INTRODUCTION
A 57-year-old man complains of severe upper abdominal pain extending to his midback. He also has had fatigue and a loss in appetite over the last several weeks. Physical examination reveals generalized jaundice but no other significant findings. An upper endoscopy does not identify any mucosal ulcerations or masses. A CT scan of the abdomen shows a large mass in the head and body of the pancreas.
· What is the most likely diagnosis?
· What is the likely prognosis of this condition?
Summary: A 57-year-old man has severe upper abdominal pain radiating to his midback, fatigue, loss of appetite, and generalized jaundice. A large mass in the head and body of the pancreas is noted on CT imaging.
· Most likely diagnosis: Pancreatic carcinoma.
· Likely prognosis of this condition: Poor prognosis with 5-year survival less than 5 percent.
CLINICAL CORRELATION
Introduction
The vast majority of pancreatic carcinomas involve exocrine glands and are known as adenocarcinomas. The etiology is largely unknown. However, point mutations of the K-ras gene have been observed in over 90 percent of the tumors, suggesting abnormalities at the genetic level. Pain and nonspecific systemic symptoms such as weakness and weight loss are the usual first signs of malignancy. Obstructive jaundice is seen commonly because of the preference for tumors to occur in the head of the pancreas. The symptomatic course of pancreatic carcinoma is typically brief and progressive. Radiologic workups, including abdominal CT and ultrasound, are diagnostic for the cancer and are used for staging. No specific biological tests are available for screening or early detection. Cancer of the pancreas is now the fifth most common cause of cancer-related death in the United States. The median survival period from the time of diagnosis to demise is arguably the worst of any of the cancers. The median survival for untreated advanced cases is about 3.5 months; with good treatment this increases to about 6 months. The 5-year relative survival rate of patients with this cancer is only 3 to 5 percent. Even though a Whipple operation is considered the treatment of choice for localized and early disease, fewer than 15 percent of pancreatic tumors overall are resectable at the time of diagnosis. The prognosis of pancreatic carcinoma is one of the most dismal among any malignancies ever known.
Approach to Pancreatic Cancer
Definitions
Jaundice: A yellow discoloring of the skin, mucous membranes, and eyes caused by excess bilirubin in the blood. Common causes of jaundice in adults include prehepatic causes such as intravascular hemolysis, hepatic causes such as hepatitis A and hepatic tumors, and posthepatic causes, including obstruction of the bile duct as a result of infection, tumor, or gallstones.
Exocrine gland: A gland that secretes its products through ducts or canals, such as sweat glands or mammary glands. The secretion products produce their biological effects locally.
Endocrine gland:A gland, such as the pituitary or thyroid, that secretes its products, called hormones, directly into the bloodstream. Hormones generate their biological effects at distant locations.
Pancreatic cancer and adenocarcinoma of the pancreas: By definition, pancreatic cancer includes all malignant neoplasms of the pancreas. It includes the tumors arising from the exocrine portion of pancreas such as gland-forming adenocarcinoma of the pancreas, those of ductal origin, and tumors from endocrine components. Adenocarcinoma is the most common form of cancer, accounting for over 75 percent of all pancreatic cancers.
Discussion
Normal Pancreatic Histology
The pancreas is a small, spongy gland that lies just under the curvature of the stomach and deep within the abdomen. The majority of the pancreas is composed of exocrine glands, which produce enzymes necessary for food digestion. The secretions from acinar cells, the structural unit throughout the pancreas, containing salts and enzymes, are called pancreatic fluid, which eventually drains into the pancreatic duct. The pancreatic duct usually joins the bile duct and empties its combined digestive contents into the duodenum. Additionally, the pancreas has an endocrine, or hormonal, function. Inside specialized groupings of cells called the islets of Langerhans, the pancreas produces hormones such as insulin and glucagons, among other hormones. These molecules are secreted directly into the bloodstream, eliciting numerous biological effects throughout the body.
Epidemiology
Each year about 30,000 people in the United States are diagnosed with adenocarcinoma of the pancreas. Most of them will have passed away by the end of the first year. Most patients are between the ages of 60 and 80. Men tend to be affected more often than women. The median survival period from the time of diagnosis until demise is extremely short, with a mean of 3.5 months. It has been approximated that about 30 percent of the changes that initiate cancer of the pancreas are caused by smoking and that about 8 percent are "secondary to a hereditary genetic predisposition. There does not appear to be a strong correlation between the onset of pancreatic adenocarcinoma and the drinking of alcohol or coffee.
Biochemical Tests
Laboratory results often reveal nonspecific elevated bilirubin and elevated liver function enzymes as a result of biliary obstruction. The CA 19-9 marker, a Lewis blood group-related mucin, frequently is elevated in adenocarcinoma of the pancreas, but its use in screening for or diagnosis of the cancer is not accepted in general practice. High CA 19-9 levels may be associated with but do not always indicate larger tumors and with a decreased likelihood of surgical resectability. The use of this marker is accepted more widely as a running measure in a particular individual to help reflect the stability or progression of the cancer. Point mutation of K-ras is observed in 90 percent of pancreatic cancer patients. However, the utility of a screening test for K-ras mutation is not proven clinically.
Adenocarcinoma of the Pancreas
In up to 95 percent of cases, pancreatic cancer arises from the exocrine portion of the organ. Most of the exocrine tumors (approximately 90 percent) are from ductal cells¾those which line the pancreatic ducts. Further, under the microscope, the appearance and arrangement of these carcinoma cells can appear as ductlike (or "adeno"), giving the term adenocarcinoma to this most common form of pancreatic cancer. About three-quarters of exocrine tumors of the pancreas arise in the head and neck of the pancreas. It is believed that cancer is caused by the mutations of a gene, which confer increased abnormal growth potential to cells. Among other abnormalities, an oncogene called K-ras is found to be altered in up to 95 percent of ductal adenocarcinomas of the pancreas. The Whipple operation (pancreaticoduodenectomy) typically is performed in patients with tumors localized in the head of the pancreas.
Other Malignant Tumors of the Pancreas
Neuroendocrine tumors of the pancreas (islet cell tumors) are much less common than tumors arising from the exocrine pancreas. About 75 percent of these tumors are "functioning," meaning that they are found to be producing symptoms related to one or more of the hormone peptides they secrete. The predominant peptide secreted gives the functioning islet cell tumor its name. The hormones produced by neuroendocrine tumors include insulin, gastrin, glucagon, somatostatin, neurotensin, pancreatic polypeptide (PP), vasoactive intestinal peptide (VIP), growth hormone-releasing factor (GRF), and adronocorticotropic hormone (ACTH), among others.
Typically, the symptoms produced by the excess secretion of the predominant hormone in a functioning endocrine tumor lead to the eventual diagnosis. It is not possible to determine malignancy from the histologic appearance. Malignancy is determined by finding additional metastatic sites. The natural history of neuroendocrine carcinoma tends to be favorable compared with that of pancreatic adenocarcinoma. For example, the median survival duration from the time of diagnosis for patients with nonfunctioning metastatic neuroendocrine tumors approaches 5 years. Immediate treatment of the symptomatic conditions created by the oversecretion of the hormone may be appropriate. Surgery is generally curative.
COMPREHENSION QUESTIONS
[5.1] A 51-year-old man presents with slowly progressive jaundice, weight loss, and upper abdominal pain that radiates to his midback. Physical examination finds an enlarged gallbladder in the right upper quadrant of his abdomen, and a CT scan shows an irregular mass involving the head of the pancreas. Histologic sections from this mass are most likely to reveal what abnormality?
A. Adenocarcinoma
B. Clear cell carcinoma
C. Medullary carcinoma
D. Signet ring carcinoma
E. Squamous cell carcinoma
[5.2] Which one of the tumor markers listed below is most likely to be used by a clinician who is following a 64-year-old man after surgery for pancreatic cancer to look for possible recurrence of the pancreatic cancer?
A. CA 15-3
B. CA 19-9
C. CA 27-29
D. CA-50
E. CA-125
[5.3] A 44-year-old woman presents with worsening episodes of feeling "light-headed and dizzy." She says that her symptoms are relieved if she quickly eats a candy bar. Laboratory evaluation finds that during one of these episodes her serum glucose level is decreased and her serum insulin level is increased. What is the most likely cause of her symptoms?
A. Carcinoid tumor
B. Functional hamartoma
C. Islet cell adenoma
D. Microcystic adenoma
E. Tubulovillous adenoma
ANSWERS
[5.1] A. Adenocarcinoma is the most common type of pancreatic malignancy arising from the pancreatic ducts. In contrast, squamous cell carcinomas usually originate from stratified squamous epithelium, such as the esophagus. Clear cell carcinomas can be found in the kidneys, and signet cell carcinomas can be found in the stomach. A medullary carcinoma is a type of carcinoma of the thyroid gland.
[5.2] B. CA 19-9 is currently the best available tumor marker used clinically to look for possible recurrence of pancreatic cancer after surgery. Other markers have been studied in patients with pancreatic cancer, including CA-50, SPAN-1, and DUPAN-1, but these markers have not been as useful as CA 19-9. In contrast, CA-125 is associated with ovarian cancer, whereas CA 15-3 and CA 27-29 are associated with breast cancer, particularly advanced breast cancer.
[5.3] C. Elevated serum levels of insulin that result in hypoglycemia can be caused by a tumor that secretes insulin; an insulinoma is a type of islet cell tumor of the pancreas. In contrast, carcinoid tumors, which are found in the appendix and small intestine, may secrete vasoactive substances such as serotonin. A microcystic adenoma is a rare type of benign tumor of the pancreas, and a tubulovillous adenoma is a type of neoplastic polyp of the colon.
PATHOLOGY PEARLS
· Pancreatic cancer usually has a very poor prognosis.
· Adenocarcinoma is the most common type of primary pancreatic cancer, usually arsing from the exocrine glands.
· Neuroendocrine tumors of the pancreas tend to have a better prognosis than do adenocarcinomas.
· Painless obstructive jaundice is a common presentation of pancreatic cancer.
· Depression can herald an occult pancreatic cancer.
REFERENCES
Hruban RH, Wilentza RE. The pancreas. In: Kumar V, Assas AK, Fausto N, eds. Robbins and Cotran pathologic basis of disease, 7th ed. Philadelphia: Elsevier Saunders, 2004:939-953.
Mayer RJ. Pancreatic cancer. In: Kasper DL, Fauci AS, Longo DL, et al., eds. Harrison's principles of internal medicine, 16th ed. New York: McGraw-Hill, 2004:537-538.
Copyright © 2006 by the McGraw-Hill Companies, Inc. All rights reserved.
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