose lymphoma in Sl % of patients who underwent a biopsy with a 1.2- to I.S-mm Menghini biopsy instrument. Patients were limited to those who had a mass at least 4 cm in size and less than 3 cm from the chest wall. Mediastinoscopy, anterior mediastinotomy, or even median sternotomy or thoracotomy may be required to obtain adequate tissue. Mediastinoscopy has historically been the procedure of choice because it is a safe, well-tolerated procedure that has a high likelihood of obtaining a diagnosis with minimal morbidity.7 However, most mediastinal lymphomas present as anterior mediastinal masses, with the bulk of tumor in the prevascular tissue planes. Although tumor bulk may give the impression that the tumor is in a paratracheal location, if it is arising anterior to the great vessels it may be difficult or impossible to achieve a tissue diagnosis by the cervical mediastinoscopy approach. However, mediastinoscopy provides excellent access and is the preferred approach for adenopathy or tumor in the paratracheal, subcarinal, or tracheobronchial angle portions of the middle mediastinum. An anterior (parasternal) mediasti-

notomy, or Chamberlain procedure, provides the best surgical access for biopsy of a mass presenting in the anterior mediastinum. Elia et al 8 compared cervical mediastinoscopy with anterior mediastinotomy for the diagnosis of mediastinal lymphoma. Patients were divided into 4 groups. Twenty-two patients with an anterior mediastinal mass underwent mediastinoscopy, 19 with a middle mediastinal mass underwent mediastinoscopy, and the remaining 54 patients were randomly selected to undergo either mediastinoscopy or anterior mediastinotomy. The overall diagnostic accuracy was SO.43% for cervical mediastinoscopy and 95.91 % for anterior mediastinotomy. This difference was statistically significant (P < .025). Nine patients who underwent a cervical mediastinoscopy required a median sternotomy or thoracotomy to obtain the diagnosis, whereas 2 patients who underwent anterior mediastinotomy required a second procedure. Both procedures appear to have a high likelihood of success in obtaining the diagnosis, but they require surgical knowledge of the mediastinal planes and procedural limitations to define the optimal approach with the highest diagnostic yield. Anterior mediastinotomy should be performed for anterior mediastinal lesions to avoid the frustration or diagnostic errors of an inappropriate mediastinoscopy, whereas mediastinoscopy is the preferred approach for most tumors in the upper middle mediastinum. Occasionally a patient may present with an extensive mediastinal mass strongly suggestive of a lymphoma, yet biopsies performed on large tissue samples obtained at mediastinoscopy or anterior mediastinotomy show only fibrosis and a possible inflammatory infiltrate. These patients may be incorrectly diagnosed with a variety of pathologies, including fibrosing mediastinitis or a desmoid tumor. If the clinical suspicion for lymphoma remains high, more aggressive techniques of tissue biopsy should be used to obtain larger pieces of diagnostic material. This may require a video-assisted thoracic surgical approach, median sternotomy, or thoracotomy. In our experience, specimens as large as 5 X 10 cm may be required to establish a firm diagnosis in cases of sclerosing Hodgkin's lymphoma with a large fibrotic and desmoplastic component. Patients with a bulky mediastinal mass may occasionally present with airway obstruction that requires intubation and mechanical ventilation. Therapeutic bronchoscopy can almost always provide immediate airway palliation by tracheal or tracheobronchial stenting to allow stabilization of the patient in order

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to complete the diagnostic workup, obtain a tissue diagnosis, and initiate therapy.9 Similarly, acute SVC syndrome with neurologic deterioration can usually be palliated by endovascular stenting to stabilize the patient until a response is seen in therapy. If it is necessary to initiate empiric therapy before obtaining a tissue diagnosis, a single dose of an alkylating agent or steroids may provide sufficient tumor shrinkage to relieve the acute symptoms while maintaining the malignant architecture necessary to achieve an accurate diagnosis. 2 On the other hand, radiation before a tissue diagnosis may preclude an accurate histologic diagnosis and therefore may compromise eventual curative therapy. Once the biopsy sample is obtained, it should be processed in a manner that permits classification of the lymphoma. Whenever lymphoma is suspected, a portion of the biopsy sample should be processed while it is fresh to perform flow cytometry and cytogenetics. Fresh frozen tissue should be maintained to perform additional studies such as cell surface marker studies, immunoglobulin gene rearrangement studies, or T-cell receptor studies. Although routine histologic studies may confirm the diagnosis of a lymphoproliferative disorder, cell surface marker studies may be necessary to distinguish Hodgkin's disease from non-Hodgkin's lymphoma or B-cell from T-cell non-Hodgkin's lymphoma. The three most common mediastinal lymphomas have distinct immunophenotypes.1O Hodgkin's disease usually expresses cluster differentiation antigens CDl5 and CD30. Large cell lymphoma of the mediastinum, which is a B-cell process, is usually positive for CD45 as well as the B-cell lineage markers CD19, CD20, and CD22. Lymphoblastic lymphoma is usually a T-cell malignancy that commonly affects children and young adults. The immunophenotypic markers for this lymphoma reflect T-cell origin, with positive markers including the lymphoid marker CD45 and that for terminal deoxynucleotidyl transferase (TdT) , but lymphoblastic lymphoma also expresses the pan-T-cell markers CD2, CD3, CD5, CD7, CD43, and CD45RO. Many of these antibodies are effective only on fresh frozen tissue, so all biopsies samples should be processed to have both frozen and paraffin-embedded tissue available for study.

well as extent of disease. Staging procedures are standard for every patient with lymphoma. These studies include a detailed history with attention to shortness of breath and B symptoms, which include fever (greater than 10 1OF), night sweats, and weight loss. Physical examination should include measurement of palpable lymph nodes, liver, and spleen. Laboratory evaluation should include a complete blood count with differential, renal function evaluation, liver function tests including lactate dehydrogenase (LDH) determination, determination of the uric acid level, and an arterial blood gas measurement if there is any evidence of respiratory compromise. The LDH level is an important prognostic factor because it is frequently elevated in high-grade lymphomas such as Burkitt's lymphoma, diffuse large cell lymphoma, and lymphoblastic lymphoma. The LDH also can be used to assess response during treatment. Additional imaging studies should be performed for both Hodgkin's disease and nonHodgkin's lymphoma to determine the extent of disease, which is critical when constructing the therapeutic plan and establishing the prognosis, particularly for Hodgkin's disease. These studies should include a CT scan of the chest, abdomen, and pelvis and a bone marrow examination. These studies should permit clinical staging of the patient by the Ann Arbor Staging System (Table 2). Surgical staging of the mediastinum and hilar nodes is not required to enhance this staging. The definitive staging procedure for Hodgkin's disease, the staging laparotomy, is almost never performed given advances in management of this disease using chemotherapy. Additional studies such as gallium scanning or fluorodeoxyglucose-I8-Positron Emission Tomography (FDG-PET) may be very useful in guiding Table 2. Ann Arbor Staging System for Lymphoma Stage I Stage II

Stage III

Stage IV

Evaluation and Staging The management of lymphoproliferative disorders is determined by histologic analysis of the neoplasm as

Involvement of a single lymph node region or a single extralymphatic organ or site Involvement of 2 or more lymph node regions on the same side of the diaphragm or localized to an extralymphatic organ or site by extension Involvement oflymph node regions on both sides of the diaphragm or localized involvement of an extralymphatic site (IIIe), spleen (Ills), or both (IIIse) Diffuse or disseminated involvement of I or more extralymphatic organs with or without associated nodal involvement

System abbreviations used for all stages: A, asymptomatic; B, fever > 10 1°F, night sweats, and weight loss greater than 10% of body weight; E, extranodal site; S, spleen.

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therapy and assessing response, particularly for those patients who present with a large mediastinal mass. Imaging with FDG-PET may provide additional staging information that may not be detected by CT.!!

Management of Specific Mediastinal Lymphomas Hodgkin's Disease Hodgkin's disease is the most common primary lymphoma of the mediastinum. Hodgkin's disease is associated with a bimodal age distribution, affecting young adults and the elderly. It is usually characterized by an orderly progression of lymph node involvement so that patients with extensive mediastinal Hodgkin's disease may present with low cervical or supraclavicular lymphadenopathy. Mediastinal involvement with Hodgkin's disease is more common in young women, who often present with rapid onset of symptoms caused by bulky mediastinal adenopathy. These patients may have evidence of SVC syndrome as well classic B symptoms such as fever, night sweats, and weight loss. There are 5 histologic subtypes of Hodgkin's disease (Table 3). Patients with lymphocyte-predominant and nodular sclerosing Hodgkin's disease generally have a better prognosis; furthermore, these subtypes typically present with early-stage disease. Patients with mixed cellularity or lymphocytedepleted Hodgkin's disease are more likely to present with advanced disease. The majority of patients with mediastinal Hodgkin's disease have the nodular sclerosing subtype. The treatment of Hodgkin's disease is determined by the stage of disease. All histologic subtypes are treated in a similar manner, so staging of the disease is essential to determine appropriate therapy. Staging procedures have been previously described; rarely, procedures such as lymphangiography are also performed in addition to routine imaging. Historically, the purpose of staging is to determine whether patients can be treated with radiotherapy alone. Patients with stage III and stage IV Table 3. Histologic Subtypes of Hodgkin's Disease Subtype

Frequency (%)

Lymphocyte-predominant Nodular sclerosing Mixed cellularity Lymphocyte-depleted Lymphocyte-rich classic Hodgkin's disease

5-15 50-70 20-40 5-10 5-10

disease should be treated with chemotherapy for 6 to 8 cycles. Radiotherapy is particularly appropriate for early-stage, asymptomatic Hodgkin's disease; up to 95% of patients with pathologically staged (ie, staging proven with exploratory laparotomy) IA or IIA Hodgkin's disease and low-volume mediastinal adenopathy can be cured by mantle radiotherapy.!2 Patients who are symptomatic with B symptoms are less likely to be cured, with 75% of these patients achieving long-term disease-free survival with radiotherapy alone.!3 Although radiotherapy has been shown to be an effective therapy for early-stage Hodgkin's disease, long-term complications such as cardiovascular disease and secondary neoplasms are increased in patients who receive radiotherapy, which adversely impacts long-term survival. Since radiotherapy was introduced as the modality of choice for early-stage Hodgkin's disease, effective chemotherapy regimens have been developed that may be associated with decreased long-term complications. Clinical trials are currently underway to determine whether patients with stage IA, IB, and IIA lowvolume disease should be treated with limited chemotherapy such as 2 to 4 cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) and involvedfield radiotherapy rather than extensive radiotherapy. The addition of chemotherapy to the treatment of patients with low volume disease obviates the need for staging laparotomy. Early results from such an approach appear quite promising. Santoro et aP4 from Milan treated 114 patients with stage IA, IB, and IIA disease with 4 cycles of ABVD followed by radiotherapy. With a median follow-up time of 38 months, there is 94% disease-free survival rate. Similar results have been reported by other groups. Although there has been no randomized trials published to date supporting such an approach and it is too early to know whether long-term complications will arise, combined modality therapy is rapidly being accepted as a standard approach for early-stage Hodgkin's disease. Patients with Hodgkin's disease and bulky mediastinal adenopathy at any stage of disease have a high rate of relapse when treated with radiotherapy or chemotherapy alone. Bulky adenopathy is defined as adenopathy greater than one third of the chest diameter on an upright anteroposterior chest radiograph. Similarly, large mediastinal adenopathy may also be defined as a thoracic ratio of 0.35 on CT scan. 15 The Stanford group!6 has reported a 45% disease-free survival rate for those patients with stage I or II disease and large mediastinal adenopa-

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thy treated with radiotherapy alone. Other studies have shown a similar poor prognosis for these patients treated with radiation therapy aloneP Patients treated with chemotherapy alone have a similarly poor prognosis. Combined modality therapy with radiotherapy and chemotherapy appears to provide a marked improvement in outcome for those patients with large mediastinal adenopathy. Although those patients who relapse after treatment with radiotherapy alone may achieve a remission with chemotherapy, the overall survival rate is still inferior to that of patients treated with initial combined modality therapy. IS In light of the poor outcome with single modality therapy, the standard of care for patients with large mediastinal adenopathy is combined modality therapy. Different approaches to combined modality therapy have been attempted with different sequences of treatment and different chemotherapeutic regimens. Combined modality therapy has been administered in different orders, including chemotherapy-radiotherapy, radiotherapy-chemotherapy, or the sandwich technique, in which half the chemotherapy is delivered before radiotherapy and the remainder is delivered at the conclusion of radiotherapy. Behar et al 19 from Stanford reported 48 patients with bulky mediastinal adenopathy treated between 1980 and 1988. Radiotherapy was administered to 40 Gy, with a shrinking field technique used after 15 to 20 Gy had been delivered. Chemotherapy consisted of either MOPP (nitrogen mustard, vincristine, procarbazine, and prednisone), ABVD, or pAVE (melphalan, vinblastine, and procarbazine). The actuarial survival and freedom from relapse rates were 84% and 89% at 9 years of follow-up. Other centers have produced similar results for combined modality therapy. Combined modality therapy with involved field radiotherapy is also appropriate for those patients with stage ill or stage N disease with large mediastinal adenopathyP In all large mediastinal adenopathy cases, patients should receive a full course of chemotherapy rather than the 2 to 4 cycles given for early-stage, nonbulky, disease. Although a very high proportion of patients with Hodgkin's disease and even those patients with large mediastinal adenopathy are cured, treatment-related complications have been observed in a significant percentage of patients. Most of these treatmentrelated sequelae are due to the effects of radiation therapy in the field. These complications include an increased risk of secondary malignancies, particularly breast cancer. Now that women who were cured

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of Hodgkin's disease are living longer, there appears to be an increased risk of breast cancer in those women treated with mantle radiotherapy. The risk appears greatest in those women who are under the age of 15 (relative risk, 136) at the time of treatment, but all women under the age of 30 appear to be at increased risk. These risks are also greater for those women who have received chemotherapy with the MOPP-based regimen. In the study by Hancock et al,2° the relative risk of dying from breast cancer for all women treated with mantle radiotherapy compared with a normal population was calculated to be 5.1. Women who have received mantle radiotherapy clearly need close observation, including early and frequent mammograms, to detect the possible occurrence of breast cancer. Likewise, the risk of lung cancer increases for those patients who have received mediastinal and lung radiotherapy. This is particularly true for those patients who continue to smoke cigarettes. The risk of secondary neoplasm continues to increase over time for those patients who receive radiotherapy and/or nitrogen-mustard-based chemotherapy. The risk of second neoplasm is much lower for those patients who receive ABVD. Several other complications may occur as a result of mediastinal and thoracic radiotherapy. Acute pericarditis with an effusion occurs in 20% to 50% of patients. 21 Chronic cardiac disease, including chronic constrictive pericarditis and an increased risk of coronary artery disease, may also occur after radiotherapy.22 Because the normal lung is invariably part of the radiation field, acute radiation fibrosis will occur in up to 20% of patients with Hodgkin's disease. A minority of these patients proceed to develop pulmonary fibrosis. Finally, because the thyroid gland is involved in the mantle field, thyroid dysfunction ranging from clinical hypothyroidism to Grave's disease or malignant thyroid nodules occurs in up to two thirds of patients. 23 Hypothyroidism may be a late phenomenon occurring more than 5 years after therapy. As a result of the high success rate but risk of long-term complications with current therapy for Hodgkin's disease, current clinical trials seek to optimize cure rate while minimizing long-term morbidity. Current issues being investigated include optimal chemotherapy and duration of therapy. For example, although ABVD is a preferable combination with regard to risk of second neoplasms, would a MOPP regimen be preferable to an ABVD regimen in combined modality treatment in which the cardiac (doxorubicin) and pulmonary (bleomycin) toxicities

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of ABVD may be exacerbated by radiotherapy to the thorax? One approach has been to administer intensive therapy on a weekly basis but to decrease the use of nitrogen mustard, adriamycin, and bleomycin when compared with a standard regimen such as MOPP or ABVD. This regimen, Stanford V, also combines involved-field radiotherapy. Early results from Stanford are promising, where 94 patients with bulky stage II disease or stage ill and N disease were treated. 24 The 6-year freedom-from-progression rate is 89%, but it is too early to assess long-term complications. At the completion of therapy for Hodgkin's disease with large mediastinal adenopathy, a residual mass often remains on chest radiograph or CT scan. This is particularly common in those patients with nodular sclerosing Hodgkin's disease. 25 The clinical dilemma raised by a residual mass is whether this represents persistent disease or fibrosis. Several approaches have been taken to resolve this dilemma. The most conservative approach is to monitor the mass by serial CT scans obtained every 4 to 12 weeks for a year. If there is no change in the mass, the residual mass probably represents fibrosis. Any increase in size of the mass is suspicious for tumor and should prompt a biopsy of the mass. Gallium scanning may be a useful diagnostic test; a negative gallium scan result, particularly in the setting of a positive pretreatment scan, can help distinguish fibrosis from residual disease. 26 Usually, either serial radiologic evaluation with CT scans or gallium scanning can provide sufficient information to indicate whether the mass is suspicious for residual tumor. Recently, the introduction ofFDG-PET scanning has been shown to be a more sensitive modality than gallium imaging for assessment of the viability of the residual mass. ii In general, this residual mass resolves over a time period of months to years.

Non-Hodgkin's Lymphoma Mediastinal involvement with non-Hodgkin's lymphoma is much more likely to be part of a generalized process than is Hodgkin's disease. Unlike Hodgkin's disease, for which treatment is determined by stage, management of non-Hodgkin's lymphoma is driven primarily by histology and only secondarily by the stage. The histologic designation describes the size and malignant appearance of the cells. There are multiple classification systems in existence. In the older Working Formulation, there are 10 subtypes of non-Hodgkin's lymphoma. 27 The histologic subtypes are classified in terms of their appearance as well as

their behavior, so that lymphomas are classified as low, intermediate, or high grades. The newer Revised European-American Classification of Lymphoid Neoplasms also encompasses lymphoid malignancies that are not well described in the Working Formulation. 28 One of these newly designated lymphomas is the primary mediastinal large B-cell lymphoma; this acknowledges that this mediastinal lymphoma is a unique entity. Once the histologic subtype is determined, staging procedures to establish the Ann Arbor stage should be pursued. The staging studies appropriate for patients with these or any of the other nonHodgkin's lymphomas include the same laboratory studies (including LDH determination) that would be obtained for patients with Hodgkin's disease: CT scans of the chest, abdomen, and pelvis and bilateral bone marrow biopsies. For patients with high-grade lymphomas with marrow involvement or patients with lymphoblastic lymphoma, lumbar puncture with cerebrospinal fluid examination should also be performed. Most patients have stage ill or N disease and are treated with chemotherapy. Follicular or low-grade lymphomas rarely present with bulky adenopathy or disease limited to the mediastinum. Patients with mediastinal adenopathy that is part of a generalized process who do not have bulky disease should be treated as appropriate for the subtype of lymphoma. Of all patients with non-Hodgkin's lymphoma, approximately 20% will have mediastinal involvement at the time of initial evaluation, and fewer than one third of these patients will have disease limited to the mediastinum. 29 Of patients with non-Hodgkin's lymphoma limited to the mediastinum, the vast majority of patients have either primary mediastinal large B-celllymphoma or T-cell lymphoblastic lymphoma. Lymphoblastic lymphoma. T-cell lymphoblastic lymphoma is a high-grade lymphoma that represents the lymphomatous version of acute lymphoblastic leukemia (ALL). Lymphoblastic lymphoma is less likely to be associated with circulating blasts and cytopenia when compared with ALL. This entity is typically found in children or young adults. There is a 2: 1 ratio of men to women with this disease. T-cell lymphoblastic lymphoma accounts for one third to two thirds of childhood lymphomas. 3D Between 75% and 80% of patients will present with an anterior mediastinal tumor mass that may be associated with SVC syndrome, pleural effusion, or pericardial effusion. 3i The cytologic evaluation of the pleural and pericardial fluid is rarely positive.

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The cell of origin for T-cell lymphoblastic lymphoma is probably the immature thymic T cell, although the cells seen in T-cell AlL are derived from a more primitive T-cell precursor. The cells are TdT positive, which is pathognomic oflymphoblastic lymphoma. Most patients present with a mediastinal mass, but adenopathy in other sites may be limited. However, bone marrow and central nervous system involvement is common in T -cell lymphoblastic lymphoma. All patients with lymphoblastic lymphoma need examination of the cerebrospinal fluid and subsequent treatment directed to the central nervous system with intrathecal chemotherapy and/or craniospinal radiotherapy. Lymphoblastic lymphoma is nearly always a T-cell process in children, and it is a T-cell process in 80% to 90% of adults. B-celllymphoblastic lymphoma is relatively rare; it is not associated with a mediastinal mass but often has marrow involvement and is characterized by a very aggressive course. If patients with lymphoblastic lymphoma are treated with a regimen intended for other lymphomas, such as CHOP (cyclophosphamide, hydroxydaunomycin, Oncovin, and prednisone), the prognosis is quite poor. However, significant improvement in therapy has been made by treating this disease in a manner similar to that used for childhood acute lymphoblastic leukemia. Most regimens use an intensive anthracycline-based induction regimen with consolidation, central nervous system prophylaxis with intrathecal chemotherapy with or without cranial radiotherapy, and maintenance therapy. Coleman et aPI have reported treatment results in 44 patients treated with a 4-phase protocol with induction, central nervous system prophylaxis, consolidation with 4 cycles of the induction therapy, and maintenance therapy with oral methotrexate and 6-mercaptopurine for I year. The overall complete response rate was 95%, with a 3-year freedom from relapse of 58%.31 Other investigators have had similar results with a high rate of complete response with this type of treatment approach. 32 Although these patients often present with bulky mediastinal disease, the use of mediastinal radiotherapy is uncommon because most patients achieve a complete response with chemotherapy. There has been no proven benefit from the addition of mediastinal radiotherapy in this setting. Patients at high risk of relapse appear to be those who present with an LDH greater than 1.5 times the normal value or those who present with stage IV disease. 33 The presence of bulky adenopathy, bone marrow, or cerebrospinal fluid involvement

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does not appear to confer a worse prognosis. For those patients who achieve a remission but are at high risk of relapse or those who do eventually relapse, more intensive treatments such as bone marrow transplantation should be considered. Mediastinal large cell B-cell lymphoma. Large cell lymphoma is the most common subtype of primary non-Hodgkin's lymphoma of the mediastinum in adults. This lymphoma appears to be a distinct clinical entity, given the differences in the behavior or natural history of diffuse large cell lymphoma in other locations, although some investigators believe that clinical features and outcome may not be dissimilar to large cell lymphoma in other locations. 34.35 This entity accounted for 2.4% of 1,403 patients reviewed for the Non-Hodgkin's Lymphoma Classification Project36 and may account for up to 7% of patients with non-Hodgkin's lymphoma seen in referral centers for thoracic surgery.4 The histologic features of this lymphoma are notable for large, clear cells and intertwined fibrous tissue. All 57 patients in Kirn et aI's studf7 had evidence of sclerosis, but the amount of sclerosis was variable. In fact, several investigators,35,37 including Todeschini et al,38 have noted the extensive sclerosis often found in mediastinal large cell lymphoma. However, the amount of sclerosis does not appear to affect the prognosis. This lymphoma is from B-cell lineage, and the cells are positive for markers CD45, CDI9, and CD20. These cells do not express CD21, which is characteristic ofB cells found in the thymus, suggesting a thymic origin for this neoplasm. Finally, these cells do not express surface immunoglobulin, which is unusual for B-cell neoplasms. 4 Evaluation of gene rearrangements in these patients raises the possibility of a relationship to Burkitt's lymphoma. Scarpa et aP9 evaluated 6 patients with this entity for the presence of the c-rrryc oncogene and the protooncogene bcl-2 and for evidence of the Epstein-Barr virus DNA sequences in the genome of these neoplastic populations. None of the patients had evidence of bcl-2 rearrangement or the Epstein-Barr-virus genome. There was evidence of alternation of c-nryc in 3 of the patients; 2 of these patients had rearrangements similar to that seen in endemic Burkitt's lymphoma and the third had a rearrangement similar to that seen in spontaneous Burkitt's lymphoma. Mediastinal large cell lymphoma has a number of unique clinical features. In general, this entity is most often seen in young women. The median age of diagnosis in most series is the early thirties. In most patients, the disease is limited to the thorax at

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presentation and is in stage I or II. Although typically limited to the thorax, when this lymphoma does spread it may be associated with unusual sites of spread, including an increased frequency of renal involvement. Although the lymphoma appears to originate from the mediastinum, most patients have disease extending beyond the mediastinal lymph nodes into the pleura, pericardium, and lung, with all of the complications of similar large mediastinal masses. As such, most patients present because of symptoms from the invasive lymphoma that may produce chest pain, cough, dyspnea, or symptoms from obstruction of the SVc. In general, these lymphomas are characterized by bulky adenopathy (> 10 cm) and are limited to the thorax with pleural and pericardial effusions. 4o Those patients who present with clinically significant pericardial or pleural effusions may require drainage, but few patients require pleurodesis, given the chemotherapy responsiveness of this neoplasm. The prognosis associated with the diagnosis of mediastinal large cell lymphoma has historically been thought to be poor; however, recent data suggest that the prognosis may not be so dismal. An early series by Lichtenstein et aP4 noted a 20% long-term disease-free survival rate. Newer series show improvement in survival (Table 4) that is similar to survival when diffuse large cell lymphoma presents in other locations. Most patients achieve a remission, and the majority of patients are cured. All patients were treated with an anthracycline-based regimen. Although none of the patients in the Todeschini study 8 obtained a complete remission with CHOP and all required more intensive regimens, patients in the other studies obtained complete responses with CHOP as well as with more intensive regimens. The optimal chemotherapy regimen for mediastinal large cell lymphoma has not been determined, but CHOP has not been proven to be inferior to more intensive regimens in the treatment of Table 4. Treatment Outcome for Patients With Mediastinal Large Cell Lymphoma

Study

Jacobson et al4 ! Todeschini et aP8 Kim et aP7 Abou-Elella et al35

5-Year Disease-Free % Number Complete Survival Rate if Bulk Remission (%) Patients Disease Rate ("h)

30 21 57 43

65 76 75 53

80 62 53 63

59 57 45 38

diffuse large cell lymphoma in other locations. 41 However, there is a suggestion that combined modality therapy with chemotherapy and radiotherapy is superior to chemotherapy alone. In early studies, combined modality therapy with mediastinal radiotherapy was used sporadically. Twenty patients in the Kim study 7 received radiotherapy; there was a decreased overall relapse rate in the radiotherapy group that did not achieve statistical significance. Other studies have likewise suggested a benefit for combined therapy.4 Prognostic features have been analyzed in each of the aforementioned series. In the review by Jacobson et al,41 the presence of bulky disease was associated with an increased risk of relapse. In the larger series by Kim, the presence of pleural of pericardial effusion was the single most significant risk factor for relapse, and the presence of effusion did not correlate with the presence of bulky disease. Almost all patients with pleural effusion relapsed. Other investigators have not shown the adverse effect of pleural effusion on presentation. Bulky mediastinal adenopathy was a risk factor if an effusion was not present. Other factors associated with an increased risk of relapse include the presence of 2 or more extranodal sites of disease at presentation, residual mass at the conclusion of chemotherapy, the presence of a positive gallium 67 scan result at the conclusion of chemotherapy, or an LDH level 3 times higher than normal at presentation. Smith40 has reported that patients who have 100 mL of residual tumor on posttreatment CT scan have an increased risk of relapse. Like patients treated for Hodgkin's disease, patients with mediastinal B-celllymphoma may have a residual mass after therapy. These patients should be followed-up closely with serial CT scans or be considered for FDG-PET imaging or gallium scanning. Once these patients relapse, they should be considered for autologous stem cell transplant. Fortunately, the majority of patients do well with aggressive initial therapy.

Conclusion The mediastinum is a common site for the development oflymphoma in children and young adults. The most notable mediastinal lymphomas-Hodgkin's disease, lymphoblastic lymphoma, and mediastinal large cell lymphoma-present with bulky adenopathy, and patients are symptomatic from the invasive lymphoma. Careful pathologic diagnosis as well as staging is critical to a successful outcome. Inadequate

~)lmplwproliferative Disorders

diagnosis and staging may lead to inappropriate therapy and a poor outcome in a situation in which the patient may rapidly deteriorate. These lymphomas are aggressive, but they are curable with chemotherapy and, when clinically indicated, radiotherapy. Recognition of the uniqu e behavior of mediastinal Hodgkin's disease with large mediastinal adenopathy, lymphoblastic lymphoma, and mediastinal large cell lymphoma should lead to appropriate management and, ultimately, to further clinical investigation to define the optimal management of patients with mediastinallymphoproliferative disorders.

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