Waldenstrom macroglobulinemia (WM) is an uncommon monoclonal B-cell lymphoproliferative disorder that is characterized by lymphadenopathy, organomegaly, and a circulating monoclonal IgM paraprotein9,15 that may lead to a hyperviscosity syndrome12. In his original report of 3 patients with the syndrome that bears his name, Waldenstrom included 1 patient with diarrhea as a prominent feature of the disease33. However, when patients with WM present with diarrhea, primary gastrointestinal disorders are usually considered and the potential enteric complications of WM are often ignored. This approach is justifiable, at least initially, because enteric involvement by WM is rare8,10. A search of the medical literature discloses scattered reports about these complications, but no overall incidence of gastrointestinal complications in WM is given1,2,4-6,16,18,19,24,27,28,30-32. It is important for physicians treating patients with WM to be aware of these complications, since they are eminently treatable as our index case will demonstrate.
A 35-year-old African-American woman in previously good health developed persistent diarrhea. She had up to 5 bowel movements per day including nocturnal defecation. She did not have any hematochezia but due to persistent symptoms, she consulted her local physician. In the initial evaluation, esophago-gastroduodenoscopy with biopsies, small bowel imaging, stool studies, and colonoscopy could not identify any etiology for her symptoms. Shortly thereafter the patient was found to have portal and splenic vein thromboses based on Doppler ultrasound examination of the abdomen. Despite adequate anticoagulation with Coumadin, she experienced additional venous thrombotic events. Further testing revealed the presence of an antiphospholipid antibody and a warm antibody mediated (antiglobulin test-positive) autoimmune hemolytic anemia. The patient was started on oral glucocorticosteroids. In a repeat evaluation of her diarrhea while she was on a normal diet, the clinician found evidence of fat malabsorption based on 72-hour fecal fat estimation, and a small bowel biopsy demonstrated mucosal edema and infiltration by foamy histiocytes. The patient developed a spontaneous empyema in her left hemithorax that required decortication, and she was transferred to our institution (Mayo Clinic, Rochester, MN) for further evaluation.
On admission, a computed tomography scan identified a colonic perforation at the splenic flexure that required a segmental colectomy with fashioning of a temporary colostomy. Histologic examination of the excised colon showed that the only notable abnormalities were a perforation and chronic serositis without any evidence of colonic ischemia. The patient had low levels of protein C and S, as well as Factor II and VII, consistent with either oral anticoagulant effect or vitamin K deficiency. However, these did not correct with oral vitamin K supplementation and cessation of the anticoagulant. The presence of an IgM anticardiolipin antibody was confirmed. Serum protein electrophoresis revealed hypoalbuminemia (1.9 g/dL) and a monoclonal protein spike of 1.0 g/dL, which on immunofixation was found to be IgM kappa. Serum IgG, IgA, and IgE levels were all below normal limits. In addition, the patient had a type I cryoglobulin. A repeat upper gastrointestinal endoscopy showed mucosal edema (Figure 1), and multiple biopsies were taken. Microscopic evaluation of small bowel biopsies showed intestinal lymphangiectasia (Figure 2A), infiltration of the mucosa by foamy histiocytes, and intralymphatic acellular material (Figure 2B) that was PAS positive and Congo red negative. Immunohistochemical analysis showed that the acellular material was IgM (Figure 2C). The plasmacytoid cells were also kappa light chain restricted. Examination of her bone marrow revealed a population of CD20 negative, kappa-restricted B cells that comprised 10%-20% of the bone marrow cellularity. Stool studies showed an elevated α-1-antitrypsin at 121 mg/day (normal ≤54 mg/d) and increased fecal fat of 20.2 g/24 hours (normal range, 2-7 g/24 h) while on a normal fat diet.
A diagnosis of Waldenstrom macroglobulinemia with primary involvement of the small bowel was established. The patient was supported with total parenteral nutrition and started on chemotherapy with cyclophosphamide, vincristine, and prednisone. The patient's diarrhea resolved within 72 hours, and her levels of protein C and S normalized. The lower extremity edema completely resolved over the next several weeks. She was treated with 6 cycles of cyclophosphamide, vincristine, and prednisone chemotherapy with a sustained response.
At Mayo Clinic Rochester, all patient diagnoses are maintained in an electronic database that allows rapid retrieval of relevant clinical diagnoses. After approval by the Institutional Review Board in compliance with federal regulations, we used the resources of this database to cross-reference all patients seen at our institution who had both WM or monoclonal gammopathy of undetermined significance and diarrhea or lymphangiectasia listed as diagnoses at any time in their history. All patients had given permission for the use of their medical record for research purposes.
All the identified medical records were reviewed by the first author, and any patient with an identifiable etiology for the diarrhea was eliminated from further analysis. Our search strategy identified 466 charts, which were all reviewed. Out of these charts, we identified 6 patients who had both intestinal lymphangiectasia and a monoclonal IgM on protein electrophoresis and immunofixation. All patients in this group had a small bowel biopsy that was reviewed by pathologists at our institution.
We identified 6 patients with a monoclonal IgM and concomitant intestinal lymphangiectasia, and no other explanation for the gastrointestinal symptoms, for an overall incidence of 1.3%. The relevant demographic and clinic features of this cohort are presented in Table 1. Five patients were men and 1 was a woman, and the median age was 58 years (range, 34-72 yr). In 5 patients, unexplained diarrhea had been present for a median of 5 years. Two patients had unexplained thrombotic events.
The amount of the monoclonal protein varied among the patients, with an average IgM of 1314 mg/dL (range, 159-5350; normal range, 60-300 mg/dL). The IgM was kappa restricted in 4 of these patients, and lambda restricted in 2. None of the patients had evidence of light chain deposition disease (often present with kappa light chains) or amyloidosis on special stains of the intestinal mucosa. Intestinal lymphangiectasia was present in all 6 patients, and 3 patients had a plasma cell infiltrate in the intestinal mucosa. Two patients had biochemical evidence of protein-losing enteropathy with an elevated fecal α-1 antitrypsin level. Two patients were treated for the lymphoproliferative disorder, and both had improvement of their gastrointestinal symptoms.
To our knowledge, over the last 40 years there have been 19 reports of intestinal lymphangiectasia with a monoclonal IgM (Table 2). The median age of these patients was 60 years (range, 33-89 yr), which is similar to both our cohort and that of WM in general21. Although the disease is reportedly more common in men17, the sex distribution for the combined group of published patients and our cohort is equally split between males and females. Kappa and lambda light chain types were reported in only 13 patients (including 1 patient who had both lambda and kappa light chain deposition). When combined with our cohort of 6 patients, 10 patients had IgM kappa and 8 patients had IgM lambda. In general, IgM levels in the published cases were higher than in our cohort of patients with a median of 24.8 g/L (range, 8.0-80.0; mean, 30.5 g/L). The majority of these patients were treated with chlorambucil and prednisone or cyclophosphamide, and most patients experienced an improvement in their diarrhea. We opted to avoid the use of an alkylating agent such as chlorambucil in our young patient due to the associated risk of myelodysplastic syndrome. However, she had a prompt response to cyclophosphamide, vincristine, and prednisone. In our index patient, the neoplastic lymphoplasmacytoid cells did not express CD20, and thus, rituximab could not be used.
Gastrointestinal involvement in WM is rare, but in principle, WM can affect the gut via several mechanisms. The most common mode of involvement is via the deposition of immunoglobulin light chain fragments as amyloid protein that should be visible with Congo red staining11,13. Lymphoplasmacytic cells can also infiltrate the wall of the gastrointestinal tract with local production of monoclonal IgM. The IgM produced within the lamina propria of the intestine is cleared by the lymphatic channels, but the high viscosity of the interstitial fluid may lead to lymphatic dilatation and obstruction with secondary lymphangiectasia16. Infiltration of the mesenteric lymph nodes can distort the anatomy and function of these nodes, leading to the same problem; this is well described in low-grade lymphoma3. The IgM may also be deposited in the wall of the intestine, interfering with its function, and can present as a pseudo-obstruction syndrome. This monoclonal IgM deposition does not stain with Congo red and by definition is distinct from amyloidosis14. In addition, WM may be associated with hypogammaglobulinemia23, including selective deficiency of the secretory piece and IgA26. These can predispose patients to bacterial overgrowth or infection with Giardia that presents with chronic diarrhea and malabsorption, although they should not lead to a protein-losing enteropathy.
In all previous publications describing intestinal lymphangiectasia with WM, the IgM levels were very high (median, 2480 mg/dL). While it is tempting to consider the deposition of IgM in the mucosa and intestinal lymphangiectasia as part of a continuum of increasing severity related to the levels of IgM produced, our data do not support this hypothesis since some of our patients had confirmed lymphangiectasia in the presence of modest elevations of IgM. This suggests that some other physical characteristic of the monoclonal IgM, and not the concentration, determines whether the protein is deposited in intestinal lymphatics resulting in secondary obstruction. IgM is a pentamer that is restricted to the intravascular compartment. Thus, the IgM that is detectable in the intestinal lymphatics is most likely due to production by lymphoplasmacytoid cells located within the gastrointestinal mucosa. This may explain why lymphangiectasia is not routinely seen in all patients with IgM-related disorders. The mechanisms behind the local accumulation of malignant B cells in some patients are not known, but presumably relate to differential expression of adhesion molecules with specificity for the gastrointestinal tract in some patients but not in others. It is also pertinent to note that while amyloidosis is usually associated with lambda light chain deposition (λ/κ ratio, 3:1) and the nonamyloidogenic monoclonal immunoglobulin deposition diseases associated with kappa light chains25, no such skewing is observed in intestinal lymphangiectasia, where both types of light chains are essentially equally represented (λ/κ ratio, 4:5).
The clinical manifestation of intestinal lymphangiectasia is a protein-losing enteropathy with diarrhea and malabsorption syndrome16,18. The endoscopist can often suspect the diagnosis after visual inspection of the intestinal mucosa due to the presence of distended villi and mucosal edema (see Figure 1).
Two of the patients in our cohort had evidence of arterial or venous thrombosis. In our index case the hypercoagulable state was initially attributed to the presence of an antiphospholipid antibody. Tait et al30 also reported 1 patient with WM complicated by intestinal lymphangiectasia, who also had an IgM antiphospholipid antibody. Their patient died of myocardial ischemia and was found to have segmental infarction in the spleen and kidneys at autopsy. However, patients with protein-losing enteropathy may be at increased risk of thrombosis due to enteric loss of anticoagulant proteins as a result of the intestinal lymphangiectasia itself. Based on these observations, it seems that thrombosis is not an uncommon feature of this syndrome, with an incidence of at least 12% (3 of 25 patients).
There appears to be limited awareness about the intestinal complications of WM. We identified several patients with chronic diarrhea who underwent extensive evaluations for their symptoms, and a monoclonal IgM protein was identified. The possibility of amyloidosis was entertained and invariably excluded. However, the association of intestinal lymphangiectasia with the paraprotein was not considered as a diagnostic possibility in any of these patients, and a potentially treatable cause of the diarrhea was missed. While one can consider some of these patients to have an IgM monoclonal gammopathy of undetermined significance21,22, we believe that in such situations specific testing for deposition of the monoclonal protein in intestinal biopsies may establish the underlying etiology and provide a rationale for therapy. The present case and the available literature suggest that therapy of the underlying lymphoproliferative disorder may lead to amelioration if not complete resolution of symptoms. However, the potential reporting bias whereby investigators report only patients with a positive outcome cannot be excluded. Nonetheless, it appears that responses are fairly rapid and a short therapeutic trial may resolve the problem relatively quickly.
In conclusion, WM may affect the gastrointestinal tract in a variety of ways, leading to malabsorption syndrome as well as a prothrombotic state. Physician awareness of the potential association of WM with these gastrointestinal manifestations may expedite diagnosis and lead to rational therapy for these patients.
1. Bedine MS, Yardley JH, Elliott HL, Banwell JG, Hendrix TR. Intestinal involvement in Waldenstrom's macroglobulinemia. Gastroenterology
2. Beker S, Grases PJ, Merino F, Arends T, Guevara J. Intestinal malabsorption in macroglobulinemia. Am J Dig Dis
3. Bonadonna G, Pizzetti F, Musumeci R, Valagussa P, Banfi A, Veronesi U. Staging laparotomy in non-Hodgkin's lymphomata. Br J Cancer
. 1975;31(Suppl 2):252-260.
4. Bradley J, Hawkins CF, Rowe DS, Stanworth DR. Macroglobulinaemia and steatorrhoea. Gut
5. Brandt LJ, Davidoff A, Bernstein LH, Biempica L, Rindfleisch B, Goldstein ML. Small-intestine involvement in Waldenstrom's macroglobulinemia. Case report and review of the literature. Dig Dis Sci
6. Cabrera A, Delapava S, Pickren JW. Intestinal localization of Waldenstrom's disease. Arch Intern Med
7. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 3-1990. A 66-year-old woman with Waldenstrom's macroglobulinemia, diarrhea, anemia, and persistent gastrointestinal bleeding. N Engl J Med
8. Cohen RJ, Bohannon RA, Wallerstein RO. Waldenstrom's macroglobulinemia. A study of ten cases. Am J Med
9. Dimopoulos MA, Kyle RA, Anagnostopoulos A, Treon SP. Diagnosis and management of Waldenstrom's macroglobulinemia. J Clin Oncol
10. Dutcher TF, Fahey JL. The histopathology of the macroglobulinemia of Waldenstrom. J Natl Cancer Inst
11. Gardyn J, Schwartz A, Gal R, Lewinski U, Kristt D, Cohen AM. Waldenstrom's macroglobulinemia associated with AA amyloidosis. Int J Hematol
12. Gertz MA. Waldenstrom's macroglobulinemia: a review of therapy. Leuk Lymphoma
13. Gertz MA, Kyle RA, Noel P. Primary systemic amyloidosis: a rare complication of immunoglobulin M monoclonal gammopathies and Waldenstrom's macroglobulinemia. J Clin Oncol
14. Gertz MA, Merlini G, Treon SP. Amyloidosis and Waldenstrom's macroglobulinemia. Hematology Am Soc Hematol Educ Program
15. Ghobrial IM, Gertz MA, Fonseca R. Waldenstrom macroglobulinaemia. Lancet Oncol
16. Harris M, Burton IE, Scarffe JH. Macroglobulinaemia and intestinal lymphangiectasia: a rare association. J Clin Pathol
17. Herrinton LJ, Weiss NS. Incidence of Waldenstrom's macroglobulinemia. Blood
18. Hoang C, Halphen M, Galian A, Brouet JC, Marsan C, Leclerc JP, Rambaud JC. [Intestinal involvement and exudative enteropathy in Waldenstrom's macroglobulinemia]. Gastroenterol Clin Biol
19. Khilnani MT, Keller RJ, Cuttner J. Macroglobulinemia and steatorrhea: roentgen and pathologic findings in the intestinal tract. Radiol Clin North Am
20. Krawitt EL, Beeken WL. Case report: intestinal clearance of calcium and protein in Waldenstrom's macroglobulinemia. Am J Med Sci
21. Kyle RA, Garton JP. The spectrum of IgM monoclonal gammopathy in 430 cases. Mayo Clin Proc
22. Kyle RA, Therneau TM, Rajkumar SV, Offord JR, Larson DR, Plevak MF, Melton LJ 3rd. Long-term follow-up of IgM monoclonal gammopathy of undetermined significance. Semin Oncol
23. Kyrtsonis MC, Vassilakopoulos TP, Angelopoulou MK, Siakantaris P, Kontopidou FN, Dimopoulou MN, Boussiotis V, Gribabis A, Konstantopoulos K, Vaiopoulos GA, Fessas P, Kittas C, Pangalis GA. Waldenstrom's macroglobulinemia: clinical course and prognostic factors in 60 patients. Experience from a single hematology unit. Ann Hematol
24. Mattila J, Alavaikko M, Jarventie G, Lehtinen M, Pitkanen R. Macroglobulinemia with abdominal symptoms caused by intestinal extracellular macroglobulin. Virchows Arch A Pathol Anat Histol
25. Merlini G, Stone MJ. Dangerous small B-cell clones. Blood
26. Nussinson E, Lahav M, Berebi A, Estrov Z, Zur S, Resnitzky P. Secretory piece and IgA deficiency in a patient with Waldenstrom's macroglobulinemia. Am J Gastroenterol
27. Pruzanski W, Warren RE, Goldie JH, Katz A. Malabsorption syndrome with infiltration of the intestinal wall by extracellular monoclonal macroglobulin. Am J Med
28. Rusynyk RA, Ghosh MS, Babameto GP, Grundfast MB. Endoscopic diagnosis of Waldenstrom's macroglobulinemia masquerading as chronic diarrhea. Gastrointest Endosc
29. Schechterman L, Tyler SJ. Waldenstrom's macroglobulinemia. Localization in ileum and lacrimal glands. N Y State J Med
30. Tait RC, Oogarah PK, Houghton JB, Farrand SE, Haeney MR. Waldenstrom's macroglobulinaemia secreting a paraprotein with lupus anticoagulant activity: possible association with gastrointestinal tract disease and malabsorption. J Clin Pathol
31. Tubbs RR, McLaughlin JP, Winkelman EI, Deodhar SD, Hewlett JS. Macroglobulinemia and malabsorption. Cleve Clin Q
. 1977;44: 189-197.
32. Veloso FT, Fraga J, Saleiro JV. Macroglobulinemia and small intestinal disease. A case report with review of the literature. J Clin Gastroenterol
33. Waldenstrom J. Three new cases of purpura hyperglobulinemica. A study in long-lasting benign increase in serum globulin. Acta Med Scand Suppl