- Email: [email protected]
Lymphoid follicular proctitis mimicking rectal lymphoma: diagnosis by EMR
V Shami, I Waxman
Lymphoid follicular proctitis mimicking rectal lymphoma
young, life-long follow-up would have been required, and the tumor was the source of epigastric pain. EUS-TCB will provide a more representative specimen from GISTs and will improve the evaluation of histopathologic and molecular prognostic indicators. Although data are limited, EUS-TCB with immunohistochemical analysis appears to be superior to EUS-FNA for the diagnosis and the evaluation of GISTs. Prospective comparative studies of yield, cost, and safety are needed. REFERENCES 1. Rader AE, Avery A, Wait CL, McGreevey LS, Faigel D, Heinrich MC. Fine-needle aspiration biopsy diagnosis of gastrointestinal stromal tumors using morphology, immunocytochemistry, and mutation analysis of c-kit. Cancer 2001; 93:269-75. 2. Yadav D, Levy MJ, Schwartz D, Jondal ML, Clain J, Wiersema MJ. EUS-guided trucut biopsy for diagnosis of an esophageal stromal tumor: a case report. Gastrointest Endosc 2003;58:457-60. 3. Fletcher CD, Berman JJ, Corless C, Gorstein F, Lasota J, Longley BJ, et al. Diagnosis of gastrointestinal stromal tumors: a consensus approach. Hum Pathol 2002;33: 459-65. 4. Ruiz AR, Nassar AJ, Fromm H. Multiple malignant gastric stromal tumors presenting with GI bleeding: a case report and a review of the literature. Gastrointest Endosc 2000;51: 225-8. 5. Davis GB, Blanchard DK, Hatch GF, Wertheimer-Hatch L, Hatch K, Foster RS, et al. Tumors of the stomach. World J Surg 2000;24:412-20. 6. Caletti G, Zani L, Bolondi L, Brocchi E, Rollo V, Barbara L. Endoscopic ultrasonography in the diagnosis of gastric submucosal tumor. Gastrointest Endosc 1989;35:413-8. 7. Kameyama H, Niwa Y, Arisawa T, Goto H, Hayakama T. Endoscopic ultrasonography in the diagnosis of submucosal lesion of the large intestine. Gastrointest Endosc 1997;46: 406-11.
Lymphoid follicular proctitis mimicking rectal lymphoma: diagnosis by EMR Vanessa M. Shami, MD, Irving Waxman, MD
Lymphoid follicular proctitis (LFP) is a rare benign condition of the rectum. Patients most often present with rectal bleeding and endoscopically have
Current affiliation: Department of Endoscopy and Therapeutics, The University of Chicago, Chicago, Illinois. Reprint requests: Irving Waxman, MD, The University of Chicago, Section of Gastroenterology, 5758 S. Maryland Ave., MC 9028, Chicago, IL 60637. Copyright Ó 2004 by the American Society for Gastrointestinal Endoscopy 0016-5107/$30.00 PII: S0016-5107(04)01886-3 648
GASTROINTESTINAL ENDOSCOPY
8. Chak A, Canto MI, Rosch T, Dittler HJ, Hawes RH, Tio TL, et al. Endosonographic differentiation of benign and malignant stromal cell tumors. Gastrointest Endosc 1997;45: 468-73. 9. Ando N, Goto H, Niwa Y, Hirooka Y, Ohmiya N, Nagasaka T, et al. The diagnosis of GI stromal tumors with EUS-guided fine needle aspiration with immunohistochemical analysis. Gastrointest Endosc 2002;55:37-43. 10. Ribeiro A, Vazquez-Sequeiros E, Wiersema LM, Wang KK, Clain JE, Wiersema MJ. EUS guided fine-needle aspiration combined with flow cytometry and immunocytochemistry in the diagnosis of lymphoma. Gastrointest Endosc 2001;53: 485-91. 11. Wiersema MJ, Levy MJ, Harewood GC, VazquezSequeiros E, Jondal ML, Wiersema LM. Initial experience with EUS-guided trucut needle biopsies of perigastric organs. Gastrointest Endosc 2002;56:275-8. 12. Palazzo L, Landi B, Cellier C, Cuilerier E, Roseau G, Barbier JP. Endosonographic features predictive of benign and malignant gastrointestinal stromal cell tumors. Gut 2000;46:88-92. 13. Takahashi R, Tanaka S, Kitadai Y, Sumii M, Yoshihara M, Haruma K, et al. Expression of vascular endothelial growth factor and angiogenesis in gastrointestinal stromal tumor of the stomach. Oncology 2003;64:266-74. 14. Yan H, Marchettini P, Gething SA, Brun E, Sugarbaker PH. Prognostic assessment of gastrointestinal stromal tumor. Am J Clin Oncol 2003;26:221-8. 15. Seidal T, Edvardsson H. Expression of c-kit (CD117) and Ki-67 provides information about the possible cell origin and clinical course of gastrointestinal stromal tumors. Histopathology 1999;34:416-24. 16. Chin KF, Greenman J, Reusch P, Gardiner E, Marme D, Monson JR. Vascular endothelial growth factor and soluble Tie-2 receptor in colorectal cancer: associations with disease recurrence. Eur J Surg Oncol 2003;29:497-505. 17. Verstovsek S, Lunin S, Kantarjian H, Manshouri T, Faderl S, Cortes J, et al. Clinical relevance of VEGF receptors 1 and 2 in patients with chronic myelogenous leukemia. Leuk Res 2003;27:661-9. 18. Rosen LS. Angiogenesis inhibition in solid tumors. Cancer J 2001;7(Suppl 3):S120-8.
a finely granular and nodular mucosa. The pathogenesis of LFP is unknown. It often is misdiagnosed as malignant lymphoma because atypical lymphoid cells are found in biopsy specimens. A case of LFP mimicking lymphoma is described in which EUS and EMR were used to establish the correct diagnosis. CASE REPORT A 33-year-old woman presented with intermittent rectal bleeding. The medical history included mitral valve prolapse. The patient denied a history of sexually transmitted diseases and anal intercourse. She was taking no medication and did not smoke tobacco or drink alcohol. There was no family history of colon cancer or inflammatory bowel disease. Examination was unremarkable. Colonoscopy at another hospital revealed nodular mucosa limited to the rectum (Fig. 1). Biopsy specimens disclosed an extremely dense, abnormal lymphoid infiltrate VOLUME 60, NO. 4, 2004
Lymphoid follicular proctitis mimicking rectal lymphoma
V Shami, I Waxman
Figure 1. Colonoscopic view of rectum, showing congested, finely granular, and nodular mucosa. (Fig. 2A); abundant atypical-appearing lymphocytes with numerous mitotic figures were noted (Fig. 2B). Immunohistochemical staining for the B-cell associated antigen CD20 disclosed that virtually all of the neoplastic lymphoid cells expressed this antigen (Fig. 3A). In addition, nearly 95% of the cells were proliferative, as judged from the Ki67 staining pattern (Fig. 3B). Because of the monotony and the invasiveness of the large size lymphoid cells, as well as the high proliferative fraction, a presumptive diagnosis of a malignant high-grade rectal lymphoma was made. Lymphoma staging and high-dose chemotherapy were recommended. CT, gallium scintigraphy, and a bone marrow biopsy specimen were normal. The patient was referred to our institution 2 weeks later for a second opinion. At colonoscopy, numerous smooth nodules were present from 1 to 25 cm from the anus, as described at the previous colonoscopy (Fig. 4). EUS revealed mild thickening limited to the mucosa and submucosa, without evidence of lymphadenopathy, findings suggestive of a benign process (Fig. 5). EMR was performed to obtain a larger and deeper tissue sample and thereby better characterize the follicular architecture (Fig. 6). Histopathologic assessment of the EMR specimen disclosed numerous large lymphoid nodules that appeared to be composed of expansile germinal centers (Fig. 7). Immunohistochemical staining for CD21 clarified the germinal center origin of the nodules by delineating follicular dendritic cells in most of the nodules (Fig. 8). Although there was a suggestion of some architectural distortion, this was not a consistent finding. In addition, there was no phenotypic, molecular genetic, or cytogenetic evidence of a malignant process. These findings were thought to be more consistent with LFP. The patient was treated with mesalamine suppositories (500 mg per rectum twice a day). Sigmoidoscopy 1 month later revealed slight improvement in the rectal nodularity. Because of the clinical and endoscopic improvement, treatment was continued with the mesalamine suppositories. Endoscopy 11 months after presentation VOLUME 60, NO. 4, 2004
Figure 2. A, Photomicrograph of rectal biopsy specimen, showing extremely dense, abnormal-appearing lymphoid infiltrate (H&E, orig. mag. 3100). B, Photomicrograph showing numerous atypical-appearing lymphoid cells and numerous mitotic figures (H&E, orig. mag. 3400). revealed complete resolution of the nodules and normalappearing rectal mucosa (Fig. 9).
DISCUSSION Lymphoid tissue is normally present in the mucosa throughout the GI tract, and, thus, the gut is a common site for lymphoproliferative disorders.1 GASTROINTESTINAL ENDOSCOPY
649
V Shami, I Waxman
Lymphoid follicular proctitis mimicking rectal lymphoma
Figure 4. Colonoscopic view of rectum, showing numerous nodules.
Figure 3. A, Photomicrograph showing that virtually all atypical-appearing lymphoid cells express the B-cell associated antigen CD20 (immunohistochemical stain, orig. mag. 3200). B, Photomicrograph demonstrating markedly increased proliferative rate within lymphoid cells (immunostaining for Ki67, orig. mag. 3200).
In the distal colon, lymphoid tissue is present predominantly as solitary nodules that develop in utero and increase in number rapidly after birth.2 LFP is a rare inflammatory condition that is confined to the rectum and the distal sigmoid colon, where there is hyperplasia of the lymphoid follicles. 650
GASTROINTESTINAL ENDOSCOPY
Figure 5. EUS image of rectum, showing thickening limited to mucosal and submucosal layers and no perirectal lymphadenopathy.
The pathogenesis is unknown. The most common presentation of LFP is bleeding per rectum. Endoscopically, a congested, finely granular, and nodular mucosa without ulceration is often noted. Early descriptions of enlarged colonic follicles emphasized the similarity to malignant diseases, and, therefore, radical surgery, radiotherapy, and cytotoxic drugs were used to treat LFP.3,4 Subsequently, LFP was considered a variation of ulcerative colitis, but, in more recent reports, it is regarded as a distinct entity.1,5,6 VOLUME 60, NO. 4, 2004
Lymphoid follicular proctitis mimicking rectal lymphoma
V Shami, I Waxman
Figure 6. Colonoscopic view of rectum, showing mucosal resection site.
Figure 8. Photomicrograph showing germinal center origin of nodules by delineation of follicular dendritic cells (immunohistochemical stain for CD21, orig. mag. 3100).
Figure 7. Photomicrograph of EMR specimen, showing numerous large lymphoid nodules with expansile germinal centers (H&E, orig. mag. 3100).
Figure 9. Colonoscopic view of rectum, showing normal mucosa and absence of nodules.
LFP must be distinguished from 3 other conditions that also are confined to the rectum.6 As in the present case, the most important, yet challenging, histopathologic distinction is between LFP and primary lymphoma of the rectum. Primary lymphomas of the rectum are rare (<1% of all malignant rectal lesions).7-10 In the series of 70 patients with benign rectal lymphoma reported by Helwig and Hansen,11 about half were originally diagnosed microscopically as malignant lymphoma or sarcoma.
Histopathologically, LFP can be distinguished from malignant lymphoma by the polymorphic nature of the infiltrate, the absence of significant cytologic atypia, and the presence of reactive follicles within the lesion.1 In addition, in LFP, mitotic figures are frequent in the germinal centers but absent in the surrounding lymphoid tissue.12 The lymphoid infiltrate usually is confined to the mucosa and the submucosa; involvement of the muscularis mucosa is unlikely. In contrast, lymphomas have an
VOLUME 60, NO. 4, 2004
GASTROINTESTINAL ENDOSCOPY
651
V Shami, I Waxman
infiltrative growth pattern, an indistinct follicular architecture, and immature lymphoblastic cells are scattered beyond the germinal centers and also infiltrate through the muscularis propria.13,14 Immunocytochemical and gene rearrangement techniques also are helpful in establishing the diagnosis. LFP also should be distinguished from allergic proctitis, which histopathologically resembles chronic ulcerative colitis. Immunologically, there are increased numbers of immunoglobulin E containing cells in the lamina propria of the rectal mucosa in allergic proctitis.15 Lastly, LFP must be differentiated from benign lymphoid polyps of the rectum. These usually are sessile but may be pedunculated and often cause intermittent bleeding. Lymphoid polyps are benign lesions characterized by lymphoid follicular hyperplasia in the submucosa; they do not warrant extensive surgical resection or chemotherapy. Polypectomy is the treatment of choice.13 When there is a discrepancy between clinical and histopathologic findings, it is essential to obtain more tissue. If a rectal biopsy specimen is too small, the follicular pattern of LFP can easily be missed. For example, simple biopsy specimens a few millimeters in size may contain only the germinal center of a lymphoid follicle, in which case, the lymphocytes may be identified as abnormal and, consequently, an erroneous diagnosis can be made. A diagnosis, therefore, should be made only after evaluation of large tissue fragments taken from representative portions of the lesion.12 EMR can provide large specimens sufficient for determining the broad extent of a lesion.5 To our knowledge, the present case is only the second in which EMR assisted the diagnosis of LFP. In addition, EUS can be helpful in distinguishing lymphoma from lymphoid follicular hyperplasia. Infiltration beyond the submucosa and detection of lymph nodes in the perirectal fat would favor the diagnosis of malignant lymphoma.16 There is no consensus regarding treatment of LFP. It typically does not respond to orally administered sulfasalazine or topical corticosteroid therapy. Treatment of LFP with sulfasalazine suppositories was said to be successful in a letter to the editor.5 In the present case, there was complete clinical and endoscopic resolution in response to treatment with mesalamine suppositories. In summary, LFP is a rare inflammatory condition that most commonly manifests clinically as rectal bleeding. Endoscopically, the mucosa is congested and nodular. The pathogenesis is unknown. LFP often is misdiagnosed as malignant lymphoma because atypical lymphoid cells are noted in biopsy specimens. EMR, together with EUS, may better 652
GASTROINTESTINAL ENDOSCOPY
Lymphoid follicular proctitis mimicking rectal lymphoma
characterize the follicular architecture and depth of involvement, thereby leading to the correct diagnosis. An aggressive effort to reach the correct diagnosis is warranted when there is a discrepancy between clinical observation and biopsy findings, because the treatments for lymphoma and LFP are substantially different. Aggressive pursuit of the correct diagnosis in the case presented prevented the patient from being unnecessarily exposed to the untoward effects of high-dose chemotherapy. REFERENCES 1. Ranchod M, Lewin KJ, Dorfman RF. Lymphoid hyperplasia of the gastrointestinal tract. A study of 26 cases and review of the literature. Am J Surg Pathol 1978;2:383-400. 2. Whitehead R, Skinner J. Morphology of the gut associated lymphoid system in health and disease: a review. Pathology 1978;10:3-16. 3. Louw JH. Polypoid lesions of the large bowel in children with particular reference to benign lymphoid polyposis. J Pediatr Surg 1968;3:195-209. 4. Cosens CG. Gastro-intestinal pseudoleukemia: a case report. Ann Surg 1958;148:129-33. 5. Toyoda H, Yamaguchi M, Uemura Y, Mukai K, Sawa H, Suzuki H, et al. Successful treatment of lymphoid follicular proctitis with sulfasalazine suppositories [letter]. Am J Gastroenterol 2000;95:2403-4. 6. Flejou JF, Potet F, Bogomoletz WV, Rigaud C, Fenzy A, Le Quintrec Y, et al. Lymphoid follicular proctitis. A condition different from ulcerative proctitis? Dig Dis Sci 1988;33: 314-20. 7. Shepard NA, Hall PA, Coates PJ, Levison DA. Primary malignant lymphoma of the colon and rectum: a histopathological and immunohistochemical analysis of 45 cases with clinicopathological correlations. Histopathology 1988;12: 235-52. 8. Flemming ID, Mitchell S, Dilawari RA. The role of surgery in the management of gastric lymphoma. Cancer 1982;49: 1135-41. 9. Jinnai D, Iwasa Z, Watanuki T. Malignant lymphoma of the large intestine: operative results in Japan. Jpn J Surg 1983; 13:331-6. 10. Perry PM, Cross RM, Morson BC. Primary malignant lymphoma of the rectum (22 cases). Proc Roy Soc Med 1972; 65:72. 11. Helwig EB, Hansen J. Lymphoid polyps (benign lymphomas) and malignant lymphoma of the rectum and anus. Surg Gynecol Obstet 1951;92:233-43. 12. Cornes JS, Wallace MH, Morson BC. Benign lymphomas of the rectum and anal canal: a study of 100 cases. J Pathol Bacteriol 1961;82:371-82. 13. Bryne WJ, Jimenez JF, Euler AR, Golladay ES. Lymphoid polyps (focal lymphoid hyperplasia) of the colon in children. Pediatrics 1982;69:598-600. 14. Katsuyuki A, Ohsawa M, Toshihiro S, Sugiyama H, Yano Y, Shimano T, et al. Malignant lymphoma of the rectum. Jpn J Clin Oncol 1990;20:380-6. 15. Heatly RV, Rhodes J, Calcraft BJ, Whitehead RH, Fifield R, Newcombe RG. Immunoglobulin E in rectal mucosa of patients with proctitis. Lancet 1975;II:1010-2. 16. Gavioli M, Bagni A, Garoia C, Piccagli I, Biscardi A, Natalini G. Role of endosonography in rectal lymphoma [letter]. Haematologica 2000;85:882-3. VOLUME 60, NO. 4, 2004
Lymphoid follicular proctitis mimicking rectal lymphoma
young, life-long follow-up would have been required, and the tumor was the source of epigastric pain. EUS-TCB will provide a more representative specimen from GISTs and will improve the evaluation of histopathologic and molecular prognostic indicators. Although data are limited, EUS-TCB with immunohistochemical analysis appears to be superior to EUS-FNA for the diagnosis and the evaluation of GISTs. Prospective comparative studies of yield, cost, and safety are needed. REFERENCES 1. Rader AE, Avery A, Wait CL, McGreevey LS, Faigel D, Heinrich MC. Fine-needle aspiration biopsy diagnosis of gastrointestinal stromal tumors using morphology, immunocytochemistry, and mutation analysis of c-kit. Cancer 2001; 93:269-75. 2. Yadav D, Levy MJ, Schwartz D, Jondal ML, Clain J, Wiersema MJ. EUS-guided trucut biopsy for diagnosis of an esophageal stromal tumor: a case report. Gastrointest Endosc 2003;58:457-60. 3. Fletcher CD, Berman JJ, Corless C, Gorstein F, Lasota J, Longley BJ, et al. Diagnosis of gastrointestinal stromal tumors: a consensus approach. Hum Pathol 2002;33: 459-65. 4. Ruiz AR, Nassar AJ, Fromm H. Multiple malignant gastric stromal tumors presenting with GI bleeding: a case report and a review of the literature. Gastrointest Endosc 2000;51: 225-8. 5. Davis GB, Blanchard DK, Hatch GF, Wertheimer-Hatch L, Hatch K, Foster RS, et al. Tumors of the stomach. World J Surg 2000;24:412-20. 6. Caletti G, Zani L, Bolondi L, Brocchi E, Rollo V, Barbara L. Endoscopic ultrasonography in the diagnosis of gastric submucosal tumor. Gastrointest Endosc 1989;35:413-8. 7. Kameyama H, Niwa Y, Arisawa T, Goto H, Hayakama T. Endoscopic ultrasonography in the diagnosis of submucosal lesion of the large intestine. Gastrointest Endosc 1997;46: 406-11.
Lymphoid follicular proctitis mimicking rectal lymphoma: diagnosis by EMR Vanessa M. Shami, MD, Irving Waxman, MD
Lymphoid follicular proctitis (LFP) is a rare benign condition of the rectum. Patients most often present with rectal bleeding and endoscopically have
Current affiliation: Department of Endoscopy and Therapeutics, The University of Chicago, Chicago, Illinois. Reprint requests: Irving Waxman, MD, The University of Chicago, Section of Gastroenterology, 5758 S. Maryland Ave., MC 9028, Chicago, IL 60637. Copyright Ó 2004 by the American Society for Gastrointestinal Endoscopy 0016-5107/$30.00 PII: S0016-5107(04)01886-3 648
GASTROINTESTINAL ENDOSCOPY
8. Chak A, Canto MI, Rosch T, Dittler HJ, Hawes RH, Tio TL, et al. Endosonographic differentiation of benign and malignant stromal cell tumors. Gastrointest Endosc 1997;45: 468-73. 9. Ando N, Goto H, Niwa Y, Hirooka Y, Ohmiya N, Nagasaka T, et al. The diagnosis of GI stromal tumors with EUS-guided fine needle aspiration with immunohistochemical analysis. Gastrointest Endosc 2002;55:37-43. 10. Ribeiro A, Vazquez-Sequeiros E, Wiersema LM, Wang KK, Clain JE, Wiersema MJ. EUS guided fine-needle aspiration combined with flow cytometry and immunocytochemistry in the diagnosis of lymphoma. Gastrointest Endosc 2001;53: 485-91. 11. Wiersema MJ, Levy MJ, Harewood GC, VazquezSequeiros E, Jondal ML, Wiersema LM. Initial experience with EUS-guided trucut needle biopsies of perigastric organs. Gastrointest Endosc 2002;56:275-8. 12. Palazzo L, Landi B, Cellier C, Cuilerier E, Roseau G, Barbier JP. Endosonographic features predictive of benign and malignant gastrointestinal stromal cell tumors. Gut 2000;46:88-92. 13. Takahashi R, Tanaka S, Kitadai Y, Sumii M, Yoshihara M, Haruma K, et al. Expression of vascular endothelial growth factor and angiogenesis in gastrointestinal stromal tumor of the stomach. Oncology 2003;64:266-74. 14. Yan H, Marchettini P, Gething SA, Brun E, Sugarbaker PH. Prognostic assessment of gastrointestinal stromal tumor. Am J Clin Oncol 2003;26:221-8. 15. Seidal T, Edvardsson H. Expression of c-kit (CD117) and Ki-67 provides information about the possible cell origin and clinical course of gastrointestinal stromal tumors. Histopathology 1999;34:416-24. 16. Chin KF, Greenman J, Reusch P, Gardiner E, Marme D, Monson JR. Vascular endothelial growth factor and soluble Tie-2 receptor in colorectal cancer: associations with disease recurrence. Eur J Surg Oncol 2003;29:497-505. 17. Verstovsek S, Lunin S, Kantarjian H, Manshouri T, Faderl S, Cortes J, et al. Clinical relevance of VEGF receptors 1 and 2 in patients with chronic myelogenous leukemia. Leuk Res 2003;27:661-9. 18. Rosen LS. Angiogenesis inhibition in solid tumors. Cancer J 2001;7(Suppl 3):S120-8.
a finely granular and nodular mucosa. The pathogenesis of LFP is unknown. It often is misdiagnosed as malignant lymphoma because atypical lymphoid cells are found in biopsy specimens. A case of LFP mimicking lymphoma is described in which EUS and EMR were used to establish the correct diagnosis. CASE REPORT A 33-year-old woman presented with intermittent rectal bleeding. The medical history included mitral valve prolapse. The patient denied a history of sexually transmitted diseases and anal intercourse. She was taking no medication and did not smoke tobacco or drink alcohol. There was no family history of colon cancer or inflammatory bowel disease. Examination was unremarkable. Colonoscopy at another hospital revealed nodular mucosa limited to the rectum (Fig. 1). Biopsy specimens disclosed an extremely dense, abnormal lymphoid infiltrate VOLUME 60, NO. 4, 2004
Lymphoid follicular proctitis mimicking rectal lymphoma
V Shami, I Waxman
Figure 1. Colonoscopic view of rectum, showing congested, finely granular, and nodular mucosa. (Fig. 2A); abundant atypical-appearing lymphocytes with numerous mitotic figures were noted (Fig. 2B). Immunohistochemical staining for the B-cell associated antigen CD20 disclosed that virtually all of the neoplastic lymphoid cells expressed this antigen (Fig. 3A). In addition, nearly 95% of the cells were proliferative, as judged from the Ki67 staining pattern (Fig. 3B). Because of the monotony and the invasiveness of the large size lymphoid cells, as well as the high proliferative fraction, a presumptive diagnosis of a malignant high-grade rectal lymphoma was made. Lymphoma staging and high-dose chemotherapy were recommended. CT, gallium scintigraphy, and a bone marrow biopsy specimen were normal. The patient was referred to our institution 2 weeks later for a second opinion. At colonoscopy, numerous smooth nodules were present from 1 to 25 cm from the anus, as described at the previous colonoscopy (Fig. 4). EUS revealed mild thickening limited to the mucosa and submucosa, without evidence of lymphadenopathy, findings suggestive of a benign process (Fig. 5). EMR was performed to obtain a larger and deeper tissue sample and thereby better characterize the follicular architecture (Fig. 6). Histopathologic assessment of the EMR specimen disclosed numerous large lymphoid nodules that appeared to be composed of expansile germinal centers (Fig. 7). Immunohistochemical staining for CD21 clarified the germinal center origin of the nodules by delineating follicular dendritic cells in most of the nodules (Fig. 8). Although there was a suggestion of some architectural distortion, this was not a consistent finding. In addition, there was no phenotypic, molecular genetic, or cytogenetic evidence of a malignant process. These findings were thought to be more consistent with LFP. The patient was treated with mesalamine suppositories (500 mg per rectum twice a day). Sigmoidoscopy 1 month later revealed slight improvement in the rectal nodularity. Because of the clinical and endoscopic improvement, treatment was continued with the mesalamine suppositories. Endoscopy 11 months after presentation VOLUME 60, NO. 4, 2004
Figure 2. A, Photomicrograph of rectal biopsy specimen, showing extremely dense, abnormal-appearing lymphoid infiltrate (H&E, orig. mag. 3100). B, Photomicrograph showing numerous atypical-appearing lymphoid cells and numerous mitotic figures (H&E, orig. mag. 3400). revealed complete resolution of the nodules and normalappearing rectal mucosa (Fig. 9).
DISCUSSION Lymphoid tissue is normally present in the mucosa throughout the GI tract, and, thus, the gut is a common site for lymphoproliferative disorders.1 GASTROINTESTINAL ENDOSCOPY
649
V Shami, I Waxman
Lymphoid follicular proctitis mimicking rectal lymphoma
Figure 4. Colonoscopic view of rectum, showing numerous nodules.
Figure 3. A, Photomicrograph showing that virtually all atypical-appearing lymphoid cells express the B-cell associated antigen CD20 (immunohistochemical stain, orig. mag. 3200). B, Photomicrograph demonstrating markedly increased proliferative rate within lymphoid cells (immunostaining for Ki67, orig. mag. 3200).
In the distal colon, lymphoid tissue is present predominantly as solitary nodules that develop in utero and increase in number rapidly after birth.2 LFP is a rare inflammatory condition that is confined to the rectum and the distal sigmoid colon, where there is hyperplasia of the lymphoid follicles. 650
GASTROINTESTINAL ENDOSCOPY
Figure 5. EUS image of rectum, showing thickening limited to mucosal and submucosal layers and no perirectal lymphadenopathy.
The pathogenesis is unknown. The most common presentation of LFP is bleeding per rectum. Endoscopically, a congested, finely granular, and nodular mucosa without ulceration is often noted. Early descriptions of enlarged colonic follicles emphasized the similarity to malignant diseases, and, therefore, radical surgery, radiotherapy, and cytotoxic drugs were used to treat LFP.3,4 Subsequently, LFP was considered a variation of ulcerative colitis, but, in more recent reports, it is regarded as a distinct entity.1,5,6 VOLUME 60, NO. 4, 2004
Lymphoid follicular proctitis mimicking rectal lymphoma
V Shami, I Waxman
Figure 6. Colonoscopic view of rectum, showing mucosal resection site.
Figure 8. Photomicrograph showing germinal center origin of nodules by delineation of follicular dendritic cells (immunohistochemical stain for CD21, orig. mag. 3100).
Figure 7. Photomicrograph of EMR specimen, showing numerous large lymphoid nodules with expansile germinal centers (H&E, orig. mag. 3100).
Figure 9. Colonoscopic view of rectum, showing normal mucosa and absence of nodules.
LFP must be distinguished from 3 other conditions that also are confined to the rectum.6 As in the present case, the most important, yet challenging, histopathologic distinction is between LFP and primary lymphoma of the rectum. Primary lymphomas of the rectum are rare (<1% of all malignant rectal lesions).7-10 In the series of 70 patients with benign rectal lymphoma reported by Helwig and Hansen,11 about half were originally diagnosed microscopically as malignant lymphoma or sarcoma.
Histopathologically, LFP can be distinguished from malignant lymphoma by the polymorphic nature of the infiltrate, the absence of significant cytologic atypia, and the presence of reactive follicles within the lesion.1 In addition, in LFP, mitotic figures are frequent in the germinal centers but absent in the surrounding lymphoid tissue.12 The lymphoid infiltrate usually is confined to the mucosa and the submucosa; involvement of the muscularis mucosa is unlikely. In contrast, lymphomas have an
VOLUME 60, NO. 4, 2004
GASTROINTESTINAL ENDOSCOPY
651
V Shami, I Waxman
infiltrative growth pattern, an indistinct follicular architecture, and immature lymphoblastic cells are scattered beyond the germinal centers and also infiltrate through the muscularis propria.13,14 Immunocytochemical and gene rearrangement techniques also are helpful in establishing the diagnosis. LFP also should be distinguished from allergic proctitis, which histopathologically resembles chronic ulcerative colitis. Immunologically, there are increased numbers of immunoglobulin E containing cells in the lamina propria of the rectal mucosa in allergic proctitis.15 Lastly, LFP must be differentiated from benign lymphoid polyps of the rectum. These usually are sessile but may be pedunculated and often cause intermittent bleeding. Lymphoid polyps are benign lesions characterized by lymphoid follicular hyperplasia in the submucosa; they do not warrant extensive surgical resection or chemotherapy. Polypectomy is the treatment of choice.13 When there is a discrepancy between clinical and histopathologic findings, it is essential to obtain more tissue. If a rectal biopsy specimen is too small, the follicular pattern of LFP can easily be missed. For example, simple biopsy specimens a few millimeters in size may contain only the germinal center of a lymphoid follicle, in which case, the lymphocytes may be identified as abnormal and, consequently, an erroneous diagnosis can be made. A diagnosis, therefore, should be made only after evaluation of large tissue fragments taken from representative portions of the lesion.12 EMR can provide large specimens sufficient for determining the broad extent of a lesion.5 To our knowledge, the present case is only the second in which EMR assisted the diagnosis of LFP. In addition, EUS can be helpful in distinguishing lymphoma from lymphoid follicular hyperplasia. Infiltration beyond the submucosa and detection of lymph nodes in the perirectal fat would favor the diagnosis of malignant lymphoma.16 There is no consensus regarding treatment of LFP. It typically does not respond to orally administered sulfasalazine or topical corticosteroid therapy. Treatment of LFP with sulfasalazine suppositories was said to be successful in a letter to the editor.5 In the present case, there was complete clinical and endoscopic resolution in response to treatment with mesalamine suppositories. In summary, LFP is a rare inflammatory condition that most commonly manifests clinically as rectal bleeding. Endoscopically, the mucosa is congested and nodular. The pathogenesis is unknown. LFP often is misdiagnosed as malignant lymphoma because atypical lymphoid cells are noted in biopsy specimens. EMR, together with EUS, may better 652
GASTROINTESTINAL ENDOSCOPY
Lymphoid follicular proctitis mimicking rectal lymphoma
characterize the follicular architecture and depth of involvement, thereby leading to the correct diagnosis. An aggressive effort to reach the correct diagnosis is warranted when there is a discrepancy between clinical observation and biopsy findings, because the treatments for lymphoma and LFP are substantially different. Aggressive pursuit of the correct diagnosis in the case presented prevented the patient from being unnecessarily exposed to the untoward effects of high-dose chemotherapy. REFERENCES 1. Ranchod M, Lewin KJ, Dorfman RF. Lymphoid hyperplasia of the gastrointestinal tract. A study of 26 cases and review of the literature. Am J Surg Pathol 1978;2:383-400. 2. Whitehead R, Skinner J. Morphology of the gut associated lymphoid system in health and disease: a review. Pathology 1978;10:3-16. 3. Louw JH. Polypoid lesions of the large bowel in children with particular reference to benign lymphoid polyposis. J Pediatr Surg 1968;3:195-209. 4. Cosens CG. Gastro-intestinal pseudoleukemia: a case report. Ann Surg 1958;148:129-33. 5. Toyoda H, Yamaguchi M, Uemura Y, Mukai K, Sawa H, Suzuki H, et al. Successful treatment of lymphoid follicular proctitis with sulfasalazine suppositories [letter]. Am J Gastroenterol 2000;95:2403-4. 6. Flejou JF, Potet F, Bogomoletz WV, Rigaud C, Fenzy A, Le Quintrec Y, et al. Lymphoid follicular proctitis. A condition different from ulcerative proctitis? Dig Dis Sci 1988;33: 314-20. 7. Shepard NA, Hall PA, Coates PJ, Levison DA. Primary malignant lymphoma of the colon and rectum: a histopathological and immunohistochemical analysis of 45 cases with clinicopathological correlations. Histopathology 1988;12: 235-52. 8. Flemming ID, Mitchell S, Dilawari RA. The role of surgery in the management of gastric lymphoma. Cancer 1982;49: 1135-41. 9. Jinnai D, Iwasa Z, Watanuki T. Malignant lymphoma of the large intestine: operative results in Japan. Jpn J Surg 1983; 13:331-6. 10. Perry PM, Cross RM, Morson BC. Primary malignant lymphoma of the rectum (22 cases). Proc Roy Soc Med 1972; 65:72. 11. Helwig EB, Hansen J. Lymphoid polyps (benign lymphomas) and malignant lymphoma of the rectum and anus. Surg Gynecol Obstet 1951;92:233-43. 12. Cornes JS, Wallace MH, Morson BC. Benign lymphomas of the rectum and anal canal: a study of 100 cases. J Pathol Bacteriol 1961;82:371-82. 13. Bryne WJ, Jimenez JF, Euler AR, Golladay ES. Lymphoid polyps (focal lymphoid hyperplasia) of the colon in children. Pediatrics 1982;69:598-600. 14. Katsuyuki A, Ohsawa M, Toshihiro S, Sugiyama H, Yano Y, Shimano T, et al. Malignant lymphoma of the rectum. Jpn J Clin Oncol 1990;20:380-6. 15. Heatly RV, Rhodes J, Calcraft BJ, Whitehead RH, Fifield R, Newcombe RG. Immunoglobulin E in rectal mucosa of patients with proctitis. Lancet 1975;II:1010-2. 16. Gavioli M, Bagni A, Garoia C, Piccagli I, Biscardi A, Natalini G. Role of endosonography in rectal lymphoma [letter]. Haematologica 2000;85:882-3. VOLUME 60, NO. 4, 2004