ACR Appropriateness Criteria® Localized Nodal Indolent Lymphoma

The present guidelines review epidemiology, pathology, presentation, workup, staging, prognostic factors, and treatment options for patients with localized nodal indolent lymphoma, with an emphasis on radiation guidelines, including radiation dose, field design, and radiation techniques. Following a discussion of the current literature and available data for treatment and outcomes of patients with indolent lymphoma, several different example cases are reviewed to help physicians make appropriate treatment decisions. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) by which the panel rates the appropriateness of imaging and treatment procedures. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

Summary of Literature Review

Introduction

Patients with indolent lymphomas are predominantly found to have advanced-stage disease (stage III and IV) at diagnosis. Although effective therapies exist for patients found to have early-stage disease (stage I or II, nonbulky), the patients with advanced disease are incurable. Fortunately, the typical slow progression of indolent lymphomas, even with observation alone, and their high responsiveness to a number of different therapeutic agents, translates into longer survival times compared with most other malignancies.

Epidemiology

An estimated 70,000 people were diagnosed with non-Hodgkin lymphoma (NHL) in the United States in 2012, which will result in close to 20,000 deaths.[1,2] Indolent lymphomas make up over 35% of NHL cases, of which two-thirds are follicular lymphoma and the remainder include small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL) and marginal zone lymphoma.[3]

The average age at diagnosis is approximately 60 years, and indolent lymphoma is rarely diagnosed in children.[4] There is a slight male predominance (1.2:1) of follicular lymphoma and a higher predominance among whites (white-to-black, 2.5:1; white-to-Asian, 2.4:1).[5] Additionally, a higher incidence has been noted in families of patients with follicular lymphoma.[6]

Pathology, Immunophenotype, and Genetics

Follicular lymphoma is graded according to the extent to which large centroblasts are visible in the biopsy:

• Grade 1: 0 to 5 centroblasts/high-power field (hpf); ~50% of cases.

• Grade 2: 6 to 15 centroblasts/hpf; ~30% of cases.

• Grade 3: > 15 centroblasts/hpf; ~20% of cases.

Grade 3 can be divided into grade 3a, with centrocytes present, and grade 3b, with solid sheets of centroblasts. Grade 3 follicular lymphoma behaves more like aggressive NHL, and its treatment therefore follows the same guidelines as those used for a diffuse large B-cell lymphoma.[7]

Follicular lymphomas express pan–B-cell antigens (CD19, CD20, CD22) and lack T-cell antigens (CD5, CD43). Approximately 85% of follicular lymphoma patients have a chromosomal translocation, t(14;18)(q32;q21), which results in an upregulation of the BCL-2 oncogene.[8]

Presentation and Staging

Patients typically present with painless peripheral adenopathy that may wax and wane in size. Classical B symptoms, including fevers, drenching night sweats, or unintentional weight loss of > 10% in the 6 months before presentation, occur in about 20% of patients.

Follicular lymphoma is staged by the Ann Arbor system used for other lymphomas.[9] Distribution by stage is approximately 17% for stage I, 15% for stage II, 30% for stage III, and 37% for stage IV. It is critical to perform a careful physical examination of all the lymph node regions, including the liver (involved in up to 50% of cases) and spleen (involved in up to 40% of cases). Important tests to order include a complete blood count, liver function tests, lactate dehydrogenase (LDH) level, bone marrow biopsy (involved in up to 60% to 70% of cases),[10] and a computed tomography (CT) scan of the neck, chest, abdomen, and pelvis. Additional fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT scans may be useful in confirming localized involvement (stage I and II) and for radiotherapy (RT) treatment planning. In a study by Wirth et al,[11] 42 patients with stage I/II follicular lymphoma staged by physical examination, CT, and bone marrow biopsy underwent FDG-PET imaging to evaluate the additional impact it would have on staging. Of these patients, 31% were upstaged to either stage III or IV, which would have led to a change in management from involved-field radiation therapy (IFRT) to either expectant management or systemic therapy. An additional 14% of patients were found to have more sites of nodal disease without having stage III or IV disease, and thus required more IFRT than previously anticipated. In a similar study by Le Dortz et al,[12] 45 patients with follicular lymphoma underwent CT and PET/CT staging. PET imaging increased the Ann Arbor staging in 18% of patients, including 11% who were upstaged from stage I or II disease to stage III or IV and were thus not eligible for curative treatment with RT. Upstaging patients with PET imaging can impact not only current and future studies but also how we evaluate older pre–PET-era studies that report on treatment outcomes in patients with stage I and II disease.

Follicular Lymphoma International Prognostic Index (FLIPI)

Follicular lymphoma has its own prognostic index: the Follicular Lymphoma International Prognostic Index, or FLIPI. The FLIPI includes five risk factors and comprises a low-risk group (no more than one factor), an intermediate-risk group (two factors), and a high-risk group (three or more factors). The five factors are: age ≥ 60 years, stage III or IV, hemoglobin level < 12 g/dL, serum LDH > upper limit of normal, and number of involved nodal sites (not per Ann Arbor) ≥ 5. For the low-, intermediate-, and high-risk groups, the 10-year overall survival (OS) rates are 71%, 51%, and 26%, respectively.[13] The FLIPI has been validated in patients diagnosed with early-stage disease, where it was demonstrated that patients with two factors had a worse outcome than those with no more than one factor, including median failure-free survival time (11.1 years vs 2.4 years; P = .02) and median OS time (not reached vs 7.4 years; P = .01).[14] Additionally, the FLIPI has been validated in patients undergoing rituximab and chemotherapy,[15] and has been validated for predicting risk of transformation.[16] Recently a newer prognostic index was developed, FLIPI2. The risk factors it includes are: beta-2 microglobulin level, longest diameter of lymph node involvement (> 6 cm), bone marrow involvement, hemoglobin level < 12 g/dL, and age > 60 years; FLIPI2 has been shown to be predictive of progression-free survival (PFS) and OS times.[17]

VARIANT 1

58-year-old woman with stage IA follicular lymphoma (grade 1 or 2) involving multiple 2-cm lymph nodes in the right cervical neck

Transformation Into Aggressive Non-Hodgkin Lymphoma

Histologic transformation from an indolent lymphoma into an aggressive NHL is most commonly seen in follicular lymphoma transforming into diffuse large B-cell lymphoma. Studies have reported incidences between 15% and 30% at 10 years following initial diagnosis of the indolent lymphoma.[16,18,19] Little is currently understood about the events leading to transformation. Treatment is directed based on newly transformed histology, with median survival times of 1 to 2 years.[16]

Early-Stage Follicular Lymphoma

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