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Colonoscopic red ring sign due to chronic lymphocytic leukemia
Colonoscopic red ring sign due to chronic lymphocytic leukemia Mark E. Stark, William J. Maples, James T. Wolfe III, David M. Menke,
MD MD MD MD
T h e "red ring sign" is a r e c e n t l y described colonoscopic a p p e a r a n c e of p r o m i n e n t l y m p h o i d a g g r e g a t e s in t h e colonic mucosa. IG I t consists of a circular red r i n g 2 to 3 m m in d i a m e t e r s u r r o u n d i n g a pale, slightly raised, 1 m m c e n t r a l area. T h e pale c e n t r a l a r e a is a well-circumscribed l y m p h o i d nodule, a n d t h e red r i n g m a y be due to h y p e r e m i a in t h e s u r r o u n d i n g m u c o s a l blood vessels. 2-5 I t h a s b e e n s u g g e s t e d t h a t t h e colonoscopic red r i n g a p p e a r a n c e is highly specific for underlying b e n i g n l y m p h o i d a g g r e g a t e s . 1 We r e p o r t a case in w h i c h t h e colonoscopic red r i n g sign w a s due to colonic m u c o s a l infiltration b y neoplastic l y m p h o cytes in B-cell chronic l y m p h o c y t i c l e u k e m i a (CLL). CASE REPORT
A 72-year-old man had transient loose stools following chemotherapy for B-cell CLL and was referred for flexible sigmoidoscopy. CLL had been diagnosed 3~ years previously, when asymptomatic peripheral blood lymphocytosis was noted. Immunocytochemical studies performed on cytospin preparations of peripheral blood lymphocytes were HLA-DR positive and weakly expressed CD20, consistent with B-cell CLL. He developed progressive lymphocytosis and lymphadenopathy 6 months later, and during the next 2~ y e a r s lymphocytosis and lymphadenopathy were controlled with chlorambucil, with or without prednisone. A pruritic, erythematous, papular rash was present intermittently during the year before sigmoidoscopy; biopsy of the rash showed cutaneous infiltration by B-cell CLL. Four months prior to the sigmoidoscopy he developed increased adenopathy and progressive skin lesions. Chlorambucil was stopped and he was given a cycle of cyclophosphamide, vincristine, and high-dose prednisone, then continued on 10 to 20 mg of prednisone each day. During the week after systemic chemotherapy he had mild diarrhea and some anal seepage of fluid or mucus. The diarrhea and seepage resolved and his bowel movements returned to normal. Several weeks later he was referred for sigmoidoscopy to check for colonic disease before the subsequent course of chemotherapy. He had no fevers, weight loss, abdominal pain, or other symptoms. The lymphadenopathy improved after the course of chemotherapy, but he continued to be troubled by the p~ritic rash. He had no other medical problems. His From the Division of Gastroenterology, Division of Hematology / Oncology, and Department of Pathology, Mayo Clinic Jacksonville, Jacksonville, Florida. Reprint requests: Mark E. Stark, MD, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224. 0016-5107/97/4502-019755.00 + 0 GASTROINTESTINAL ENDOSCOPY Copyright © 1997 by the American Society for Gastrointestinal Endoscopy 37/4/75809
VOLUME 45, NO. 2, 1997
Figure 1. Endoscopic appearance of sigmoid colon showing the red ring sign. Red circles 2 to 3 mm in diameter surround a 1 mm pale area.
medications on referral included prednisone 10 mg daily, aspirin 325 mg daily, and diphenhydramine 50 mg daily. Physical examination showed a normal temperature, an enlarged submandibular lymph node (2 cm diameter), and several erythematous papular skin lesions on his extremities. Results of examination of the mouth, heart, and lungs were normal. Abdominal examination showed no tenderness, mass, or organomegaly. Rectal examination was norma]. White blood cell count was 12,000/mm 3 (normal 3,500 to 10,500/ram3), with 45% lymphocytes (17.8% to 41.5%), 45% granulocytes (44.4% to 70.9%), 8% monocytes (4.7% to 14.8%), and 2% eosinophils (0.8% to 7.2%); there were scattered smudge cells without blasts or significant numbers of prolymphocytes. Hemoglobin, platelet count, chemistry panel, and sedimentation rate were all normal. After sodium phosphate enema preparation, flexible videosigmoidoscopy was performed to the midsigmoid colon (Olympus CF100S sigmoidoscope, Olympus EVIS CV100 image processor, Olympus America Inc., Melville, N.Y.). The mucosa of the upper rectum and lower sigmoid colon showed multiple erythematous ring-like lesions with an estimated diameter of 2 to 3 m m (Fig. 1). In the center of each ring was a pale, slightly raised nodule with an estimated diameter of 1 ram. The mucosa was otherwise normal, with no exudate, erosion, or evidence of active colitis. Biopsy of the red ring lesions showed prominent nodular perivascular lymphoid infiltrates consisting of uniform mature lymphocytes of B-cell phenotype (CD20 positive), with an associated mucosal corona of polymorphous T-lymphocytes and plasma cells, indicating colonic mucosal infiltration by B-cell CLL (Fig. 2).
DISCUSSION The endoscopic findings in this case of B-cell CLL infiltrating the colonic mucosa appear identical to the red r i n g sign of p r o m i n e n t colonic l y m p h o i d aggreg a t e s described in previous reports. 1-6 T h e red r i n g sign h a s also b e e n called t h e halo sign 1 or t h e freckle sign .4 I n previous reports, t h e colonic red r i n g sign w a s due to b e n i g n l y m p h o i d a g g r e g a t e s , 1"6 a n d s o m e aut h o r s h a v e s u g g e s t e d t h a t this endoscopic finding is 100% specific for b e n i g n l y m p h o i d a g g r e g a t e s . 1 This GASTROINTESTINAL ENDOSCOPY
197
Figure 2. Histologic section of endoscopic biopsy of circular red lesions seen in Figure 1. There is a diffuse uniform infiltrate of small mature lymphocytes consistent with CLL. (H&E; original magnification xl00.)
case demonstrates that the colonoscopic red ring sign may be due to mucosal involvement with a neoplastic lymphoid infiltrate (B-cell CLL). Lymphoid tissue is a normal component of the mucosa of the gastrointestinal tract. The lymphoid tissue is arranged in three forms: (1) as lymphocytes mixed with plasma cells distributed diffusely throughout the mucosa of the small intestine and colon; (2) as solitary lymphoid nodules present anywhere in the gastrointestinal tract, but most numerous in the distal colon; and (3) as aggregate or organized lymphoid nodules (Peyer's patches) in the appendix and small intestine. 7 Prominent or endoscopically visible solitary colonic lymphoid nodules are seen in more t h a n 50% of pediatric endoscopies, but are not commonly noted in adults. 1, 3, 8, 9 Pathologic, radiographic, or endoscopic studies have found prominent colonic lymphoid nodules in adults with a variety of gastrointestinal and systemic diseases, as well as in people without apparent disease. 1' 3, 5, 9-20 These reports do not allow conclusions about whether the prominent lymphoid nodules are incidental findings or somehow related to the associated conditions. The endoscopic appearance of colonic lymphoid tissue is quite variable. Reported descriptions include small nodules, papules, plaques, and red spots, as well as the red ring sign. 1-6,9,10-13, 17,18 The colonoscopic red ring sign is probably a nonspecific indicator of prominent lymphoid aggregates in the colonic mucosa, inasmuch as it has been reported in patients with a variety of colonic and systemic diseases, as well as in people without obvious disease. 15 In the present case, the red ring sign was due to colonic mucosal infiltrates of B-cell CLL. CLL is the most common leukemia in th e United States, with 10,000 new cases diagnosed annually. 21 Autopsy studies demonstrate gross leukemic involvement of some portion of the gastrointestinal tract in 12% to 16% of patients w i t h CLL; most cases are 198 G A S T R O I N T E S T I N A L E N D O S C O P Y
asymptomatic.22, 23 Reported manifestations of gastrointestinal CLL include leukemic infiltrates of the esophagus, 23 esophageal varices due to liver infiltration and portal hypertension, 24 thickened gastric folds,22, 25-27 gastric ulceration, 22, 28-30 and polypoid or nodular infiltration of the small bowel. 22, 27, 31, 32 CLL infiltrates the colon in 5% to 20% of autopsy cases; gross pathologic findings include thickened irregular folds, plaque-like mucosal thickening, small nodules, polypoid masses, and small ulcers. 22, 23, 25, 26, 31, 33 A few case reports describe endoscopic appearances t h a t correspond to colonic infiltration by CLL or to the closely related, well-differentiated B-cell small lymphocytic lymphoma. The reported endoscopic appearances have included polyps, ulcers, granularity, submucosal nodules, and erythema. 27,29,34-36 None of these previous reports describe the colonic mucosal red ring sign in patients with CLL. Endoscopists should be aware of the colonoscopic red ring sign, which appears to be one appearance of prominent colonic lymphoid tissue. Although the red ring sign may be a normal variant appearance of benign colonic lymphoid tissue, the clinical importance of the red ring sign is not certain, and there is very limited information about the prevalence of this finding in health and disease. All reports of this finding to date demonstrate associated prominent lymphoid tissue, but a systematic study of this finding has not been performed to determine if there are other histologic correlates. The association of the red ring sign with colonic infiltration by CLL in this case demonstrates t h a t this finding cannot be considered to be specific for benign lymphoid aggregate s . Until more is known about disease associations and histopathologic correlates, endoscopists should carefully consider the clinical setting and make appropriate use of biopsy before concluding t h a t the colonoscopic red ring sign is a normal variant due to benign lymphoid aggregates. REFERENCES 1. BharadhwajG, TriadafilopoulosG. Endoscopicappearances of coloniclymphoidnodules:new faces of an old histopathologic entity. Am J Gastroenterol 1995;90:946-50. 2. KimuraM, MikiK, IchinoseM, HoshinoE, SanoJ, Kawamura N, et al. Red ring sign--a new endoscopicfindingofinflammatory bowel disease [abstract]. Gastroenterology1990;98:A181. 3. SmithMB,BlackstoneMO.Coloniclymphoidnodules:another cause of the red ring sign [letter]. Gastrointest Endosc 1991; 37:206-7. 4. FleshnerPR, AckroydFW, ShellitoPC. The frecklesign--a new endoscopicfeatureofthe cecum.Dis ColonRectum1990;33:836-9. 5. Straub RF, WilcoxCM, SchwartzDA. Variable endoscopicappearance ofcoloniclymphoidtissue. J ClinGastroenterol1994; 19:158-65. 6. WilcoxCM. Anorectum.In: WilcoxCM, editor.Atlas ofclinical gastrointestinalendoscopy.Philadelphia:W.B.Saunders, 1995: 289-90. 7. Lewin KJ, Riddell RH, Weinstein WM. Gastrointestinal pathology and its clinicalimplications.New York: Igaku-Shoin, 1992:105-50. 8. Riddlesberger MM, Lebenthal E. Nodular colonic mucosa of childhood:normal or pathologic?Gastroenterology1980;79:26570. VOLUME 45, NO. 2, 1997
9. Colarian J, Calzada R, Jaszewski R. Nodular lymphoid hyperplasia of the colon in adults: is it common? Gastrointest Endosc 1990;36:421-2. 10. Kenney PJ, Koehler RE, Shackleford GD. The clinical significance of large lymphoid follicles of the colon. Radiology 1982; 142:41-6. 11. Burbige EJ, Sobky RZ. Endoscopic appearance of colonic lymphoid nodules: a normal variant. Gastroenterology 1977;72: 524-6. 12. Kelvin FM, Max RJ, Norton GA, et al. Lymphoid follicular pattern of the colon in adults. AJR Am J Roentgenol 1979;133: 821-5. 13. Watanabe H, Margulis AR, Harter L. The occurrence of lymphoid nodules in the colon of adults. J Clin Gastroenterol 1983;5:535-9. 14. O'Leary AD, Sweeney EL. Lymphoglandular complexes of the colon; structure and distribution. Histopathology 1986;10:267-83. 15. Ell SR, Frank PH. Spectrum of lymphoid hyperplasia: colonic manifestations of sarcoidosis, infectious mononucleosis, and Crohn's disease. Gastrointest Radiol 1981;6:329-32. 16. Lechner GL, Frank W, Jantsch H, et al. Lymphoid follicular hyperplasia in excluded colonic segments: a radiologic sign of diversion colitis. Radiology 1990;176:135-6. 17. Levendoglu H, Rosen Y. Nodular lymphoid hyperplasia of the gut in HIV infection. Am J Gastroenterol 1992;87:1200-2. 18. DeSmet AA, Tubergen DG, Martel W. Nodular lymphoid hyperplasia 0f the colon associated with dysgammaglobulh~emia. AJR Am J Roentgenol 1976;127:515-7. 19. Bronen RA, Glick SN, Teplick SK. Diffuse lymphoid follicles of the colon associated with colonic carcinoma. AJR Am J Roentgenol 1984;142:105-9. 20. Yoong P, House R. Nodular lymphoid hyperplasia and colorectal carcinoma. Australas Radiol 1981;25:21-2. 21. Foon KA, Rai KR, Gale RP. Chronic lymphocytic leukemia: new insights into biology and therapy. Ann Intern Med 1990;113: 525-39. 22. Cornes JS, Jones TG, Fisher GB. Leukaemic lesions of the gastrointestinal tract. J Clin Pathol 1962;15:305-13.
23. Prolla JC, Kirsner JB. The gastrointestinal lesions and complications of the leukemias. Ann Intern Med 1964;61:1084-103. 24. Ikegami M, Toyonaga A, Iwao T, Tanikawa K. Chronic lymphocytic leukemia with esophageal varices. Dig Dis Sci 1993; 38:2142-2. 25. Ikeda K. Gastric manifestations of lymphatic aleukemia (pseudoleukemia gastrointestinalis). Am J Clin Patho] 1931;1: 167-85. 26. Pearson B, Stasney J, Pizzolato P. Gastrointestinal involvement in lymphatic leukemia. Arch Pathol 1943;35:21-8. 27. Halkin H, Meytes D, Militeanu J, et al. Multiple lymphomatous polyposis of the gastrointestinal tract. Isr J Med Sci 1973;9: 648-54. 28. Cornes JS, Jones TG, Fisher GB. Gastroduodenal ulceration and massive hemorrhage in patients with leukemia, multiple myeloma, and malignant tumors of lymphoid tissue. Gastroenterology 1961;41:337-44. 29. Lahti R, Lehtola J, Suramo I. Gastrointestinal manifestations of chronic lymphocytic leukemia. Diagnostic Imaging 1979;48: 149-53. 30. Feigel DO, Vaughn DJ, Furth EE, et al. Chronic lymphocytic leukemia: an unusual cause of upper gastrointestinal hemorrhage. Am J Gastroenterol 1995;90:635-7. 31. Mead C. Chronic lymphatic leukemia involving the gastrointestinal tract. Radiology 1933;21:351-65. 32. Wasser AH, Spector JI. Endoscopic evaluation of small-bowel leukemia. Dig Dis 1977;22:1028-32. 33. Klener P, Donner L, Bocanova M, et al. Gastrointestinal lesions and complications of haemoblastoses. Folia Haematologica 1973;100:57-66. 34. Scharschmidt BF. Chronic lymphocytic leukemia presenting as colitis. Dig Dis Sci 1978;23(suppl):9S-12S. 35. Gedgaudas-McClees RK, Maglinte DDT. Aphthous lesions in nodular lymphoma of the colon. South Med J 1986;79:907-8. 36. Sagar S, Selby P, Sloane J, et al. Colorectal lymphoma simulating inflammatory colitis and diagnosed by immunohistochemistry. Postgrad Med J 1986;62:51-3.
Colonic histoplasmosis in AIDS: unusual endoscopic findings in two cases
tigation, a specific organism can be identified in the majority of these cases. 1 In patients with AIDS, commonly isolated intestinal pathogens of the small and l a r g e i n t e s t i n e i n c l u d e c y t o m e g a l o v i r u s , Mycobacter i u m a v i u m intracellulare, C r y p t o s p o r i d i u m , Isospora belli, M i c r o s p o r i d i a , S a l m o n e l l a , Shigella, C a m p y l o bacter, G i a r d i a l a m b l i a , E n t a m o e b a histolytica, a n d C l o s t r i d i u m difficile f l 2 H i s t o p l a s m a c a p s u l a t u m is b e i n g r e c o g n i z e d a s a n increasingly important pathogen in patients with AIDS. 3 This fungus, which produces a self-limited and subclinical respiratory illness in immunocompetent i n d i v i d u a l s , f r e q u e n t l y s p r e a d s to o t h e r o r g a n s i n y o u n g children and immunocompromised adults in a disease known as progressive disseminated histoplasmosis (PDH). S i n c e 1987, e x t r a p u l m o n a r y h i s t o p l a s m o s i s is n o w i n c l u d e d on t h e l i s t of A i D S - d e f i n i n g infections i n i n d i v i d u a l s p o s i t i v e for h u m a n i m m u n o d e f i c i e n c y v i r u s (HIV). 4 D e s p i t e t h e g r o w i n g r e c o g n i t i o n o f P D H a m o n g p a t i e n t s w i t h A I D S , 4~6 t h e specific p a t h o g e n i c role o f H. c a p s u l a t u m in t h e g a s t r o i n t e s t i n a l t r a c t is l e s s we]] a p p r e d a t e d . S e v e r a l r e c e n t r e v i e w s o n t h e s u b j e c t of g a s t r o i n t e s t i n a l i n v o l v e m e n t i n A I D S fail to l i s t t h i s o r g a n i s m a s a p o t e n t i a l i n t e s t i n a l p a t h o g e n . 2, 7-9
Allan G. Halline, MD Mario Maldonado-Lutomirsky, MD Jei W. Ryoo, MD Alice Pau, PharmD Kenneth Pursell, MD Opportunistic infections of the gastrointestinal tract a r e c o m m o n c o m p l i c a t i o n s a m o n g p a t i e n t s w i t h acquired immune deficiency syndrome (AIDS). Sympt o m s o f l o w e r g a s t r o i n t e s t i n a l i n f e c t i o n ( i n c l u d i n g diarrhea, abdominal pain, or bleeding) occur in over half of all patients with AIDS and, with aggressive inves-
From the Departments of Medicine and Pathology, University of Illinois at Chicago, and VA Westside Medical Center, Chicago, Illinois. Allan G. Halline, MD, is a recipient of a Merit Review Award from the Veterans Affairs Research. Reprint requests: Allan G. Halline, MD, Medicine (M / C 787), Section of Digestive and Liver Diseases, 840 S. Wood St., Chicago, IL 60612. 37/4/76050
VOLUME 45, NO. 2, 1997
GASTROINTESTINAL ENDOSCOPY 199
MD MD MD MD
T h e "red ring sign" is a r e c e n t l y described colonoscopic a p p e a r a n c e of p r o m i n e n t l y m p h o i d a g g r e g a t e s in t h e colonic mucosa. IG I t consists of a circular red r i n g 2 to 3 m m in d i a m e t e r s u r r o u n d i n g a pale, slightly raised, 1 m m c e n t r a l area. T h e pale c e n t r a l a r e a is a well-circumscribed l y m p h o i d nodule, a n d t h e red r i n g m a y be due to h y p e r e m i a in t h e s u r r o u n d i n g m u c o s a l blood vessels. 2-5 I t h a s b e e n s u g g e s t e d t h a t t h e colonoscopic red r i n g a p p e a r a n c e is highly specific for underlying b e n i g n l y m p h o i d a g g r e g a t e s . 1 We r e p o r t a case in w h i c h t h e colonoscopic red r i n g sign w a s due to colonic m u c o s a l infiltration b y neoplastic l y m p h o cytes in B-cell chronic l y m p h o c y t i c l e u k e m i a (CLL). CASE REPORT
A 72-year-old man had transient loose stools following chemotherapy for B-cell CLL and was referred for flexible sigmoidoscopy. CLL had been diagnosed 3~ years previously, when asymptomatic peripheral blood lymphocytosis was noted. Immunocytochemical studies performed on cytospin preparations of peripheral blood lymphocytes were HLA-DR positive and weakly expressed CD20, consistent with B-cell CLL. He developed progressive lymphocytosis and lymphadenopathy 6 months later, and during the next 2~ y e a r s lymphocytosis and lymphadenopathy were controlled with chlorambucil, with or without prednisone. A pruritic, erythematous, papular rash was present intermittently during the year before sigmoidoscopy; biopsy of the rash showed cutaneous infiltration by B-cell CLL. Four months prior to the sigmoidoscopy he developed increased adenopathy and progressive skin lesions. Chlorambucil was stopped and he was given a cycle of cyclophosphamide, vincristine, and high-dose prednisone, then continued on 10 to 20 mg of prednisone each day. During the week after systemic chemotherapy he had mild diarrhea and some anal seepage of fluid or mucus. The diarrhea and seepage resolved and his bowel movements returned to normal. Several weeks later he was referred for sigmoidoscopy to check for colonic disease before the subsequent course of chemotherapy. He had no fevers, weight loss, abdominal pain, or other symptoms. The lymphadenopathy improved after the course of chemotherapy, but he continued to be troubled by the p~ritic rash. He had no other medical problems. His From the Division of Gastroenterology, Division of Hematology / Oncology, and Department of Pathology, Mayo Clinic Jacksonville, Jacksonville, Florida. Reprint requests: Mark E. Stark, MD, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224. 0016-5107/97/4502-019755.00 + 0 GASTROINTESTINAL ENDOSCOPY Copyright © 1997 by the American Society for Gastrointestinal Endoscopy 37/4/75809
VOLUME 45, NO. 2, 1997
Figure 1. Endoscopic appearance of sigmoid colon showing the red ring sign. Red circles 2 to 3 mm in diameter surround a 1 mm pale area.
medications on referral included prednisone 10 mg daily, aspirin 325 mg daily, and diphenhydramine 50 mg daily. Physical examination showed a normal temperature, an enlarged submandibular lymph node (2 cm diameter), and several erythematous papular skin lesions on his extremities. Results of examination of the mouth, heart, and lungs were normal. Abdominal examination showed no tenderness, mass, or organomegaly. Rectal examination was norma]. White blood cell count was 12,000/mm 3 (normal 3,500 to 10,500/ram3), with 45% lymphocytes (17.8% to 41.5%), 45% granulocytes (44.4% to 70.9%), 8% monocytes (4.7% to 14.8%), and 2% eosinophils (0.8% to 7.2%); there were scattered smudge cells without blasts or significant numbers of prolymphocytes. Hemoglobin, platelet count, chemistry panel, and sedimentation rate were all normal. After sodium phosphate enema preparation, flexible videosigmoidoscopy was performed to the midsigmoid colon (Olympus CF100S sigmoidoscope, Olympus EVIS CV100 image processor, Olympus America Inc., Melville, N.Y.). The mucosa of the upper rectum and lower sigmoid colon showed multiple erythematous ring-like lesions with an estimated diameter of 2 to 3 m m (Fig. 1). In the center of each ring was a pale, slightly raised nodule with an estimated diameter of 1 ram. The mucosa was otherwise normal, with no exudate, erosion, or evidence of active colitis. Biopsy of the red ring lesions showed prominent nodular perivascular lymphoid infiltrates consisting of uniform mature lymphocytes of B-cell phenotype (CD20 positive), with an associated mucosal corona of polymorphous T-lymphocytes and plasma cells, indicating colonic mucosal infiltration by B-cell CLL (Fig. 2).
DISCUSSION The endoscopic findings in this case of B-cell CLL infiltrating the colonic mucosa appear identical to the red r i n g sign of p r o m i n e n t colonic l y m p h o i d aggreg a t e s described in previous reports. 1-6 T h e red r i n g sign h a s also b e e n called t h e halo sign 1 or t h e freckle sign .4 I n previous reports, t h e colonic red r i n g sign w a s due to b e n i g n l y m p h o i d a g g r e g a t e s , 1"6 a n d s o m e aut h o r s h a v e s u g g e s t e d t h a t this endoscopic finding is 100% specific for b e n i g n l y m p h o i d a g g r e g a t e s . 1 This GASTROINTESTINAL ENDOSCOPY
197
Figure 2. Histologic section of endoscopic biopsy of circular red lesions seen in Figure 1. There is a diffuse uniform infiltrate of small mature lymphocytes consistent with CLL. (H&E; original magnification xl00.)
case demonstrates that the colonoscopic red ring sign may be due to mucosal involvement with a neoplastic lymphoid infiltrate (B-cell CLL). Lymphoid tissue is a normal component of the mucosa of the gastrointestinal tract. The lymphoid tissue is arranged in three forms: (1) as lymphocytes mixed with plasma cells distributed diffusely throughout the mucosa of the small intestine and colon; (2) as solitary lymphoid nodules present anywhere in the gastrointestinal tract, but most numerous in the distal colon; and (3) as aggregate or organized lymphoid nodules (Peyer's patches) in the appendix and small intestine. 7 Prominent or endoscopically visible solitary colonic lymphoid nodules are seen in more t h a n 50% of pediatric endoscopies, but are not commonly noted in adults. 1, 3, 8, 9 Pathologic, radiographic, or endoscopic studies have found prominent colonic lymphoid nodules in adults with a variety of gastrointestinal and systemic diseases, as well as in people without apparent disease. 1' 3, 5, 9-20 These reports do not allow conclusions about whether the prominent lymphoid nodules are incidental findings or somehow related to the associated conditions. The endoscopic appearance of colonic lymphoid tissue is quite variable. Reported descriptions include small nodules, papules, plaques, and red spots, as well as the red ring sign. 1-6,9,10-13, 17,18 The colonoscopic red ring sign is probably a nonspecific indicator of prominent lymphoid aggregates in the colonic mucosa, inasmuch as it has been reported in patients with a variety of colonic and systemic diseases, as well as in people without obvious disease. 15 In the present case, the red ring sign was due to colonic mucosal infiltrates of B-cell CLL. CLL is the most common leukemia in th e United States, with 10,000 new cases diagnosed annually. 21 Autopsy studies demonstrate gross leukemic involvement of some portion of the gastrointestinal tract in 12% to 16% of patients w i t h CLL; most cases are 198 G A S T R O I N T E S T I N A L E N D O S C O P Y
asymptomatic.22, 23 Reported manifestations of gastrointestinal CLL include leukemic infiltrates of the esophagus, 23 esophageal varices due to liver infiltration and portal hypertension, 24 thickened gastric folds,22, 25-27 gastric ulceration, 22, 28-30 and polypoid or nodular infiltration of the small bowel. 22, 27, 31, 32 CLL infiltrates the colon in 5% to 20% of autopsy cases; gross pathologic findings include thickened irregular folds, plaque-like mucosal thickening, small nodules, polypoid masses, and small ulcers. 22, 23, 25, 26, 31, 33 A few case reports describe endoscopic appearances t h a t correspond to colonic infiltration by CLL or to the closely related, well-differentiated B-cell small lymphocytic lymphoma. The reported endoscopic appearances have included polyps, ulcers, granularity, submucosal nodules, and erythema. 27,29,34-36 None of these previous reports describe the colonic mucosal red ring sign in patients with CLL. Endoscopists should be aware of the colonoscopic red ring sign, which appears to be one appearance of prominent colonic lymphoid tissue. Although the red ring sign may be a normal variant appearance of benign colonic lymphoid tissue, the clinical importance of the red ring sign is not certain, and there is very limited information about the prevalence of this finding in health and disease. All reports of this finding to date demonstrate associated prominent lymphoid tissue, but a systematic study of this finding has not been performed to determine if there are other histologic correlates. The association of the red ring sign with colonic infiltration by CLL in this case demonstrates t h a t this finding cannot be considered to be specific for benign lymphoid aggregate s . Until more is known about disease associations and histopathologic correlates, endoscopists should carefully consider the clinical setting and make appropriate use of biopsy before concluding t h a t the colonoscopic red ring sign is a normal variant due to benign lymphoid aggregates. REFERENCES 1. BharadhwajG, TriadafilopoulosG. Endoscopicappearances of coloniclymphoidnodules:new faces of an old histopathologic entity. Am J Gastroenterol 1995;90:946-50. 2. KimuraM, MikiK, IchinoseM, HoshinoE, SanoJ, Kawamura N, et al. Red ring sign--a new endoscopicfindingofinflammatory bowel disease [abstract]. Gastroenterology1990;98:A181. 3. SmithMB,BlackstoneMO.Coloniclymphoidnodules:another cause of the red ring sign [letter]. Gastrointest Endosc 1991; 37:206-7. 4. FleshnerPR, AckroydFW, ShellitoPC. The frecklesign--a new endoscopicfeatureofthe cecum.Dis ColonRectum1990;33:836-9. 5. Straub RF, WilcoxCM, SchwartzDA. Variable endoscopicappearance ofcoloniclymphoidtissue. J ClinGastroenterol1994; 19:158-65. 6. WilcoxCM. Anorectum.In: WilcoxCM, editor.Atlas ofclinical gastrointestinalendoscopy.Philadelphia:W.B.Saunders, 1995: 289-90. 7. Lewin KJ, Riddell RH, Weinstein WM. Gastrointestinal pathology and its clinicalimplications.New York: Igaku-Shoin, 1992:105-50. 8. Riddlesberger MM, Lebenthal E. Nodular colonic mucosa of childhood:normal or pathologic?Gastroenterology1980;79:26570. VOLUME 45, NO. 2, 1997
9. Colarian J, Calzada R, Jaszewski R. Nodular lymphoid hyperplasia of the colon in adults: is it common? Gastrointest Endosc 1990;36:421-2. 10. Kenney PJ, Koehler RE, Shackleford GD. The clinical significance of large lymphoid follicles of the colon. Radiology 1982; 142:41-6. 11. Burbige EJ, Sobky RZ. Endoscopic appearance of colonic lymphoid nodules: a normal variant. Gastroenterology 1977;72: 524-6. 12. Kelvin FM, Max RJ, Norton GA, et al. Lymphoid follicular pattern of the colon in adults. AJR Am J Roentgenol 1979;133: 821-5. 13. Watanabe H, Margulis AR, Harter L. The occurrence of lymphoid nodules in the colon of adults. J Clin Gastroenterol 1983;5:535-9. 14. O'Leary AD, Sweeney EL. Lymphoglandular complexes of the colon; structure and distribution. Histopathology 1986;10:267-83. 15. Ell SR, Frank PH. Spectrum of lymphoid hyperplasia: colonic manifestations of sarcoidosis, infectious mononucleosis, and Crohn's disease. Gastrointest Radiol 1981;6:329-32. 16. Lechner GL, Frank W, Jantsch H, et al. Lymphoid follicular hyperplasia in excluded colonic segments: a radiologic sign of diversion colitis. Radiology 1990;176:135-6. 17. Levendoglu H, Rosen Y. Nodular lymphoid hyperplasia of the gut in HIV infection. Am J Gastroenterol 1992;87:1200-2. 18. DeSmet AA, Tubergen DG, Martel W. Nodular lymphoid hyperplasia 0f the colon associated with dysgammaglobulh~emia. AJR Am J Roentgenol 1976;127:515-7. 19. Bronen RA, Glick SN, Teplick SK. Diffuse lymphoid follicles of the colon associated with colonic carcinoma. AJR Am J Roentgenol 1984;142:105-9. 20. Yoong P, House R. Nodular lymphoid hyperplasia and colorectal carcinoma. Australas Radiol 1981;25:21-2. 21. Foon KA, Rai KR, Gale RP. Chronic lymphocytic leukemia: new insights into biology and therapy. Ann Intern Med 1990;113: 525-39. 22. Cornes JS, Jones TG, Fisher GB. Leukaemic lesions of the gastrointestinal tract. J Clin Pathol 1962;15:305-13.
23. Prolla JC, Kirsner JB. The gastrointestinal lesions and complications of the leukemias. Ann Intern Med 1964;61:1084-103. 24. Ikegami M, Toyonaga A, Iwao T, Tanikawa K. Chronic lymphocytic leukemia with esophageal varices. Dig Dis Sci 1993; 38:2142-2. 25. Ikeda K. Gastric manifestations of lymphatic aleukemia (pseudoleukemia gastrointestinalis). Am J Clin Patho] 1931;1: 167-85. 26. Pearson B, Stasney J, Pizzolato P. Gastrointestinal involvement in lymphatic leukemia. Arch Pathol 1943;35:21-8. 27. Halkin H, Meytes D, Militeanu J, et al. Multiple lymphomatous polyposis of the gastrointestinal tract. Isr J Med Sci 1973;9: 648-54. 28. Cornes JS, Jones TG, Fisher GB. Gastroduodenal ulceration and massive hemorrhage in patients with leukemia, multiple myeloma, and malignant tumors of lymphoid tissue. Gastroenterology 1961;41:337-44. 29. Lahti R, Lehtola J, Suramo I. Gastrointestinal manifestations of chronic lymphocytic leukemia. Diagnostic Imaging 1979;48: 149-53. 30. Feigel DO, Vaughn DJ, Furth EE, et al. Chronic lymphocytic leukemia: an unusual cause of upper gastrointestinal hemorrhage. Am J Gastroenterol 1995;90:635-7. 31. Mead C. Chronic lymphatic leukemia involving the gastrointestinal tract. Radiology 1933;21:351-65. 32. Wasser AH, Spector JI. Endoscopic evaluation of small-bowel leukemia. Dig Dis 1977;22:1028-32. 33. Klener P, Donner L, Bocanova M, et al. Gastrointestinal lesions and complications of haemoblastoses. Folia Haematologica 1973;100:57-66. 34. Scharschmidt BF. Chronic lymphocytic leukemia presenting as colitis. Dig Dis Sci 1978;23(suppl):9S-12S. 35. Gedgaudas-McClees RK, Maglinte DDT. Aphthous lesions in nodular lymphoma of the colon. South Med J 1986;79:907-8. 36. Sagar S, Selby P, Sloane J, et al. Colorectal lymphoma simulating inflammatory colitis and diagnosed by immunohistochemistry. Postgrad Med J 1986;62:51-3.
Colonic histoplasmosis in AIDS: unusual endoscopic findings in two cases
tigation, a specific organism can be identified in the majority of these cases. 1 In patients with AIDS, commonly isolated intestinal pathogens of the small and l a r g e i n t e s t i n e i n c l u d e c y t o m e g a l o v i r u s , Mycobacter i u m a v i u m intracellulare, C r y p t o s p o r i d i u m , Isospora belli, M i c r o s p o r i d i a , S a l m o n e l l a , Shigella, C a m p y l o bacter, G i a r d i a l a m b l i a , E n t a m o e b a histolytica, a n d C l o s t r i d i u m difficile f l 2 H i s t o p l a s m a c a p s u l a t u m is b e i n g r e c o g n i z e d a s a n increasingly important pathogen in patients with AIDS. 3 This fungus, which produces a self-limited and subclinical respiratory illness in immunocompetent i n d i v i d u a l s , f r e q u e n t l y s p r e a d s to o t h e r o r g a n s i n y o u n g children and immunocompromised adults in a disease known as progressive disseminated histoplasmosis (PDH). S i n c e 1987, e x t r a p u l m o n a r y h i s t o p l a s m o s i s is n o w i n c l u d e d on t h e l i s t of A i D S - d e f i n i n g infections i n i n d i v i d u a l s p o s i t i v e for h u m a n i m m u n o d e f i c i e n c y v i r u s (HIV). 4 D e s p i t e t h e g r o w i n g r e c o g n i t i o n o f P D H a m o n g p a t i e n t s w i t h A I D S , 4~6 t h e specific p a t h o g e n i c role o f H. c a p s u l a t u m in t h e g a s t r o i n t e s t i n a l t r a c t is l e s s we]] a p p r e d a t e d . S e v e r a l r e c e n t r e v i e w s o n t h e s u b j e c t of g a s t r o i n t e s t i n a l i n v o l v e m e n t i n A I D S fail to l i s t t h i s o r g a n i s m a s a p o t e n t i a l i n t e s t i n a l p a t h o g e n . 2, 7-9
Allan G. Halline, MD Mario Maldonado-Lutomirsky, MD Jei W. Ryoo, MD Alice Pau, PharmD Kenneth Pursell, MD Opportunistic infections of the gastrointestinal tract a r e c o m m o n c o m p l i c a t i o n s a m o n g p a t i e n t s w i t h acquired immune deficiency syndrome (AIDS). Sympt o m s o f l o w e r g a s t r o i n t e s t i n a l i n f e c t i o n ( i n c l u d i n g diarrhea, abdominal pain, or bleeding) occur in over half of all patients with AIDS and, with aggressive inves-
From the Departments of Medicine and Pathology, University of Illinois at Chicago, and VA Westside Medical Center, Chicago, Illinois. Allan G. Halline, MD, is a recipient of a Merit Review Award from the Veterans Affairs Research. Reprint requests: Allan G. Halline, MD, Medicine (M / C 787), Section of Digestive and Liver Diseases, 840 S. Wood St., Chicago, IL 60612. 37/4/76050
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