Endoscopic diagnosis of follicular lymphoma with small-bowel involvement using video capsule endoscopy and double-balloon endoscopy: a case series

• Introduction
• Patients and methods
• Patients
• Methods
• Results
• Discussion
• References

The aims of this study were to compare the detection rates of gastrointestinal follicular lymphoma lesions by video capsule endoscopy (VCE) and double-balloon endoscopy (DBE), and to determine the pathologic diagnostic yields of DBE-directed biopsies. A total of 27 consecutive patients were enrolled. No significant difference in detection rates was observed in 12 patients who underwent total enteroscopy at both VCE and DBE. Pathologic diagnostic yields stratified by location were 91 % in the proximal duodenum at esophagogastroduodenoscopy, 88 % in the jejunum at antegrade DBE, 52 % in the ileum at retrograde DBE, and 57 % in the terminal ileum at colonoscopy. VCE and DBE were helpful in determining treatment in 44 % of patients.

Introduction

Extranodal gastrointestinal follicular lymphoma (GI-FL) has been increasingly detected around the ampulla of Vater in the duodenum at esophagogastroduodenoscopy (EGD) [1]. The recent advent of video capsule endoscopy (VCE) and double-balloon endoscopy (DBE) has revealed that GI-FL is frequently complicated, with lesions being scattered deep in the small bowel and in particular small whitish polypoid lesions observed in the duodenum [2] [3] [4]. As GI-FL lesions are only rarely (especially in the early stages) identified by positron emission tomography with 18F-fluorodeoxyglucose and/or computed tomography, VCE and DBE may help to determine the prevalence and treatment of these lesions [5] [6] [7]. Akamatsu et al. reported that VCE showed similar small-bowel findings to DBE in two patients with primary GI-FL prior to chemotherapy [8]. To our knowledge, there have been no reports comparing the detection rates of small-bowel follicular lymphoma lesions by VCE and DBE in patients undergoing both examinations. In the current case series, the detection rates of small-bowel follicular lymphoma lesions were compared between VCE and DBE in 12 patients who underwent total enteroscopy at both examinations. In addition, the pathologic diagnostic yield of biopsy specimens taken at DBE were determined in 27 patients with GI-FL. The endoscopic and pathologic response rates of small-bowel lesions after treatment were also assessed.

Patients and methods

Patients

Of 156 consecutive patients with small-bowel tumors/polyps who underwent DBE between June 2003 and January 2011 at Nagoya University Hospital, 27 (17 %) were diagnosed with small-bowel follicular lymphoma.

Methods

VCE and DBE were carried out as previously described [9] [10] [11]. The detection rates of GI-FL lesions by VCE and DBE were compared using the Mann – Whitney test. Biopsy specimens were taken from polypoid lesions ([Fig. 1]), wall changes ([Fig. 2]), and Peyer’s patches ([Fig. 1]), and pathologic diagnostic yields were assessed using chi-squared statistics. Patients received a confirmed diagnosis of GI-FL when the tumor cells were immunohistochemically positive with anti-CD10, CD20, and Bcl-2 antibodies. Differences were considered significant when the P values were less than 0.05.

This study was reviewed and approved by the Institutional Review Board of Nagoya University Graduate School of Medicine. Informed consent was obtained from all patients.

Results

The clinical characteristics of follicular lymphomas in 27 patients are shown in [Table 1]. Total enteroscopy rates at VCE and DBE were 90 % (19/21) and 64 % (14/22), respectively (P = 0.0689). Total enteroscopy was successful at both VCE and DBE in 12 patients (10 in stage I; 2 in stage IV). The detection rates of polypoid lesions and wall changes were not statistically significant between VCE and DBE examinations in the entire small bowel, jejunum, or ileum (P = 0.291) ([Table 2]).

The pathologic yield of polypoid lesions and wall changes were significantly higher than that of Peyer’s patches (P = 0.001 and P < 0.0001, respectively). Pathologic yields of polypoid lesions and Peyer’s patches in the ileum were 56 % (46/82) and 31 % (5/16), respectively ([Table 3]).

Of 27 patients with small-bowel follicular lymphoma, 14 received rituximab monotherapy, 9 received rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), 1 received radiation treatment only, and 3 were followed up by watchful waiting only (i. e. without treatment). A total of 10 patients underwent antegrade and retrograde DBE following both endoscopic and pathologic confirmation of complete remission in the proximal duodenum at EGD over the median follow-up period of 23 months after treatment (8 – 36 months). Positive pathology for lymphoid follicles or reduced polypoid lesions were found in 8/28 specimens (29 %) and 3/10 patients (30 %) at antegrade DBE and in 3/27 specimens (11 %) and 2/10 patients (20 %) at retrograde DBE. Eventually, complete remission was achieved in 7/10 patients (70 %) and partial remission in 3/10 (30 %). Pathologically positive lesions could not be differentiated from negative lymphoid follicles by endoscopy findings alone.

Discussion

In the current study, which included 27 patients with GI-FL and small-bowel involvement, 25 (93 %) harbored GI-FL lesions in the proximal duodenum. Of these 25 patients, 24 (96 %) also had involvement of the duodenal second portion and harbored multiple GI-FL lesions from the distal duodenum to the terminal ileum. A multicenter Japanese analysis of 125 patients with GI-FL throughout the alimentary tract reported that the most frequently involved site was the duodenal second portion (81 %), followed by the jejunum (40 %); 85 % of patients with involvement of the duodenal second portion had concomitant jejunal or ileal lesions [4]. Thus, many patients with GI-FL harbored the multiple small-bowel lesions. The current study, however, demonstrated that these small-bowel lesions were also detected in the terminal ileum in 15/27 patients (56 %) using colonoscopy with ileal intubation, suggesting that VCE and DBE are indeed useful for detection of lesions in the remaining small bowel in up to 44 % of patients.

To our knowledge, the current study is the first to show that VCE detected small-bowel GI-FL lesions at a similar rate to DBE. In patients with Peutz – Jeghers syndrome, it has been demonstrated previously that VCE detection rates of small-bowel polyps are similar to those of DBE [12]. As VCE is less invasive than DBE, VCE may be recommended to determine whether or not such lesions are present deep within the small bowel prior to treatment. The jejunal polypoid lesions are easy to detect because they are whitish and physiological lymphoid follicles are rarely identified in the jejunum. Ileal lesions, however, are occasionally difficult to diagnose because they exhibit the same configuration and color as physiological lymphoid follicles in the ileum. If a few polypoid lesions are observed only in the ileum at VCE, DBE with biopsy is needed to confirm small-bowel involvement.

The management of GI-FL differs according to its staging. Radiotherapy remains the treatment of choice if early-stage GI-FL lesions are located only within the duodenum [13]. Many patients, however, harbor multiple lesions deep within the small bowel, as described above. At early stages, no initial therapy [14] or rituximab monotherapy is preferable. At late stages, combined chemotherapy including R-CHOP with or without surgical resection is chosen. Therefore, identification of the distribution of the small-bowel lesions by VCE and DBE is essential to select the appropriate treatment.

After treatment, endoscopic findings alone are not sufficient to evaluate the antitumor responses; pathologic findings of biopsy specimens taken at endoscopy are the only reliable diagnostic tool. Therefore, antitumor responses should be assessed first by EGD and colonoscopy with ileal intubation depending on whether the original GI-FLs were present in the upper gastrointestinal tract or terminal ileum, respectively. Following pathological assessment of biopsy specimens taken at EGD and colonoscopy, DBE with biopsy should be selected to assess the lesions deep within the small bowel.

In conclusion, this case series highlights the usefulness of combined VCE and DBE for the diagnosis and assessment after treatment of GI-FL deep within the small bowel.

Competing interests: None.

• References

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• 8 Akamatsu T, Kaneko Y, Ota H et al. Usefulness of double balloon enteroscopy and video capsule endoscopy for the diagnosis and management of primary follicular lymphoma of the gastrointestinal tract in its early stages. Dig Endosc 2010; 22: 33-38
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• 9 Ohmiya N, Taguchi A, Shirai K et al. Endoscopic resection of Peutz–Jeghers polyps throughout the small intestine at double-balloon enteroscopy without laparotomy. Gastrointest Endosc 2005; 61: 140-147
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• 10 Nakamura M, Niwa Y, Ohmiya N et al. Preliminary comparison of capsule endoscopy and double-balloon enteroscopy in patients with suspected small-bowel bleeding. Endoscopy 2006; 38: 59-66
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• 11 Arakawa D, Ohmiya N, Nakamura M et al. Outcome after enteroscopy for patients with obscure GI bleeding: diagnostic comparison between double-balloon endoscopy and videocapsule endoscopy. Gastrointest Endosc 2009; 69: 866-874
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• 12 Ohmiya N, Nakamura M, Takenaka H et al. Management of small-bowel polyps in Peutz–Jeghers syndrome by using enteroclysis, double-balloon enteroscopy, and videocapsule endoscopy. Gastrointest Endosc 2010; 72: 1209-1216
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• 13 Mac Manus MP, Hoppe RT. Is radiotherapy curative for stage I and II low-grade follicular lymphoma? Results of a long-term follow-up study of patients treated at Stanford University.. J Clin Oncol 1996; 14: 1282-1290
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• 14 Advani R, Rosenberg SA, Horning SJ. Stage I and II follicular non-Hodgkin’s lymphoma: long-term follow-up of no initial therapy. J Clin Oncol 2004; 22: 1454-1459
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Corresponding author

• References

• 1 Yoshino T, Miyake K, Ichimura K et al. Increased incidence of follicular lymphoma in the duodenum. Am J Surg Pathol 2000; 24: 688-693
  CrossrefPubMedSearch in Google Scholar
• 2 Matsumoto T, Nakamura S, Esaki M et al. Double-balloon endoscopy depicts diminutive small bowel lesions in gastrointestinal lymphoma. Dig Dis Sci 2010; 55: 158-165
  CrossrefPubMedSearch in Google Scholar
• 3 Chowdhury M, Endo M, Chiba T et al. Characterization of follicular lymphoma in the small intestine using double-balloon endoscopy. Gastroenterol Res Pract 2009; 2009 835258. Epub 2009 Nov 5. PubMed PMID: 19901998; PubMed Central PMCID: PMC2773429
  PubMedSearch in Google Scholar
• 4 Takaka K, Okada H, Ohmiya N et al. Primary gastrointestinal follicular lymphoma involving the second portion is a distinct entity: a multicenter, retrospective analysis in Japan. Cancer Sci 2011; 102: 1532-1536
  CrossrefPubMedSearch in Google Scholar
• 5 Higuchi N, Sumida Y, Nakamura K et al. Impact of double-balloon endoscopy on the diagnosis of jejunoileal involvement in primary intestinal follicular lymphomas: a case series. Endoscopy 2009; 41: 175-178
  Thieme ConnectPubMedSearch in Google Scholar
• 6 Kodama M, Kitadai Y, Shishido T et al. Primary follicular lymphoma of the gastrointestinal tract: a retrospective case series. Endoscopy 2008; 40: 343-346
  Thieme ConnectPubMedSearch in Google Scholar
• 7 Flieger D, Keller R, May A et al. Capsule endoscopy in gastrointestinal lymphomas. Endoscopy 2005; 37: 1174-1180
  Thieme ConnectPubMedSearch in Google Scholar
• 8 Akamatsu T, Kaneko Y, Ota H et al. Usefulness of double balloon enteroscopy and video capsule endoscopy for the diagnosis and management of primary follicular lymphoma of the gastrointestinal tract in its early stages. Dig Endosc 2010; 22: 33-38
  CrossrefPubMedSearch in Google Scholar
• 9 Ohmiya N, Taguchi A, Shirai K et al. Endoscopic resection of Peutz–Jeghers polyps throughout the small intestine at double-balloon enteroscopy without laparotomy. Gastrointest Endosc 2005; 61: 140-147
  CrossrefPubMedSearch in Google Scholar
• 10 Nakamura M, Niwa Y, Ohmiya N et al. Preliminary comparison of capsule endoscopy and double-balloon enteroscopy in patients with suspected small-bowel bleeding. Endoscopy 2006; 38: 59-66
  Thieme ConnectPubMedSearch in Google Scholar
• 11 Arakawa D, Ohmiya N, Nakamura M et al. Outcome after enteroscopy for patients with obscure GI bleeding: diagnostic comparison between double-balloon endoscopy and videocapsule endoscopy. Gastrointest Endosc 2009; 69: 866-874
  CrossrefPubMedSearch in Google Scholar
• 12 Ohmiya N, Nakamura M, Takenaka H et al. Management of small-bowel polyps in Peutz–Jeghers syndrome by using enteroclysis, double-balloon enteroscopy, and videocapsule endoscopy. Gastrointest Endosc 2010; 72: 1209-1216
  CrossrefPubMedSearch in Google Scholar
• 13 Mac Manus MP, Hoppe RT. Is radiotherapy curative for stage I and II low-grade follicular lymphoma? Results of a long-term follow-up study of patients treated at Stanford University.. J Clin Oncol 1996; 14: 1282-1290
  CrossrefPubMedSearch in Google Scholar
• 14 Advani R, Rosenberg SA, Horning SJ. Stage I and II follicular non-Hodgkin’s lymphoma: long-term follow-up of no initial therapy. J Clin Oncol 2004; 22: 1454-1459
  CrossrefPubMedSearch in Google Scholar