Cancer in Chronic Ulcerative Colitis Diagnostic Role of Segmental Colonic Lavage S. KATZ, MD, I. K A T Z K A , MD, N. P L A T T , MD, E.O. HAJDU, MD, and E. BASSETT, MD
Saline colonic lavage in 74 patients with chronic ulcerative colitis was performed utilizing a commercially available dental irrigating unit through a polyethylene catheter in the biopsy channel of a colonoscope or through a sigmoidoscope via a lavage-aspirating double-lumen probe. Six patients were found with colonic carcinoma. Two diagnoses of malignancy were established by cytologic smears and cell block alone. Two patients had positive mucosal biopsies and cell block. One patient with a hepatic flexure carcinoma and a second patient with a malignancy proximal to a left colon stricture were missed by these techniques. Considering the established proclivityfor carcinoma in these patients, it is felt that segmental lavage in areas o f stricture, grossly distorted mucosa, or endoscopically inaccessible areas represents a valuable adjunct in the diagnosis of carcinoma in chronic ulcerative colitis.
It is well ,established that patients with ulcerative colitis have an increased risk of developing colon cancer (1-13). This is believed particularly true for that patient population in which the following criteria are met: (1) involvement of entire colon, (2) long duration of disease, usually greater than 10 years, (3) onset in childhood or adolescence, and (4) a severe initial attack with a subsequent chronic continuous course of active disease (10). Early detection of carcinoma is difficult to recognize radiographically or endoscopically in face of widespread inflammatory disease (11-13). Further complicating factors include the failure of patient's history or clinical examination to reveal the tumor until it is extensive and, all too frequently, unresectable. Experience to date in cancer detection in this highly s u s c e p t i b l e p o p u l a t i o n has b e e n dismal (1, 2). Indeed it has been poor enough for some to advise prophylactic proctocolectomy in the young patient meeting the criteria described (8). From the Departments of Medicine and Pathology, Long Island Jewish-Hillside Medical Center, New Hyde Park, New York, and the Departments of Medicine and Pathology, North Shore University Hospital, Manhasset, New York and Departments of Medicine and Pathology, Cornell University Medical College, New York City, New York. Address for reprint requests: Dr. Seymour Katz, 1300 Union Turnpike, New Hyde Park, New York 11040. Digestive Diseases, Vol. 22, No. 4 (April 1977)
Our experience with recent technological advances in obtaining cytopathologic material has stimulated a more aggressive approach utilizing rectocolonic cytology via sigmoidoscopes, flexible fiberoptic colonoscopes, and a multiple biopsy technique, in addition to the conventional endoscopicradiographic evaluation (14-16). The purpose of this report is to summarize our initial experience with segmental colonic lavage in retrieving diagnostic material as an adjunct in cancer detection in chronic ulcerative colitis in hopes of facilitating an " e a r l y " diagnosis in future cases. MATERIALS AND METHODS
The technique for obtaining cytopathologic material through a rigid sigmoidoscope utilizing a pulsatile saline lavage and simultaneous suction has been previously described (14). The same principle has been adapted to flexible fiberoptic endoscopes (15) when indicated for further clarification of x-ray appearance of stricture or suspected tumor mass. Segmental colonic lavage was performed, particularly in areas of stricture and mucosal irregularity, or if colonoscopic biopsy was not technically feasible (16). Over the past six years, 74 patients with documented chronic ulcerative colitis with generalized or leftcolon involvement were studied. There were 34 males and 40 females, with mean ages of 48 and 42, respectively. The mean duration of disease was 11 years. These in-
355
K A T Z ET A L
Fig 1. Colonscope with dental irrigating unit attached to polythylene catheter.
cluded 8 patients from New York Hospital, 9 patients from Memorial Hospital, and the remaining from Long Island Jewish-Hillside and North Shore University Hospitals. Approximately 500-1000 cc saline was introduced as a pulsafile lavage through a polyethylene catheter powered by a commercially available dental irrigating unit in the biopsy channel of the colonoscope (Figure 1). Fluid was retrieved simultaneously in a suction trap containing equal volumes of 95% alcohol. The aspirate was centrifuged at 2500 rpm for 15 rain. Papanicolau smears were obtained from the sediment and the remaining material was processed according to cell-block technique and examined in tissue sections. Rectocolonic biopsies were obtained, when possible, via rigid and flexible endoscopes and examined according to the criteria of Morson and Pang (17). Six patients were found to have cancer of the colon. All but one of the six underwent laparotomy, and there are two survivors at the time of this report. Case 1. L.W., a 34-year-old housewife with 15 years of generalized colitis, presented with a pelvic mass unresponsive to trial of corticosteroid or antibiotic therapy.
356
Biopsies obtained at laparotomy revealed chronic inflammatory tissue. Postoperatively, cytologic studies revealed adenocarcinoma which was confirmed at reexploration of the abdomen (Figure 2). Case 2. Wm.McC., a 22-year-old male student with 12 year history of ulcerative colitis, was admitted for evaluation of jaundice, weight loss, and persistent diarrhea. A liver biopsy was compatible with viral hepatitis. Rectocolonic cytology was interpreted as positive for malignancy (Figure 3). A biopsy of a palpable scalene node revealed mucin-producing adenocarcinoma. Subsequently, a barium enema examination demonstrated an irregular area of the hepatic flexure suggestive of carcinoma. Surgery as well as a subsequent postmortem examination was refused. Case 3. Wm.A., a 29-year-old white man with 10 years of chronic ulcerative colitis, presented with progression of fever, anemia, hypoalbuminemia, and weight loss. Sigmoidoscopy revealed a rectal stricture with biopsy and cytology evidence of infiltrating "signet cell" carcinoma (Figure 4). Case 4. A.B., a 68-year-old housewife with a 2-year history of active ulcerative colitis limited to left colon, develDigestive Diseases, VoL 22, No. 4 (April 1977)
C A N C E R IN C O L I T I S
Fig 2. (a) Cell-block (colowash) fragments of adenocarcinoma (• patient as in (a). Colonic wall infiltrated by adenocarcinoma (x50).
Digestive Diseases, Vol. 22, No. 4 (April 1977)
(b) Resected specimen, same
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KATZ ET AL
Fig 3. Cytologic smear (colowash); cluster of malignant cells (• 1000).
oped fever and bloody diarrhea unresponsive to increased dosage of corticosteroid. Biopsy and cytology of rectal polypoid tissue demonstrated adenocarcinoma (Figure 5). Case 5. C.S., a 49-year-old housewife with 19 years of chronic ulcerative colitis with strictured colon and arthritis, developed progressive unrelenting diarrhea. Cytologic studies were negative. Laparotomy revealed a marked colonic stricture with carcinoma in the hepatic flexure. Cytologic studies were negative. Laparotomy revealed a marked colonic stricture with carcinoma in the hepatic flexure. Case 6. T.L., a 56-year-old woman with 38 years of chronic ulcerative colitis, developed a sigmoid colon stricture. Cytologic washings and biopsy were negative. Laparotomy was identified 8 cm proximal to the stricture. Nine patients had mucosal biopsies compatible with the diagnosis of "precancer" as described by Morson and Pang (17). Of the 6 patients with proven cancer, 3 had precancerous mucosal biopsies elsewhere in the resected specimen but only one of these three had such changes on rectal biopsy.
358
Rectal biopsies of 6 patients revealed adenomatous hyperplasia. Two of these subsequently underwent laparotomy for progression of symptoms unresponsive to medical therapy. No carcinoma was identified in these resected specimens. The remaining 4 patients are under close scrutiny with semiannual observation.
RESULTS AND DISCUSSION The difficulty in detecting carcinoma in chronic ulcerative colitis stems f r o m m a n y factors: (1) the inability to accurately identify the time when the chronic ulcerative colitis patient m a y develop colon cancer, (2) the failure of the patient's history or clinical e x a m to reveal t u m o r until it is widespread and frequently unresectable, (3) the m a n y disguises of the t u m o r often mimicking the inflammatory process itself, and (4) the limited diagnostic techniques in detecting t u m o r at an early stage. Digestive Diseases, Vol. 22, No. 4 (April 1977)
CANCER IN COLITIS
Fig 4. (a) Cell-block (colowash) fragments of colonic mucosa infiltrated by "signet-ring" carcinoma (x 200); (b) Resected specimen, same patient as in (a) Colonic wall infiltrated by "signet-ring" carcinoma (x200).
Digestive Diseases, Vol. 22, No. 4 (April 1977)
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KATZ ET AL
Fig 5. (a) Cell-block (colowash) fragments of adenocarcinoma (x 200); (b) Resected specimen, same patient as in (a). Rectal wall infiltrated by adenocarcinoma (x50).
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Digestive Diseases, Vol. 22, No. 4 (April 1977)
CANCER IN COLITIS TABLE 1. CANCER AND CHRONIC ULCERATIVE COLITIS*
Patient
X-ray
Endoscopy
Biopsy
Cell block and cytology
1. L . W .
Pelvic mass
-
-
+
2. A . B . 3. W . A .
CUC CUC
-
+ +
+ +
4. W . M c .
CUC
-
0
+
5. C . S .
CUC
-
0
-
6. J . L .
CUC descending c o l o n w i t h stricture
-
-
-
*CUC = Chronic ulcerative colitis, + = positive criteria for malignancy, tained.
Susceptibility The need for closer surveillance of this vulnerable younger population is apparent from the statistical risk of developing cancer (2, 4, 8). The oftquoted rate of cancer developing in 23% of colitic patients by 20 years and 43% by 35 years after the onset of disease approaches the figures for the malignant potential in familial polyposis (8, 10). Children face the greatest threat with a peculiarly higher cancer susceptibility than that quoted above if the onset of the disease is between 5 and 9 years (8). In contrast to established "precancer" criteria, the absence of generalized colitis, the relatively short duration of disease, or the presence of active inflammatory disease is not necessarily a protective feature, as witnessed by the cases reported here and those of Cook and Goligher (9) or Edwards and Truelove (4). Conceivably, a more aggressive diagnostic approach in patient with colitis with less than 10 years of disease, left-colon involvement rather than pancolitis, or continuous active inflammation may be productive in distinguishing carcinomas. A reassessment of the " t r u l y " susceptible populations of ulcerative colitis is clearly indicated.
Pathologic Characteristics The pathologic disguises of carcinoma arising in ulcerative colitis make early detection exceedingly difficult. These cancers may be multicentric (3, 13) or may not be grossly apparent as a tumor mass or ulcerated surface (9, 11). Although they are deDigestive Disc . . . . . Vol. 22, No. 4 (April 1977)
Comment Adenocarcinoma identified on reexploration Adenocarcinoma of sigmoid S i g n e t cell c a r c i n o m a o f sigmoid Positive scalene node of mucinous adenoca Adenocarcinoma of stricture at laparotomy Benign stricture; carcinoma proximal to stricture
= negative criteria for malignancy, 0 = no tissue ob-
scribed to be more frequent in the flat mucosa apparently uninvolved by the polypoid inflammatory process, this has not been a consistent finding. Indeed, the distinction of a mass or stricture due to inflammation or superimposed malignancy can be treacherous (9, 11, 12). The difficulty in delineating active disease from cancer exposes the limitations of x-ray and endoscopic observations. This clearly mandates the need for more precise information such as multiple biopsy technique and cytologic analysis.
Diagnostic Evaluation Endoscopy. The usefulness of the rigid sigmoidoscope in viewing diseased areas of the rectum remains unchallenged. However, the carcinomas in ulcerative colitis may be multiple and are more evenly distributed throughout the bowel, with 25% in the rectal segment compared to distribution of 40% in noncolitic cancers (3, 9), thereby limiting the value of the rigid sigmoidoscope. The increased use of the flexible fiberoptic colonoscopes has permitted access to hitherto endoscopically inaccessible areas of the colon (18). The potential here is great but again prone to the frailties of random biopsy in the face of a grossly distorted inflamed mucosa without macroscopic evidence of tumor. Although not meant as initial screening procedure, flexible colonoscopy (with adequate precautions and specific indication), coupled with a multiple biopsy and cytologic sampling technique, may prove to be of considerable
361
KATZ ET AL value in detecting cancer in chronic ulcerative colitis. Rectal Biopsy. This has been promulgated among the modalities attempting to meet the challenge of an early cancer diagnosis (14-17). Precancerous changes (of epithelial dysplasia) have been described in rectal biopsies of colitic colons heralding or coexisting with cancer elsewhere in the colon, yet this has not been consistently true and at best the experience is still too limited (8, 12, 14, 19, 20). Although epithelial dysplasia does occur in some colitic specimens with cancer, random rectal biopsies were not necessarily productive since the dysplasia is often patchy and, indeed, may spare the rectum as in eight of the colitic cancers of Cook and Goligher's patients (9). Similar rectal epithelial changes may occur in actively inflamed mucosa without evidence of cancer elsewhere in the resected specimen. Clearly then, a negative rectal biopsy offers no protection against the threat of supervening carcinoma. Cytology and Cell Block Experience with exfoliative cytology in ulcerative colitis is limited (21, 22). This is primarily due to the technical difficulties of obtaining an adequate specimen free of debris yet that will not compromise the p a t i e n t ' s clinical condition with multiple purgatives or enemata. A variety of techniques utilizing direct smears or aspirates of visualized lesions, millipore filtration and differential centrifugation, silicone casts of the colon, as well as conventional enemas, attest to the difficulties in securing representative material (14). The burden of nurse-physician reluctance in processing fecal specimens, the additional time expendit u r e r e q u i r e d , and t h e l a c k of t r a i n e d cytotechnologists have deterred all but the most zealous of medical personnel. Nevertheless the yield with colonic cytology and cell block in experienced centers has proven to be highly accurate and definitive (23). Utilizing the techniques described here, this extensive time commitment has been significantly shortened. The use of a closed aspirating lavage system has improved acceptance by medical personnel and has facilitated the handling of specimens. Our initial experience with the pulsatile lavage retrieval system through the standard sigmoidoscope and the flexible endoscope (14) clearly circumvented many of these difficulties and subsequently
362
was extended to survey "premalignant" populations (16, 24). The instrument provides a continual pulsatile lavage averaging 500-1000 cc saline under controlled pressure with a simultaneous suction for collection of aspirated material for standard cytologic Pap smears and cell-block examination. Samplings through the colonoscope may be obtained for focal areas of colonic mucosal aberrancy or stricture (segmental colonic lavage) not lending themselves to adequate coverage by random biopsy. The initial encouraging results in obtaining representative material in the detection of malignant tumors prompted this survey of inflammatory mucosa in which the extensive inflammatory change may mask a malignant neoplasm. Six patients with proven colitic cancers are reported, four with cytology and biopsy diagnoses and two with cell block and cytologic criteria alone as positive evidence for malignancy preoperatively. Of two patients missed by these preoperative techniques, one had hepatic flexure carcinoma and was not colonoscoped. The other had a benign left-colon stricture but tumor was present 10 cm proximal to this partial obstruction. The two nonconclusive studies were obtained at the onset of this study and may well represent initial inexperience with this technique. Additional information provided by this method included evidence for an active inflammatory process with reactive epithelial inflammatory atypia in colonic and rectal stumps thought to be "inactive" on endoscopic criteria alone. Adenomatous hyperplasia was detected by cell block and biopsy material in 3 patients. Smears prepared and stained according to the Papanicolau technique from colonic lavage of patients with ulcerative colitis show a variety of abnormal epithelial cells ranging from hyperplastic to atrophic colonic cells. There is a tendency to exfoliate singly or in small clusters. The presence of inflammatory cells and debris may make accurate assessment of the epithelial changes difficult. The mixture of large numbers polymorphonuclear leukocytes, histiocytes, and eosinophils with atypical epithelial cells, short of clear evidence of malignant criteria, should be viewed as suggestive of active ulcerative colitis. The tumor cells of colonic adenocarcinoma in ulcerative colitis show, in smear preparations, striking similarity to the neoplastic cells of adenocarcinoma of the colon without ulcerative colitis. Accurate cytologic diagnosis can be rendered easily. However, it must be emphasized that technically Digestive Diseases, Vol. 22, No. 4 (April 1977)
C A N C E R IN C O L I T I S
good preparations are mandatory for proper cytologic preparation. Colonic'. cytology techniques have been extended to include thymidine labeling for proliferation kinetic data (24, 26, 27) and cytogenetic studies (28). Conceivably the use of cytologic sampling by lavage, c o u p l e d with c a r c i n o e m b r y o n i c antigen (CEA) levels in the aspirate (29), might enhance the specificity of detection of cancer in this population with a number of significant "false-positive" serum CEA titers (30). Other modalities of study of this aspirate and bioptic material, such as lactic acid dehydrogenase (LDH) (31) or increased concentration of nonsulfated acid mucins in premalignant rectal mucosa (32), are intriguing and must be further evaluated. The clinical value of rectocolonic exfoliative cytology and cell-block technique via segmental larage is apparent by its accuracy and specificity. Its contributiion to the diagnosis of cancer in the highly vulnerable patients with ulcerative colitis is apparent but remains to be fully established by further study. The problem at present is one of overcoming patient and physician reluctance to undertake the preparation and time commitment considered prerequisite for adequate specimen collection. Hopefully the efforts outlined here can alter this attitude and permit an early recognition of cancerous mucosa.
ACKNOWLEDGMENTS The autlhors are grateful to Drs. William Nickel and H e r m a n Steinberg for permitting the study of patients 2 and 6, and to Drs. Paul Sherlock and Sidney W i n a w e r for the study of the 9 Memorial Hospital patients. W e are indebted to Dr. John Seybolt of N e w Y o r k Hospital, Drs. Myron M e l a m e d and S t e v e n H a j d u of Memorial Hospital, for their interpretation of cytopathologic material from their r e s p e c t i v e institutions. The authors are grateful to Mrs. Marion H o r n and Mrs. C e v i a L i p p e r of N o r t h Shore University Hospital for their invaluable technical assistance. This study was supported in part by the National Digestive Disease Foundation.
REFERENCES 1. Rosenquist H, Ohrling H, Lagercrantz R, et al: Ulcerative colitis and carcinoma coll. Lancet 1:906-908, 1959 2. Slaney G, Brooke BN: Cancer in ulcerative colitis. Lancet 2:694-698, 1959 3. Edling NPG, Eklof O: Distribution of malignancy in ulcerative colitis. Gastroenterology 41:465.466, 1961 Digestive Diseases, Vol. 22, No. 4 (April 1977)
4. Edwards FC, Truelove SC: The course and prognosis IV: Carcinoma of the colon. Gut 5:15-22, 1964 5. Goldgraber MG, Kirsner JB: Carcinomaofthe colon in ulcerative colitis. Cancer 17:657-665, 1964 6. MacDougall IPM: The cancer risk in ulcerative colitis. Lancet 2:655-658, 1964 7. de Dombal FT, Watts JM, Watkinson G, et al: Local complications of ulcerative colitis: Stricture, pseudo-polyposis and carcinoma of colon and rectum. Br Med J 1:1442-1445, 1966 8. De Vroede GJ, Taylor WF, Sauer WG, et al: Cancer risk and life expectancy of children with ulcerative colitis. N Engl J Med 285:17-21, 1971 9. Cook MG, Goligher JC: Carcinoma and epithelial dysplasis complicating ulcerating colitis. Gastroenterology 68:11271136, 1975 10. Truelove SC: Ulcerative colitis beginning in childhood. N Engl J Med 285:51-52, 1972 11. Counsell PB, Dukes CE: The association of chronic ulcerative colitis and carcinoma of the rectum and colon. Br J Surg 39:485--495, 1952 12. Goulston SJM, McGovern VJ: The value of rectal biopsies. Med J Aust 1:1234-1238, 1972 13. Hinton JM: Risk of malignant change in ulcerative colitis. Gut 7:427-432, 1966 14. Katz S, Sherlock P, Winawer SJ: Rectcolonic exfoliative cytology: A new approach. Am J Dig Dis 17:110%1116, 1972 15. Katz S, Sherlock P, Winawer SJ: Irrigating device for gastrointestinal cytology. Gastrointest Endoscop 18:184, 1972 16. Katz S, Katzka I, Platt N: Exfoliative cytology in diagnosing cancer in ulcerative colitis. Gastroenterology 66:A-67/721, 1974 17. Morson BP, Pang LSC: Rectal biopsy as an aid to cancer control in ulcerative colitis. Gut 8:423-434, 1967 18. Teague RH, Read AE: Polyposis in ulcerative colitis. Gut 16:792-795, 1975 19. Evans DJ, Pollock DJ: In situ and invasive carcinoma of colon in patient with ulcerative colitis. Gut 13:556-571, 1972 20. Myrvold HE, Kock NG, Ahren CHR: Rectal biopsy and precancer in ulcerative colitis. Gut 15:301-304, 1975 21. Baddington MM, Truelove SC: Abnormal epithelial cells in ulcerative colitis. Br Med J 1:1318-1321, 1956 22. Galambos JT, Massey BW, Klayman MI, et al: Exfoliative cytology in chronic ulcerative colitis. Cancer 9:152-159, 1956 23. Raskin HF, Pletickat S: The cytologic diagnosis of cancer of the colon. Acta Cytol 8:131-138, 1964 24. Deschner EE, Long FC, Katz S: Autoradiographic method for an expanded assessment of colonic cytology. Acta Cytol 17:435.438, 1973 25. Fenoglio CM, Pascal RR: Adenomatous epithelium, intrapithelial anaplasia and invasive carcinoma in ulcerative colitis. Am J Dig Dis 556-562, 1973 26. Bleiberg H, Mainguet P, Galand P, et al: Cell renewal in the human rectum: In vitro autoradiography study on active ulcerative colitis. Gastroenterology 64:383-390, 1973 27. Eastwood GL, Trier JS: Epithelial cell renewal in cultured rectal biopsies in ulcerative colitis. Gastroenterology 64:383-390, 1973 28. Xavier RG, Prolla JC, Bemvenutti GA, et al: Tissue cytogenetic studies in chronic ulcerative colitis and carcinoma of the colon. Cancer 34:684-695, 1975
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KATZ ET AL 29. Winawer SJ, Fleisher M, Melamed M, et al: Cytologic immunological (CEA) and isotope labeling studies based on gastrointestinal endoscopic lavage. Gastroenterology 66:A-146/ 800, 1974 30. Zamchek N: Carcinoembryonic antigen: Quantitative variations in circulating levels in benign and malignant digestive tract diseases. Adv Intern Med 19:413-2133, 1974
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31. Lewis B, Morson BC, Feruary AW, et al: Abnormal lactic dehydrogenase isoenzyme patterns in ulcerative colitis with precancerous change. Gut 12:1679, 1971 32. Filipe IM: Value of a study of the mucosubstances in rectal biopsies from patients with carcinoma of the rectum and lower sigmoid in the diagnosis of premalignant mucosa. J Clin Pathol 25:123-128, 1972
Digestive Diseases, Vol. 22, No. 4 (April 1977)
Saline colonic lavage in 74 patients with chronic ulcerative colitis was performed utilizing a commercially available dental irrigating unit through a polyethylene catheter in the biopsy channel of a colonoscope or through a sigmoidoscope via a lavage-aspirating double-lumen probe. Six patients were found with colonic carcinoma. Two diagnoses of malignancy were established by cytologic smears and cell block alone. Two patients had positive mucosal biopsies and cell block. One patient with a hepatic flexure carcinoma and a second patient with a malignancy proximal to a left colon stricture were missed by these techniques. Considering the established proclivityfor carcinoma in these patients, it is felt that segmental lavage in areas o f stricture, grossly distorted mucosa, or endoscopically inaccessible areas represents a valuable adjunct in the diagnosis of carcinoma in chronic ulcerative colitis.
It is well ,established that patients with ulcerative colitis have an increased risk of developing colon cancer (1-13). This is believed particularly true for that patient population in which the following criteria are met: (1) involvement of entire colon, (2) long duration of disease, usually greater than 10 years, (3) onset in childhood or adolescence, and (4) a severe initial attack with a subsequent chronic continuous course of active disease (10). Early detection of carcinoma is difficult to recognize radiographically or endoscopically in face of widespread inflammatory disease (11-13). Further complicating factors include the failure of patient's history or clinical examination to reveal the tumor until it is extensive and, all too frequently, unresectable. Experience to date in cancer detection in this highly s u s c e p t i b l e p o p u l a t i o n has b e e n dismal (1, 2). Indeed it has been poor enough for some to advise prophylactic proctocolectomy in the young patient meeting the criteria described (8). From the Departments of Medicine and Pathology, Long Island Jewish-Hillside Medical Center, New Hyde Park, New York, and the Departments of Medicine and Pathology, North Shore University Hospital, Manhasset, New York and Departments of Medicine and Pathology, Cornell University Medical College, New York City, New York. Address for reprint requests: Dr. Seymour Katz, 1300 Union Turnpike, New Hyde Park, New York 11040. Digestive Diseases, Vol. 22, No. 4 (April 1977)
Our experience with recent technological advances in obtaining cytopathologic material has stimulated a more aggressive approach utilizing rectocolonic cytology via sigmoidoscopes, flexible fiberoptic colonoscopes, and a multiple biopsy technique, in addition to the conventional endoscopicradiographic evaluation (14-16). The purpose of this report is to summarize our initial experience with segmental colonic lavage in retrieving diagnostic material as an adjunct in cancer detection in chronic ulcerative colitis in hopes of facilitating an " e a r l y " diagnosis in future cases. MATERIALS AND METHODS
The technique for obtaining cytopathologic material through a rigid sigmoidoscope utilizing a pulsatile saline lavage and simultaneous suction has been previously described (14). The same principle has been adapted to flexible fiberoptic endoscopes (15) when indicated for further clarification of x-ray appearance of stricture or suspected tumor mass. Segmental colonic lavage was performed, particularly in areas of stricture and mucosal irregularity, or if colonoscopic biopsy was not technically feasible (16). Over the past six years, 74 patients with documented chronic ulcerative colitis with generalized or leftcolon involvement were studied. There were 34 males and 40 females, with mean ages of 48 and 42, respectively. The mean duration of disease was 11 years. These in-
355
K A T Z ET A L
Fig 1. Colonscope with dental irrigating unit attached to polythylene catheter.
cluded 8 patients from New York Hospital, 9 patients from Memorial Hospital, and the remaining from Long Island Jewish-Hillside and North Shore University Hospitals. Approximately 500-1000 cc saline was introduced as a pulsafile lavage through a polyethylene catheter powered by a commercially available dental irrigating unit in the biopsy channel of the colonoscope (Figure 1). Fluid was retrieved simultaneously in a suction trap containing equal volumes of 95% alcohol. The aspirate was centrifuged at 2500 rpm for 15 rain. Papanicolau smears were obtained from the sediment and the remaining material was processed according to cell-block technique and examined in tissue sections. Rectocolonic biopsies were obtained, when possible, via rigid and flexible endoscopes and examined according to the criteria of Morson and Pang (17). Six patients were found to have cancer of the colon. All but one of the six underwent laparotomy, and there are two survivors at the time of this report. Case 1. L.W., a 34-year-old housewife with 15 years of generalized colitis, presented with a pelvic mass unresponsive to trial of corticosteroid or antibiotic therapy.
356
Biopsies obtained at laparotomy revealed chronic inflammatory tissue. Postoperatively, cytologic studies revealed adenocarcinoma which was confirmed at reexploration of the abdomen (Figure 2). Case 2. Wm.McC., a 22-year-old male student with 12 year history of ulcerative colitis, was admitted for evaluation of jaundice, weight loss, and persistent diarrhea. A liver biopsy was compatible with viral hepatitis. Rectocolonic cytology was interpreted as positive for malignancy (Figure 3). A biopsy of a palpable scalene node revealed mucin-producing adenocarcinoma. Subsequently, a barium enema examination demonstrated an irregular area of the hepatic flexure suggestive of carcinoma. Surgery as well as a subsequent postmortem examination was refused. Case 3. Wm.A., a 29-year-old white man with 10 years of chronic ulcerative colitis, presented with progression of fever, anemia, hypoalbuminemia, and weight loss. Sigmoidoscopy revealed a rectal stricture with biopsy and cytology evidence of infiltrating "signet cell" carcinoma (Figure 4). Case 4. A.B., a 68-year-old housewife with a 2-year history of active ulcerative colitis limited to left colon, develDigestive Diseases, VoL 22, No. 4 (April 1977)
C A N C E R IN C O L I T I S
Fig 2. (a) Cell-block (colowash) fragments of adenocarcinoma (• patient as in (a). Colonic wall infiltrated by adenocarcinoma (x50).
Digestive Diseases, Vol. 22, No. 4 (April 1977)
(b) Resected specimen, same
357
KATZ ET AL
Fig 3. Cytologic smear (colowash); cluster of malignant cells (• 1000).
oped fever and bloody diarrhea unresponsive to increased dosage of corticosteroid. Biopsy and cytology of rectal polypoid tissue demonstrated adenocarcinoma (Figure 5). Case 5. C.S., a 49-year-old housewife with 19 years of chronic ulcerative colitis with strictured colon and arthritis, developed progressive unrelenting diarrhea. Cytologic studies were negative. Laparotomy revealed a marked colonic stricture with carcinoma in the hepatic flexure. Cytologic studies were negative. Laparotomy revealed a marked colonic stricture with carcinoma in the hepatic flexure. Case 6. T.L., a 56-year-old woman with 38 years of chronic ulcerative colitis, developed a sigmoid colon stricture. Cytologic washings and biopsy were negative. Laparotomy was identified 8 cm proximal to the stricture. Nine patients had mucosal biopsies compatible with the diagnosis of "precancer" as described by Morson and Pang (17). Of the 6 patients with proven cancer, 3 had precancerous mucosal biopsies elsewhere in the resected specimen but only one of these three had such changes on rectal biopsy.
358
Rectal biopsies of 6 patients revealed adenomatous hyperplasia. Two of these subsequently underwent laparotomy for progression of symptoms unresponsive to medical therapy. No carcinoma was identified in these resected specimens. The remaining 4 patients are under close scrutiny with semiannual observation.
RESULTS AND DISCUSSION The difficulty in detecting carcinoma in chronic ulcerative colitis stems f r o m m a n y factors: (1) the inability to accurately identify the time when the chronic ulcerative colitis patient m a y develop colon cancer, (2) the failure of the patient's history or clinical e x a m to reveal t u m o r until it is widespread and frequently unresectable, (3) the m a n y disguises of the t u m o r often mimicking the inflammatory process itself, and (4) the limited diagnostic techniques in detecting t u m o r at an early stage. Digestive Diseases, Vol. 22, No. 4 (April 1977)
CANCER IN COLITIS
Fig 4. (a) Cell-block (colowash) fragments of colonic mucosa infiltrated by "signet-ring" carcinoma (x 200); (b) Resected specimen, same patient as in (a) Colonic wall infiltrated by "signet-ring" carcinoma (x200).
Digestive Diseases, Vol. 22, No. 4 (April 1977)
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KATZ ET AL
Fig 5. (a) Cell-block (colowash) fragments of adenocarcinoma (x 200); (b) Resected specimen, same patient as in (a). Rectal wall infiltrated by adenocarcinoma (x50).
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Digestive Diseases, Vol. 22, No. 4 (April 1977)
CANCER IN COLITIS TABLE 1. CANCER AND CHRONIC ULCERATIVE COLITIS*
Patient
X-ray
Endoscopy
Biopsy
Cell block and cytology
1. L . W .
Pelvic mass
-
-
+
2. A . B . 3. W . A .
CUC CUC
-
+ +
+ +
4. W . M c .
CUC
-
0
+
5. C . S .
CUC
-
0
-
6. J . L .
CUC descending c o l o n w i t h stricture
-
-
-
*CUC = Chronic ulcerative colitis, + = positive criteria for malignancy, tained.
Susceptibility The need for closer surveillance of this vulnerable younger population is apparent from the statistical risk of developing cancer (2, 4, 8). The oftquoted rate of cancer developing in 23% of colitic patients by 20 years and 43% by 35 years after the onset of disease approaches the figures for the malignant potential in familial polyposis (8, 10). Children face the greatest threat with a peculiarly higher cancer susceptibility than that quoted above if the onset of the disease is between 5 and 9 years (8). In contrast to established "precancer" criteria, the absence of generalized colitis, the relatively short duration of disease, or the presence of active inflammatory disease is not necessarily a protective feature, as witnessed by the cases reported here and those of Cook and Goligher (9) or Edwards and Truelove (4). Conceivably, a more aggressive diagnostic approach in patient with colitis with less than 10 years of disease, left-colon involvement rather than pancolitis, or continuous active inflammation may be productive in distinguishing carcinomas. A reassessment of the " t r u l y " susceptible populations of ulcerative colitis is clearly indicated.
Pathologic Characteristics The pathologic disguises of carcinoma arising in ulcerative colitis make early detection exceedingly difficult. These cancers may be multicentric (3, 13) or may not be grossly apparent as a tumor mass or ulcerated surface (9, 11). Although they are deDigestive Disc . . . . . Vol. 22, No. 4 (April 1977)
Comment Adenocarcinoma identified on reexploration Adenocarcinoma of sigmoid S i g n e t cell c a r c i n o m a o f sigmoid Positive scalene node of mucinous adenoca Adenocarcinoma of stricture at laparotomy Benign stricture; carcinoma proximal to stricture
= negative criteria for malignancy, 0 = no tissue ob-
scribed to be more frequent in the flat mucosa apparently uninvolved by the polypoid inflammatory process, this has not been a consistent finding. Indeed, the distinction of a mass or stricture due to inflammation or superimposed malignancy can be treacherous (9, 11, 12). The difficulty in delineating active disease from cancer exposes the limitations of x-ray and endoscopic observations. This clearly mandates the need for more precise information such as multiple biopsy technique and cytologic analysis.
Diagnostic Evaluation Endoscopy. The usefulness of the rigid sigmoidoscope in viewing diseased areas of the rectum remains unchallenged. However, the carcinomas in ulcerative colitis may be multiple and are more evenly distributed throughout the bowel, with 25% in the rectal segment compared to distribution of 40% in noncolitic cancers (3, 9), thereby limiting the value of the rigid sigmoidoscope. The increased use of the flexible fiberoptic colonoscopes has permitted access to hitherto endoscopically inaccessible areas of the colon (18). The potential here is great but again prone to the frailties of random biopsy in the face of a grossly distorted inflamed mucosa without macroscopic evidence of tumor. Although not meant as initial screening procedure, flexible colonoscopy (with adequate precautions and specific indication), coupled with a multiple biopsy and cytologic sampling technique, may prove to be of considerable
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KATZ ET AL value in detecting cancer in chronic ulcerative colitis. Rectal Biopsy. This has been promulgated among the modalities attempting to meet the challenge of an early cancer diagnosis (14-17). Precancerous changes (of epithelial dysplasia) have been described in rectal biopsies of colitic colons heralding or coexisting with cancer elsewhere in the colon, yet this has not been consistently true and at best the experience is still too limited (8, 12, 14, 19, 20). Although epithelial dysplasia does occur in some colitic specimens with cancer, random rectal biopsies were not necessarily productive since the dysplasia is often patchy and, indeed, may spare the rectum as in eight of the colitic cancers of Cook and Goligher's patients (9). Similar rectal epithelial changes may occur in actively inflamed mucosa without evidence of cancer elsewhere in the resected specimen. Clearly then, a negative rectal biopsy offers no protection against the threat of supervening carcinoma. Cytology and Cell Block Experience with exfoliative cytology in ulcerative colitis is limited (21, 22). This is primarily due to the technical difficulties of obtaining an adequate specimen free of debris yet that will not compromise the p a t i e n t ' s clinical condition with multiple purgatives or enemata. A variety of techniques utilizing direct smears or aspirates of visualized lesions, millipore filtration and differential centrifugation, silicone casts of the colon, as well as conventional enemas, attest to the difficulties in securing representative material (14). The burden of nurse-physician reluctance in processing fecal specimens, the additional time expendit u r e r e q u i r e d , and t h e l a c k of t r a i n e d cytotechnologists have deterred all but the most zealous of medical personnel. Nevertheless the yield with colonic cytology and cell block in experienced centers has proven to be highly accurate and definitive (23). Utilizing the techniques described here, this extensive time commitment has been significantly shortened. The use of a closed aspirating lavage system has improved acceptance by medical personnel and has facilitated the handling of specimens. Our initial experience with the pulsatile lavage retrieval system through the standard sigmoidoscope and the flexible endoscope (14) clearly circumvented many of these difficulties and subsequently
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was extended to survey "premalignant" populations (16, 24). The instrument provides a continual pulsatile lavage averaging 500-1000 cc saline under controlled pressure with a simultaneous suction for collection of aspirated material for standard cytologic Pap smears and cell-block examination. Samplings through the colonoscope may be obtained for focal areas of colonic mucosal aberrancy or stricture (segmental colonic lavage) not lending themselves to adequate coverage by random biopsy. The initial encouraging results in obtaining representative material in the detection of malignant tumors prompted this survey of inflammatory mucosa in which the extensive inflammatory change may mask a malignant neoplasm. Six patients with proven colitic cancers are reported, four with cytology and biopsy diagnoses and two with cell block and cytologic criteria alone as positive evidence for malignancy preoperatively. Of two patients missed by these preoperative techniques, one had hepatic flexure carcinoma and was not colonoscoped. The other had a benign left-colon stricture but tumor was present 10 cm proximal to this partial obstruction. The two nonconclusive studies were obtained at the onset of this study and may well represent initial inexperience with this technique. Additional information provided by this method included evidence for an active inflammatory process with reactive epithelial inflammatory atypia in colonic and rectal stumps thought to be "inactive" on endoscopic criteria alone. Adenomatous hyperplasia was detected by cell block and biopsy material in 3 patients. Smears prepared and stained according to the Papanicolau technique from colonic lavage of patients with ulcerative colitis show a variety of abnormal epithelial cells ranging from hyperplastic to atrophic colonic cells. There is a tendency to exfoliate singly or in small clusters. The presence of inflammatory cells and debris may make accurate assessment of the epithelial changes difficult. The mixture of large numbers polymorphonuclear leukocytes, histiocytes, and eosinophils with atypical epithelial cells, short of clear evidence of malignant criteria, should be viewed as suggestive of active ulcerative colitis. The tumor cells of colonic adenocarcinoma in ulcerative colitis show, in smear preparations, striking similarity to the neoplastic cells of adenocarcinoma of the colon without ulcerative colitis. Accurate cytologic diagnosis can be rendered easily. However, it must be emphasized that technically Digestive Diseases, Vol. 22, No. 4 (April 1977)
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good preparations are mandatory for proper cytologic preparation. Colonic'. cytology techniques have been extended to include thymidine labeling for proliferation kinetic data (24, 26, 27) and cytogenetic studies (28). Conceivably the use of cytologic sampling by lavage, c o u p l e d with c a r c i n o e m b r y o n i c antigen (CEA) levels in the aspirate (29), might enhance the specificity of detection of cancer in this population with a number of significant "false-positive" serum CEA titers (30). Other modalities of study of this aspirate and bioptic material, such as lactic acid dehydrogenase (LDH) (31) or increased concentration of nonsulfated acid mucins in premalignant rectal mucosa (32), are intriguing and must be further evaluated. The clinical value of rectocolonic exfoliative cytology and cell-block technique via segmental larage is apparent by its accuracy and specificity. Its contributiion to the diagnosis of cancer in the highly vulnerable patients with ulcerative colitis is apparent but remains to be fully established by further study. The problem at present is one of overcoming patient and physician reluctance to undertake the preparation and time commitment considered prerequisite for adequate specimen collection. Hopefully the efforts outlined here can alter this attitude and permit an early recognition of cancerous mucosa.
ACKNOWLEDGMENTS The autlhors are grateful to Drs. William Nickel and H e r m a n Steinberg for permitting the study of patients 2 and 6, and to Drs. Paul Sherlock and Sidney W i n a w e r for the study of the 9 Memorial Hospital patients. W e are indebted to Dr. John Seybolt of N e w Y o r k Hospital, Drs. Myron M e l a m e d and S t e v e n H a j d u of Memorial Hospital, for their interpretation of cytopathologic material from their r e s p e c t i v e institutions. The authors are grateful to Mrs. Marion H o r n and Mrs. C e v i a L i p p e r of N o r t h Shore University Hospital for their invaluable technical assistance. This study was supported in part by the National Digestive Disease Foundation.
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4. Edwards FC, Truelove SC: The course and prognosis IV: Carcinoma of the colon. Gut 5:15-22, 1964 5. Goldgraber MG, Kirsner JB: Carcinomaofthe colon in ulcerative colitis. Cancer 17:657-665, 1964 6. MacDougall IPM: The cancer risk in ulcerative colitis. Lancet 2:655-658, 1964 7. de Dombal FT, Watts JM, Watkinson G, et al: Local complications of ulcerative colitis: Stricture, pseudo-polyposis and carcinoma of colon and rectum. Br Med J 1:1442-1445, 1966 8. De Vroede GJ, Taylor WF, Sauer WG, et al: Cancer risk and life expectancy of children with ulcerative colitis. N Engl J Med 285:17-21, 1971 9. Cook MG, Goligher JC: Carcinoma and epithelial dysplasis complicating ulcerating colitis. Gastroenterology 68:11271136, 1975 10. Truelove SC: Ulcerative colitis beginning in childhood. N Engl J Med 285:51-52, 1972 11. Counsell PB, Dukes CE: The association of chronic ulcerative colitis and carcinoma of the rectum and colon. Br J Surg 39:485--495, 1952 12. Goulston SJM, McGovern VJ: The value of rectal biopsies. Med J Aust 1:1234-1238, 1972 13. Hinton JM: Risk of malignant change in ulcerative colitis. Gut 7:427-432, 1966 14. Katz S, Sherlock P, Winawer SJ: Rectcolonic exfoliative cytology: A new approach. Am J Dig Dis 17:110%1116, 1972 15. Katz S, Sherlock P, Winawer SJ: Irrigating device for gastrointestinal cytology. Gastrointest Endoscop 18:184, 1972 16. Katz S, Katzka I, Platt N: Exfoliative cytology in diagnosing cancer in ulcerative colitis. Gastroenterology 66:A-67/721, 1974 17. Morson BP, Pang LSC: Rectal biopsy as an aid to cancer control in ulcerative colitis. Gut 8:423-434, 1967 18. Teague RH, Read AE: Polyposis in ulcerative colitis. Gut 16:792-795, 1975 19. Evans DJ, Pollock DJ: In situ and invasive carcinoma of colon in patient with ulcerative colitis. Gut 13:556-571, 1972 20. Myrvold HE, Kock NG, Ahren CHR: Rectal biopsy and precancer in ulcerative colitis. Gut 15:301-304, 1975 21. Baddington MM, Truelove SC: Abnormal epithelial cells in ulcerative colitis. Br Med J 1:1318-1321, 1956 22. Galambos JT, Massey BW, Klayman MI, et al: Exfoliative cytology in chronic ulcerative colitis. Cancer 9:152-159, 1956 23. Raskin HF, Pletickat S: The cytologic diagnosis of cancer of the colon. Acta Cytol 8:131-138, 1964 24. Deschner EE, Long FC, Katz S: Autoradiographic method for an expanded assessment of colonic cytology. Acta Cytol 17:435.438, 1973 25. Fenoglio CM, Pascal RR: Adenomatous epithelium, intrapithelial anaplasia and invasive carcinoma in ulcerative colitis. Am J Dig Dis 556-562, 1973 26. Bleiberg H, Mainguet P, Galand P, et al: Cell renewal in the human rectum: In vitro autoradiography study on active ulcerative colitis. Gastroenterology 64:383-390, 1973 27. Eastwood GL, Trier JS: Epithelial cell renewal in cultured rectal biopsies in ulcerative colitis. Gastroenterology 64:383-390, 1973 28. Xavier RG, Prolla JC, Bemvenutti GA, et al: Tissue cytogenetic studies in chronic ulcerative colitis and carcinoma of the colon. Cancer 34:684-695, 1975
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KATZ ET AL 29. Winawer SJ, Fleisher M, Melamed M, et al: Cytologic immunological (CEA) and isotope labeling studies based on gastrointestinal endoscopic lavage. Gastroenterology 66:A-146/ 800, 1974 30. Zamchek N: Carcinoembryonic antigen: Quantitative variations in circulating levels in benign and malignant digestive tract diseases. Adv Intern Med 19:413-2133, 1974
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31. Lewis B, Morson BC, Feruary AW, et al: Abnormal lactic dehydrogenase isoenzyme patterns in ulcerative colitis with precancerous change. Gut 12:1679, 1971 32. Filipe IM: Value of a study of the mucosubstances in rectal biopsies from patients with carcinoma of the rectum and lower sigmoid in the diagnosis of premalignant mucosa. J Clin Pathol 25:123-128, 1972
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