156 - Mediastinal Parathyroids
Editors: Shields, Thomas W.; LoCicero, Joseph; Ponn, Ronald B.; Rusch, Valerie W.
Title: General Thoracic Surgery, 6th Edition
Copyright 2005 Lippincott Williams & Wilkins
> Table of Contents > Volume II > The Mediastinum > Section XXIX - Primary Mediastinal Tumors and Syndromes Associated with Mediastinal Lesions > Chapter 184 - Diagnosis and Treatment of Mediastinal Lymphomas
Chapter 184
Diagnosis and Treatment of Mediastinal Lymphomas
Sonali Smith
Korst van Besien
Lymphomas are heterogeneous disorders, with variable clinical presentation and course, and correct histopathologic classification is essential for their appropriate management. Recent classification systems rely heavily on disease histology, but also incorporate data from immunophenotyping, cytogenetic analysis, and molecular assays. The most commonly used system is the Revised European American Lymphoma (REAL) classification. Harris and others (1994) schema or the more recent World Health Organization (WHO) classification, published by Jaffe and collaborators (2001), represents a slightly modified version of the REAL classification. A modified classification of lymphomas for clinical use as provided by Hiddemann and colleagues (1996) is shown in Table 184-1. Most subtypes of lymphoma can occasionally involve the mediastinum, but several entities have a unique affinity for the mediastinum, and their clinical features are often related to the presence of a mediastinal mass. These include Hodgkin's lymphoma, primary mediastinal B-cell lymphoma (PMBL), and lymphoblastic lymphoma. Much of this chapter focuses on Hodgkin's lymphoma, which has been reliably diagnosed and studied for close to five decades. PMBL and lymphoblastic lymphoma have been recognized as unique disease entities with a tropism for the mediastinum in the past decade. They are discussed in some detail, as is a relatively common nonmalignant disorder called Castleman's disease. The diagnosis and management of long-term sequelae of treatment for Hodgkin's lymphoma represents a unique challenge in which thoracic surgeons are often involved and which is discussed in some detail as well.
HODGKIN'S LYMPHOMA
Since Sir Thomas Hodgkin's first description of Hodgkin's disease in 1832, Hodgkin's disease has emerged as a unique malignancy, histologically characterized by the presence of Reed-Sternberg cells, as recently reviewed by Bonadonna (2000). The disease is currently considered a subtype of lymphoma, and the term Hodgkin's lymphoma was proposed in the WHO classification by Jaffe and collaborators (2001). Radiation therapy was the first treatment modality that demonstrated curability of Hodgkin's lymphoma. Staging laparotomy was essential for design of the radiation ports and for successful radiation treatment. More recently, the use of effective combination chemotherapy regimens along with improved radiographic techniques has obviated the need for staging laparotomy in most cases. Hodgkin's lymphoma is a very chemosensitive and radiosensitive disease. High cure rates can be obtained in newly diagnosed patients and in a considerable proportion of patients with recurrences. However, the successes have been tempered by the occurrence of serious late side effects resulting from radiation therapy and chemotherapy. In pediatric patients, growth retardation and infertility are of concern. Thus, as the number of long-term Hodgkin's lymphoma survivors increases, the major thrust of current clinical research in patients with early stages of Hodgkin's lymphoma is to minimize long-term toxicity while maintaining the high cure rate.
Epidemiology and Etiology
Hodgkin's lymphoma is a relatively uncommon malignancy with an estimated 7,000 new cases and 1,400 deaths in 2002. Medeiros and Greiner (1995) showed that there are generally two peaks in incidence: teenagers/young adults (ages 15 to 34 years) and adults over the age of 55 years. Overall, the recent American Cancer Society report (2002) suggests that the incidence is similar in men and women.
As with most malignancies, the etiology of Hodgkin's lymphoma is not definitively known. However, several risk factors have been proposed, including infection with lymphotrophic viruses, higher socioeconomic status, and aberrancies of the immune system. The contribution of Epstein-Barr
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virus (EBV) in the pathogenesis of Hodgkin's lymphoma has been investigated for nearly four decades. Reports by Herbst (1996), Jarrett (1996), and Glaser (1997) and their colleagues, as well as by many others, suggest that 25% to 50% of Hodgkin's lymphoma cases are associated with infection with EBV. Clonal EBV DNA has been detected in Reed-Sternberg cells (the malignant cell of origin for Hodgkin's lymphoma) by Anagnostopoulos (1989), Gledhill (1991), and Pallesen (1991) and their associates, as well as by many others. Recently, Skinnider and Mak (2002) summarized the data supporting the influence of EBV on cytokine production, which may underlie the clinical and pathologic manifestations of Hodgkin's lymphoma.
Table 184-1. Clinical Classification of Lymphoid Malignancies | ||
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Hodgkin's lymphoma also occurs in the setting of human immunodeficiency virus (HIV) infection. As such, it was one of the first malignancies designated as an acquired immunodeficiency syndrome (AIDS)-defining illness. Spina and colleagues (2000) reported a more aggressive course for HIV-associated Hodgkin's lymphoma, whereas a review of cases by Tsimberidou and colleagues (2001) showed a clinical outcome similar to that of patients without HIV infection.
Clinical Presentation
The majority of patients with Hodgkin's lymphoma present with nontender adenopathy, usually in the neck or supraclavicular area. Mediastinal involvement is commonly present and may become very large. It sometimes is the only site of disease. Mauch and colleagues (1993) reviewed 719 cases of Hodgkin's lymphoma and noted that 60% present with either cervical or mediastinal adenopathy. Regional disease presenting initially below the diaphragm (so-called subdiaphragmatic Hodgkin's disease) is distinctly rare.
Mediastinal involvement in Hodgkin's lymphoma, especially when bulky, is a poor prognostic factor. In the revised Ann Arbor staging system, bulky mediastinal adenopathy is defined as a mediastinal to thoracic width ratio of greater than one third. As reported by Hasenclever and Diehl (1998), as many as two thirds of patients present with mediastinal involvement. Those with very large masses have an inferior rate of freedom from progression and overall survival in a univariate (but not multivariate) analysis. The adverse prognostic factors in this analysis include low serum albumin, anemia (hemoglobin <10.5 g/dL), male gender, stage IV disease, age greater than or equal to 45 years, leukocytosis (>15,000 white blood cells/mm3), and lymphopenia (<600 lymphocytes/mm3).
Constitutional symptoms occur in approximately one third of patients and may consist of fatigue, diffuse pruritus, weight loss, fevers, or night sweats. The latter three symptoms comprise the classic B symptoms of malignant lymphomas. When present, they typically infer a more aggressive course of disease. As elegantly summarized by Kaplan (1972) other notable, but less common, symptoms
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attributable to Hodgkin's lymphoma include alcohol-induced pain and Pel-Epstein fevers. The pain associated with alcohol intake typically occurs quickly after consuming the beverage and may last from minutes to hours. Pel-Epstein fevers, first described in 1887, are cyclic temperature elevations typically with a 1- to 2-week periodicity. The fevers usually occur in the late afternoon and evening, only to normalize by morning. The prognostic significance of constitutional symptoms other than the classic B symptoms previously described is not known. However, recurrence of symptoms in a previously treated patient may signal disease relapse.
Diagnostic Evaluation
The diagnostic workup of Hodgkin's lymphoma includes obtaining an adequate tissue sample and a staging evaluation. The differential diagnosis of patients presenting with a mediastinal mass includes Hodgkin's lymphoma, PMBL, lymphoblastic lymphoma, Ki-1-positive anaplastic large cell lymphoma, primary mediastinal germ cell tumors, and rarely, thymomas and carcinomas. With rare exceptions, an accurate diagnosis of lymphoma can only be established by obtaining tissue for immunophenotyping, cytogenetics, and molecular assays in addition to classic histologic examination. Many of these tests require viable tissue, and it is therefore of the utmost importance that in addition to fixed specimens, fresh tissue be provided to the pathologist whenever a diagnosis of lymphoma is suspected. Mediastinal lymphomas, be they Hodgkin's or non-Hodgkin's lymphoma, are often fibrotic, and small biopsies may be difficult to interpret. A diagnosis of benign versus malignant process may be difficult, and subclassification may be impossible. In Hodgkin's lymphoma in particular, the malignant cell of origin, the Reed-Sternberg cell, is relatively rare in comparison with the intense background lymphoid reaction. Its recognition is essential for diagnosis, and such cells may not be present if the biopsy is small. Tissue obtained by fine-needle aspiration (FNA) or core biopsy is generally not sufficient for diagnosis. Samples obtained by mediastinoscopy, an excellent technique for staging carcinomas, are not always adequate for diagnosis of mediastinal lymphomas. If no easily accessible peripheral lymph node is present, a video-assisted thoracic surgical (VATS) procedure or a limited thoracotomy may be required for establishing the diagnosis.
Once a diagnosis of Hodgkin's lymphoma is confirmed, standard staging consists of total body computed tomographic (CT) scans and a bone marrow biopsy core and aspirate, as discussed by Cheson and associates (1999). Blood tests for lymphoma staging should include routine blood counts, serum lactate dehydrogenase (an important prognostic marker in many lymphomas), liver function tests, and kidney function tests. This allows determination of a clinical stage, which then guides further management.
Staging laparotomy with splenectomy and lymph node sampling has been widely used in the past. The importance of staging laparotomy in Hodgkin's lymphoma is based on an early observation by Rosenberg and Kaplan (1966) that Hodgkin's lymphoma spreads in an orderly and predictable fashion. This allows precise pathologic staging, thus avoiding the risk of undertreatment or overtreatment. However, the use of systemic chemotherapy even in early-stage disease, the ability to effectively salvage patients who relapse, and improvements in radiologic staging have all decreased the need for precise surgical staging. Staging laparotomy is therefore no longer considered part of the standard approach to Hodgkin's lymphoma. Exploratory laparotomy is still occasionally recommended in patients for whom chemotherapy is contraindicated, usually because of concern for infertility or risk for secondary malignancies.
Lower extremity lymphangiography was also part of standard staging in the past because its sensitivity exceeds that of abdominal CT scans. Because combined modality therapy is more commonly used and the expertise with lymphangiography has decreased, this test is now rarely used.
An area of considerable interest and controversy is the role of gallium 67 (67Ga) or positron emission tomographic (PET) scanning in Hodgkin's lymphoma and other malignant lymphomas. Both are extremely sensitive imaging tools, but their optimal use is as yet undefined. Potential applications include using them as part of routine staging, to evaluate response to treatment, to evaluate residual masses following treatment, and to predict risk for relapse in such patients. As summarized by Bekerman and co-workers (1984), 67Ga is preferentially taken up by active tumor as compared with fibrous tissue, which is particularly helpful in evaluating abnormal mediastinal masses in patients with Hodgkin's lymphoma. Kostakoglu and colleagues (1992) performed a retrospective analysis of 30 adult Hodgkin's lymphoma patients with mediastinal masses following therapy and compared histologic examination with 67Ga with single-photon emission computed tomographic (SPECT) imaging. They reported a sensitivity and specificity of 96% and 80%, respectively. Many other investigators also find 67Ga with SPECT a useful tool in assessing response to therapy, particularly for residual mediastinal abnormalities following treatment. Bogart and coinvestigators (1998) found 67Ga uptake following treatment predictive of recurrence but not helpful in defining remission.
More recently, fluorine 18 fluorodeoxyglucose PET scanning has received increasing attention. Several groups, including Mikhaeel and associates (2000), have used PET to assess residual masses in Hodgkin's lymphoma and non-Hodgkin's lymphoma following treatment. In the latter study, 32 lymphoma patients had residual masses (15 with Hodgkin's lymphoma) after initial treatment; PET yielded positive results in 9 patients, of whom, with a median follow-up of 38 months, 8 eventually relapsed. Of the 23 patients with negative PET scans, only 2 relapsed. Two other reports, both by Jerusalem and colleagues (1999, 2001),
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suggested that PET positivity during treatment predicts for treatment failure and that PET positivity following treatment connotes a poorer prognosis. For example, among 54 patients with malignant lymphomas, all 6 patients with positive PET results after treatment relapsed, whereas only 5 of 19 (26%) patients with a positive CT scan and negative PET results relapsed. This resulted in a positive predictive value (PPV) of 100% for PET as compared with a PPV of 42% for CT scanning. However, more recent reports by de Wit and co-workers (2001) show a PPV of only 45%, indicating that not all patients with residual PET positivity are destined to relapse. In summary, the exact role of either 67Ga or PET is not clear, although it is likely that these tools will continue to be used and a more precise understanding of the significance of positive scans will be developed.
Management
The management of Hodgkin's lymphoma has evolved considerably over time. Initial reports showing the efficacy of radiation therapy led to significant optimism that Hodgkin's lymphoma could be cured. In the 1970s through the 1990s, knowing the precise stage of Hodgkin's lymphoma was critical in determining the treatment plan. The staging of Hodgkin's lymphoma based on the Ann Arbor classification and Cotswolds revision as reported by Lister and associates (1989) is summarized in Table 184-2. Staging laparotomies with splenectomy and lymph node sampling determined the radiation ports. This staging method was called pathologic staging as opposed to clinical staging, which relied on physical examination and radiologic tests. Currently, management of Hodgkin's lymphoma, with the exception of very early-stage favorable disease, uses chemotherapy as the mainstay of treatment, with radiation therapy used mainly as a consolidative modality. Improved radiographic technology and the use of systemic chemotherapy has obviated the need for pathologic staging. An excellent summary of the history of Hodgkin's lymphoma is provided by Bonadonna (2000).
Early-Stage Disease
The traditional management of patients with early-stage Hodgkin's lymphoma (stage IA to IIA) has been entirely radiation based. Using extended field radiation and pathologic staging, cure rates of 80% to 90% are achieved in such patients. The high incidence of secondary malignancies and other treatment sequelae (as will be noted) in this otherwise favorable risk group has called the radiation ports and doses into scrutiny. Modern treatment protocols often involve a moderate amount of chemotherapy and limited ( involved field ) irradiation. As reported by Press and colleagues (2001) on behalf of a large intergroup randomized phase III trial, such combined modality therapy was superior to subtotal lymphoid radiation in terms of failure-free survival (94% vs. 81%, p < 0.001). Given the relatively short follow-up of just over 3 years, the impact on overall survival and late toxicities remain to be determined. Other studies by Horning (1997) and Brusamolino (2000) and their colleagues also support the use of combined modality treatment for early-stage disease. The optimal treatment of patients with early-stage Hodgkin's lymphoma is still evolving, and whenever possible, enrollment in a clinical trial should be advocated.
Advanced Disease
The foundation of treatment of patients with advanced-stage Hodgkin's lymphoma (i.e., those with stage III and stage IV disease, as well as those with constitutional symptoms) is systemic chemotherapy. The original MOPP regimen (mechlorethamine, vincristine, procarbazine, prednisone), has largely been supplanted with the equally effective and less toxic ABVD regimen (adriamycin, bleomycin, vinblastine, dacarbazine) proposed by Bonadonna and associates (1986). Canellos and colleagues (1992)
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reported a randomized phase III study comparing MOPP and ABVD and an MOPP/ABVD combination. ABVD produced an 82% complete remission rate and 93% overall response rate compared with a 77% complete remission rate and 93% overall response rate for MOPP. The combination of MOPP/ABVD was equally efficient to ABVD, but more toxic. Canellos and Niedzwiecki (2002) recently updated these data with a median follow-up of more than 14 years. ABVD had a superior failure-free survival rate of approximately 60% at 10 years compared with approximately 40% with MOPP chemotherapy. Other advantages of ABVD compared with MOPP include a decreased incidence of infertility and of secondary malignancies. On the other hand, bleomycin-induced pulmonary toxicity and adriamycin-related cardiac toxicity are of concern.
Table 184-2. Hodgkin's Lymphoma Staging: Ann Arbor Classification (Cotswold Revision) | ||||||||||
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Among patients with advanced disease, disease recurrence is still relatively common, and newer and more intensive regimens, including combined modality approaches, are actively being investigated. For example, the Stanford group, as reported by Horning and coinvestigators (2002), has advocated an abbreviated course of intensive chemotherapy, called the Stanford V regimen, followed by adjuvant radiation therapy to sites of bulky disease, whereas the German Hodgkin's Lymphoma Study Group is examining the BEACOPP regimen (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone). Diehl and associates (2001) recently reported a randomized study that showed that an escalated BEACOPP regimen resulted in improved survival compared to ABVD in patients with advanced Hodgkin's disease. Despite these data, the escalated BEACOPP regimen has not (yet) found widespread acceptance in the United States, mainly because of concerns over early toxicity and the potential for secondary leukemia. A randomized multiinstitutional intergroup study comparing ABVD versus Stanford V in advanced Hodgkin's lymphoma is currently underway in the United States. Preliminary results of an Italian randomized study reported by Levis and collaborators (2002) do not indicate an advantage to the Stanford V regimen.
Relapsed Disease
For patients with relapsed Hodgkin's lymphoma, and for those with primary refractory disease, the standard of care is high-dose chemotherapy followed by autologous hematopoietic stem cell rescue. Josting and colleagues (2000) showed that half of patients with primary refractory Hodgkin's lymphoma (defined as disease progression during front-line chemotherapy or progression within 3 months of completing front-line chemotherapy) were alive at 5 years if they underwent autologous stem cell transplantation (ASCT); this is compared with no survivors at 5 years for patients not undergoing ASCT. A prospective analysis by Ferme and associates (2002) shows a slightly lower overall survival rate of 30% at 5 years for this same group of primary refractory patients. Patients who initially respond to front-line therapy but eventually relapse fare quite a bit better with the use of ASCT. In the French GELA prospective analysis by Ferme and colleagues (2002), this group of relapsed patients enjoyed a 5-year overall survival rate of 76% following ASCT. However, other (albeit retrospective) analyses, such as one performed by Akpek and associates (2001), show only 37% overall survival at 5 years. Newer strategies in relapsed and refractory Hodgkin's lymphoma include allogeneic hematopoietic stem cell transplantation using either standard-dose or reduced-intensity conditioning regimens. Occasional patients with limited recurrences that occur outside the radiation fields can be successfully salvaged with localized radiation therapy.
Late Sequelae of Treatment
The successes in curing Hodgkin's lymphoma have unfortunately been countered by late treatment-related toxicity. Hancock and Hoppe (1996), as well as Mauch (1996) and Hudson (1998) and their colleagues, among others, have demonstrated that cumulative mortality from Hodgkin's lymphoma declines over time; however, among survivors, after 12 to 15 years following treatment, the mortality from nonlymphoma-related causes continues to increase and actually exceeds Hodgkin's lymphoma related deaths. Non-Hodgkin's lymphoma causes of death in long-term survivors can be mostly attributed to secondary malignancies (both solid tumors and hematologic malignancies) and to cardiovascular events. A population-based study by Dores and associates (2002) of over 30,000 patients with Hodgkin's lymphoma showed an increased risk for secondary cancers up to 25 years following treatment; the actuarial risk of a secondary solid tumor in this study was 21.9%. Both chemotherapy and radiation therapy appear to increase the risk for secondary malignancies. A recent review by Ng and associates (2002a) of 1,080 patients with early-stage Hodgkin's lymphoma confirmed and extended these observations. They reported a relative risk (RR) of 4.0 for death from non-Hodgkin's disease related causes even 20 years following treatment. This was primarily due to secondary cancers (RR = 11.2), including leukemia, non-Hodgkin's lymphoma, lung cancer, breast cancer, and sarcoma.
Another report by Ng and colleagues (2002b) evaluated more than 1,300 long-term Hodgkin's lymphoma survivors and found 181 second cancers and 18 third cancers. Seventy-two percent of the second malignancies were solid tumors, and a history of exposure to both chemotherapy and radiation therapy (i.e., combined modality therapy) increased the risk as opposed to treatment with either modality alone. Young women who receive radiation therapy to the mediastinum during puberty are at particular risk for the development of breast cancer, especially in medial locations, and should follow rigorous screening programs. Finally, the contribution of laparotomy and splenectomy to risk of secondary malignancies should be considered. Although
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laparotomy is no longer routinely performed, several investigators such as Ng (2002b), Dietrich (1994), and Munker (1999) and their associates have shown a higher incidence of secondary malignancies in this population. Whether this is related to chronic immunosuppression after splenectomy or another phenomenon is unknown.
Therapy-related myelodysplasia and secondary leukemias (t-MDS/t-AML) are of special concern among long-term Hodgkin's lymphoma survivors. These secondary leukemias are associated with typical cytogenetic aberrations and have a uniformly poor prognosis. The initial combination chemotherapy regimens such as MOPP proved to be very leukemogenic, with an estimated incidence of 3% to 5% in Hodgkin's lymphoma survivors, as reported by Delwail (2002) and Brusamolino (1998) and their associates. More current regimens, such as the widely used ABVD regimen, are less leukemogenic, with these same groups reporting less than 1% incidence for ABVD without radiation therapy. Several reports by Pedersen-Bjergaard (1993), one of us (SS) (2003), and Kantarjian (1986) and colleagues have demonstrated that t-MDS/t-AML can also occur after radiation therapy in the absence of chemotherapy. Whether radiation therapy is additive or synergistic with chemotherapy remains widely debated. At least two forms of t-MDS/t-AML have been described. The first type usually occurs after exposure to alkylating agents with a latency of 5 to 7 years following chemotherapy. Most patients have a deletion involving chromosomes 5 or 7. The second type of t-MDS/t-AML is associated with exposure to topoisomerase II inhibitors (such as the epidophyllotoxins and anthracyclines). This type frequently involves a balanced rearrangement of the MLL gene at chromosome 11q23. As mentioned previously, t-MDS/t-AML has a grim prognosis. Although a select few can be cured by allogeneic stem cell transplantation, one of us (SS) (2003) and Ng (2002b) and coinvestigators, among others, reported a median survival of only 4 to 8 months.
Survivors of Hodgkin's lymphoma are also at a higher risk for cardiovascular complications, including accelerated coronary artery disease, chronic pericardial disorders, and valvular disease. The majority of cardiovascular complications can be attributed to mediastinal radiation therapy. Several groups, including Applefeld and Wiernik (1983), have found a high incidence of cardiac abnormalities in long-term Hodgkin's lymphoma survivors (46 of 48 patients) receiving 30 to 40 cGy to the chest. In contrast, Piovaccari and colleagues (1995) found only an 11% incidence (12 of 108 patients). A more recent review of 49 patients by Girinsky and colleagues (2000) showed a 21% incidence of cardiac complications at 15 years following treatment of Hodgkin's lymphoma. In this study, a radiation dose of greater than 40 Gy (but not the fraction size) appeared to increase the likelihood of cardiac complications. In each of these studies, radiation therapy emerged as the major risk factor for cardiovascular complications, while the contribution of chemotherapy appeared to be minimal. However, as Glanzmann and colleagues (1998) commented, few patients in these studies had received anthracyclines along with mediastinal irradiation, which precludes a more statistically significant analysis of chemotherapy effect. Anthracyclines, including adriamycin, have well established cardiac toxicity. It is possible that more recent patients, treated with anthracycline-containing chemotherapy regimens and irradiation will be at higher risk for late cardiac complications.
The most common radiation-related cardiac abnormalities appear to be pericardial disease and valvular disease (up to 60%), although these are usually not symptomatic. More uncommon, but of greater concern are accelerated coronary artery disease and sudden death. Radiation therapy appears to be the major risk factor for coronary artery disease, but Glanzmann and associates (1998) found that the risk for coronary artery disease in patients without typical cardiovascular risk factors (such as obesity, tobacco use, diabetes mellitus, hypertension, and hypercholesterolemia) was actually not higher than population controls. An important concept in management of patients exposed to mediastinal irradiation, discussed by Handa and colleagues (1999) and in a brief report by Mittal and associates (1996), who become candidates for coronary artery bypass grafting is that the majority have coexisting valvular abnormalities that may require concomitant surgical repair.
Children and adolescents comprise a significant minority of patients with Hodgkin's lymphoma, and special consideration of long-term treatment-related complications in this population is warranted. Historically, in the treatment era of Hodgkin's lymphoma, high doses of radiation formed the backbone of therapy. This translated into severe consequences for children and adolescents in terms of musculoskeletal growth retardation, as discussed by Donaldson and Kaplan (1982), and early breast cancer, as reviewed by Bhatia and co-workers (1996), as well as by Donaldson and Hancock (1996). In addition, the same risks for secondary malignancies and cardiovascular complications in adults discussed previously apply to children. Hancock and colleagues (1993) reported their experience in 635 patients who were treated for Hodgkin's lymphoma prior to the age of 21 years. With a median follow-up of over 10 years, 12 have died of cardiovascular complications, including myocardial infarction, pericarditis, and valvular heart disease. In this study, the occurrence of cardiac complications was restricted to children who had received high-dose radiation therapy to the mediastinum. Mertens and associates (2001) recently reported a review of more than 20,000 5-year survivors of childhood cancer, including 2,383 patients with Hodgkin's lymphoma. Although disease recurrence contributed to death in 136 patients with Hodgkin's lymphoma, 192 patients died of second cancers, as well as cardiac and pulmonary complications of therapy. The transition to lower-dose (or elimination of) radiation therapy and increasing use of chemotherapy-based treatment plans has become more popular in pediatric populations, as demonstrated by a number of recent publications by Nachman (2002) and Schellong (1999) and their collaborators for
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cooperative groups. This may ultimately result in a reduced incidence of long-term side effects.
Finally, infertility used to be a major problem after MOPP chemotherapy, but is much less frequent after treatment with ABVD. In contrast, pulmonary fibrosis, mainly related to the use of bleomycin in the ABVD regimen is occurring more frequently.
PRIMARY MEDIASTINAL B-CELL LYMPHOMA
Hodgkin's lymphoma is the most common type of primary lymphoma of the mediastinum in teenagers and young adults. PMBL is slightly more common in patients in their late twenties and thirties. PMBL is a distinct clinicopathologic entity with unique phenotypic and molecular features that arises from an intrathymic B-cell population, as reviewed by one of us (KvB) and associates (2001). The disease can be difficult to distinguish from other diffuse large B-cell lymphomas (DLBCLs) by classic pathologic criteria, but has a quite distinctive clinical presentation. In most series there is a slight preponderance of women. Patients with PMBL present with a rapidly growing mass, originating from the anterior and superior mediastinum and surrounding structures. Patients with PMBL are commonly diagnosed because of symptoms arising from compression of mediastinal structures. This is in contrast to patients with Hodgkin's lymphoma who rarely have symptoms relating to a mediastinal mass. At initial presentation, superior vena cava syndrome is the most common complication occurring in approximately 30% of patients. Phrenic nerve palsy also occurs and when bilateral, can lead to respiratory failure. Dysphagia, hoarseness of voice, bilateral breast swelling in women, chest pain, and productive cough can also be among the presenting symptoms.
Clinical Presentation
At diagnosis, the mediastinal tumor may be palpable in the supraclavicular fossa, and PMBL often invades the lungs, pleura, and pericardium. Involvement of the bone marrow or extrathoracic structures is uncommon. As shown by Kirn (1993), Todeschini (1990), and Lazzarino (1993) and their colleagues, as well as by many others, at the time of disease recurrence, spread to parenchymal organs such as liver, kidneys, and brain is much more common. In those organs, a pattern of multiple metastases, reminiscent of hematogenous metastatic spread, can occur. Staging should be performed as recommended by the lymphoma working party and as described under the section for Hodgkin's lymphoma. Pleural or pericardial effusions are common and may be due to lymphomatous invasion or to obstruction of lymphatic return. Thoracentesis is useful to determine the nature of the effusion. Gallium scan and PET scanning are routinely used, although all the considerations to their use previously discussed under Hodgkin's lymphoma, apply here.
Diagnosis and Staging Workup
As in Hodgkin's lymphoma, accurate diagnosis of PMBL is dependent on an adequate tissue sample for histology, immunophenotyping, and molecular studies. Microscopically, there is a diffuse proliferation of medium-sized to large B-cells with a heterogenous morphology including diffuse mixed cell, diffuse large cell, and immunoblastic types. In many cases, cells with abundant cytoplasm, so called clear cells that are typical for PMBL, are preponderant. Strands of fibers or sclerosis are present to a variable degree in approximately half of the cases. PMBL is a B-cell tumor, as indicated by the rearrangement of the immunoglobulin gene and the expression of B-cell markers. [For a review of disease histology, see the report by one of us (KvB) and co-workers (2001).]
Etiology
The location of PMBL, occasional presence of epithelial-lined cysts, thymic lobules, and Hassall's corpuscles in biopsy specimens all indicate a thymic origin. Although the thymus is a major site of T-cell maturation, a thymic B-cell population with a unique immunophenotype characterized by expression of CD19, CD20, CD22, immunoglobulin M and absence of CD21 was initially described by Isaacson and associates (1987). PMBL likely originates from this CD19+/CD21+ thymic B-cell population. In contrast to some other lymphoma subtypes, diagnostic chromosomal abnormalities or molecular markers have not been found in PMBL.
Management of Primary Mediastinal B-cell Lymphoma
Anthracycline-containing chemotherapy, in the United States usually the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone), is generally accepted as the optimal initial management for patients with newly diagnosed PMBL, as it is for other patients with intermediate-grade lymphoma. As reported by Perez-Soler (1984) and Yahalom (1997) and their colleagues, emergency radiation therapy for patients with superior vena cava syndrome is usually not necessary. Some disagreement exists on which chemotherapy regimen to use and whether or not to consolidate some or all patients with high-dose chemotherapy or radiation therapy. Some centers have reported excellent results with standard anthracycline-based chemotherapy followed by radiation therapy to residual masses. Others have used intensive chemotherapy without consolidative radiation therapy with similar long-term
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results. There is general agreement that achievement of a complete remission is the best predictor for outcome in PMBL, and many centers have recommended consolidation with autologous transplantation for patients with bulky masses.
Patients with PMBL who achieve a response lasting longer than 18 months after diagnosis are likely to be cured. Treatment failure usually occurs either during initial treatment or within the first 6 to 12 months after completion of treatment. This again contrasts with Hodgkin's lymphoma, where late recurrences are much more common.
Radiation therapy has often been used as salvage treatment for patients with recurrences in the mediastinum. In contrast to patients with recurrent Hodgkin's disease, no durable remissions have been obtained in patients with recurrent PMBL. Hence, we do not recommend the use of radiation therapy for salvage. High-dose chemotherapy and autologous transplantation, on the other hand, have been relatively successful in patients with recurrent and refractory PMBL. Popat and coinvestigators (1998) reported a series of patients with recurrent or refractory DLBCL treated with high-dose chemotherapy and found that having PMBL was a favorable prognostic feature. Sehn and colleagues (1998) also performed a retrospective analysis of 35 patients with PMBL treated with high-dose cyclophosphamide, carmustine, and etoposide (CBV) plus ABMT. Patients with primary refractory disease had 58% long-term disease-free survival, and patients with relapsed disease had 27% long-term disease-free survival. The strongest predictor of progression-free survival was chemotherapy responsiveness immediately before transplantation. But even in chemotherapy-refractory patients, 33% long-term survival was observed.
LYMPHOBLASTIC LYMPHOMA
Clinical Presentation
Lymphoblastic lymphoma is a rapidly growing tumor of T-cell phenotype. The cells are morphologically indistinguishable from those of T-cell acute lymphoblastic leukemia. Patients are usually young men and present with bone marrow involvement, blood involvement, and a mediastinal mass. For an excellent review on this disorder, we refer to the review of Thomas and Kantarjian (2001).
Diagnosis and Staging Workup
In unusual cases, the disease is limited to the mediastinum, and a biopsy may be required for diagnosis. In most instances bone marrow biopsy and examination of the peripheral blood lead to a diagnosis, and lymph node or mediastinal biopsy is not necessary.
Lymphoblastic lymphomas are rapidly growing tumors. Expeditious diagnosis is essential and should be followed by prompt initiation of treatment. Prolonged staging procedures should be avoided, although most physicians obtain CT scans of the chest/abdomen and pelvis. Due to the propensity of high-grade lymphoma to spread to the central nervous system (CNS), a lumbar puncture should be a part of routine evaluation in each case.
Management and Prognosis
Intensive multiagent chemotherapy regimens designed for acute lymphoblastic leukemia are commonly used and result in a complete response rate of approximately 80%, with a long-term survival rate of up to 45%. Such regimens include a phase of intensive multiagent therapy, combined with and followed by CNS prophylaxis. CNS prophylaxis consists of chemotherapy or irradiation directed at minimizing the risk for relapse in the CNS. The last phase of treatment is a prolonged phase of approximately 2 years of low-dose maintenance chemotherapy. Similar regimens are used for the occasional patient with disease limited to the mediastinum. Radiation therapy to large residual masses can be considered after completion of treatment. Patients with adverse prognostic factors may be considered for consolidation with high-dose chemotherapy with autologous or allogeneic stem cell transplantation.
CASTLEMAN'S DISEASE
Castleman's disease consists of a massive growth of lymphoid tissue, either presenting in a localized or in a multicentric fashion. Histologically there is follicular hyperplasia and marked capillary proliferation. In the plasma-cell variant, there is a massive accumulation of polyclonal plasma cells in the interfollicular space. The localized form of the disease is usually asymptomatic and is found incidentally on chest radiographs as a mediastinal mass. Cases of abdominal localization have also been reported. As reviewed by Herrada and Cabanillas (1995) localized Castleman's disease is a self-limited process; surgical resection is usually curative.
As described by Peterson and Frizzera (1993) the multicentric form of Castleman's disease is a much more aggressive disorder. Patients present with widespread adenopathy or constitutional symptoms. Hepatic or splenic enlargement is present in the majority of cases. Infections, transformation to non-Hodgkin's lymphoma, and development of Kaposi's sarcoma constitute common causes of death. Only limited information is available on the treatment of this disorder. Treatment with prolonged courses of high-dose steroids (e.g., prednisone 1 2 mg/kg/day for several months) has been reported to result in durable remission. Other treatment strategies have consisted of the administration of
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combination chemotherapy regimens, or of radiation treatment to areas of bulky disease. Responses to interferon treatment have also been reported. Recently, Said (1997) and Gessain (1996) and associates showed that Castleman's disease is related to infection with HHV-8, the virus responsible for Kaposi's sarcoma.
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