Case study 39.1

A 75-year-old retired schoolteacher notes an increase in some nontender bilateral neck lymph nodes (LNs) (the largest are now in the 3 cm range), which he first recalls noticing ∼1 year ago. Otherwise, he feels well overall. During an annual visit to his primary care physician, he describes the neck adenopathy. When his preferred medical doctor (PMD) notes no change in adenopathy after a 10-day course of oral antibiotics, he is suspicious that his patient may have low-grade lymphoma (note: the patient is a nonsmoker and denies alcohol use), and he is referred for surgical consultation.

1. Which of the following choices regarding LN biopsy techniques is the best in order to make a definitive diagnosis for suspected indolent lymphoma?

Fine needle aspiration
Core biopsy
Excisional or incisional biopsy
Any of the above biopsy techniques—they are all equivalent

Optimally, excision of an enlarged LN is necessary to make a histologic diagnosis of indolent lymphoma (i.e., follicular histology (FL) being the most common histology) by a hematopathologist. A fine needle aspirate is not adequate and does not permit the pathologist to “grade” the FL (e.g., grade 1, 2, 3a, or 3b) because that requires an evaluation of LN architecture. A needle core biopsy may consist predominately of the diffuse or the interfollicular component of FL and result in an inaccurate diagnosis. An excisional or incisional biopsy provides adequate material for flow cytometry, immunohistochemistry, and molecular studies, but it also can rule out the possibility of large-cell transformation in the biopsy material. An accurate histopathologic diagnosis of lymphoma subtype by a hematopathologist on an adequate tumor biopsy strongly contributes to the therapy prescribed by the oncologist.

Case study 39.2

A 69-year-old woman has had an excisional biopsy of an enlarged axillary node that was performed to evaluate extensive nonbulky LA, and the pathology reveals FL, grade 2.

1. Which of the following tests is not part of the current recommendations for the initial work-up of a patient with FL (following a full history and physical)?

Routine bloodwork, which includes a complete blood count (CBC), a full comprehensive metabolic profile (plus uric acid and lactate dehydrogenase (LDH)), and beta-2 microglobulin
Virological testing for hepatitis B and C
Unilateral bone marrow aspiration and biopsy
Computed tomography (CT) scans of neck, chest, abdomen, and pelvis (with oral and IV contrast, unless contraindicated)
Whole-body fluoro-deoxyglucose positron emission tomography (FDG-PET) scan

All of the above, except whole-body FDG-PET scan, should be part of the “current” routine assessment of FL based on review of the literature. FL is an FDG-avid disease (i.e., ∼90% of FL patients have PET-positive disease, and the sensitivity of PET scans is in the 95%+ range). Two recently published studies (i.e., Trotman (retrospective) and Dupuis (prospective)) show that posttreatment FDG-PET scans in high-tumor-burden FL patients treated with primarily rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) improve the accuracy of response assessment and appear to be better than conventional methods in predicting progression-free survival (PFS) and possibly overall survival (OS). The effect of different induction therapies and/or maintenance therapy on posttreatment PET scans is unknown. Although very promising, the routine use of FDG-PET needs further validation before it will be added to the routine staging of FL as part of the revised international working criteria (IWC).

2. True or false? FL patients (grade 1, 2, or 3a) with stage I or II disease receiving involved-field radiation therapy (IFRT) may achieve excellent outcomes and maybe even be cured.

True
False

FL is a highly radiosensitive disease. Up to 25% of FL patients present with clinical stage I or II disease. Most of the data on the impact of IFRT in early-stage FL come from retrospective analyses and demonstrate 10-year OS rates in the range of 60–80% and a median survival of ∼20 years. Relapse after 10 years is uncommon. Risk factors associated with relapse in these patients include elevated LDH, age >60, and size of lymph nodes (>3 cm and >5 cm). Relapse following IFRT is usually outside of the radiation field. In an attempt to identify “true” early-stage FL patients who would theoretically be optimal candidates for IFRT, the clinician should fully stage the patient, including consideration of molecular testing (e.g., polymerase chain reaction (PCR) assay for t(14:18) chromosomal rearrangement and/or immunoglobulin gene rearrangement) of blood and bone marrow for occult disease and also a whole-body FDG-PET scan to assess for additional disease not identified by CT scans. The last two tests would be able to identify patients with more extensive disease who either would not be optimal candidates for IFRT alone and/or could theoretically benefit from the addition of systemic therapy (e.g., rituximab +/− chemotherapy). In these patients with disease localized to abdominal and pelvic areas at risk for significant post-RT morbidity, then observation or systemic therapy is reasonable alternatives.

Case study 39.3

A 62-year-old policeman was referred to a local hematologist-oncologist for work-up of FL, grade 1, which was found on biopsy of one of several 1–2 cm enlarged left cervical nodes. Staging work-up was consistent with asymptomatic stage IIIA (low-tumor-burden) disease.

1. Which of the following therapeutic approaches would you choose at this time?

Watchful waiting (WW)
Rituximab induction
Rituximab induction + 2 years of maintenance rituximab (MR)
Rituximab-chemotherapy combination immunochemotherapy
Either A or B

In general, “low”-tumor-burden patients are those who do not meet the definitions of patients who “require therapy” that have been previously published in the pre-rituximab era by various lymphoma study groups (i.e., the British National Lymphoma Investigation and Group d’Etude des Lymphomes Folliculaires (GELF); see Table 39.1). In addition, low-tumor-burden patients should have serum LDH and serum beta-2 microglobulin levels below the upper normal values and no significant impairment of performance status associated with their lymphoma diagnosis.

Table 39.1 Criteria consistent with high tumor burden requiring therapy.

British National Lymphoma Investigation criteria
Presence of B-symptoms or pruritis Rapid generalized disease progression (within 3 months) Significant bone marrow (BM) involvement with BM compromise Localized bone lesions Renal infiltration (even with normal renal function) Macroscopic liver involvement
Group d’Etude des Lymphomes Folliculaires criteria
Presence of B-symptoms Involvement of >3 nodal sites, each with a diameter >3 cm Nodal or extranodal mass >7 cm diameter Risk of vital organ compression Cytopenias (Hgb <10 g/dL, ANC <1.5 × 10⁹/L, and platelets <100 × 10⁹/L) Serous effusions (pleural effusion or peritoneal ascites) Splenomegaly (>16 cm on CT scan) or symptomatic splenic enlargement Leukemic phase (>5.0 × 10⁹/L malignant cells)

ANC, absolute neutrophil count; CT, computed tomography; Hgb, hemoglobin.

In the pre-rituximab era, randomized controlled trials evaluated WW to initial therapy with oral alkylating agent, interferon alpha 2b (IFNα-2b), or ProMACE-MOPP (prednisone (oral), methotrexate, adriamycin, cyclophosphamide, etoposide, mechlorethamine, vincristine, and procarbazine). There was no evidence of improved OS in the immediate treatment arms compared to WW.

In addition, deferring initial toxic chemotherapy could be supported by the following: systemic therapy-associated side effects would negatively impact the patient’s quality of life (QOL) and/or early intervention with toxic chemotherapy might impact negatively on bone marrow reserve and the ability to tolerate future treatment at relapse or transformation.

In the rituximab era, WW versus single-agent rituximab in asymptomatic nonbulky FL patients was studied by Ardeshna et al. (2012) in 463 patients randomized to one of three arms: A, watch and wait (n = 187); B, rituximab (four weekly infusions) induction (n = 84; closed early); and C, rituximab induction + 2-year maintenance (n = 192). Primary endpoint was time to initiation of new therapy. Three years after randomization, ∼50% of WW patients had not received further therapy, whereas 80% of patients in the rituximab induction arm and 91% of patients in the rituximab induction + maintenance arm had not initiated new therapy. No difference in OS was seen between the three arms (i.e., 95% of patients alive at 3 years). There were some benefits associated with immediate rituximab therapy (i.e., improved DFS, longer time to first chemotherapy, and less anxiety in a subset of patients) compared to WW. The RESORT (E4402) trial should also be mentioned here. Of the 384 low-tumor-bulk FL patients enrolled on the RESORT trial, 274 (71%) responded to rituximab (R) induction (i.e., four weekly infusions) and were then randomized to rituximab retreatment (RR: n = 134) versus maintenance rituximab (MR: n = 140). With a median follow-up of 3.8 years: (i) RR was as effective as MR for “time to treatment failure,” (ii) MR was slightly better than RR for “time to first chemotherapy,” and (iii) MR patients received (on average) 3.5 times more rituximab than RR patients. Thus, it could be concluded that RR is preferable to MR if single-agent rituximab is used to treat low-tumor-burden FL patients. Currently, no information is available on whether there exists any difference in sensitivity to subsequent “R-chemotherapy” between the RR versus MR arms. It should be noted that single-agent rituximab given weekly 4× in previously untreated FL patients can result in long-term remission durations in a significant subset of patients.

Based on the above discussion, E would be the best answer. With the advent of a number of targeted therapeutic agents with excellent therapeutic indices, it will be very interesting to see how the incorporation of these novel agents will change treatment paradigms and the future treatment approach of FL (including asymptomatic, low-tumor-burden patients).

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