Lymphoma: An update on evolving trends in staging and management.

Abstract

Because lymphoma frequently manifests as a neck mass, otolaryngologists are often the first to evaluate and diagnose it. Excisional biopsy of lymph nodes generally provides the definitive diagnosis. After diagnosis, however, the otolaryngologist's involvement generally wanes as subsequent treatment of the patient is provided by an oncology team. Nevertheless, it is important for the otolaryngologist to be familiar with current concepts in the comprehensive evaluation and treatment of lymphoma patients. This knowledge allows us to participate in and facilitate timely testing, which helps avoid undue delays between the documentation of physical findings and the initiation of treatment. Otolaryngologists also need to be up to date on recent developments in the treatment of lymphomas in order to be able to answer questions regarding staging and prognosis, to make the proper referrals, and to help our patients understand current controversies and treatment practices.

Introduction

Lymphoma is a lymphoproliferative disorder that is often identified first by otolaryngologists and head and neck surgeons. Once the diagnosis is made, however, the patient is treated principally with radiation therapy and by medical oncologists. Thus, as the patient's treatment progresses, the involvement of the otolaryngologist tends to diminish.

There are many controversies in the management of lymphoma, from categorization to staging to treatment options. Familiarity with these controversies and with the current state of the art in diagnosis and treatment is essential in order for the otolaryngologist to participate in a meaningful way as a member of the multidisciplinary team. Although the lymphoma management team includes oncologists, general surgeons, radiologists, radiation oncologists, and others, otolaryngologists are often the ones who make the diagnosis following an evaluation of a neck mass, and we establish a rapport and relationship with the patient. Patients and referring physicians look to otolaryngologists for expertise in the management of neck masses. It is important for us to remain knowledgeable resources for both our patients and primary care physicians and to remain involved in and familiar with total patient management beyond the biopsy.

Disease characteristics

Lymphoma accounts for about 4% of all new cases of cancer in the United States every year. [1] It is second only to squamous cell carcinoma as the most common head and neck cancer. [1] Lymphoma is typically categorized as either Hodgkin's or non-Hodgkin's disease.

Disease presentations vary according to their natural histories. Hodgkin's disease typically spreads by contiguity, while non-Hodgkin's usually does not. About 80% of Hodgkin's patients have cervical adenopathy, whereas about 33% of non-Hodgkin's patients have nodal disease in the neck.' Patients with both types of disease can also have hematologic disorders, mediastinal complaints, central nervous system symptoms, gastrointestinal disorders, or other difficulties.

Hodgkin's disease. Hodgkin's disease usually affects patients in the third and the seventh decades of life, and it is more common among men than women. The already higher relative risk of Hodgkin's disease conferred by a positive family history rises tenfold when a same-sex sibling has the disease. [1] A possible causal relationship exists between Hodgkin's disease and the presence of Epstein-Barr virus (EBV). [1]

The cell of origin in Hodgkin's disease is not yet well defined. Hodgkin's disease is characterized by the presence of the pathognomonic multinucleated Reed-Sternberg cell. The cellular background defines the four histologic subtypes: nodular sclerosis, lymphocyte predominance, mixed cellularity, and lymphocyte depletion.2 The cellular milieu might or might not have prognostic significance. [34]

Non-Hodgkin's disease. In the head and neck, non-Hodgkin's lymphoma is five times more common than Hodgkin's disease. In fact, it is the second most common head and neck malignancy in and of itself. A subtype of non-Hodgkin's disease, Burkitt's lymphoma, has been shown to be strongly associated with EBV. [1] There is also a strong association between non-Hodgkin's lymphoma and human immunodeficiency virus in patients who have adult T-cell leukemia.

In approximately 90% of cases, non-Hodgkin's disease is derived from B cells, while the remainder are T-cell-derived. Most patients do not have systemic symptoms ("A" status); approximately 10% of patients do ("B" status). These symptoms include unexplained fever ([greater than]38[degrees] C), unexplained weight loss ([greater than]10% of body weight), and night sweats. A patient's A or B status is routinely taken into account during staging, although this remains a subject of ongoing debate.

The immunologic status of the cells and the histology of the nodes are used to characterize non-Hodgkin's lymphoma. Over time, this categorization has taken on many forms, including the simultaneous use of six different systems internationally. [5] Among these systems are the Rappaport, Kiel, and Lukes-Collins classifications. The current classification system for non-Hodgkin's lymphoma was adopted in 1982 to provide a unifying schema (table 1). In 1994, an international group of pathologists met and developed the revised European-American lymphoma (REAL) classification system for lymphoid neoplasms. [5] The REAL system was an attempt to establish a more clinically useful categorization of lymphoid neoplasms. Even so, the 1982 classification system is still widely used.

Staging

As is the case with all malignancies, the staging of lymphoma is designed to predict risk. Laparotomy and radiologic studies can help accomplish this, as can prognostic factors derived from retrospective analyses and, of course, the clinical examination. The Ann Arbor staging system is used to stratify risk for both Hodgkin's and non-Hodgkin's lymphoma (table 2). [6]

Proper staging ultimately means that the patient will experience neither the morbidity of overtreatment nor the mortality of undertreatment. And even in ideal doses, treatments themselves are not benign. For example, radiation therapy can still cause hypothyroidism, pneumonitis, pericarditis, sterility, and other problems. Likewise, chemotherapy can cause nausea and vomiting, neuropathies, leukopenia, sterility, and possibly the induction of acute myelogenous leukemia. [7] Clearly, these modalities should be used only when they are essential to improving outcomes.

Laparotomy staging. Ever since its inception, staging by laparotomy has prompted much controversy. This procedure is used to determine whether or not supradiaphragmatic stage I and II Hodgkin's disease has crossed the diaphragm. If it has, the disease is classified as at least stage III. The essential question then becomes, Is the information gained by staging laparotomy sufficient to justify the means used to acquire it?

The rate of discovery of pathologic nodes via laparotomy can be as high as 30%. [8] Morbidity and mortality rates associated with the procedure, which vary among surgical centers, are in the range of 15 and 1%, respectively. [9] Laparotomy carries the risk of overwhelming sepsis by encapsulated organisms in both the short and long term. [10-13] This risk has been reported to be about 2 to 4%. [10,14-20] The use of pneumococcal vaccine can decrease the risk of late infection, which makes laparotomy a more reasonable option.

In many retrospective studies, researchers have tried to identify factors that predict the positivity or negativity of staging laparotomy, and they have been successful in identifying certain subgroups of patients in whom the use or avoidance of laparotomy makes sense. Leibenhaut et al studied 915 patients with clinical stage (CS) I and II Hodgkin's disease who underwent laparotomy, and they were able to identify specific subgroups in whom laparotomy had a low yield [14] These patients included women with CS I disease, patients with mediastinum-only CS I disease, and men with CS I disease who had either lymphocyte predominance or interfollicular histologies. All these groups had less than a 5% risk of subdiaphragmatic disease. Moreover, their B status did not correlate with advanced disease. On the other hand, male sex in general and histologic findings of mixed cellularity did carry an increased risk of subdiaphragmatic disease.

Likewise, Mauch et al reported on 692 patients with supradiaphragmatic disease who underwent laparotomy. [15] Again, women with CS I disease and men with CS I disease and a lymphocyte predominance had a low probability of subdiaphragmatic disease. Moreover, men who had CS I disease high in the neck were also in the low-probability group. Conversely, a high probability of subdiaphragmatic disease was associated with B status, male sex, age greater than 40 years, and mixed cellularity or lymphocyte depletion on histology. Although laparotomy is still the gold-standard staging procedure, it is certainly not the only option.

Radiologic staging. Radiologic studies also provide useful information. Lymphangiography was once the mainstay of radiologic diagnosis for lymphoma, and it is still used in some centers. However, computed tomography (CT), magnetic resonance imaging (MRI), gallium scans, and 2-[F-18]-fluoro-2-deoxy-D-glucose positronemission tomography (FDG-PET) have all come into use, and they provide physiologic as well as anatomic data.

CT is typically the primary radiologic study for lymphoma. It provides a rapid, cost-effective study for both staging and followup. But it is not the best choice for all patients. For example, one of the difficulties in following patients after treatment is that tumors can still be physically present but physiologically sterilized. Gallium scans and FDG-PET are especially helpful in assessing these cases.

Gallium scans. Draisma et al compared the utility of gallium and MRI scans for detecting mediastinal lymphoma in 189 patients. [21] They found that the sensitivity and specificity of gallium were 90 and 97%, respectively, compared with 89 and 89% with MRI.

Similarly, Setoain et al studied 53 patients who were imaged with both gallium and CT after treatment. [22] They found that the sensitivity and specificity for detecting tumor recurrence were 88 and 100% with gallium, compared with 59 and 72% with CT--again demonstrating the superiority of gallium as a followup study. Additionally, they reported that all four of the treatment failures in their study were evident on gallium scans.

The value of gallium scans in helping guide post-chemotherapy decisions was further documented by Stroszczynski et al in their study of 28 patients who were imaged with both gallium and CT. [23] Sensitivity and specificity were 94 and 100% with gallium, compared with 83 and 93% with CT.

In a finding that is perhaps most important, Kaplan et al found that gallium scans can predict complete and lasting remissions when patients are gallium-positive before treatment and gallium-negative afterward. [24]

PET scans. The use of PET also merits attention. Newman et al studied 16 patients who had undergone both CT and FDG-PET prior to being treated. [25] All tumor sites that were seen on CT were also seen on PET, and three patients who had negative laparotomies also had negative abdominal CT and PET scans. PET thus demonstrated excellent sensitivity and specificity in this small sample.

Moog et al imaged 60 patients with both modalities to evaluate 740 lymph node regions. [26] CT identified 160 positive regions, while PET identified all 160 plus 25 others that were undetected by CT. PET findings resulted in the restaging of four patients, while CT altered staging in only one. Other authors support the use of PET, particularly because of its value in detecting the activity of tumors after treatment. [27]

In view of these findings, it appears to be reasonable not to subject selected patients in low-probability categories to the morbidity of laparotomy--provided that they are followed closely with clinical, laboratory, and radiologic assessments.

Treatment

Once risk has been determined, treatment must be instituted that will attack the disease while sparing the patient. In both Hodgkin's and non-Hodgkin's disease, the more disseminated the disease, the higher the risks. Suitable therapeutic strategies have been widely agreed upon for both diseases (table 3). Treatment options include observation, involved-field radiation, subtotal lymphoid irradiation, chemotherapy with or without radiation, and bone marrow transplant. The more advanced the disease, of course, the more aggressive--and hence toxic--the treatment. Although there are general treatment guidelines, some basic questions linger, and controversy attends the treatment of all stages of disease. The treatment of early-stage Hodgkin's disease remains particularly controversial.

Controversy extends to the issue of avoiding under-treatment. For example, Haybittle et al reported that undertreatment with radiation monotherapy can significantly increase mortality. [3] To the contrary, Hoppe et al argued that salvage chemotherapy following failed radiation therapy yields survival rates that are equal to those of chemotherapy alone in early-stage disease, and therefore limited radiation as a primary treatment does not put the patient at risk for increased mortality. [28] They also reported that relapse rates are the same after chemotherapy in both groups.

Moreover, there is evidence that chemotherapy without radiation as a primary treatment of early-stage disease produces morbidity and mortality rates that are somewhat comparable to those of radiation therapy alone. [29] Other studies have shown that rates of cure and relapse-free survival following combination chemotherapy were comparable to those of radiation therapy alone in early-stage Hodgkin's disease. [30,31] Furthermore, considering that radiation therapy treats only local disease and chemotherapy treats systemic disease, staging laparotomy would become virtually useless if these data are borne out in forthcoming studies.

Prognosis

Pre- and post-treatment factors have been analyzed to help determine prognosis in non-Hodgkin's disease. One multivariate analysis of 2,031 patients identified several independent risk factors for poor survival. [32] These factors were age greater than 60 years, late-stage disease, elevated serum lactate dehydrogenase levels, impaired performance status, and extranodal involvement. This study also found that 5-year survival rates were 73% for patients with zero or one risk factors, 51% for those with two, 43% with three risk factors, and 26% for patients with four or five. Additionally, pretreatment clinical features that predicted a relapse from complete remission included advanced stage, age greater than 60, and abnormal serum lactate dehydrogenase levels.

Certain treatment-related prognostic factors have also been noted. Two studies found that the faster a patient achieved a complete remission, the longer he or she survived. [33,34] However, Kwak et al reported that the administration of cyclophosphamide early during treatment decreased the chance of a complete remission and increased the chance of relapse from complete remission. [35] Of particular note was the discovery by Kaplan et al, mentioned earlier in this article, that gallium scans can predict prolonged complete remissions. [24] In their study, 70% of patients who were transformed from gallium-positive to gallium-negative by four to six cycles of chemotherapy had long-term complete remissions. Conversely, only 24% of patients who were still gallium-positive after treatment had long-term complete remissions.

Cellular and molecular features can also help stratify risk. One such method is to monitor the rate of tumor cell proliferation for the presence or absence of Ki-67--the "nuclear proliferation antigen." Grogan et al reported that patients whose tumors had Ki-67 antigen in more than 60% of cells had a median survival of only 8 months, whereas those who had Ki-67 in less than 60% of cells had a median survival of 39 months. [36]

The immunology of a tumor's cells plays a strong role in predicting its aggressiveness. For example, Miller et al reported that when the major histocompatibility complex (MHC) antigen HLA-DR was absent, median survival was only 6 months; when the antigen was present, survival exceeded 2.8 years. [37] Moreover, [beta]-2 microglobulin--a small protein that attaches to MHC class I molecules and which is detectable in serum--has been correlated directly with high tumor burdens and shortened survival in patients with aggressive non-Hodgkin's lymphoma. [38] Also, survival is correlated with the ability of a tumor to spread, and adhesion molecules can play a role in that spread. Lymphocyte homing receptors facilitate lymphocyte binding and extravasation into nodes. [39] Aggressive lymphomas that are negative for lymphocyte homing receptors have been reported to be less likely to disseminate than lymphomas with greater expression. [40-43] Furthermore, studies have shown that about half of all patients with high expression levels had advanced disease, compared with slightly more than 10% who had low expression levels. [42-44]

In conclusion, the management of lymphoma remains dynamic. Diagnosis, staging, and treatment planning are all undergoing their own independent evolutions. We anticipate that the use of the REAL staging system will become more popular and that gallium and PET scans will replace staging laparotomy in select patient groups. We also believe that less toxic chemotherapeutic regimens will play an increasing role in the treatment of early-stage Hodgkin's disease. Otolaryngologists will continue to play a crucial role in diagnosing lymphoma, and so it is essential that we are knowledgeable members of the oncologic team and that we remain familiar with the latest trends in comprehensive lymphoma care.

From the Department of Otolaryngology, Albert Einstein College of Medicine, Bronx, N.Y. (Dr. Dailey), and the Department of Otolaryngology-Head and Neck Surgery, Graduate Hospital, Philadelphia, and the Department of Otolaryngology, Thomas Jefferson University, Philadelphia (Dr. Sataloff).

Reprint requests: RobertT. Sataloff, MD, 1721 Pine St., Philadelphia, PA 19103. Phone: [phone]; fax: [phone]; e-mail: [e-mail]

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Table 1. Classification of non-Hodgkin's lymphoma
Low-grade                  Intermediate-grade      High-grade
lymphomas                  lymphomas               lymphomas
Small, lymphocytic         Follicular, large       Immunoblastic
Follicular, small cleaved  Diffuse, small cleaved  Lymphoblastic
Follicular, mixed          Diffuse, mixed          Small, noncleaved
                           Diffuse, large cell
Table 2. Ann Arbor staging system for lymphoma
Stage   Description
I       A single lymph node or extralymphatic
        site
II      Two or more lymph node regions on the
        same side of the diaphragm or localized
        extralymphatic with one or more lymph
        node regions on the same side of the
        diaphragm
III     Lymph node regions on both sides of the
        diaphragm and possible localized
        involvement of an extralymphatic site
        or the spleen
IV      Disseminated involvement of one or more
        extralymphatic sites with or without
        associated lymph node involvement, or
        isolated extralymphatic organ
        involvement with distant (nonregional)
        nodal involvement
A or B  Denotes absence (A) or presence (B) of
        unexplained weight loss ([greater than]
        10% of body weight), unexplained fever
        ([greater than]38[degrees] C), or night
        sweats (note: pruritus is not a B
        symptom)
Table 3. Recommended treatment for Hodgkin's and non-Hodgkin's
lymphoma
Stage                      Treatment
Hodgkin's lymphoma
I, IIA, favorable          Subtotal lymphoid irradiation
I, IIB, favorable          Combination chemotherapy
                           or lymphoid irradiation or
                           combined modality
IIIA, favorable            Combination chemotherapy
                           or subtotal lymphoid irradiation
I, II, unfavorable*        Combination chemotherapy
(A or B)                   with or without irradiation to
                           bulky sites of disease
III, IV, unfavorable*      Combination chemotherapy
(A or B)                   with or without irradiation to
                           bulky sites of disease
Non-Hodgkin's lymphoma
I, low grade               Observation or involved-
                           field radiation
I, intermediate grade      Chemotherapy and involved-
                           field radiation
I, high grade              High-dose chemotherapy
II-IV, low grade           Observation or chemotherapy
II-IV, intermediate grade  Chemotherapy
II-IV, high grade          High-dose chemotherapy with
                           evaluation for bone marrow
                           transplant if response is
                           inadequate
(*)Bulky disease--i.e., nodes [greater than] 10 cm, mediastinal
widening morethan one-third chest diameter, or multiple extranodal
sites.