Case 20-2005 — A 58-Year-Old Man with Locally Advanced Pancreatic Cancer
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《新英格兰医药杂志》
Presentation of Case
A 58-year-old man was seen in the gastrointestinal oncology clinic of the cancer center of this hospital for management of pancreatic cancer.
He had been in his usual state of health until four months earlier, when abdominal computed tomography (CT), performed to evaluate a kidney stone, revealed an incidental finding of a small abdominal aortic aneurysm, for which further evaluation was advised. One month later, abdominal ultrasonography showed an ectatic aorta with a maximal anteroposterior diameter of 2.9 cm; no definite aneurysm was identified. One month later, abdominal and pelvic CT performed with oral and intravenous contrast material disclosed an aneurysm 3.8 cm in diameter, with a mural thrombus. There was a rounded, low-attenuation mass, 1.9 cm by 2.4 cm, in the head and neck of the pancreas, with dilatation of the pancreatic duct and atrophy of the pancreatic tail.
Two weeks later, the patient was evaluated by a gastroenterologist. The symptoms that he described at this evaluation included vague discomfort in the left upper quadrant and left epigastrium, which he said he had had for the preceding year and which usually began one hour after meals and subsided after one to two hours. A trial of histamine H2–receptor antagonists had not provided relief. The discomfort was associated with a feeling of fullness in his abdomen, which increased with physical exertion but did not awaken him at night. He had lost 2 to 3 kg of weight, which he attributed to a reluctance to eat large meals. The results of a physical examination that included a rectal examination were normal; the stool guaiac test was negative.
Endoscopic retrograde cholangiopancreatography was performed two weeks after the examination by the gastroenterologist; abrupt termination of the main pancreatic duct within the neck of the pancreas was revealed. A cholangiogram showed no abnormalities. Endoscopic ultrasonography revealed an irregular hypoechoic mass in the pancreatic head that was 23 mm in maximal cross-sectional diameter and encased the confluence of the superior mesenteric vein with the portal vein. Fine-needle aspiration of the pancreas was performed. Cytologic examination of a specimen from the neck of the pancreas was positive for adenocarcinoma; specimens from the head and tail of the pancreas did not show malignant cells.
One month later, the patient was evaluated in the gastrointestinal oncology clinic at this hospital. He had borderline hypertension and hypercholesterolemia, coronary artery disease with an inferior-wall myocardial infarction that had occurred nine years earlier, and nephrolithiasis. His medications included a daily regimen of atorvastatin and aspirin and frequent ibuprofen; he had no allergies. He had smoked 20 cigarettes a day for 40 years and had recently decreased his smoking to 5 or 6 cigarettes a day. He consumed one to two cups of coffee and one to two alcoholic beverages a day. He lived with his wife and two children and had a stressful job in sales. His mother had died of a cerebral aneurysm; his father was living, with coronary artery disease.
On physical examination, he appeared well. The weight was 85.9 kg, the height 177.5 cm, the blood pressure 142/78 mm Hg, the pulse 60 beats per minute, and the temperature 35.8°C. The physical examination revealed no abnormalities. The results of urinalysis were normal; the level of CA 19-9 in the blood was 510 U per milliliter; the results of other laboratory tests, including the complete blood count, tests of liver function, and levels of electrolytes, total protein, and albumin, were all within normal ranges.
The day after the patient's evaluation at the gastrointestinal oncology clinic, staging laparoscopy was performed. Biopsy specimens of a peritoneal nodule and a whitish nodule, 2 mm in diameter, in the left lateral segment of the liver were obtained, as were peritoneal washings. Cytologic examination of the peritoneal washings revealed no malignant cells; pathological examination of the liver showed benign hepatic parenchyma; the peritoneal nodule was a benign peritoneal inclusion cyst.
Differential Diagnosis
Dr. David P. Ryan: May we review the imaging studies?
Dr. Dushyant Sahani: CT scanning of the abdomen, performed after the administration of intravenous and oral contrast material, showed a mass, 1.9 cm by 2.4 cm, in the pancreatic head and neck (Figure 1A), with dilatation of the pancreatic duct and atrophy of the tail of the pancreas (Figure 1B). The tumor indented the confluence of the superior mesenteric vein and portal vein and encased more than 50 percent of its circumference (Figure 1C). No signs of metastatic disease or lymphadenopathy were seen in the abdomen or pelvis.
Figure 1. Axial Contrast-Enhanced CT Images through the Pancreas.
A low-density mass is present (arrows, Panel A), which involves the neck and head of the pancreas. Dilatation of the pancreatic duct (arrow) is seen in Panel B, with an abrupt transition in the neck of the pancreas where the mass is located. The mass (thin arrow, Panel C) indents the confluence of the superior mesenteric vein and portal vein (thick arrow) and encases more than 50 percent of its circumference. An axial image obtained after treatment from contrast-enhanced CT (Panel D) shows that the mass no longer indents the vein, and there is less than 50 percent encasement of the circumference of the vein. The thin arrow indicates the mass, and the thick arrow indicates the superior mesenteric vein.
Dual-phase helical CT, which is the preferred method of evaluating pancreatic carcinomas, is performed after the intravenous administration of a bolus of contrast material and generates images during the phase of arterial perfusion of the pancreas and, after about 20 seconds, during the phase of portal venous enhancement. The rapid acquisition of data with the helical technique also allows for three-dimensional reconstruction. The relationship of the tumor to the surrounding structures (in particular, the vasculature) can be examined in detail, and the presence of liver metastases and enlarged lymph nodes can be evaluated. This method has a very high positive predictive value for unresectability (90 to 100 percent), but it is less accurate for predicting resectability (70 to 80 percent).1,2 With the introduction of newer multislice CT scanners, the performance of CT has been enhanced still further. A recently published series reported that for detection of vascular invasion, multidetector-row CT yielded a negative predictive value of 100 percent, with no false negative findings, and an accuracy of 99 percent.3
In the patient under discussion, this technique was not used, as the pancreatic cancer was unsuspected. Repeated CT scanning was performed later, specifically for staging, but unfortunately, the dedicated protocol was not used, and it was decided not to perform the study a third time. The technique that was used might have underestimated the extent of vascular involvement, but since vascular involvement, including deformation of the vessel by the tumor, was seen even when this less sensitive technique was used, the likelihood that the tumor could have been resected was low.
Dr. William R. Brugge: Endoscopic retrograde cholangiopancreatography was used to examine both the common bile duct and the pancreatic duct. The common bile duct appeared normal. In the pancreatic duct, retrograde injection of contrast material through the papilla revealed narrowing and then complete obstruction in the neck of the pancreas. There was no contrast material in the body or tail of the pancreas. These findings were highly suggestive of a tumor, either primary or secondary, in the neck of the pancreas.
The patient then underwent an endoscopic ultrasonographic examination. The image shows a hypoechoic focus, 2.3 cm in diameter, in the head of the pancreas (Figure 2A) that is directly adjacent to the confluence of the superior mesenteric vein with the portal vein over an area 1.5 cm long. Even though tumor is not seen within the lumen of the vein, the degree of contact is most consistent with local invasion of the vein wall. The anatomical features under discussion are illustrated in a diagram (Figure 2B).
Figure 2. Endoscopic Ultrasonographic Examination.
Panel A shows a hypoechoic mass, 2.3 cm in diameter, in the head of the pancreas, which is in contact with the wall of the superior mesenteric vein for a distance of 1.5 cm. The diagram (Panel B) shows the course of the superior mesenteric and portal veins, which are often invaded by locally advanced cancers of the pancreas. In each panel, the arrow indicates the area in which the tumor in this patient was in contact with the anterior wall of the confluence of the portal and superior mesenteric veins. The patient's anterior aspect is to the right and posterior aspect to the left.
Fine-needle aspiration guided by endoscopic ultrasonography was performed by placing a 22-gauge needle through the duodenal wall; material was aspirated from the hypoechoic area in the neck of the pancreas.
Dr. Elena F. Brachtel: Cytologic examination of the aspirated material showed cohesive, three-dimensional clusters of neoplastic glandular cells (Figure 3) with necrosis, mucin, and blood in the background. These cells had irregular, enlarged, and hyperchromatic nuclei, an increased nuclear-to-cytoplasmic ratio, and intracytoplasmic mucin (Figure 3, inset) — all findings that are characteristic of adenocarcinoma.4
Figure 3. Cytologic Examination of the Specimen Obtained by Fine-Needle Aspiration of the Pancreas (Papanicolaou Stain).
There are large, tightly packed groups of neoplastic glandular cells, with mucin in the background. The groups are three-dimensional, with papillary configurations and nuclear features associated with tumor (crowding of enlarged, irregular, and hyperchromatic nuclei and increased nuclear-to-cytoplasmic ratio). There is abundant single-cell necrosis, also a feature of cancer. The inset image shows tumor cells with intracytoplasmic mucin.
Issues in the Management of Pancreatic Cancer
Dr. Ryan: In summary, this 58-year-old man had an incidentally discovered pancreatic adenocarcinoma, 2.3 cm in diameter, with apparent venous invasion at the confluence of the superior mesenteric vein and portal vein. In retrospect, he had had symptoms possibly related to the cancer for about one year. His presentation illustrates a common problem in our multidisciplinary gastrointestinal cancer center: the patient with what is considered a "borderline-resectable" pancreatic cancer. To clarify the multidisciplinary approach in terms of surgical evaluation as well as evaluation for combined therapy, a brief overview of pancreatic cancer is necessary.
Risk factors for pancreatic cancer include increasing age, cigarette smoking, obesity, diabetes mellitus, chronic pancreatitis, and family history; the BRCA2 gene is emerging as an important locus in familial pancreatic cancer. The patient under discussion was slightly younger than the median age of patients with pancreatic cancer and was a long-time cigarette smoker, but he had no other risk factors. Although 50 percent of patients present with jaundice,5 his presentation was fairly typical for patients who present without jaundice — namely, nonspecific abdominal symptoms and weight loss.6
Most clinicians specializing in the care of patients with pancreatic cancer divide the cases into three categories: resectable, locally advanced, and metastatic. Surgery cures approximately 20 percent of patients who undergo a complete resection, whereas long-term survival for patients with either locally advanced or metastatic pancreatic cancer is rare. Chemoradiation therapy may prolong survival in patients with locally advanced disease, but the median survival is approximately one year. Patients with metastatic disease who are treated with chemotherapy have a median survival of six months. This patient had a tumor that was on the borderline between being resectable and being locally advanced because of the involvement at portal-vein confluence.
The most important decisions regarding the care of patients such as this one with pancreatic cancer are surgical. Can the tumor be resected, by whom, and at which hospital? The surgical mortality rate associated with pancreatic-cancer resection has fallen from more than 20 percent in some series in the 1950s and 1960s to less than 3 percent in high-volume single institutions in the 1990s.7,8,9,10 In a recent study using the Medicare database,11 the mortality rate after pancreatectomy ranged from 14.7 percent with surgeons who performed fewer than two operations per year to 4.6 percent with those who performed more than four per year. Thus, the experience of the surgeon is critical.
Surgical Management of Pancreatic Cancer
Dr. Carlos Fernandez-del Castillo: At the time of diagnosis, 40 to 45 percent of patients with pancreatic cancer have distant metastases, another 40 to 45 percent have localized tumors that are unresectable (mostly because of vascular invasion), and only 15 to 20 percent have localized and resectable tumors. The treatment and prognosis are very different for these three groups, and therefore, accurate clinical staging is paramount. Currently, the three most frequently used tools for staging are CT, endoscopic ultrasonography, and laparoscopy — all of which were used in the case of this patient.
As Dr. Sahani mentioned, CT scanning has a 20 to 30 percent false negative rate for predicting whether or not the tumor is resectable, because of the presence of small peritoneal and liver implants, and the false negative rate as such constitutes the rationale for the use of laparoscopy in pancreatic cancer. Laparoscopy is particularly useful in patients with tumors of the body and tail of the pancreas, where the frequency of metastatic disease not identified by CT approaches 50 percent (as compared with 10 to 20 percent for tumors located in the head of the pancreas). This diagnostic method is also used in patients with unresectable tumors, since the detection of distant metastases will preclude any survival benefit from radiation therapy. In the patient under discussion, at laparoscopy we found a small peritoneal nodule and a whitish nodule, 2 mm in diameter, in the left lateral segment of the liver, both of which proved to be benign. Peritoneal washings obtained at the time of laparoscopy show malignant cells in a small number of patients (6 percent) without visible metastases and are associated with a poor prognosis; in this patient, they were negative.12
In the past several years, endoscopic ultrasonography has emerged as a powerful and versatile imaging method that can identify and guide biopsy of small pancreatic tumors. Although tissue diagnosis is not required by most pancreatic surgeons in order to proceed with resection, it is necessary when neoadjuvant treatment is planned or in cases of unresectable or metastatic tumors. In experienced hands, endoscopic ultrasonography can be as good as CT for staging.13 Its limitations include the inability to evaluate the liver and the more distal superior mesenteric vein, as well as the fact that its reliability is heavily dependent on the skill of the operator. In this case, endoscopic ultrasonography confirmed venous invasion and provided diagnostic tissue from the tumor.
The contraindications to resection of pancreatic cancer are listed in Table 1. Because some of the elements involved are subjective, it is important that the decision to proceed or not to proceed with resection be made by an experienced pancreatic surgeon. When the portal vein is involved, the proportion of the circumference that is affected is important in determining resectability. If it is less than 50 percent, the tumor can probably be resected with repair of the vein, whereas if it is more than 50 percent, the possibility of resection may be less likely. In the case being discussed, CT and endoscopic ultrasonography suggested involvement of more than 50 percent of the circumference of the vein. Because of this, we thought that the probability that this tumor could be completely resected was low, and we decided together with the medical and radiation oncologist to proceed with neoadjuvant treatment in the hope of reducing the size of the tumor and the degree of vascular involvement, so that resection with clear margins would be possible.
Table 1. Contraindications to Surgical Resection of Pancreatic Cancer.
Preoperative and Postoperative Chemotherapy and Radiation
Dr. Christopher G. Willett: After surgery for resectable pancreatic cancer, local recurrence has been reported in 50 to 85 percent of patients even in subgroups with the most favorable conditions.14,15,16 The likely explanation is the presence of residual disease at the retroperitoneal and soft-tissue margins at the time of surgery. Multiple series have now shown that a microscopically positive margin is an important prognostic feature at the time of resection, reducing the median survival to that among patients with locally advanced disease.17,18 The retroperitoneal margin is the one that is most frequently positive. In this patient, the presence of venous involvement placed him at very high risk for having a positive retroperitoneal margin if resection was the first therapeutic method attempted.
Efforts to improve local control and thus survival include the administration of chemotherapy and radiation therapy, either postoperatively or preoperatively. Of three important randomized trials of chemoradiation in the postoperative setting, one showed a survival benefit with chemoradiation therapy, and the other two did not.19,20,21 All the studies have serious limitations, and it is not possible to draw any definitive conclusions because of flaws in the trials. Single-institution trials that have evaluated chemoradiation therapy both for locally advanced tumors and as an adjuvant to resection have shown good local control with satisfactory tolerance when modern irradiation techniques have been used.15,22
A more recent approach to improve local control has been the application of preoperative chemoradiation — so-called neoadjuvant therapy — for patients with resectable disease; studies have demonstrated local control in 87 to 100 percent of patients.23,24 There are two arguments for the use of preoperative chemoradiation therapy. First, it ensures the delivery of chemoradiation therapy to patients undergoing resection, since approximately 20 to 25 percent of patients will not receive postoperative therapy because of a prolonged recovery period after surgery. Second, in approximately 20 to 25 percent of patients, metastatic disease will become apparent while they are receiving preoperative therapy; thus they can avoid an operation that would not be curative. It should be noted that preoperative therapy is not associated with improved median survival rates when compared with historical controls who received postoperative therapy, and only occasionally does downstaging occur.
Dr. Ryan: This patient had a tumor that was on the borderline between being resectable and being considered locally advanced, because of the involvement of about 50 percent of the circumference of the confluence of the portal and superior mesenteric veins. After an interdisciplinary consultation, we thought that preoperative therapy would offer improved local control and might increase the likelihood that the tumor in this patient would be resectable. We offered him enrollment in a phase 1 study of concurrent gemcitabine, fluorouracil, and external-beam radiation with a CT-based multifield technique (50.4 Gy in 28 fractions), and he accepted. He had few side effects, his abdominal pain diminished almost to the point of disappearance, and he regained his lost weight.
Dr. Sahani: A post-treatment CT scan shows a mass, 1.7 cm in diameter, in the head of the pancreas, involving slightly less than 50 percent of the circumference of the superior mesenteric vein, without indenting it (Figure 1D).
Dr. Fernandez-del Castillo: An exploratory laparotomy was performed after the completion of chemoradiation. The tumor was easily dissected from the portal and superior mesenteric veins, and no evidence of metastatic disease was found. A Whipple procedure was performed.
Dr. Brachtel: An ill-defined, firm fibrotic area measuring 2 cm by 2 cm by 1 cm was noted macroscopically in the neck of the pancreas, which was close to the distal resection margin and came to within 1.5 cm of the uncinate and within 1 cm of the retroperitoneal margin. Residual microscopic foci of ductal adenocarcinoma embedded in dense fibrous stroma were present on histologic examination (Figure 4A). Acellular mucin (Figure 4B) and pancreatic intraepithelial neoplasia grade 3 were present at the distal resection margin (Figure 4C), but all resection margins were free of viable tumor, as were four peripancreatic lymph nodes.25,26
Figure 4. Sections of the Resected Pancreas (Hematoxylin and Eosin).
Rare, highly abnormal glands are embedded in dense fibrous stroma, which represent residual carcinoma (Panel A). The nuclei are large, hyperchromatic, and irregular; some of the atypical features may be due to therapy. A preserved islet is present in the lower right corner of the image. There are collections of light blue acellular mucin (Panel B), intimately associated with nerves, indicating that tumor had been present in these areas. The distal resection margin also showed pancreatic intraepithelial neoplasia, grade 3 (Panel C). The duct is lined by papillary excrescences into the lumen; nuclear crowding and atypical features are visible, with no invasive tumor identified.
Dr. Ryan: The final pathological stage of this patient's tumor was T1N0 pancreatic cancer. During his recovery after the operation, the patient had persistent abdominal discomfort, which made the administration of additional chemotherapy impossible. Thus, he did fall into the category of 20 to 25 percent of patients who are not able to receive adjuvant chemotherapy postoperatively. Four years after the Whipple procedure, he remains free of recurrent or metastatic cancer and works full-time.
Anatomical Diagnosis
Ductal adenocarcinoma of the pancreas, with residual microscopic tumor after chemoradiation therapy.
Pancreatic intraepithelial neoplasia, grade 3, present at the distal resection margin. Resection margins and lymph nodes free of invasive carcinoma.
Dr. Ryan reports having received consulting fees and lecture fees from Lilly Oncology.
Source Information
From the Departments of Hematology and Oncology (D.P.R.), Surgery (C.F.-C.), Radiology (D.S.), and Pathology (E.F.B.), and the Division of Gastroenterology, Department of Medicine (W.R.B.), Massachusetts General Hospital, Boston; the Departments of Medicine (D.P.R., W.R.B.), Surgery (C.F.-C.), Radiology (D.S.), and Pathology (E.F.B.), Harvard Medical School, Boston; and the Department of Radiation Oncology, Duke University Medical Center, Durham, N.C. (C.G.W.).
References
Lu DS, Reber HA, Krasny RM, Kadell BM, Sayre J. Local staging of pancreatic cancer: criteria for unresectability of major vessels as revealed by pancreatic-phase, thin-section helical CT. AJR Am J Roentgenol 1997;168:1439-1443.
Ichikawa T, Haradome H, Hachiya J, et al. Pancreatic ductal adenocarcinoma: preoperative assessment with helical CT versus dynamic MR imaging. Radiology 1997;202:655-662.
Vargas R, Nino-Murcia M, Trueblood W, Jeffrey RB Jr. MDCT in pancreatic adenocarcinoma: prediction of vascular invasion and resectability using a multiphasic technique with curved planar reformations. AJR Am J Roentgenol 2004;182:419-425.
Neoplasms of the exocrine and endocrine pancreas. In: Centeno BA, Pitman MB. Fine needle aspiration biopsy of the pancreas. Boston: Butterworth–Heinemann, 1999:109-60.
Permert J, Larsson J, Ihse I, Pour PM. Diagnosis of pancreatic cancer: alteration of glucose metabolism. Int J Pancreatol 1991;9:113-117.
Bakkevold KE, Arnesjo B, Kambestad B. Carcinoma of the pancreas and papilla of Vater: presenting symptoms, signs, and diagnosis related to stage and tumour site: a prospective multicentre trial in 472 patients: Norwegian Pancreatic Cancer Trial. Scand J Gastroenterol 1992;27:317-325.
Crist DW, Sitzmann JV, Cameron JL. Improved hospital morbidity, mortality and survival after the Whipple procedure. Ann Surg 1987;206:358-365.
Heywood G, Vezeridis MP, Wanebo HJ. Surgical therapy of pancreatic cancer. Front BioSci 1998;3:E175-80.
Balcom JH 4th, Rattner DW, Warshaw AL, Chang Y, Fernandez-del Castillo C. Ten year experience with 733 pancreatic resections: changing indications, older patients, and decreasing length of hospitalization. Arch Surg 2001;136:391-398.
Sohn TA, Yeo CJ, Cameron JL, et al. Resected adenocarcinoma of the pancreas-616 patients: results, outcomes, and prognostic indicators. J Gastrointest Surg 2000;4:567-579.
Birkmeyer JD, Stukel TA, Siewers AE, Goodney PP, Wennberg DE, Lucas FL. Surgeon volume and operative mortality in the United States. N Engl J Med 2003;349:2117-2127.
Jimenez RE, Warshaw AL, Rattner DW, Willett CG, McGrath D, Fernandez-del Castillo C. Impact of laparoscopic staging in the treatment of pancreatic cancer. Arch Surg 2000;135:409-414.
Rosch T, Braig C, Gain T, et al. Staging of pancreatic and ampullary carcinoma by endoscopic ultrasonography: comparison with conventional sonography, computed tomography, and angiography. Gastroenterology 1992;102:188-199.
Tepper JE. Adjuvant irradiation of gastrointestinal malignancies: impact on local control and tumor cure. Int J Radiat Oncol Biol Phys 1986;12:667-671.
Westerdahl J, Andren-Sandberg A, Ihse I. Recurrence of exocrine pancreatic cancer -- local or hepatic? Hepatogastroenterology 1993;40:384-387.
Whittington R, Bryer MP, Haller DG, Solin LJ, Rosato EF. Adjuvant therapy of resected adenocarcinoma of the pancreas. Int J Radiat Oncol Biol Phys 1991;21:1137-1143.
Willett CG, Lewandrowski K, Warshaw AL, Efird J, Compton CC. Resection margins in carcinoma of the head of the pancreas: implications for radiation therapy. Ann Surg 1993;217:144-148.
Neoptolemos JP, Stocken DD, Dunn JA, et al. Influence of resection margins on survival for patients with pancreatic cancer treated by adjuvant chemoradiation and/or chemotherapy in the ESPAC-1 randomized controlled trial. Ann Surg 2001;234:758-768.
Gastrointestinal Tumor Study Group. Further evidence of effective adjuvant combined radiation and chemotherapy following curative resection of pancreatic cancer. Cancer 1987;59:2006-2010.
Klinkenbijl JH, Jeekel J, Sahmoud T, et al. Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC Gastrointestinal Tract Cancer Cooperative Group. Ann Surg 1999;230:776-782.
Neoptolemos JP, Dunn JA, Stocken DD, et al. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet 2001;358:1576-1585.
Foo ML, Gunderson LL, Nagorney DM, et al. Patterns of failure in grossly resected pancreatic ductal adenocarcinoma treated with adjuvant irradiation ±5-fluorouracil. Int J Radiat Oncol Biol Phys 1993;26:483-489.
Spitz FR, Abbruzzese JL, Lee JE, et al. Preoperative and postoperative chemoradiation strategies in patients treated with pancreaticoduodenectomy for adenocarcinoma of the pancreas. J Clin Oncol 1997;15:928-937.
Hoffman JP, Lipsitz S, Pisansky T, Weese JL, Solin L, Benson AB III. Phase II trial of preoperative radiation therapy and chemotherapy for patients with localized, resectable adenocarcinoma of the pancreas: an Eastern Cooperative Oncology Group study. J Clin Oncol 1998;16:317-323.
Kl?ppel G, Hruban RH, Longnecker DS, Adler G, Kern SE, Partanen TJ. Ductal adenocarcinoma of the pancreas. In: Hamilton SR, Aaltonen LA, eds. Pathology and genetics of tumours of the digestive system. Vol. 2 of World Health Organization classification of tumours. Lyon, France: IARC Press, 2000:221-30.
Evans DB, Rich TA, Byrd DR, et al. Preoperative chemoradiation and pancreaticoduodenectomy for adenocarcinoma of the pancreas. Arch Surg 1992;127:1335-1339.(David P. Ryan, M.D., Carl)
A 58-year-old man was seen in the gastrointestinal oncology clinic of the cancer center of this hospital for management of pancreatic cancer.
He had been in his usual state of health until four months earlier, when abdominal computed tomography (CT), performed to evaluate a kidney stone, revealed an incidental finding of a small abdominal aortic aneurysm, for which further evaluation was advised. One month later, abdominal ultrasonography showed an ectatic aorta with a maximal anteroposterior diameter of 2.9 cm; no definite aneurysm was identified. One month later, abdominal and pelvic CT performed with oral and intravenous contrast material disclosed an aneurysm 3.8 cm in diameter, with a mural thrombus. There was a rounded, low-attenuation mass, 1.9 cm by 2.4 cm, in the head and neck of the pancreas, with dilatation of the pancreatic duct and atrophy of the pancreatic tail.
Two weeks later, the patient was evaluated by a gastroenterologist. The symptoms that he described at this evaluation included vague discomfort in the left upper quadrant and left epigastrium, which he said he had had for the preceding year and which usually began one hour after meals and subsided after one to two hours. A trial of histamine H2–receptor antagonists had not provided relief. The discomfort was associated with a feeling of fullness in his abdomen, which increased with physical exertion but did not awaken him at night. He had lost 2 to 3 kg of weight, which he attributed to a reluctance to eat large meals. The results of a physical examination that included a rectal examination were normal; the stool guaiac test was negative.
Endoscopic retrograde cholangiopancreatography was performed two weeks after the examination by the gastroenterologist; abrupt termination of the main pancreatic duct within the neck of the pancreas was revealed. A cholangiogram showed no abnormalities. Endoscopic ultrasonography revealed an irregular hypoechoic mass in the pancreatic head that was 23 mm in maximal cross-sectional diameter and encased the confluence of the superior mesenteric vein with the portal vein. Fine-needle aspiration of the pancreas was performed. Cytologic examination of a specimen from the neck of the pancreas was positive for adenocarcinoma; specimens from the head and tail of the pancreas did not show malignant cells.
One month later, the patient was evaluated in the gastrointestinal oncology clinic at this hospital. He had borderline hypertension and hypercholesterolemia, coronary artery disease with an inferior-wall myocardial infarction that had occurred nine years earlier, and nephrolithiasis. His medications included a daily regimen of atorvastatin and aspirin and frequent ibuprofen; he had no allergies. He had smoked 20 cigarettes a day for 40 years and had recently decreased his smoking to 5 or 6 cigarettes a day. He consumed one to two cups of coffee and one to two alcoholic beverages a day. He lived with his wife and two children and had a stressful job in sales. His mother had died of a cerebral aneurysm; his father was living, with coronary artery disease.
On physical examination, he appeared well. The weight was 85.9 kg, the height 177.5 cm, the blood pressure 142/78 mm Hg, the pulse 60 beats per minute, and the temperature 35.8°C. The physical examination revealed no abnormalities. The results of urinalysis were normal; the level of CA 19-9 in the blood was 510 U per milliliter; the results of other laboratory tests, including the complete blood count, tests of liver function, and levels of electrolytes, total protein, and albumin, were all within normal ranges.
The day after the patient's evaluation at the gastrointestinal oncology clinic, staging laparoscopy was performed. Biopsy specimens of a peritoneal nodule and a whitish nodule, 2 mm in diameter, in the left lateral segment of the liver were obtained, as were peritoneal washings. Cytologic examination of the peritoneal washings revealed no malignant cells; pathological examination of the liver showed benign hepatic parenchyma; the peritoneal nodule was a benign peritoneal inclusion cyst.
Differential Diagnosis
Dr. David P. Ryan: May we review the imaging studies?
Dr. Dushyant Sahani: CT scanning of the abdomen, performed after the administration of intravenous and oral contrast material, showed a mass, 1.9 cm by 2.4 cm, in the pancreatic head and neck (Figure 1A), with dilatation of the pancreatic duct and atrophy of the tail of the pancreas (Figure 1B). The tumor indented the confluence of the superior mesenteric vein and portal vein and encased more than 50 percent of its circumference (Figure 1C). No signs of metastatic disease or lymphadenopathy were seen in the abdomen or pelvis.
Figure 1. Axial Contrast-Enhanced CT Images through the Pancreas.
A low-density mass is present (arrows, Panel A), which involves the neck and head of the pancreas. Dilatation of the pancreatic duct (arrow) is seen in Panel B, with an abrupt transition in the neck of the pancreas where the mass is located. The mass (thin arrow, Panel C) indents the confluence of the superior mesenteric vein and portal vein (thick arrow) and encases more than 50 percent of its circumference. An axial image obtained after treatment from contrast-enhanced CT (Panel D) shows that the mass no longer indents the vein, and there is less than 50 percent encasement of the circumference of the vein. The thin arrow indicates the mass, and the thick arrow indicates the superior mesenteric vein.
Dual-phase helical CT, which is the preferred method of evaluating pancreatic carcinomas, is performed after the intravenous administration of a bolus of contrast material and generates images during the phase of arterial perfusion of the pancreas and, after about 20 seconds, during the phase of portal venous enhancement. The rapid acquisition of data with the helical technique also allows for three-dimensional reconstruction. The relationship of the tumor to the surrounding structures (in particular, the vasculature) can be examined in detail, and the presence of liver metastases and enlarged lymph nodes can be evaluated. This method has a very high positive predictive value for unresectability (90 to 100 percent), but it is less accurate for predicting resectability (70 to 80 percent).1,2 With the introduction of newer multislice CT scanners, the performance of CT has been enhanced still further. A recently published series reported that for detection of vascular invasion, multidetector-row CT yielded a negative predictive value of 100 percent, with no false negative findings, and an accuracy of 99 percent.3
In the patient under discussion, this technique was not used, as the pancreatic cancer was unsuspected. Repeated CT scanning was performed later, specifically for staging, but unfortunately, the dedicated protocol was not used, and it was decided not to perform the study a third time. The technique that was used might have underestimated the extent of vascular involvement, but since vascular involvement, including deformation of the vessel by the tumor, was seen even when this less sensitive technique was used, the likelihood that the tumor could have been resected was low.
Dr. William R. Brugge: Endoscopic retrograde cholangiopancreatography was used to examine both the common bile duct and the pancreatic duct. The common bile duct appeared normal. In the pancreatic duct, retrograde injection of contrast material through the papilla revealed narrowing and then complete obstruction in the neck of the pancreas. There was no contrast material in the body or tail of the pancreas. These findings were highly suggestive of a tumor, either primary or secondary, in the neck of the pancreas.
The patient then underwent an endoscopic ultrasonographic examination. The image shows a hypoechoic focus, 2.3 cm in diameter, in the head of the pancreas (Figure 2A) that is directly adjacent to the confluence of the superior mesenteric vein with the portal vein over an area 1.5 cm long. Even though tumor is not seen within the lumen of the vein, the degree of contact is most consistent with local invasion of the vein wall. The anatomical features under discussion are illustrated in a diagram (Figure 2B).
Figure 2. Endoscopic Ultrasonographic Examination.
Panel A shows a hypoechoic mass, 2.3 cm in diameter, in the head of the pancreas, which is in contact with the wall of the superior mesenteric vein for a distance of 1.5 cm. The diagram (Panel B) shows the course of the superior mesenteric and portal veins, which are often invaded by locally advanced cancers of the pancreas. In each panel, the arrow indicates the area in which the tumor in this patient was in contact with the anterior wall of the confluence of the portal and superior mesenteric veins. The patient's anterior aspect is to the right and posterior aspect to the left.
Fine-needle aspiration guided by endoscopic ultrasonography was performed by placing a 22-gauge needle through the duodenal wall; material was aspirated from the hypoechoic area in the neck of the pancreas.
Dr. Elena F. Brachtel: Cytologic examination of the aspirated material showed cohesive, three-dimensional clusters of neoplastic glandular cells (Figure 3) with necrosis, mucin, and blood in the background. These cells had irregular, enlarged, and hyperchromatic nuclei, an increased nuclear-to-cytoplasmic ratio, and intracytoplasmic mucin (Figure 3, inset) — all findings that are characteristic of adenocarcinoma.4
Figure 3. Cytologic Examination of the Specimen Obtained by Fine-Needle Aspiration of the Pancreas (Papanicolaou Stain).
There are large, tightly packed groups of neoplastic glandular cells, with mucin in the background. The groups are three-dimensional, with papillary configurations and nuclear features associated with tumor (crowding of enlarged, irregular, and hyperchromatic nuclei and increased nuclear-to-cytoplasmic ratio). There is abundant single-cell necrosis, also a feature of cancer. The inset image shows tumor cells with intracytoplasmic mucin.
Issues in the Management of Pancreatic Cancer
Dr. Ryan: In summary, this 58-year-old man had an incidentally discovered pancreatic adenocarcinoma, 2.3 cm in diameter, with apparent venous invasion at the confluence of the superior mesenteric vein and portal vein. In retrospect, he had had symptoms possibly related to the cancer for about one year. His presentation illustrates a common problem in our multidisciplinary gastrointestinal cancer center: the patient with what is considered a "borderline-resectable" pancreatic cancer. To clarify the multidisciplinary approach in terms of surgical evaluation as well as evaluation for combined therapy, a brief overview of pancreatic cancer is necessary.
Risk factors for pancreatic cancer include increasing age, cigarette smoking, obesity, diabetes mellitus, chronic pancreatitis, and family history; the BRCA2 gene is emerging as an important locus in familial pancreatic cancer. The patient under discussion was slightly younger than the median age of patients with pancreatic cancer and was a long-time cigarette smoker, but he had no other risk factors. Although 50 percent of patients present with jaundice,5 his presentation was fairly typical for patients who present without jaundice — namely, nonspecific abdominal symptoms and weight loss.6
Most clinicians specializing in the care of patients with pancreatic cancer divide the cases into three categories: resectable, locally advanced, and metastatic. Surgery cures approximately 20 percent of patients who undergo a complete resection, whereas long-term survival for patients with either locally advanced or metastatic pancreatic cancer is rare. Chemoradiation therapy may prolong survival in patients with locally advanced disease, but the median survival is approximately one year. Patients with metastatic disease who are treated with chemotherapy have a median survival of six months. This patient had a tumor that was on the borderline between being resectable and being locally advanced because of the involvement at portal-vein confluence.
The most important decisions regarding the care of patients such as this one with pancreatic cancer are surgical. Can the tumor be resected, by whom, and at which hospital? The surgical mortality rate associated with pancreatic-cancer resection has fallen from more than 20 percent in some series in the 1950s and 1960s to less than 3 percent in high-volume single institutions in the 1990s.7,8,9,10 In a recent study using the Medicare database,11 the mortality rate after pancreatectomy ranged from 14.7 percent with surgeons who performed fewer than two operations per year to 4.6 percent with those who performed more than four per year. Thus, the experience of the surgeon is critical.
Surgical Management of Pancreatic Cancer
Dr. Carlos Fernandez-del Castillo: At the time of diagnosis, 40 to 45 percent of patients with pancreatic cancer have distant metastases, another 40 to 45 percent have localized tumors that are unresectable (mostly because of vascular invasion), and only 15 to 20 percent have localized and resectable tumors. The treatment and prognosis are very different for these three groups, and therefore, accurate clinical staging is paramount. Currently, the three most frequently used tools for staging are CT, endoscopic ultrasonography, and laparoscopy — all of which were used in the case of this patient.
As Dr. Sahani mentioned, CT scanning has a 20 to 30 percent false negative rate for predicting whether or not the tumor is resectable, because of the presence of small peritoneal and liver implants, and the false negative rate as such constitutes the rationale for the use of laparoscopy in pancreatic cancer. Laparoscopy is particularly useful in patients with tumors of the body and tail of the pancreas, where the frequency of metastatic disease not identified by CT approaches 50 percent (as compared with 10 to 20 percent for tumors located in the head of the pancreas). This diagnostic method is also used in patients with unresectable tumors, since the detection of distant metastases will preclude any survival benefit from radiation therapy. In the patient under discussion, at laparoscopy we found a small peritoneal nodule and a whitish nodule, 2 mm in diameter, in the left lateral segment of the liver, both of which proved to be benign. Peritoneal washings obtained at the time of laparoscopy show malignant cells in a small number of patients (6 percent) without visible metastases and are associated with a poor prognosis; in this patient, they were negative.12
In the past several years, endoscopic ultrasonography has emerged as a powerful and versatile imaging method that can identify and guide biopsy of small pancreatic tumors. Although tissue diagnosis is not required by most pancreatic surgeons in order to proceed with resection, it is necessary when neoadjuvant treatment is planned or in cases of unresectable or metastatic tumors. In experienced hands, endoscopic ultrasonography can be as good as CT for staging.13 Its limitations include the inability to evaluate the liver and the more distal superior mesenteric vein, as well as the fact that its reliability is heavily dependent on the skill of the operator. In this case, endoscopic ultrasonography confirmed venous invasion and provided diagnostic tissue from the tumor.
The contraindications to resection of pancreatic cancer are listed in Table 1. Because some of the elements involved are subjective, it is important that the decision to proceed or not to proceed with resection be made by an experienced pancreatic surgeon. When the portal vein is involved, the proportion of the circumference that is affected is important in determining resectability. If it is less than 50 percent, the tumor can probably be resected with repair of the vein, whereas if it is more than 50 percent, the possibility of resection may be less likely. In the case being discussed, CT and endoscopic ultrasonography suggested involvement of more than 50 percent of the circumference of the vein. Because of this, we thought that the probability that this tumor could be completely resected was low, and we decided together with the medical and radiation oncologist to proceed with neoadjuvant treatment in the hope of reducing the size of the tumor and the degree of vascular involvement, so that resection with clear margins would be possible.
Table 1. Contraindications to Surgical Resection of Pancreatic Cancer.
Preoperative and Postoperative Chemotherapy and Radiation
Dr. Christopher G. Willett: After surgery for resectable pancreatic cancer, local recurrence has been reported in 50 to 85 percent of patients even in subgroups with the most favorable conditions.14,15,16 The likely explanation is the presence of residual disease at the retroperitoneal and soft-tissue margins at the time of surgery. Multiple series have now shown that a microscopically positive margin is an important prognostic feature at the time of resection, reducing the median survival to that among patients with locally advanced disease.17,18 The retroperitoneal margin is the one that is most frequently positive. In this patient, the presence of venous involvement placed him at very high risk for having a positive retroperitoneal margin if resection was the first therapeutic method attempted.
Efforts to improve local control and thus survival include the administration of chemotherapy and radiation therapy, either postoperatively or preoperatively. Of three important randomized trials of chemoradiation in the postoperative setting, one showed a survival benefit with chemoradiation therapy, and the other two did not.19,20,21 All the studies have serious limitations, and it is not possible to draw any definitive conclusions because of flaws in the trials. Single-institution trials that have evaluated chemoradiation therapy both for locally advanced tumors and as an adjuvant to resection have shown good local control with satisfactory tolerance when modern irradiation techniques have been used.15,22
A more recent approach to improve local control has been the application of preoperative chemoradiation — so-called neoadjuvant therapy — for patients with resectable disease; studies have demonstrated local control in 87 to 100 percent of patients.23,24 There are two arguments for the use of preoperative chemoradiation therapy. First, it ensures the delivery of chemoradiation therapy to patients undergoing resection, since approximately 20 to 25 percent of patients will not receive postoperative therapy because of a prolonged recovery period after surgery. Second, in approximately 20 to 25 percent of patients, metastatic disease will become apparent while they are receiving preoperative therapy; thus they can avoid an operation that would not be curative. It should be noted that preoperative therapy is not associated with improved median survival rates when compared with historical controls who received postoperative therapy, and only occasionally does downstaging occur.
Dr. Ryan: This patient had a tumor that was on the borderline between being resectable and being considered locally advanced, because of the involvement of about 50 percent of the circumference of the confluence of the portal and superior mesenteric veins. After an interdisciplinary consultation, we thought that preoperative therapy would offer improved local control and might increase the likelihood that the tumor in this patient would be resectable. We offered him enrollment in a phase 1 study of concurrent gemcitabine, fluorouracil, and external-beam radiation with a CT-based multifield technique (50.4 Gy in 28 fractions), and he accepted. He had few side effects, his abdominal pain diminished almost to the point of disappearance, and he regained his lost weight.
Dr. Sahani: A post-treatment CT scan shows a mass, 1.7 cm in diameter, in the head of the pancreas, involving slightly less than 50 percent of the circumference of the superior mesenteric vein, without indenting it (Figure 1D).
Dr. Fernandez-del Castillo: An exploratory laparotomy was performed after the completion of chemoradiation. The tumor was easily dissected from the portal and superior mesenteric veins, and no evidence of metastatic disease was found. A Whipple procedure was performed.
Dr. Brachtel: An ill-defined, firm fibrotic area measuring 2 cm by 2 cm by 1 cm was noted macroscopically in the neck of the pancreas, which was close to the distal resection margin and came to within 1.5 cm of the uncinate and within 1 cm of the retroperitoneal margin. Residual microscopic foci of ductal adenocarcinoma embedded in dense fibrous stroma were present on histologic examination (Figure 4A). Acellular mucin (Figure 4B) and pancreatic intraepithelial neoplasia grade 3 were present at the distal resection margin (Figure 4C), but all resection margins were free of viable tumor, as were four peripancreatic lymph nodes.25,26
Figure 4. Sections of the Resected Pancreas (Hematoxylin and Eosin).
Rare, highly abnormal glands are embedded in dense fibrous stroma, which represent residual carcinoma (Panel A). The nuclei are large, hyperchromatic, and irregular; some of the atypical features may be due to therapy. A preserved islet is present in the lower right corner of the image. There are collections of light blue acellular mucin (Panel B), intimately associated with nerves, indicating that tumor had been present in these areas. The distal resection margin also showed pancreatic intraepithelial neoplasia, grade 3 (Panel C). The duct is lined by papillary excrescences into the lumen; nuclear crowding and atypical features are visible, with no invasive tumor identified.
Dr. Ryan: The final pathological stage of this patient's tumor was T1N0 pancreatic cancer. During his recovery after the operation, the patient had persistent abdominal discomfort, which made the administration of additional chemotherapy impossible. Thus, he did fall into the category of 20 to 25 percent of patients who are not able to receive adjuvant chemotherapy postoperatively. Four years after the Whipple procedure, he remains free of recurrent or metastatic cancer and works full-time.
Anatomical Diagnosis
Ductal adenocarcinoma of the pancreas, with residual microscopic tumor after chemoradiation therapy.
Pancreatic intraepithelial neoplasia, grade 3, present at the distal resection margin. Resection margins and lymph nodes free of invasive carcinoma.
Dr. Ryan reports having received consulting fees and lecture fees from Lilly Oncology.
Source Information
From the Departments of Hematology and Oncology (D.P.R.), Surgery (C.F.-C.), Radiology (D.S.), and Pathology (E.F.B.), and the Division of Gastroenterology, Department of Medicine (W.R.B.), Massachusetts General Hospital, Boston; the Departments of Medicine (D.P.R., W.R.B.), Surgery (C.F.-C.), Radiology (D.S.), and Pathology (E.F.B.), Harvard Medical School, Boston; and the Department of Radiation Oncology, Duke University Medical Center, Durham, N.C. (C.G.W.).
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