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Low-Grade Follicular Lymphoma of the Small Intestine: A Challenge for Management
Seminars in Oncology, 6, 38, pages 714 - 720
At times we encounter clinical problems for which there are no directly applicable evidence-based solutions, but we are compelled by circumstances to act. When doing so we rely on related evidence, general principles of best medical practice, and our experience. Each ”Current Clinical Practice” feature article in Seminars in Oncology describes such a challenging presentation and offers treatment approaches from selected specialists. We invite readers' comments and questions, which, with your approval, will be published in subsequent issues of the Journal. It is hoped that sharing our views and experiences will better inform our management decisions when we next encounter similar challenging patients. Please send your comments on the articles, your challenging cases, and your treatment successes to me at Gloria.Morris@hemonc1.com . I look forward to a lively discussion.
Gloria J. Morris, MD, PhD
Current Clinical Practice Feature Editor
Non-Hodgkin lymphoma (NHL), when extranodal, is most commonly seen in the gastrointestinal tract (GI) with an incidence as high as 20%. 1 Follicular lymphoma (FL) in the GI tract is rare. It most commonly occurs in the small bowel, accounting for 5 to 9% of all the lymphomas of the GI tract, with the highest incidence seen in the duodenum (35%). 2 In the last two decades, the incidence of primary small bowel lymphoma's in the United States almost doubled, likely related to the significant increase in conditions associated with immunosuppression (whether inherent to the disease itself or its treatment). 3
It is important to distinguish between primary GI lymphoma and systemic lymphoma with GI tract involvement, since it has important prognostic implications. 1 A whole-body positron emission tomography (PET) scan and bone marrow biopsy can help distinguish between the two. Management of small bowel lymphoma, especially low-grade lymphomas, is often a challenge as no guidelines exist as to the best management approach. The present case illustrates these therapeutic challenges.
A 43-year-old man presented to our clinic with a 6-month history of intermittent rectal bleeding, which was initially attributed to an anal fissure. He also complained of increased fatigue over the last 6 months, and occasional episodes of abdominal bloating without diarrhea or constipation. A history of drenching night sweats was elicited as well. According to the patient, the night sweats started 8 years ago. A work-up at that time did not reveal an etiology. He denied fever, weight loss, or loss of appetite. He had also noticed bilateral inguinal lymphadenopathy intermittently.
The patient gave a history of chronic sinusitis, and mitral valve prolapse with a normal stress test. He reported a 9 pack-year smoking history. He quit 25 years ago. His family history was significant for brain cancer in his father at 62 years of age, and leukemia in a maternal uncle. Physical examination revealed a relatively healthy, well-nourished, middle-aged man with no abdominal masses and no lymphadenopathy. Rectal exam did not detect any rectal source of bleeding. The remainder of the examination was unremarkable.
A colonoscopy was ordered. Two prominent nodules were noticed in the terminal ileum. Pathology showed abundant lymphoid infiltrates with follicular architecture, and a majority of small cleaved cells ( Figure 1 ). Immunohistochemistry staining showed cells positive for CD10, CD20, Bcl-2, and Bcl-6. Twenty percent to 30% of the cells were positive for KI-67. These findings were consistent with a FL grade 1–2 ( Figure 1 ). Fluorescence in situ hybridization (FISH) analysis was positive for IgH/Bcl-2 translocation.
A bone marrow biopsy showed no evidence of involvement by the lymphoma.
A whole-body PET scan subsequently did not reveal any uptake in the abdomen and no hypermetabolic lymph nodes. Clinically the patient was diagnosed as having a stage I, low-grade primary FL of the GI tract.
The patient received different medical opinions regarding management of his disease. Below are experts' opinions.
Medical Oncologist's Opinion
Primary intestinal FL is a well-recognized, extranodal variant of FL. 4 Due to the low incidence of these tumors, however, there is limited evidence to guide management. Therefore, the clinician must base treatment-related decisions on case reports/series, experience with related lymphomas, and biological rationale.
The role of the oncologist is to offer curative therapy when possible, to prolong survival if cure is not possible, and always to maintain or improve quality of life. Short of allogeneic hematopoietic stem cell transplant, there is no cure for disseminated FL. This perspective provides a compelling argument to offer potentially curative local therapy to those rare cases of stage I FL. Indeed, many cases of stage I FL never recur following radiation.
The homing of normal lymphocytes to nodal and extranodal tissues is guided by the complex interplay of antigens, cytokines, chemokines and their respective receptors. Primary intestinal indolent lymphomas (eg, FL and marginal zone lymphoma) appear to arise from chronic antigenic stimulation of B-lymphocytes that express homing receptors to intestinal mucosa.5 and 6 Interestingly, these lymphomas rarely disseminate to peripheral lymph nodes, although extension to local nodes may occur. However, in 15% to 40% of cases, lymphoma may exist in multiple locations within the GI tract.7, 8, 9, and 10 Similarly, patients who are initially treated with local therapy may relapse at another location within the GI tract. 8 This is consistent with experience with patients with primary cutaneous FL, who commonly experience cutaneous relapse following local therapy. 11
The challenge, therefore, is to determine which cases are truly stage I and therefore curable. In this case, a PET scan failed to reveal any hypermetabolic foci within the GI tract or elsewhere. Although PET is clearly more sensitive than computed tomography (CT) at staging aggressive nodal lymphomas, 12 its role in FL is unclear. In the case of intestinal lymphomas, it is conceivable that low-grade lesions in the bowel might be obscured by normal metabolic activity within the bowel. At the very least, both upper and lower endoscopy should be performed. Because the whole bowel cannot be directly visualized via endoscopy, it is not possible to know whether there are any additional lesions that were not initially apparent.
More importantly, it is unclear that choice of therapy has any impact on survival. In a large, single-center series, patients with limited-stage FL who were not eligible for local radiation had a similar survival to patients who had received treatment with curative intent. 13 Available data from patients with primary intestinal FL suggest that these patients have an excellent prognosis and that lymphoma-related deaths are rare regardless of first-line therapy.5, 7, 8, 9, 10, and 14
Given the uncertainty regarding potential for cure and impact on survival, the management in many cases should be based on expected impact on quality of life. In patients without symptoms, watchful waiting is a reasonable approach and may spare patients significant morbidity. In this case, the patient's symptoms preclude expectant management. However, the fact that he has been symptomatic for 8 years and had more than one polyp in the cecum suggests that he may be at higher risk of having additional undetected lesions elsewhere in the GI tract. Single-agent rituximab would be expected to have a response rate of over 70% 15 with minimal short-term or long-term side effects and would be my first choice in this patient. In the event that the patient relapsed following rituximab, I would strongly consider a clinical trial with a novel targeted agent, with the goal of improving his symptoms and maintaining his quality of life thereafter.
Peter Martin, MD
Assistant Professor of Medicine, Weill Cornell Medical College
Assistant Attending Physician, New York-Presbyterian Hospital
New York, NY
Medical Oncologists' Opinion
Primary GI FL is a rare entity that overall is infrequently cured but simultaneously marked by slow progression of disease and spontaneous regressions. In the realm of medical oncology it is true that the goal should be first to cure, and then to palliate when cure is not possible. For cases of primary GI FL, it remains questionable if cure can be attained by any means. Reports have demonstrated mixed responses, with disease relapsing despite resection in several cases. 10 This fact is complicated by difficulty fully staging patients by visualizing all areas of the bowel, as well as the complications that arise from bowel resection to include enteropathies, formation of adhesions, bowel obstructions, etc. Additionally, although FL is a radiosensitive disease with potential for cure via radiation in localized areas, it is widely agreed that the complications of radiation of the bowel outweigh the benefit in this variant of FL. There are insufficient data to recommend radioimmunotherapy outside the realm of a clinical trial. Thus we are led to question the utility of chemotherapy and monoclonal antibody therapy—both for palliation and for cure.
The majority of data regarding FL of the GI tract are recorded in case series, which overall suggest that there may not be a significant improvement in either progression-free survival or overall survival with any treatment of this disease at the time of diagnosis. In 2003, Damaj et al reported on 25 patients in whom there was no difference between two groups of patients treated by either conventional chemotherapy with rituximab (median relapse-free time, 31 months), and patients without therapy based on the “watch and wait” concept (median time to disease progression, 37.5 months). 9 More recently, among 63 patients with low-grade duodenal FL followed for at least 6 years, 24 patients were managed expectantly. Of these seven showed spontaneous complete regression and 17 had stable disease; only two patients developed nodal FL, and none transformed to large cell lymphoma. Only five of these patients were treated with anti-CD20 antibody monotherapy, resulting in complete regression in four patients and stable disease in one patient. 16
We agreed that the goal of therapy in this case would be for palliation of symptoms. However, since this patient's night sweats had been ongoing for 8 years, we questioned whether they were related to this incidental FL diagnosis at all. In the cases in the literature, a majority of patients are asymptomatic. Those that report symptoms seem to have primarily vague abdominal discomfort or pain, symptoms of intestinal obstruction, or intestinal bleeding. B-symptoms such as fever, sweats, and weight loss are not recognized in case reports of primary GI FL.
As it is true that in 70% of cases 17 lymphoma may exist in other locations of the GI tract, we did recommend that the patient follow-up with wireless capsule endoscopy (WCE) or digital balloon enteroscopy (DBE) to fully visualize the small bowel. As traditional endoscopy cannot completely visualize the small bowel, improvement in methods such as DBE and WCE permit more extensive staging and thorough follow-up of these patients by enabling visualization of the entire bowel. As these methods are becoming routine for screening populations at higher risk of GI malignancies, the diagnosis of primary GI FL is increasing.
Observation alone is appropriate for disease processes for which there is no evidence that intervention prolongs life or improves its quality. In primary GI FL as with other low-grade follicular lymphomas, there is no evidence to suggest that early treatment improves outcomes. Case reports suggest that these patients have an excellent prognosis regardless of first-line therapy choice or when therapy is initiated. In a recent review of the literature in 2010, Yamamoto et al reported a review of 211 primary GI FL cases where observation without therapy was performed for 25%, while some kind of therapy was performed in 75%. In this review, chemotherapy (or combination with other therapies) was performed in about 50% of all primary GI FL patients. 17 As diagnosis of this variant of FL increases with augmented screening of high-risk GI malignancy populations, perhaps we will gain more data to support the best treatment strategy.
Kelly W. Mitchell, MD
Clinical Oncology Fellow
Sidney Kimmel Comprehensive Cancer Center
The Johns Hopkins Hospital
Richard F. Ambinder, MD, PhD
Director, Division of Hematologic Malignancies
James B. Murphy Professor of Oncology
Sidney Kimmel Comprehensive Cancer Center
The Johns Hopkins Hospital
Radiation Oncologist's Opinion
This case concerns an extranodal follicular-B cell NHL originating in the small intestine. This is a rare presentation usually handled with systemic therapy plus or minus surgery. Because the site of origin is quite mobile and is surrounded by sensitive gut tissue, the role for radiotherapy is limited. However, the acknowledged high radiosensitivity of this tumor type prompts discussion of ways to use radiotherapy beyond the realm of traditional external-beam treatment. Accordingly, there has been substantial recent interest in using biologically targeted anti-CD 20 radioimmunotherapy as a means of tumor control.
There have been very small published experiences using either yttrium-90 ibritumomab tiuxetan (Zevalin, Spectrum Phamaceuticals, Irvine, CA) or iodine-131 tositumomab (Bexxar, GlaxoSmithKline, Research Triangle Park, NC) for control of extranodal FL including those originating in the GI system. Typically, control rates on the order of 80% to 90% have been achieved for localized disease. The only major toxicity is dose-related hematosuppression and thrombocytopenia. Though most commonly discussed for gastric mucosa-associated lymphoid tissue (MALT) tumors, the present case of intestinal low-grade NHL might be considered as well.
Roger M. Macklis, MD
Professor of Medicine (Radiation Oncology)
Cleveland Clinic Lerner College of Medicine and
Taussig Cancer Institute
Cleveland Clinic, Cleveland, OH
Surgical Oncologist's Opinion
FL of the small bowel is a very rare form of malignancy. Given this reality, there are no published prospective randomized trials to inform multidisciplinary decision-making about the role of surgery in this specific disease. Patients with FL of the small bowel may be asymptomatic or may have nonspecific complaints of findings consistent with malabsorption issues such as weight loss of unapparent etiology, vague abdominal pain, or altered bowel habits. A tentative diagnosis may occasionally be rendered on the basis of radiologic findings. In other instances, persistent symptomatology in the absence of other more definitive evidence may prompt a surgical exploration with establishment of diagnosis. In the absence of diffuse GI involvement or extensive disease loci elsewhere, resection of localized disease is generally perceived as beneficial in most circumstances. Such resection may provide the tissue needed for unequivocal diagnosis, as well as an assessment of extent of disease, while providing a prospective opportunity to avoid subsequent complications such as intusseption, perforation, or frank tumor obstruction. Patients incurring the latter findings typically will present with acute abdominal signs and symptoms mandating surgical exploration. In selected individuals, the extent of resection may portend the likelihood of a surgical cure without the necessity of adjuvant chemotherapy. More commonly, however, adjuvant therapy will be advisable, particularly in the clinical setting where the diagnosis of FL is established only at the time of surgical resection in that removal of even localized small bowel disease rarely eradicates the underlying disease process. At the time of operation, the involved bowel segment must be resected with wide, demonstrably negative margins because all forms of small bowel lymphoma can track widely within the submucosal plane of the intestine. Grossly involved and/or draining mesenteric lymph nodes should be removed in-continuity with the diseased small bowel segment. Considerable surgical judgment must be exerted in determining the extent of resection, especially if long-term or even permanent malabsorption problems are to be avoided.
Raphael Pollock, MD, PhD
Professor and Head, Division of Surgery
University of Texas M.D. Anderson Cancer Center
Summary and Assessment
Primary FL of the GI tract is a rare entity and accounts only for 2% of GI NHLS.18 and 19 Two definitions have been used. According to Dawson et al, it is defined as: (1) a GI tract tumor with lymph node involvement confined to the drainage area of the primary tumor site; (2) no liver or spleen involvement or palpable lymph nodes; (3) normal chest radiograph; and (4) normal peripheral white blood cells. 20 On the other hand, Lewin et al's definition did not exclude tumors with extra-intestinal lesions. 18 The latter definition has been used by most case series, though cases with extensive extra-intestinal involvement were excluded. 17
The small intestine is most commonly affected.17 and 19 The available literature is limited to case reports or small series. As a result, no evidence-based treatment guidelines are available at the present time and those guidelines that are available are at best controversial, especially for the lower grades.
Small bowel FL most frequently presents with abdominal pain. Less commonly, it causes rectal bleeding or obstructive symptoms as suggested by observational studies conducted in one small series. 10 In our case, the patient suffered mostly from intermittent rectal bleeding and B symptoms (night sweats and fatigue). FL's clinical course is indolent, characterized by frequent remissions and relapses. 21
Diagnosis is based on endoscopy (both upper and lower) with biopsy and histology. Recent small observational studies suggest that DBE and/or WCE may identify lesions in the small bowel that can otherwise be missed with the usual colonoscopy or upper endoscopy.17 and 22 Accurate staging is important since it dictates the management. Also, it is crucial to distinguish between a primary GI FL and an extranodal NHL extending to the GI tract. The natural history, prognosis, and consequently the treatment modalities differ between these two entities.
A total-body CT scan, bone marrow biopsy, and a PET scan are all needed to evaluate the extent of the disease. Fluorine-18 fluorodeoxyglucose (FDG)-PET has shown better sensitivity and specificity in staging aggressive lymphomas, whereas concerns were raised as to its utility in evaluating GI FL. In a small study, FDG-PET was unable to detect the primary lesion in the duodenum of seven patients with duodenal FL. 23 Few reports suggest that it may be more sensitive for detecting lymph node dissemination. 17
Our patient underwent for staging purposes a bone marrow biopsy and a PET scan. Both showed no evidence of extra-intestinal disease. In order to get a more accurate appreciation of the intestinal extent of his lymphoma, a capsule endoscopy was performed, which showed few additional nodules in the jejunum.
FLs are commonly classified in three grades based on the number of centroblasts per high-power field. 24 This grading system correlates well with prognosis. 25 GI FL presents more frequently at lower grades (84.4%, 11.3%, and 4.3% for grades 1–3) as compared to nodal FL (40%–60%, 25%–35%, and ∼20% for grades 1–3), suggestive of a more aggressive course of the latter. 17 In our case report, the patient had a grade 1–2 out of 3 B-cell primary GI FL. It is clear from different series that GI FL is indolent in nature.8 and 10 In a retrospective study of patients with primary duodenal FL, 8 96% of the cases were of low-grade (grades 1 or 2), with a stage I in 74% of the cases. All patients survived with a median follow up time of approximately 48 months (up to 118.6 months). In those who received treatment upon diagnosis (52%), the overall response rate was 86%, and their estimated progression-free survival rates after 1, 2, and 3 years were 93%, 70%, and 70%, respectively, as compared to 85%, 74%, and 74%, respectively, in the remaining patients who chose not to receive treatment. 8
Even though FL is indolent, it remains an incurable disease. No prospective randomized clinical trials are available to guide management of NHL of the GI tract. Treatment modalities include the “wait and watch” approach, local radiation therapy for earlier stages (mostly for the extra-intestinal form of FL), rituximab, chemotherapy, a combination of both, and more recently radioimmunotherapy.
The concept of watch and wait has surfaced since the Stanford experience first in 1979, 26 then in 1984, 27 which suggested that in selected patients with low-grade NHL, the “observation only” group had similar outcomes compared with the “conventional treatment” group in terms of survival and time to progression and transformation. Of note, monoclonal antibodies were not yet a therapeutic option in these trials. In primary FL of GI tract, a few small studies suggest similar findings, though none have been prospective or randomized.9 and 10
With the advent of biological therapies, such as rituximab, an anti-CD20 monoclonal antibody, treatment outcomes of FL (especially its advanced nodal form) have improved, whether alone or in combination with chemotherapy agents.21, 28, 29, 30, 31, and 32 However, the optimal regimen has yet to be determined. 33 In primary GI FL, rituximab alone has been studied, but no randomized trials were conducted to compare it to conventional therapy. Due to its low toxicity, it is not unreasonable to use rituximab in symptomatic patients.
Surgical resection of the small bowel, though not curative, has been used. Recurrences are common. Since it is associated with high morbidity (malabsorption syndrome), and unless perforation or obstruction occurs, it is best avoided. Similarly, radiation therapy in the small bowel carries high morbidity.
Radioimmunotherapy is a relatively more recent therapeutic modality. It allows more targeted delivery of radiation to specific cells, in the case of NHL to the CD20 antigen. Two radio-immunoconjugates, 131I-tositumomab (Bexxar) and 90Y-ibritutomab tiuxetan (Zevalin), have been approved by the US Food and Drug Administration for the treatment of recurrent FL. 21 Most trials were done in relapsed/recurrent NHL,34 and 35 with higher response rates and/or prolonged remissions when compared to standard of care, with evidence of benefits even after failure of rituximab. 131I-tositumomab was more recently used in untreated advanced-stage FL, with complete response rates of 75%, a 5-year progression-free survival rate of 59%, and a median progression-free survival of approximately 6 years. 36 No data are yet available for the use of these radio-immunoconjugates in the treatement of the more indolent forms in primary GI FL.
In summary, low-grade primary FL of the small bowel is an indolent lymphoma for which treatment options range from observation alone to use of rituximab or chemotherapy or a combination of both. Surgery is an option for complicated cases, since it has a tendency to recur after resection. Because of the location of the lymphoma in the small bowel, which is highly mobile, radiotherapy is associated with high morbidity, so is rarely used.
Radioimmunotherapy, a new modality, has shown benefit in advanced-stage and recurrent NHL. No data are available yet for primary FL of the small bowel.
Primary small bowel FL is incurable, and has a long course marked with recurrences. Treatment is often guided by patient symptoms, patient preferences, and the experience of the physician.
In the present case, the patient consulted three medical oncologists (at two separate institutions), a surgical oncologist, and a radiation oncologist. Chemotherapy with a rituximab-CHOP (cyclophosphamide, hydroxydoxorubicin, vincristine, prednisone) regimen was recommended by one medical oncologist. Two of the three recommended the watch and wait approach with close follow-up. Radiation and surgical resection were not recommended because of the high morbidity associated with these modalities, especially since the small bowel was involved. At the end, after consideration of the differing opinions, the patient chose the watch and wait approach.
Laboratory values were followed quarterly and PET/CT was repeated at 6-month intervals for the first year. FDG avidity in the region of the ileocecal valve that was present following initial diagnosis (and colonoscopic resection), has remained stable, and was felt to be normal physiologic uptake in the bowel. A repeat colonoscopy was performed 1 year from the time of initial diagnosis and was without any evidence of disease. Specifically, the terminal ileum was without any further nodules, as this was the location of patient's presenting lesions. WCE and upper endoscopy were not repeated, as they were not likely to change management.
The patient's night sweats resolved spontaneously, with lifestyle and dietary changes, within the first 6 months following his diagnosis. There were no episodes of abdominal pain, reflux symptoms, or nausea/vomiting for 18 months following the time of diagnosis. Incidentally, the patient had sudden onset of severe abdominal pain at 18 months post-diagnosis and was found to have acute appendicitis. On exploratory laparotomy, there was no lymphadenopathy appreciated, no abnormal findings in the mesentery, and no abnormalities aside from an inflamed appendix on a thorough exploratory surgery. Pathologic review of the surgical specimen was notable only for appendiceal inflammation. At the time of this submission, the patient is doing well, and is content to continue on a watch and wait paradigm.
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