Patient with markedly elevated CA 19-9 not associated with malignancy.

Abstract: A 66-year-old white male presented with jaundice, pruritus, and a 30-pound weight loss over two months. Physical examination revealed scleral icterus. Laboratory evaluation revealed ALT 161 U/L, AST 290 U/L, alkaline phosphatase 2004 U/L, GGT 2.552 U/L, total bilirubin 10.2 mg/dL, and a carbohydrate antigen 19-9 (CA 19-9) level of 4,374 U/mL. Initial endoscopic retrograde cholangiopancreatography (ERCP) was unsuccessful due to ulceration in the duodenum healed with esomeprazole therapy. Subsequent ERCP showed a possible filling defect in the common bile duct treated with sphincterotomy and balloon sweeping of the common bile duct. Symptoms and jaundice resolved five months after initial presentation with normal labs and studies.

While elevated CA 19-9 levels occur in most patients with carcinoma of the pancreas, it can also be elevated in patients with extrapancreatic malignancies and acute cholangitis. This case illustrates the fact that a markedly elevated CA 19-9 can be secondary to causes other than carcinoma.

Key Words: carbohydrate antigen 19-9 (CA 19-9), jaundice, pancreatic cancer

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Carbohydrate antigen 19-9 (CA 19-9) is considered the most valuable serum test used in the diagnosis and management of pancreatic cancer. In addition, it is the most useful test in distinguishing between benign and malignant pancreatic disorders. (1) Early diagnosis of pancreatic cancer is essential since cancer of the pancreas has a very poor prognosis. Survival averages only 5 years in patients with stage I tumors without spread to regional lymph nodes, adjacent organs, or the liver. (2) However, a elevated CA 19-9 level does not necessarily indicate pancreatic cancer, as elevated levels may also be caused by benign conditions such as cirrhosis and acute cholangitis. (1) This case illustrates that markedly elevated CA 19-9 levels can be seen in other benign conditions.

Case Report

A 66-year-old white male presented with jaundice, pruritus, abdominal cramping, intermittent diarrhea, and a 30-pound weight loss over two months. Physical examination revealed scleral icterus but was otherwise unremarkable. Laboratory evaluation revealed ALT 161 U/L, AST 290 U/L, alkaline phosphatase 2004 U/L, GGT 2,552 U/L, total bilirubin 10.2 mg/dL, amylase 74 U/L, lipase 38 U/L, and CA 19-9 level of 4,374 U/mL (normal 0-37 U/mL). Abdominal ultrasound, hepatobiliary scan, and initial CT scan were unremarkable.

An endoscopic retrograde cholangiopancreatography (ERCP) attempted three weeks after presentation could not be performed due to ulceration, edema, and friable mucosa in the second portion of the duodenum (Fig. 1 and Fig. 2). Biopsies of the ulcer showed chronic inflammation and granulation tissue but no evidence of malignancy. Treatment with esomeprazole 40 mg daily for one month resulted in duodenal healing confirmed on repeat upper endoscopy. Gastrin level was normal one month and four months after initial endoscopy. CEA level was 3.3 ng/mL (normal 0-5 ng/mL).

One month after presentation, ERCP was performed which showed a possible filling defect in the common bile duct. Sphincterotomy and balloon sweeping of the common bile duct was performed with subsequent normal cholangiogram.

Four months after initial presentation, the patient remained asymptomatic but had elevated amylase to 402 U/L and lipase to 565 U/L that were normal at the time of repeat testing five days later. Repeat CT scan performed one year after initial presentation was notable for possible separation of the ducts draining the pancreatic body and tail consistent with possible pancreas divisum. Magnetic resonance cholangiopancreatography (MRCP) showed the main pancreatic duct draining through the duct of Santorini inserting into the duodenum above the insertion of the extrahepatic bile duct. No duct of Wirsung was identified. These findings are consistent with a pancreatic duct fusion anomaly probably representing a variant of pancreas divisum (see Fig. 3 and Fig. 4). Repeat ERCP was attempted to confirm the findings seen on CT scan and MRCP, but attempts to cannulate the pancreatic duct via the major and minor pancreatic papillae were unsuccessful.

Symptoms and jaundice resolved within five months after initial presentation with a normal CT scan, normal liver biochemistries, and a CA 19-9 level of 23 U/mL one year after initial presentation.

Discussion

The CA 19-9 antigen was first isolated by Koprowski et al (3,4) using a monoclonal antibody generated against colonic carcinoma cell lines. Subsequently, a radioimmunometric assay was developed by DelVillano et al (5) to quantify CA 19-9. CA 19-9 is tumor associated, but not tumor specific and is synthesized by normal human pancreatic and biliary ductular cells as well as by gastric, colonic, endometrial, and salivary epithelia. It can be found in large quantities in normal pancreatic juice, in the bile of patients with benign disorders, and in seminal fluid. (1) Usually, very little CA 19-9 is found in the serum of normal subjects with benign disorders. (5,6) Most patients with pancreatic carcinoma have elevated levels of serum CA 19-9. Patients can have large amounts of CA 19-9 in tumor tissue with little in the serum, and vice versa. (1)

The upper limit of normal for CA 19-9 antigen is 37 to 40 U/mL and with this limit the assay has an overall mean sensitivity of 81% and a mean specificity of 90% for the diagnosis of pancreatic cancer. (1) Sensitivity is increased by the presence of jaundice, especially at lower reference values (sensitivity of 82% with a cut off of 40 U/mL). The combination of CA 19-9 level of >100 U/mL with an imaging modality (ultrasound, CT, or ERCP) suggestive of, or equivocal for, malignancy has a positive predictive value of 100% in nonjaundiced patients. (7) At levels >1,000 U/mL, CA 19-9 specificity for pancreatic cancer is greater than 99%. Conditions that are known to cause significant elevations of this assay are acute cholangitis and cirrhosis. Craxi et al (8) reported that 62% of 118 patients with cirrhosis had elevated CA 19-9, many of which were greater than 100 U/mL. Patients with acute cholangitis can have markedly elevated levels of CA 19-9 that exceed 1,000 U/mL, but normalize after appropriate decompression of the common duct. Patients with common duct obstruction without cholangitis do not have elevations of CA 19-9. (9) Overall, 13% of patients with benign diseases and 29% of patients with extrapancreatic malignancies have elevated CA 19-9 levels. (2)

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Pancreas divisum, the most common congenital pancreatic anomaly, is found in 1 to 14% of subjects in autopsy series. (10,11) It results from failure of fusion of the ventral and dorsal pancreatic duct systems in utero. There is no known association between elevated CA 19-9 levels and pancreas divisum, but pancreas divisum has been associated with pancreatitis. Also, there are several case reports suggesting an association between pancreas divisum and pancreatic cancer. (12-14) Pancreatic symptoms are estimated to occur in less than 5% of patients with pancreas divisum. (15)

Conclusion

Carbohydrate antigen 19-9 is considered to be the "gold" standard marker that is the most useful serum test used in the diagnosis and management of pancreatic cancer. However, other conditions such as cirrhosis and acute cholangitis can also result in elevated CA 19-9 levels. (8,9) This case shows that markedly elevated CA 19-9 levels can be seen in conditions other than pancreatic cancer. The cause of the patient's elevated CA 19-9 level in this case is not clear. Possible causes include irritation of the pancreas by duodenal ulceration, or pancreatitis associated with the patient's variant of pancreas divisum.

References

1. Steinberg W. The clinical utility of the CA 19-9 tumor-associated antigen. Am J Gastroenterol 1990;84:350-355.

2. Gansauge S, Gansauge F, Beger HG. Molecular oncology in pancreatic cancer. J Mol Med 1996;74:313-320.

3. Koprowski H, Steplewski Z, Mitchell K, et al. Colorectal carcinoma antigens detected by hybridoma antibodies. Somatic Cell Genet 1979;5:957-971.

4. Koprowski H, Herlyn M, Steplewski Z, et al. Specific antigen in serum of patients with colon carcinoma. Science 1981;212:53-55.

5. DelVillano BC, Brennan S, Brock P, et al. Radioimmunometric assay for a monoclonal antibody-defined tumor marker, CA 19-9. Clin Chem 1983;29:549-552.

6. Ritts RE Jr, DelVillano BC, Go VL, et al. Initial clinical evaluation of an immunoradiometric assay for CA 19-9 using NCI serum bank. Int J Cancer 1984;33:339-345.

7. Ritts RE Jr, Nagorney DM, Jacobsen DJ, et al. Comparison of preoperative serum CA19-9 levels with results of diagnostic imaging modalities in patients undergoing laparotomy for suspected pancreatic or gallbladder disease. Pancreas 1994;9:707-716.

8. Craxi A, Patti C, Aragona E. Serum CA 19-9 levels in patients with hepatocelluar carcinoma or cirrhosis. Ital J Gastroenterol 1985;17:288-289.

9. Albert MB, Steinberg WM, Henry JP. Elevated serum levels of tumor marker CA 19-9 in acute cholangitis. Dig Dis Sci 1988;33:1223-1225.

10. Smanio T. Proposed nomenclature and classification of the human pancreatic ducts and duodenal papillae: study based on 200 post mortems. Int Surg 1969;52:125-141.

11. Stimec B, Bulajic M, Korneti V, et al. Ductal morphometry of ventral pancreas in pancreas divisum: comparison between clinical and anatomical results. Ital J Gastroenterol 1996;28:76-80.

12. Outtas O, Barthet M, De Troyer J, et al. [Pancreatic panniculitis with intraductal carcinoid tumor of pancreas divisum]. Ann Dermatol Venereol 2004;131:466-469.

13. Martin Fernandez J, Ratia T, Gutierrez A, et al. Intraductal pancreatic carcinoma associated with pancreas divisum. Rev Esp Enferm Dig 2003;95:358-363.

14. Hunerbein M, Ghadimi BM, Benhidjeb T, et al. A rare malformation of the pancreaticobiliary junction long common channel cholechochal cyst and pancreas divisum in a patient with pancreatic cancer. Hepato-gas-troenterology 1999;46:1647-1649.

15. Lehman GA, Sherman S. Anatomy and clinical significance of pancreas divisum. In: Rose BD (ed), UpToDate, Wellesley, MA, 2004.

Douglas Lowe, MD, Jeffrey Lee, MD, Robert Schade, MD, FACG, FACP, and Ayaz Chaudhary, MD, FACG, FACP

From the Department of Internal Medicine, Section of Gastroenterology/Hepatology, Medical College of Georgia and Veterans Administration Medical Center, Augusta, GA.

Reprint requests to Ayaz Chaudhary, MD, the Medical College of Georgia, Section of Gastroenterology/Hepatology, 1120 15th Street, BBR2538, Augusta, GA 30912. Email: [e-mail]

Institutional review board approval for medical record review was received.

Accepted October 14, 2005.

RELATED ARTICLE: Key Points

* CA 19-9 has been considered by some to be the "gold" standard serologic marker for the diagnosis of patients with pancreatic cancer.

* While elevated CA 19-9 levels occur in most patients with carcinoma of the pancreas, it can also be elevated in patients with extrapancreatic malignancies and acute cholangitis.

* Markedly elevated CA 19-9 levels can be secondary to causes other than carcinoma.