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Keywords:

  • mantle cell lymphoma;
  • gastrointestinal tract;
  • endoscopy;
  • patient management

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

BACKGROUND

The reported frequency of gastrointestinal (GI) tract involvement in patients with mantle cell lymphoma (MCL) is 15–30%. However, this figure most likely is an underestimate because most patients with MCL involving the GI tract previously reported were examined endoscopically only if they had GI tract symptoms. The impact of endoscopic assessment on the management of MCL patients is unknown.

METHODS

From March 1998 to May 2001 baseline upper and lower endoscopy of the GI tract was performed in consecutive untreated patients with MCL as part of a prospective therapeutic trial. Biopsies were performed on abnormal as well as macroscopically normal mucosa. Endoscopy was repeated during treatment and as part of follow-up evaluations.

RESULTS

Only 26% of patients presented with GI symptoms at the time of diagnosis. MCL was present histologically in the lower GI tract of 53 of 60 patient (88%) and in the upper GI tract of 28 of 58 patients (43%). Microscopic evidence of MCL was found in 84% of patients with normal visual (macroscopic) findings by lower endoscopy and in 45% of patients with macroscopically normal findings by upper endoscopy. Despite this high frequency of GI tract involvement, the use of upper and lower endoscopy with biopsies in this group of patients resulted in changes in clinical management in only three (4%) patients.

CONCLUSIONS

Gastrointestinal tract involvement was found to be present in most patients with MCL, usually at a microscopic level involving macroscopically normal mucosa. The use of aggressive staging evaluation of the GI tract was found to have little impact on patient management decisions in the current study. Cancer 2003;97:586–91. © 2003 American Cancer Society.

DOI 10.1002/cncr.11096

Mantle cell lymphoma (MCL) has been reported to involve the gastrointestinal (GI) tract in 15–30% of patients.1–13 However, this reported frequency may underestimate the true frequency of GI tract involvement. Endoscopy is usually performed only in patients who have GI symptoms, such as diarrhea, and most patients have undergone only colonoscopy. To our knowledge, the true frequency of GI tract involvement in MCL patients has not been studied prospectively.

Appropriate staging is important in the clinical management of patients with lymphomas for treatment planning, response assessment, and surveillance. Therefore, we included baseline upper and lower endoscopy of the GI tract as part of the staging workup in a group of consecutive, untreated patients with MCL at our institution. We have found a high frequency of microscopic involvement of the GI tract, suggesting that MCL has a propensity for homing to this anatomic site. Other clinical correlates also are discussed.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

From March 1998 to May 2001, 71 consecutive patients referred to our institution from across the U.S. with untreated aggressive MCL (diffuse or nodular pattern or their blastoid variants) were registered on protocol DM 98-327. This protocol consisted of fractionated doses of cyclophosphamide, sodium mercaptoethanesulfonate, doxorubicin, vincristine, dexamethasone, and rituximab alternated every 3 weeks with high doses of methotrexate, high-dose cytarabine, and rituximab for a total of 6–8 cycles (Table 1). This treatment did not vary, regardless of patient age or Ann Arbor stage at time of presentation. Additional criteria for inclusion in the study were adequate organ function and blood counts, unless low blood counts could be attributed to bone marrow involvement by lymphoma; performance status of ≤ 2 according to the National Cancer Institute common toxicity criteria, version 2;14 no evidence of involvement of the central nervous system; no pregnancy or human immunodeficiency virus infection; and no significant comorbid condition. Written informed consent for protocol DM 98-327 was obtained from all patients following institutional review board guidelines.

Table 1. Rituxan-HyperCVAD for Mantle Cell NHL: Treatment Doses and Schedulea
Cycle 1Cycle 2
  • IV: intravenous; IVCI: intravenous by continuous infusion; PO: oral.

  • a

    Alternate Cycles 1 and 2 every 21 days. Transplant was not performed if complete remission occurred within the first six cycles.

  • b

    Cytarabine dose reduced by two-thirds for patients older than 60 or with creatinine levels above 1.5 mg/dL. Prophylaxis includes sodium mercaptoethanesulfonate, granulocyte–colony-stimulating factor, and antifungal, antibacterial, and antiviral therapy.

Rituximab 375 mg/m2 IVRituximab 375 mg/m2 D1
Cyclophosphamide 300 mg/m2 over 3 hrs every 12 hrs × 6 Days 2–4Methotrexate 200 mg/m2 IV over 2 hrs on Day 2
Doxorubicin 16.6 mg/m2/d IVCI 72 hrs Days 5–7Methotrexate 800 mg/m2 IVCI 22 hrs Day 2
Vincristine 1.4 mg/m2 IV (maximum 2 mg) Days 5 and 12Cytarabine 3000 mg/m2 IV over 2 hrs every 12 hrs × 4 Days 3–4b
Dexamethasone 40 mg IV or PO Days 2–6 and 12–16 

All patients were required to undergo upper and lower endoscopy of the GI tract as part of the baseline evaluation, as part of extensive restaging performed after every two cycles of chemotherapy, and as part of surveillance studies performed every 4 months during the first year after treatment, then every 6 months for the next 2 years, then yearly thereafter. Biopsies were done of visually abnormal mucosa, including areas of erythema, thickness, nodularity or ulceration, masses, or polyps. Random (blind) biopsies also were performed when no mucosal lesions were observed macroscopically. In most endoscopic procedures, one random biopsy specimen was taken from each anatomic site including the stomach and duodenum as part of upper endoscopy, and the ascending, transverse, and descending colon as part of lower endoscopy.

At time of initial diagnosis of MCL, biopsy specimens from lymph nodes, bone marrow, or the GI tract were processed routinely with preparation of hematoxylin-eosin–stained sections. Because most of these specimens were obtained elsewhere and subsequently referred to our institution, their pathologic workup was highly variable and included flow cytometry immunophenotypic, conventional cytogenetic, or fluorescence in situ hybridization (FISH) studies. However, all initial diagnostic biopsy specimens were assessed immunohistochemically at the study institution using antibodies specific for CD5, CD20, and cyclin D1 and fixed, paraffin-embedded tissue sections.

Positive staging bone marrow and/or peripheral blood specimens were analyzed at the study institution using flow cytometry immunophenotypic methods, a polymerase chain reaction (PCR) technique to assess for the t(11;14)(q13;q32) involving the major translocation cluster for the bcl-1 locus as described previously.15 In addition, FISH analysis was used to assess for either 11q13 breakpoints or the t(11;14).16 The diagnosis of MCL in every patient in this study was based on compatible histologic findings combined with the presence of the t(11;14) or cyclin D1 positivity. In general, cyclin D1 immunoreactivity was shown in lymph node and GI biopsy specimens, with PCR evidence of the t(11;14) in a small subset of cases. Flow cytometry immunophenotypic, conventional cytogenetic, or FISH analysis was performed on bone marrow aspirate specimens.

When endoscopic biopsy specimens of the GI tract were obtained prospectively for this study, subsequent to the diagnosis of MCL being established, immunohistochemical studies were performed on one or more biopsy specimens from the GI tract. In each patient in this study considered to have GI tract involvement by MCL, at least one (usually two and rarely three) biopsy specimen was assessed immunohistochemically for CD5, CD20, and cyclin D1 using fixed, paraffin-embedded tissue sections and the lymphoid aggregates involving GI tract mucosa were positive for CD20 and cyclin D1, and usually positive for CD5. However, if a patient had multiple GI tract endoscopic biopsy specimens, once the diagnosis of MCL was established in at least one GI tract site, additional sites of involvement were determined histologically without immunohistochemical support. For example, in a patient with MCL involving the GI tract with five morphologically positive endoscopic GI tract specimens, at least one site was shown to be positive for CD20 and cyclin D1.

As part of restaging requirements, morphologic evaluation, flow cytometry immunophenotypic studies, and molecular studies to assess for the t(11;14) were performed on bone marrow and peripheral blood unless initially negative. Restaging and surveillance endoscopic biopsy specimens of the GI tract were immunostained for CD5, CD20, and cyclin D1.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Clinical Presentation

Table 2 shows the principal characteristics of the patients in the study group. These patients were all untreated and, as expected, were predominantly men with a median age of 62 years at time of presentation. All patients presented with advanced Stage IV disease, mostly on account of bone marrow, GI tract, or peripheral blood involvement. Five patients who presented with GI tract involvement had no evidence of bone marrow or peripheral blood involvement. Most patients presented with elevated β-2-microglobulin and normal lactate dehydrogenase serum levels, two or three extranodal sites of involvement, and a low to intermediate risk score according to the international prognostic index. The most common histopathologic pattern of involvement by MCL was diffuse. Nine patients presented without evidence of lymph node involvement. In these patients, the diagnosis was made by examination of the GI tract or bone marrow aspiration and biopsy specimens with appropriate ancillary data as outlined in the Materials and Methods.

Table 2. Clinical Features at Time of Presentation for 71 Patients with Untreated MCL
  • MCL: Mantle cell lymphoma; WHO: World Health Organization; BM: bone marrow; GI: gastrointestinal; PB: peripheral blood.

  • a

    High is ≥ 3 mg/dL.

  • b

    High is > 618 U/L.

Median age (yrs) 62 (range, 41–80)
Ann Arbor Stage IV100%
Constitutional symptoms 11%
WHO performance status 
 0 42%
 1 56%
 2  2%
Median tumor size (cm)  2.5 (range, 0–10)
Large spleen 42%
BM involvement 92%
GI tract involvement (n = 60) 88%
PB involvement 45%
Positive GI, negative BM and PB  8%
No. of extralymph node sites 
 1 11%
 2 38%
 3 45%
 4  6%
Median β-2-microglobulin (range)a  3.4 (1.3–13.5)
Median lactate dehydrogenase (range)b495 (238–2586)
International prognostic index 
 1 10%
 2 34%
 3 45%
 4 11%
MCL histology (62 patients) 
 Diffuse pattern 69%
 Nodular pattern 14%
 Blastoid variant 18%

Endoscopy Findings

Of the 71 patients with MCL registered in the study, 1 patient refused endoscopy and 3 patients needed urgent treatment and did not undergo endoscopy. Sixty-seven patients were assessed endoscopically.

Lower GI tract

Sixty-seven patients underwent colonoscopy. Seven patients did not have biopsy specimens for the following reasons: the biopsy specimen was inevaluable in one case and, in six cases, no lesion was identified to biopsy and the endoscopist neglected to perform random biopsies. Therefore, 60 patients had both biopsy specimens and gross endoscopic findings for correlation.

Upper GI tract

Sixty-two patients underwent upper endoscopy. Four patients did not have biopsy specimens for the following reasons: the biopsy specimen was inevaluable in one case and, in three cases, no lesion was identified to biopsy and the endoscopist neglected to perform random biopsies. Fifty-eight patients had both biopsy specimens and macroscopic endoscopic findings for correlation.

The macroscopic endoscopic findings are detailed in Table 3. The most common endoscopic finding was completely normal mucosa in both the upper and lower GI tract. The most frequent abnormal findings were nodules/inflammation and nodules/polyps in the upper and lower GI tract, respectively.

Table 3. Upper and Lower GI Tract Macroscopic Endoscopy Findings in Patients with MCL
FindingsUpper (n = 58)Lower (n = 60)
No. positive (%)No. positive (%)
  1. GI: gastrointestinal; MCL: mantle cell lymphoma.

Normal22 (38)31 (51)
Nodules12 (21)14 (23)
Inflammation11 (19)1 (2)
Polyps3 (5)12 (20)
Ulcers5 (9)1 (1)
Thickness3 (5)1 (2)
Masses2 (3)0 (0)

Pathologic and Endoscopic Findings

Pathologic evaluation revealed MCL in 53 of 60 (88%) patients who underwent colonoscopy and in 28 of 58 (43%) patients who underwent endoscopy of the upper GI tract. As shown in Table 4, MCL was present in 26 of 31 (84%) patients with normal colonoscopy findings and in 10 of 22 (45%) patients who had normal upper endoscopy findings. The positive predictive values of colonoscopy and upper endoscopy were 93% and 68%, respectively. The negative predictive values of colonoscopy and upper endoscopy were 16% and 17%, respectively.

Table 4. Correlation between Macroscopic and Histologic Findings in MCL Patients with Endoscopy of GI Tract
VisualBiopsy
UGI (positive)UGI (negative)LGI (positive)LGI (negative)
  1. GI: gastrointestinal; MCL: mantle cell lymphoma; UGI: upper gastrointestinal; LGI: lower gastrointestinal.

Normal1012265
Inflammation7401
Nodules102140
Polyps21111
Ulcer3210
Thickness1210
Mass1100

Of the 54 patients who underwent upper and lower endoscopy of the GI tract with biopsy, only 14 patients (26%) had abdominal or GI symptoms at time of presentation. The symptoms in these patients were as follows: abdominal pain, mostly in the left upper quadrant in association with an enlarged spleen (six patients); diarrhea (four patients; but bloody in only one patient); lower GI tract bleeding (three patients, one with bleeding internal hemorrhoids); and nausea/vomiting in one patient. All 14 patients with abdominal or GI complaints had evidence of involvement of the GI tract by MCL, mostly at the microscopic level.

As stated in Materials and Methods, all GI tract biopsy specimens positive for MCL had compatible histologic findings. In addition, in any patient with one or more positive GI tract biopsy specimens, at least one (often two and rarely three) biopsy specimen was studied immunohistochemically and shown to be positive for CD20 and cyclin D1.

Clinical Correlations

Only 1 of 54 patients who had both upper and lower GI tract endoscopy with biopsies presented initially with involvement of only the upper GI tract. All other patients had involvement of both the upper and lower GI tract, or only the colon. Five of 60 patients (8%) who had an endoscopy with a positive GI tract biopsy specimen had no evidence of bone marrow involvement. One of 71 patients developed GI bleeding as a complication of treatment. This patient had originally presented with similar symptoms at time of diagnosis.

All patients in this study achieved a clinical response and 90% achieved a complete clinical response. There were 2 patients (3%) whose treatment was altered because of a positive endoscopic GI tract biopsy specimen. Both patients had residual microscopic disease in the colon as the only site of disease on complete restaging after six cycles of chemotherapy and were offered stem cell transplant. The use of surveillance endoscopy detected recurrence in the GI tract, but at no other site, in only 1 of 16 patients who had disease recurrence (i.e., 6% of the disease recurrences).

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Our prospective systematic analysis of the GI tract in patients with MCL suggests that the involvement of the GI tract is significantly higher than previously reported. In the literature, the reported frequency of GI tract involvement in MCL patients has ranged from 15% to 30%. Our data indicate that this frequency is an underestimate of GI tract involvement in MCL patients, probably attributable to the way the GI tract has been evaluated in the past. Only patients with GI symptoms underwent endoscopy in most studies. The 26% incidence of GI symptoms in our series of patients supports this view. An argument could be made that the high incidence of GI tract involvement reported in our study reflects a referral bias. The data in Table 2 suggest that the patients being referred to our institution have typical clinical characteristics at time of presentation, which makes this possibility unlikely. In addition, protocol DM 98-327 is the only trial designed for patients with untreated MCL at our institution, which eliminates the possibility of a selection bias within our institution.

These findings suggest that MCL has a propensity to home to the GI tract. Recent developments have led to the concept of finely tuned homing mechanisms in which adhesion molecules regulate leukocyte migration and organ targeting.17, 18 The presence of adhesion molecules may predict patterns of dissemination by lymphoma.19, 20 For example, Geissmann et al.21 analyzed the expression of the mucosal homing receptor, α4β7, by MCL cells in peripheral lymph nodes of patients with newly diagnosed disease. They found that α4β7 was expressed by MCL in five of seven patients with GI tract involvement. In contrast, MCL cells in six of six patients without GI tract involvement did not express α4β7 (P = 0.03).21 Whether the patients in their study were selected for GI tract endoscopy at random, or based on the presence GI symptoms at time of presentation, is unclear. In another study, Drillenburg et al.22 demonstrated that α4β7 is commonly expressed by the neoplastic cells in the clinical syndrome known as multiple lymphomatous polyposis (MLP). Patients with MLP have multiple polyps involving the GI tract and, in most cases, the polyps are composed histologically of MCL. Low-grade B-cell lymphomas of mucosa-associated lymphoid tissue (MALT) also commonly express α4β7.22 Thus, this homing mechanism is not unique to MCL.

Another provocative possibility, although less likely, is that MCL may originate from lymphoid tissue in the gut mucosa. Mantle cell lymphoma could originate from naive B cells in the mantle zones of lymphoid follicles in digestive tract-associated lymphoid tissue. Because this tissue is only normally present in Peyer patches of the ileum, perhaps MCL could arise from this site. Alternatively, MCL could arise from acquired lymphoid tissue at other GI sites, similar to the case in MALT lymphomas. However, benign mantle zone cells in GI tract lymphoid tissue do not express the α4β7 receptor. This hypothesis for lymphomagenesis would need to include other factors such as the aberrant expression of these receptors on the surface membrane of the malignant cells.21

The correlation between the histologic findings in upper and lower GI tract endoscopic biopsy specimens argues against the need to perform upper endoscopy to confirm GI tract involvement. All but one patient with positive findings in the stomach or duodenum also had positive colon biopsy specimens.

One of the presumptions in our study was that the presence of MCL in the GI tract would predict an increased frequency of bleeding during treatment with the potential for life-threatening complications. This was not the case, as only one patient bled during therapy and this patient had presented with lower GI tract bleeding at the time of diagnosis. In addition, there were no instances of perforation during or after therapy. We conclude that initial endoscopic evaluation of the GI tract with biopsies is not needed to identify patients who could bleed from or perforate their GI tract during treatment.

Most patients with MCL present with advanced stage of disease due to the presence of bone marrow involvement. Is initial GI tract endoscopic examination needed as a part of the staging workup? In our study, only 5 of 60 (8%) patients who had endoscopy showed microscopic evidence of GI tract involvement without evidence of bone marrow involvement. The presence of GI tract disease in these five patients, however, did not alter our treatment approach. Evaluation of the GI tract is warranted only if treatment decisions were affected by initial Ann Arbor stage and if other staging procedures had failed to document evidence of Stage IV disease.

Our results suggest that practically all patients with aggressive MCL will have GI tract involvement at the time of diagnosis. A relevant issue is whether this area needs to be evaluated at the end of therapy to document true complete disease remission in MCL patients. In our experience, the likelihood of residual MCL occurring in the GI tract was low, occurring in only 2 of 71 patients (3%). If a patient is to be considered to have complete remission of disease, a colonoscopy at this time may be warranted. Both patients with residual MCL in the GI tract in our study underwent transplantation at the end of therapy, when all other restaging procedures were negative for residual lymphoma.

Is colonoscopy needed as part of surveillance studies? In our study that spanned 42 months, only 1 of 16 recurrences was detected by endoscopic biopsy of the colon without evidence of disease elsewhere. In our view, this does not warrant surveillance colonoscopies in patients who have achieved a complete response to therapy.

In conclusion, GI tract involvement is present in most patients with MCL, usually at a microscopic level in grossly normal mucosa. These findings suggest that MCL has a propensity to home to the GI tract. Although interesting at a biologic level, knowledge of GI tract involvement had little impact on patient management decisions in this study because treatment was the same, regardless of initial stage of disease. However, due to the high frequency of GI tract involvement by MCL, endoscopic evaluation of colonic mucosa is warranted for assessment of complete response after therapy.

Acknowledgements

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

The authors thank Sharon Lee Turner and Keisha Watkins for expert secretarial assistance.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
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