Diagnosis And Initial Evaluation

The diagnosis of DLBCL requires adequate tissue for histologic, flow cytometric, and immunohistochemi-cal studies. Histopathologic examination reveals a diffuse growth pattern of medium- to large-sized cells that replace the normal nodal architecture. Several morphologic variants exist (centroblastic, immunoblastic, T-cell/histiocyte rich, anaplastic)6 but do not currently influence initial treatment strategies. The classic immunophenotype of DLBCL is CD20+, CD22+, CD19+, CD79a+, and with surface and cytoplasmic immunoglobulin expression in the majority of cases. Less commonly, CD5 or CD10 may be expressed,6 necessitating differentiation from other NHL subtypes. Molecular studies such as immunoglobulin gene rearrangement studies may be needed to confirm the diagnosis in cases with weak or absent surface markers or in cases with pleomorphic morphology. Other immunohistochemical stains for markers such as Pax5

and MUM1 can identify a B-cell process and a postgerminal center process, respectively.7 Cytogenetics may also be performed on lymph node or bone marrow biopsy samples. Three recurring chromosomal abnormalities have been described: t(14;18) in 30% of cases, 3q27 in 30-40% of cases, and t(8;14) in occasional cases. However, cytogenetic analysis is currently used merely to support a diagnosis of DLBCL and is not used to subclassify the disease or guide treatment.

Once the diagnosis is established, the initial evaluation consists of staging and clinical assessment. The initial staging procedures should include imaging (most commonly CT scan or MRI) of the chest, abdomen, and pelvis, and a bone marrow aspirate and core biopsy. In many centers, bilateral bone marrow biopsies are preferred, but a single biopsy of good quality may be acceptable. An international collaboration suggests that an aggregate bone marrow biopsy of at least 2 cm is sufficient if only one side is sampled.8 A test of cardiac function in anticipation of anthracy-cline-based therapy is usually recommended as well.

Gallium scintigraphy (Ga-67) or positron emission tomography (PET) with 18fluorine fluorodeoxyglucose provide complementary information. Although neither of these tests is part of the standard response cri-teria,8 they are commonly used to provide a baseline and to aid in the evaluation of residual masses following the end of treatment. Both are extremely sensitive imaging tools that can be used as part of routine staging to evaluate response to treatment, to evaluate residual masses following treatment, and to predict risk of relapse after completion of treatment. Gallium imaging has been used for many years, but, more recently, PET scanning has received increasing interest because of its convenience of use and its greater sensitivity. Several groups have used PET to assess residual masses in Hodgkin's lymphoma and NHL following treatment. It is now fairly well established that residual PET positivity after completion of treatment correlates with an increased risk for recurrence in aggressive lymphoma, and should at the very least lead to increased surveillance for relapse.910 The optimal management of patients who have residual PET positivity after completion of treatment is not determined. Other studies suggest that PET positivity midway through treatment is a strong predictor for treatment failure.1112 Again, the optimal management of such patients remains undetermined.

In staging patients with newly diagnosed DLBCL, an important question is when to obtain a lumbar puncture and when to consider central nervous system (CNS) prophylaxis. In contrast to high-grade lymphomas such as Burkitt's or Burkitt-like subtypes, the risk of CNS involvement for intermediate grade lymphomas appears to be low at approximately 1-2%.1314 However, CNS relapse carries a grim prognosis and is uniformly fatal with less than 25% of the patients sur viving the first year following diagnosis.14 The median time to death following diagnosis is only 5 months.13 There are many reports linking clinical risk factors at diagnosis to an increased risk of CNS relapse, including blood and bone marrow involvement, testicular involvement, bulky retroperitoneal disease, sinus involvement, epidural involvement, and elevated lactate dehydrogenase (LDH). Therefore, we have recommended a lumbar puncture as part of the initial evaluation in patients with any of these characteristics.

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