Elevated CA 19-9 levels in a patient with Mirizzi syndrome: case report.

Abstract: CA 19-9 is a marker of malignancy of the pancreas and biliary tract. We report the case of a patient who had significantly elevated serum CA 19-9 levels and imaging studies suggestive of malignancy. On laparotomy, the patient was found to have Mirizzi syndrome, an uncommon cause of biliary obstruction from an impacted gallstone. This case illustrates that elevated serum CA 19-9 levels must be interpreted cautiously in cases of biliary obstruction.

Key Words: Mirizzi syndrome, CA 19-9, choledocholithiasis, cholangiocarcinoma

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This report describes the case of a 63-year-old man suspected to have cholangiocarcinoma or gallbladder cancer because of a high serum CA 19-9 level and MRI and CT scans indicating malignancy. The patient was found to have Mirizzi syndrome, an unusual cause of obstructive jaundice. Mirizzi syndrome and causes of an elevated serum concentration of CA 19-9 level are discussed.

Case Report

A 63-year-old Peruvian man presented to the emergency department with a chief complaint of episodes of weakness, chills and night sweats of 4 days' duration. The episodes lasted 30 minutes to 1 hour and were associated with a burning sensation radiating from the epigastrium to the right upper quadrant and a metallic taste. The patient also reported light colored stools and dark urine. He denied fever, nausea, vomiting, or pruritus. His past medical history was significant for diabetes mellitus diagnosed two weeks earlier. He denied any history of liver or gastrointestinal problems. On physical examination the patient was afebrile, with a blood pressure of 117/75, pulse of 80, and a respiratory rate of 16. The patient was icteric, with mild right upper quadrant and epigastric tenderness. His liver was normal in size and no Murphy sign was present. The cardiac and lung examinations were unremarkable.

The serum liver profile showed an alkaline phosphatase of 1,282 IU/L and a total bilirubin of 3.2 mg/dL. The serum AST and ALT were 93 and 162 mg/dL, respectively. His white blood cell count was 23.500 UL with a predominance of neutrophils and his nonfasting glucose was 554 mg/dL. An abdominal ultrasound showed gallstones and intrahepatic biliary dilation consistent with hepatobiliary obstruction and findings suggestive of hepatic steatosis. The surgical service was consulted and the patient was admitted with a provisional diagnosis of choledocholithiasis and was started on antibiotics.

A MRCP (Fig. 1) revealed a thickened and irregularly enhancing gallbladder wall suggestive of gallbladder carcinoma and intrahepatic biliary dilation, interpreted as secondary to extension of possible tumor into the porta hepatis. A CT of the abdomen with contrast obtained on the day 4 of hospitalization (Fig. 2) revealed findings consistent with cholangiocarcinoma versus gallbladder cancer with biliary duct dilation and likely obstruction at the level of the cystic duct with a reported less-than-one centimeter lymph node adjacent to the pancreatic head.

Endoscopic retrograde cholangiopancreatography was attempted, but the common bile duct could not becannulated. A serum CA 19-9 level was 5,128 U/mL (normal 0-37 U/mL). A CT-guided needle biopsy of the liver yielded normal hepatic parenchyma, and a needle aspiration of the biliary fluid was negative for malignant cells. Because of the high suspicion for malignancy and the need for a definitive diagnosis, the patient underwent an open biopsy.

At laparotomy, the patient was found to have severe inflammation in the area surrounding the gallbladder, multiple stones in the gallbladder, and a fistula from the gallbladder to the common hepatic duct. A choledochoscopy performed during the surgery found a left hepatic duct stone and a final diagnosis of cholelithiasis and Mirizzi syndrome was made.

Discussion

Mirizzi syndrome is an unusual cause of obstructive jaundice, (1) occurring in 0.7% to 1.4% of patients undergoing cholecystectomy. (2-3) It occurs when the common hepatic duct becomes obstructed due to extrinsic compression from an impacted gallstone in the cystic duct or the neck of the gallbladder.

Mirizzi syndrome was first described in 1948. It was subsequently divided into four major types, depending on the extent of compression of the common hepatic duct, on whether a cholecystocholedochal fistula is present, and on the size of that fistula. (4,5)

The differential diagnosis of this condition includes gallbladder carcinoma, cholangiocarcinoma or lymphadenopathy in the porta hepatis. It can be suggested by ultrasonography, computed tomography scanning, magnetic resonance imaging, and endoscopic retrograde cholangiopancreatography. Most cases are not identified before surgery, (6) and these patients are at increased risk of bile duct injury intraoperatively. (7) As with gallstone disease generally, the prevalence of this syndrome is higher among women and Native Americans. (8,9)

CA 19-9 is an intracellular adhesion molecule synthesized from normal human pancreatic, biliary, ductal, gastric, colonic, endometrial and salivary epithelial cells. (10-12) It is a tumor-associated, not a tumor specific marker and is associated with some malignant and nonmalignant diseases, although it is higher in cancer than in benign conditions. (13,14) In a one year retrospective study, CA 19-9 was found to be elevated in malignancies of the pancreas, colorectum, lung, liver and ovary, and in benign conditions of the hepatobiliary system, pneumonia, pleural effusion, renal failure, and systemic lupus erythematosus. (14)

Elevated CA 19-9 serum concentrations have a sensitivity of 80 to 90% for pancreatic cancer and 60 to 70% for biliary cancer. (12,15) Noncancerous conditions such as cirrhosis, cholestasis, cholangitis, and pancreatitis can be associated with increased concentrations of serum CA 19-9, but in these conditions, the concentrations are usually (but not always) less than 1,000 U per mL. (12) Therefore, elevations in CA 19-9 levels should be interpreted cautiously in patients with obstructive jaundice, unless the high levels persist after the obstruction has been removed. (13,16)

[FIGURE 1 OMITTED]

CA 19-9 is a serum glycoprotein and seems to be excreted in the biliary tract after being cleared by the liver. (13,17-19) In cases of benign biliary obstruction, there is a direct correlation between serum bilirubin and CA 19-9 concentration. Most likely this is due to impaired biliary excretion of CA 19-9. (13) The association between elevated serum bilirubin and CA 19-9 does not occur in malignant diseases, however, presumably because proliferating tumor cells synthesize CA 19-9. (13)

[FIGURE 2 OMITTED]

Conclusion

In patients with biliary obstruction, a diagnosis of malignancy cannot be made solely on the basis of increased concentration of CA 19-9, even when there is a high clinical suspicion and when imaging studies point to a malignant pathologic process, as in our case. Ultimately, a tissue biopsy is the only definitive diagnostic measure.

References

1. Mirizzi PL. Sindrome del conducto hepatico. J Int Chir 1948;8:731-737.

2. Csendes A, Diaz JC, Burdiles P, et al. Mirrizzi Syndrome and cholcystobiliary fistula: a unifying classification. Br J Surg 1989;76:1139-1143.

3. Pemberton M, Wells AD. The Mirizzi syndrome. Postgrad Med J 1997;73:487-490.

4. McSherry CK, Ferstenberg H, Virshup M. The Mirizzi syndrome: Suggested classification and surgical therapy. Surg. Gastroenterol 1982;1:219-225.

5. Nagakawa T, Ohta T, Kayahara M, et al. A new classification of Mirizzi syndrome from diagnostic and therapeutic viewpoints. Hepatogastroenterology 1997;44:63-7.

6. Chan CY, Liau KH, Ho CK, et al. Mirizzi Syndrome: a diagnostic and operative challenge. Surg Journal of the Royal Colleges of Surgeons of Edinburgh and Ireland 2003;1:273-278.

7. Tan KY, Chng HC, Chen CY, et al. Mirizzi syndrome: noteworthy aspects of a retrospective study in one center. ANZ J Surg 2004;74:833-837.

8. Abou-Saif A, Al-Kawas FH. Complications of gallstone disease: Mirizzi syndrome, cholecystocholedochal fistula, and gallstone ileus. Am J Gastroenterology 2002;97:149-254.

9. Curet MN, Rosendale DE, Congilosi S. Mirizzi syndrome in a Native American Population. Am J Surg 1994;168:616-621.

10. Atkinson BF, Ernst C, Herlyn M, et al. Gastrointestinal cancer associated antigen in immunoperoxidase assay. Cancer Res 1982;42:4820-4823.

11. Arends JW, Verstynen C, Bosman FT, et al. Distribution of monoclonal antibody-defined monosialoganglioside in normal and cancerous human tissues: an immunoperoxidase study. Hybridoma 1983;2:219-229.

12. Perkins GL, Slater ED, Sanders GK, et al. Serum tumor markers. Am Fam Physician 2003;68:1075-1088.

13. Mann DV, Edwards R, Ho S, et al. Elevated tumour marker CA 19-9: clinical interpretation and influence of obstructive jaundice. Eur Jour of Sur Onc 2000;26:474-479.

14. Pavai S. Yap SF. The clinical significance of elevated levels of serum CA 19-9. Med J Malaysia. 2003;58:667-72.

15. Fan ST, Lan WY, Lee MJR, et al. Cholecysto-hepaticodochal fistula, the value of pre-operative recognition. Br J Surg 1985;72:743-744.

16. Ng WW, Tong KJ, Tam TN, et al. Clinical values of CA 19-9, CA 125 and CEA in malignant obstructive jaundice. Zhonghua Yi Xue Za Zhi 1995;55:438-446.

17. Peterli R. Meyer-Wyss B. Herzog U, et al. CA 19-9 has no value as a tumor marker in obstructive jaundice. Schweiz Med Wochenschr 199;129:77-79.

18. Magnani J, Steplewski Z, Koprowski H. et al. Identification of the gastrointestinal and pancreatic cancer associated antigen detected by monoclonal antibody 19-9 in the sera of patients as a mucin. Cancer Res 1983;43:5489-5492.

19. McFarlane IG. Hepatic clearance of serum glycoproteins. Clin Sci 1983;64:127-135.

20. Kim PN, Outwater EK, Mitchell DG. Mirizzi syndrome: evaluation by MR imaging. Am J Gastroenterol 1999;94:2546-2550.

21. Becker CD, Hassler H, Terrier F. Preoperative diagnosis of the Mirizzi syndrome: limitations of sonography and computed tomography. American Journal of Roentgen 1984;143:591-596.

22. Dewar G, Chung SC, Li AK. Operative strategy in the Mirizzi syndrome. Surg Gynecol Obstet 1990;171:157-159.

23. Berland LL, Lawson TL, Stanley RJ. CT appearance of Mirizzi syndrome. J Comput Assist Tomogr 1984;8:165-166.

24. Choi BW, Kim MJ, Chung JJ, et al. Radiologic findings of Mirizzi syndrome with emphasis on MRI. Yonsei Medical Journal 2000;41:144-146.

25. Yip A WC, NG WS, Suen WS, et al. Type II Mirizzi syndrome: diagnosis by endoscopic retrograde cholangiopancreatography. J R Coll Surg Edin 1992;37:49-55.

Mayra Sanchez, MD, Hilton Gomes, MD, Erin N. Marcus, MD, MPH

From University of Miami, Jackson Memorial Hospital, Miami, FL.

Reprint requests to Erin N. Marcus, MD, MPH. University of Miami, Jackson Memorial Hospital, PO Box 019132, Miami, FL 33101. Email: [e-mail]

Accepted.

RELATED ARTICLE: Key Points

* Mirizzi syndrome occurs when the common hepatic duct becomes extrinsically obstructed by an impacted gallstone in the cystic duct or neck of the gallbladder.

* CA 19-9 is a sensitive marker for pancreatic and biliary cancer.

* Elevated serum CA 19-9 levels are usually lower than 1,000 units per mL in patients with benign reasons for obstruction.

* Elevated serum CA 19-9 levels should be interpreted cautiously in patients with benign obstruction of the biliary tree.

Table 1. Frequent imaging study findings in patients with Mirizzi
syndrome

Ultrasound (3)     -Impacted calculus or multiple calculi in the
                     gallbladder
                   -Contracted gallbladder
                   -Dilation of the common hepatic duct (CHD) and
                     intrahepatic biliary ducts above the level
                     associated with the extrinsic compression
                   -Normal diameter of the distal common bile duct (CBD)
CT Scan (3,21-23)  -Impacted calculus or multiple calculi in the
                     gallbladder
                   -Contracted gallbladder
                   -Dilatation of the CHD and intrahepatic ducts above
                     the level of obstruction
                   -Identification of the specific level of obstruction
                   -Normal diameter of the distal common bile duct
                   -Periductal inflammation presenting sometimes as mass
                     lesions
MRCP (20,24)       -Dilation of the CHD and intrahepatic biliary ducts
                   -Contracted gallbladder and wall thickening
                   -Normal CBD diameter
                   -This test may help delineate:
                     * The location of the impacted stone
                     * The level of compression of the CHD
                     * The presence or absence of cholecystocholodochal
                       fistula
ERCP (25)          -Dilatation ofthe CHD and intrahepatic ducts
                   -Gallstone(s) extrinsically obstructing the common
                     hepatic duct
                   -A contracted gallbladder
                   -Normal distal CBD
                   -Sometimes may show a cystic duct parallel to the
                     common hepatic duct with a low insertion
                   -This test may help delineate:
                     * The presence and size of a stone or stones
                     * The location of an external compression of the
                       hepatic duct
                   -This test can be useful therapeutically in removal
                     of impacted stone

Table 2. Classification of Mirizzi syndrome (5)

Type I    Presence of a stone impacted in the cystic duct or gallbladder
            neck
Type II   Presence of a fistula of the common duct
Type III  Hepatic duct stenosis due to a stone at the confluence of the
            hepatic and cystic ducts.
Type IV   Hepatic duct stenosis as a complication of cholecystitis in
            the absence of calculi impacted in the cystic duct or
            gallbladder neck