April 1995 Biliary Disorders A409

ADENOMYOMATOSIS OF THE GALLBLADDER IS NOT A HIGH RISK LESION FOR GALLBLADDER CARCINOMA. F Cetta, F Lombardo, C Baldi, M Giubbolini, M Cintorino, S Tripod/, *A Cariati. Inst. o f Surg. Clinics and Pathology, Univ. of Siena; * Surg. Clin. Univ. Genoa, ltaly. Many sporadic observations have been reported concerning the association between adenomyomatosis (ADM) of the gallbladder (GB) and gallbladder carcinoma (GBC). In addition, a recent analysis o f 3197 consecutive cholccystectomies (1) suggests a significantly higher prevalence of GBC in patients with a specific subtype of ADM, the so called "segmental ADM" (6.4%, i.e. 12 of 198 vs 3.1, i.e. 93 o f the other 3009) than in patients without Saglnental ADM. In particular, GBC developed in the mucosa of the fandal compartment distal to the anular stricture of segmental ADM in all cases. During the prospective study of 1590 consecutive patients with bile tract disease, who had systematic stone and bile analysis and histologic examination of the resected specimens, 1421 consecutive GB specimens were exmnined. ADM, i.e., an increase in nmnber and size of Rokitansky-Aschoff (RA) sinuses, was found in 285 patients (20.1%). 280 of ADM patients had gallstones (GS), which were black (alone or in association with other GS) in 128 cases (45%). In the same series 47 patients had GBC. In one case GBC was found in the fimdus distal to an anular stricture, in association with cholesterol GS. 44 patients with GBC had cholesterol or combination GS (usually larger than 1.5cm), 1 had black GS, while the last 2 patients had no GS. In the entire series 193 patients were found who had black GS: 187 as unique stones, 56 in association with other types of GS. Black GS were usually smaller than 31urn and frequently found not only in the GB lumen, but also in the RA sinuses. Intrapanctal black GS were usually detected by the so called "comet-tail" artifact and were frequently responsible for symptoms (2), even in the absence o f evident stones in the GB lumen on ultrasound exatnination. Therefore, black GS accounted for 13.6% of all GS, but only for 1.5% of GS in patients with GBC. In particular, only one of 193 patients with black GS (and of the 128 patients with black GS plus ADM), had GBC, vs. 44 of the 1120 patients with cholesterol, combination or mixed GS (p<0.05). On the basis o f the present data, we suggest that ADM (maybe except the so called "segmental" subtype, which deserves further evaluation) cannot be considered a high risk lesion for GBC. In fact, it is a frequent finding in non malignant gallbladder alterations and is fi'equently associated with a condition, the concomitance of black microstones, that is very infrequently associated with GBC. In conclusion, in patients with ADM, cholecystectomy is indicated because of the high risk of biliary symptoms, jaundice and/or pancteatitis, due to black microstones, not because o f the high risk of subsequent GBC, which in our study resulted very low. (1) T Ootani ct al. Cancer 1992; 69: 2647-2652. (2) F Cetta et al. Gastroemerology 1992; 102: A307.

AGE IS A MAJOR RISK FACTOR SPECIFIC FOR BROWN, BUT NOT FOR BLACK OR CHOLESTEROL GALLSTONES. F Cettaj F Lombardo, M Giubboltni, C Baldi, A CappellL Institute of Surg. Clinics, Univ. of Siena, ITALY. Prevalence of gallstones (GS) increases with age. We have recently snggested to consider GS not as a single entity, but as a heterogeneous disease (1). In the present study we try to assess the importance of age in the various diseases, separately. 1590 consecutive patients, who undcl'went surgery for bile tract diseases in a siugle center, had sistamatic GS and bile analysis. Age o f patients at surgery, but also presumed age of patients at initial presentation of GS were recorded. 1421 patients with GS were found. GS were cholesterol or mixed in 823 patients (57.9%, mean age 57.9, range I 1-90), black pigment in 137 (9.6%, mean age 67.4, range 6-90), brown (BS) in 98 (6.7%, mean age 73.7, range 50-92) and combination or composite in 263 (18.5%). Age difference among patients with brown and black or cholesterol resulted significant (p<0.001). In addition, the various types of GS were analyzed for decades, both at the time of GS removal and at thne of initial GS presentation. Four groups o f patients were found, according to age: before 30; 30- 5 0 , 50-70; over 70. While cholesterol GS were found mainly in the 3rd to 7th decades, BS were always found after the 5th decade. Black GS showed 2 different peaks, one after the 5th decade and another in the group of patients younger than 30 (due mainly to hemolysis and typically associated with adenomyomatosis o f the gallbladder in the 3rd decade). It is suggested that age is a non specific risk factor for all GS, but is a specific risk factor only for BS. In fact, the risk that a patient before age 50 develop BS is actually nul, while all subjects with BS were always older than 50, in patients with previous sphincterotomy or biliary enteric anastomosis, or than 72 in patients with no previous bitiary sm'gery. Obviously, either cholesterol or black GS can form in patients older than 70. The following hypothesis is suggested: in the pathogenesis o f black and cholesterol GS age could influence mainly parietal factors (the increase in size and depth of R.A. sinuses is an age dependent phenomenon), so facilitating local stasis in multiple microenviromnents and the occurrence of multiple GS. In fact, no single GS was found with documented onset after age of 60 years. In the pathogenesis o f BS age is essential to the basic "infectious" mechanism o f G S fonnation (2). In fact, old age, previous sphincterotomy and bile infection by E. colt were the 3 factors almost always associated with BS formation in a recent longitudinal study of cholecystectomized patients (3). The linkage between age and infection may be multiple: reduced gastric pH, increased colonization o f the duodenum by E. colt, reduced immunologic defence, reduced cleary capacity of the bile ducts, etc.. Ans, avay, in old patients with BS, no GS other than bray, in can reform in the future. (1) F. Cetta et al Gastroenterology 1993; 104: A356. (2) F. Cotta Ann Surg 1991; 213: 315-326. (3) F. Cetta Gastroenterology 1992; 102: A791.

CHOLESTEROL STONE RECURRENCE IN THE CYSTIC REMNANT AFTER LAPAROSCOP1C CHOLECYSTECTOMY. THE FIRST CASE REPORT DURING A FOLLOW-UP STUDY OF PATIENTS WITH OR WITHOUT POSTOPERATIVE BILE ACID THERAPY. F Cetta, F Lombardo, M Giubbotini, C Baldi, *F Garotta. lnsatute of Surg. CltnWs, University of Siena: *Farmitalta, Milan, Italy. Cholesterol stones usually do not reform primarily in the common duct after cholecystectomy, unless foreign uneleating agents (suture material, metallic clip) facilitate their formation (1). However, they can form entirely after cholecyste~tomy, even i f not primarily in the corrmaon duct, in a long cystic remnant (LCR) acting as a mini-gallbladder. This evenienee, even i f uncommmon, accounted for 17% o f all postcholecystectomy RCS (11 o f 63) in a recent prospective study (1). After the wide diffusion of laparoscopic cholecystectomy (LC), which deliberately leaves a long cystic stump, it i s presumed that also the number o f postcholecystectomy stones related to LCR is going to inorease in the long-term period. Since these stones are mostly cholesterol, possible prophylaxis using bile acid therapy could be indicated in selected cases. Therefore a trial with bile acid therapy was undertaken as a part o f a larger follow-up study on patients with previous LC. Seventy patients with a cystic stump larger than 15 m m after LC were enrolled. Patients with a presumed residual LCR were selected among those showing a particularly long and tortuous cystic duct at i.v. cholangiography. In 7 of th¢a'n the cystic duet also had a very low confluence, close to the ampulla o f Vater. Thirty- five patients were treated by tauroursodeoxychotie acid (7 mg/kg/die) to prevent cholesterol stone reformation in the LCR. The remaining 35 patients didn't receive any treamaent and were used as control group. Ultrasound exaxniunfion was scheduled every year and i.v. cholangloglaphy every 3 years. After a mean follow-up o f 18 months (maximum 40 months) one patient, belonging to the control group, was found with a single cholesterol stone in the common duct, which likely had formed prirnarily in the cystic duct. She was a 56-year-old woman, who underwent LC 36 months before. The stone, 8-ram-large, entirely cholesterol and resembling in shape the lumen of the common duet, was removed by endoscopic sphincterotomy. At previous LC, the patient had 2 large ovoidal cholesterol stones in the absence o f additional small stones. 1.v. cholanglography performed at the choleeystectomy time had also excluded the presence of a small stone that could have missed in the common duct or in the cystic remnant at first operation. In our knowledge, this is the first report o f a cholesterol stone likely reformed de nova initially in the cystic duct and them migrated into the common duct after LC, documenting that this event, already observed in patients with open cholecystuctomy (2), also occurs after laparoscopic cholecystectomy. (1) F Cetta: Arch Surg 1993;128:329-336 (2) F Cetta et AI.: Gastroenterology 1993; 104: A355.

GALLSTONES AS MARKERS OF LIFE STYLE AND DIETARY HABITS. POSSIBLE USE IN EPIDEMIOLOGIC STUDIES OF CARCINOMAS OF THE ALIMENTARY TRACT F Cetta, F Lombardo, M Giubbolmi, C Baldi. Institute of Surgical Climes, University of Siena, Italy. Gallstones (GS) have usually been considered as a unique entity. Bile tract malignancies and other cancers of the digestive tract (pancreas, colon, etc.) also have been considered as a unique entity. Carcinomas of the alimentary trace have previously been related to dietary habits. Carcinomas of the gallbladder (GBC) or of the colon (CRC) have often been related to GS During the prospective study of 1590 consecutive patients who underwent surgery for bile tract diseases all patients with GS had systematic stone and bile analysis. In the same period (1979-94) the following patients with gastrointestinal carcinomas have been obse~'ed. All of" them underwent surgery or bad at least histotogic confirmation of the cancer histotype and had classification and analysis of the associated GS (i). A total of 1421 patients with GS were found. Stones were cholesterol or mixed (CB) in 823 (57.9%), black pigment in 137 (9.6%), brown pigment in 98 (6.7%) and combination or composite stones in 263 cases (18.5%). All patients filled-up a questionnaire on dietary habits and life style. Large CH GS resulted closely associated with factors as obesity, multiple pregnancies, high fat low fiber diet and with GBC and right side CRC (p<0.001) (1). Pigment GS were associated with other risk factors and were proportionally more frequent in patients with periampullary, pancreas or liver cancer. The latter had a very low rate (4.6 to 6.3%) of associated CH GS. SITE OF CANCER N M F GS CH BLACK BROWN gallbladder 47 9 38 44 (93.6%) 42 (89.4%) 2

2t 12 9 5 (23.8%) 3 (143%) 1 1 35 16 19 g (22.8%) 2 (5.7%) 2 4 63 24 39 13 (20:6%) 4 (6.3%) 3 6

liver 65 39 26 9 (13.8%) 3 (4.6%/ 6 stomach 318 191 117 47(14.7%) 35(11%) 13 2 rightcolon 40 22 18 21 (52.5*/o) 21 (52.5%) le,[tcolon&rectum 302 t87 115 27(8.9%) 23(7.6*,/0) 2 2

Comment: Gallstones are not a unique entity, but a heterogeneous disease (2). Bile tract cancers (or colon carcinomas) also are different diseases, which are differently associated with the various types of GS. Risk factors for CH GS are different from those ~"ilitating the occurrence of periampullary carcinoma or cancer of the liver, pancreas and left colon. In addition, it is suggested: (i) to avoid to relate GS as a unique entity to bile tract or colon carcinoma, each one considered as a unique entity, since cancers of the various sites have different pathogenetic faceors and perhaps also a different biologic behaviour; (it) to consider GS, in particular CH GS, as a highly specific biologic marker, which is able to give useful informatiens on dietary habits, genetic or familiar predisposition and life style of patients. In epidemiologic studies of carcinomas of the alimentary tract it can be used in addition to, or even instead of, dietary questionnaires, which give qualitative informations` difficult to quantitate, with poor data on dietary habits of patients in previous decades, when the initial carcinoget~etic alteration firstly occurred. F Cettaet at.: Gastroenterolog), (1) 1993; 104:A356 (2) 1993; 104: A354.

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