Diagnosis and assessment of resectability for neoplasms of the pancreas and periampullary region

Diagnosis and Assessment of Resectability for Neoplasms of the Pancreas and Periampullary Region Douglas B. Evans, MD, and Richard A. Erickson, MD

cancer is the fifth leading cause of adult p ancreatic cancer-related death (following lung, colon, breast, and prostate cancers), accounting for approximately 28,200 deaths in the United States in 2000. Patient survival depends on the extent of disease and the patient's overall health status at the time of diagnosis. The extent of disease is best categorized as resectable, locally advanced, or metastatic based on the results of high-quality imaging studies. Operative intervention benefits only those patients who undergo complete resection; it adds only morbidity (with no oncologic value) for those who undergo laparotomy without complete resection. Thus, the preoperative assessment of local tumor resectability and the presence or absence of extrapancreatic metastatic disease is critical to the development of effective stage-specific therapy for patients with pancreatic cancer.

Diagnosis and Clinical (Radiographic) Staging Biliary obstruction is usually evaluated with abdominal ultrasonography to confirm the mechanical nature of the obstruction and determine whether the site of obstruction is the intrahepatic or extrahepatic portion of the biliary tree. Obstruction of the intrapancreatic portion of the bile duct is then evaluated with a combination of computed tomography (CT), endoscopic retrograde cholangiopancreatography (ERCP; see Fig 2), and endoscopic ultrasonography (EUS; see Fig 3). Our diagnostic schema for patients with suspected pancreatic cancer (Fig 1) is based on the following principles: 1. Laparotomy should be therapeutic, not diagnostic. If the primary tumor cannot be resected completely, then pancreatoduodenectomy for pancreatic cancer offers no therapeutic or survival advantage.

From the Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, and the Division of Gastroenterology, Scott & White Clinic, Temple, TX. Supported by the Various Donors Fund for Pancreatic Cancer Research at The University of Texas M. D. Anderson Cancer Center. Address reprint requests to Douglas B. Evans, MD, Department of Surgical Oncology, Box 106, U.T.M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030. Copyright 9 2001 by W.B. Saunders Company 1524-153X/01/0301-0001535.00/0 doi:10.1053/otgn.2001.21538

However, at many institutions, only 30% to 50% of patients who undergo a planned pancreatoduodenectomy have their tumors successfully removed; the remainder are found to have unsuspected liver or peritoneal metastases or local t u m o r extension to the mesenteric vessels. The recent use of laparoscopy for detection of CT-occult liver and peritoneal metastases has increased resectability rates. Nonetheless, assessm e n t of local tumor resectability remains a major problem in the surgical treatment of pancreatic cancer. Following pancreatoduodenectomy, positive margins of resection are commonly found, and in these patients the duration of survival is less than one year, no different from that achieved with palliative chemotherapy and irradiation in patients who have locally advanced, unresectable disease. This suggests that intraoperative assessment of local tumor resectability is inaccurate. Traditionally, intraoperative assessment of local tumor resectability involved two maneuvers, a Kocher maneuver to assess the relationship of the primary tumor to the superior mesenteric artery (SMA) and dissection of the neck of the pancreas from the anterior surface of the superior mesenteric vein-portal vein (SMV-PV) confluence to assess the relationship of the primary tumor to the superior mesenteric vein (SMV) and portal vein (see Figs 4 and 5). But for larger tumors, tumors containing significant peritumoral fibrosis, or reoperative cases (following a previous unsuccessful attempt at pancreatoduodenecomy), it is impossible to assess by palpation the relationship of the primary tumor to the SMA (after mobilization of the duodenum and pancreatic head) with any reasonable degree of accuracy. Similarly, regarding the relationship of a pancreatic head tumor to the SMV, tumors of the pancreatic head or uncinate process are prone to invade the lateral or posterior wall of the SMV. This invasion can be directly viewed only after gastric and pancreatic transection, by which time the surgeon has already committed to pancreatoduodenectomy (even if the entire tumor cannot be removed). We believe that the relationship of the primary tumor to the mesenteric vessels should be assessed by using high-quality CT before laparotomy. With high-quality CT images, resectability rates should be as high as 75% to 80%, and grossly positive resection margins should rarely occur.

Operative T e c h n i q u e s in General Surgery, Vol 3, No 1 (March), 2001: pp 5-16

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Diagnostic Schema for Patients With Suspected Pancreatic Cancer Contrast-enhanced thin-section CT

Unresectable

Resectable*

No low-attenuation mass in the pancreatic head

Low-attenuation mass in the pancreatic head

V EUS-guided FNA (if tissue diagnosisnot obtainedat prior laparotomy)

Positive

EUS ERCP

Negative

External-beam radiation therapy and chemotherapy (chemoradiation) Laparotomy for planned pancreatoduodenectomy

Restaging CT scan

Unresectable

Resectable*

*No extrapancreatic disease, no evidence of tumor extension to the SMA or celiac axis, patent superior mesenteric-portal vein confluence

1 Management algorithm for patients with suspected or biopsy-proven (from laparotomy before referral) adenocarcinoma of the pancreatic head or periampullary region. Patients without a histologic or cytologic diagnosis of adenocarcinoma who have a low-attenuation mass in the pancreatic head (on contrastenhanced CT) are subjected to EUS-guided FNA biopsy. The more widespread use of EUS-guided FNA biopsy will allow the frequent use of preoperative (neoadjuvant) chemoradiation. Patients with extrahepatic biliary obstruction in the absence of a mass in the pancreas undergo ERCP and EUS. EUS may identify a CT-occult pancreatic mass in some patients, making possible FNA biopsy and thus neoadjuvant therapy. Patients without a tissue diagnosis of malignancy who have clinical and radiologic findings suggesting a pancreatic or periampullary neoplasm undergo pancreatoduodenectomy; in general, we do not consider chemoradiation in the absence of a positive biopsy result. Such patients often have a neoplastic stricture of the intrapancreatic portion of the common bile duct on ERCP in the absence of a mass seen on CT or EUS.

PancreaticandPeriampullaryNeoplasms 2. Palliative laparotomy should be avoided when possible. In patients with locally advanced or metastatic pancreatic cancer, operation for palliation is rarely needed. Multiple studies have compared operative biliary decompression and endoscopic stent placement in patients with jaundice from malignant obstruction of the intrapancreatic portion of the common bile duct. The higher initial morbidity and mortality rates and longer hospital stays associated with operative biliary bypass are countered by the higher frequency of hospital readmission for stent occlusion and cholangitis with endoscopic stent placement. Physicians typically advocate either operative bypass or endoscopic stenting; however, a selective approach based on the extent of disease and patient performance status is more appropriate. Endoscopic stenting should be performed on an outpatient basis in all patients who are not candidates for pancreatoduodenectomy. In patients who have a life expectancy of three to five months (eg, those with liver or peritoneal metastases), an 11.5Fr polyethylene stent is placed. In patients who have a life expectancy of six to 12 months (ie, those with locally advanced, nonmetastatic disease), a self-expanding metal stent is preferred. Patients who develop early stent occlusion or migration or who appear to do poorly with endoscopic biliary decompression are quickly referred for operative biliary bypass. A multidisciplinary approach to these patients is critical, and the medical oncologist, gastroenterologist, and surgeon must communicate with each other and avoid overly dogmatic approaches to palliative care.

Computed Tomography To determine the extent of local-regional disease, highquality contrast-enhanced helical CT is used to define the relationship of the tumor to the celiac axis and the superior mesenteric vessels (see 6, 7, and 8). In the absence of extrapancreatic disease, the main goal of preoperative imaging studies is to determine the relationship of the low-density tumor mass to the SMA and celiac axis. This information enables accurate prediction of the likelihood of obtaining a negative retroperitoneal margin of resection. The retroperitoneal margin, also termed the mesenteric margin, corresponds to the tissue along the proximal three to four cm of the SMA (see 9). The following CT criteria define potentially resectable disease: 9 the absence of extrapancreatic disease 9 the absence of direct tumor extension to the SMA and celiac axis, as defined by the presence of a fat plane between the low-density tumor and these arterial structures 9 a patent SMV-PV confluence. The third criterion is based on the assumption that resection and reconstruction of the SMV or SMV-PV confluence are possible.

7 Pancreatic Biopsy In most patients, accurate staging and biliary decompression are achieved with CT and ERCP. Before treatment with systemic therapy or external-beam irradiation, confirmation of malignancy is required in all patients with metastatic disease. Tissue confirmation of adenocarcinoma can usually be easily obtained in such patients through biopsy of metastatic sites (eg, ultrasound-guided liver biopsy, paracentesis). In patients thought to have localized (resectable and unresectable) pancreatic cancer, EUS-guided fine-needle aspiration (FNA) is currently the procedure of choice for obtaining a cytologic diagnosis of malignancy. Recent reports of EUS-guided FNA of the pancreas have demonstrated its accuracy and safety. In patients with potentially resectable pancreatic or periampullary cancer (so determined based on preoperative imaging studies), preoperative biopsy is not needed if pancreatoduodenectomy (and postoperative adjuvant therapy) is planned. Because a negative biopsy in the appropriate clinical setting is usually due to a sampling error and thus should not influence the decision to proceed with pancreatoduodenectomy, most experienced pancreatic surgeons believe preoperative or intraoperative pancreatic biopsy to be unnecessary. However, in at least 5% to 10% of patients who undergo pancreatoduodenectomy (without a preoperative pathologic diagnosis) for a presumed pancreatic or periampullary adenocarcinoma, final pathologic review of the resected specimen reveals either benign disease (focal pancreatitis) or another histologic diagnosis. Therefore, it is generally accepted that preoperative chemoradiation, when used in patients with potentially resectable disease (before planned pancreatoduodenectomy), should be administered only on cytologic confirmation of malignancy. The growing popularity of neoadjuvant therapy is due in part to the ability to safely obtain a tissue diagnosis o[ cancer (by EUS-guided FNA) in patients with small resectable tumors.

Laparoscopy and Angiography Over the past decade, laparoscopy has been used in patients with radiologic evidence of localized pancreatic cancer to detect extrapancreatic tumors not seen on CT scans, thereby allowing laparotomy to be limited to patients with truly localized disease. The favorable initial experience with laparoscopy in the frequent identification of CT-occult metastatic disease resulted from laparoscopy being done in the absence of high-quality contrast-enhanced CT. Because most patients with pancreatic cancer have metastatic disease at the time of diagnosis, laparoscopy will have a high yield of positive findings if done early in the diagnostic sequence before high-quality CT. More recent studies on the use of laparoscopy in patients with potentially resectable pancreatic cancer sug-

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gest that CT-occuh extrapancreatic disease is found in only 10% to 15% of patients with tumors deemed resectable following high-quality CT. Thus, performing laparoscopy as a separate staging procedure may be hard to justify. However, laparoscopy performed immediately before laparotomy (under a single anesthesia induction) may avoid unnecessary laparotomy in 10% to 15% of patients with presumed resectable pancreatic cancer. Angiography was traditionally used to assess the relationship of the primary tumor to the SMA and SMV. But

angiography allows contrast enhancement of the vessel lumen only; the surrounding tumor and soft tissues cannot be evaluated. Thus, most pancreatic surgeons limit angiography to reoperative cases, in which identification of aberrant hepatic arterial anatomy may prevent iatrogenic injury during portal dissection when extensive scarfing from a previous biliary procedure is present. We previously reported a replaced or accessory right hepatic artery arising from the SMA in 26% of patients who underwent reoperative pancreatoduodenectomy.

SURGICAL TECHNIQUE

2 ERCP showing the typical "double-duct cutoff' sign representing proximal obstruction of the common bile duct (cbd) and pancreatic duct (pd) seen in a patient with adenocarcinoma of the pancreatic head. A malignant obstruction can often be accurately differentiated from choledocholithiasis and the long, smooth tapering bile duct stricture seen with chronic pancreatitis. To prevent cholangitis in patients with extrahepatic biliary obstruction who undergo diagnostic ERCP, we routinely place endoscopic stents. We also place endoscopic stents in patients with elevated bilirubin levels who are enrolled in preoperative chemoradiation protocols.

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Pancreatic and Periampullary Neoplasms

3 Linear EUS image of EUS-guided FNA of a 2.5 • 2.1-cm tumor (mass) in the uncinate portion of the pancreatic head. Two passes were made with a 22-gauge needle (FNA), yielding poorly differentiated adenocarcinoma. The SMV and SMA are shown deep to the lesion.

Duodenum

SMV SMA

Ao~a

]cava

4 Illustration of one of the two maneuvers traditionally done to assess local tumor resectability at the time of laparotomy. Shown here is a Kocher maneuver performed in an effort to palpate a plane of normal tissue between the firm tumor and the posterior pulsation of the SMA. Even the most experienced surgeon can have difficulty accurately assessing the tumor-SMA relationship with this maneuver, especially if the tumor is large or in the setting of peritumoral inflammation secondary to parlcreatitis, recent ERCP, or after pancreatic biopsy. We do not feel that accurate intraoperative assessment of local tumor resectability is possible before gastric and pancreatic transection, at which point the surgeon has committed to pancreatoduodenectomy. The difficulty in assessing the relationship of the tumor to the posterior pulsation of the SMA makes accurate preoperative assessment of this critical tumor-vessel relationship mandatory. Thin-section contrast-enhanced CT is currently the imaging modality of choice for assessing the relationship of the primary tumor to the SMA.

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Evans and Erickson

......

...:.z~..~

Gastroduodenal artery

Portal vein '

\

Splenic vein

",x, SMV

1

.

"SMA

,

5 Illustration of the second maneuver commonly performed to assess local tumor resectability at the time of laparotomy. This maneuver also is unnecessary. It was assumed that if the surgeon could separate the SMV and PV from the neck of the pancreas, then tumor involvement of the SMV or SMV-PV confluence was unlikely. In contrast, if such tumor involvement was present, then it was assumed that the patient had locally advanced, unresectable disease. But there is no anatomic rationale for this maneuver early in the operation, because tumors of the pancreatic head or uncinate process do not invade the anterior wall of the SMV or PV as do locally advanced tumors of the pancreatic neck or body. We do not perform this maneuver, because a tumor-free plane can often be developed despite fixation of the tumor to the lateral wall of the SMV. This maneuver may incorrectly suggest no tumor adherence to the SMV, with adherence then found after pancreatic transection. Further, the maneuver can cause bleeding early in the operation, long before the surgeon is prepared to proceed with pancreatic transection. Surgeons who perform pancreatoduodenectomy need to be trained in techniques for resection and reconstruction of the SMV or SMV-PV confluence, as venous involvement is frequently found after pancreatic transection that cannot be accurately assessed early in the operation.

Pancreatic and Periampullary Neoplasms

6 Contrast-enhanced helical CT scan demonstrating a resectable adenocarcinoma of the pancreatic head. Note the normal fat plane between the lowdensity tumor and both the SMA (small arrow) and the SMV (large arrow). The tumor clearly does not extend to either the superior mesenteric artery or vein. For CT, we currently prefer helical CT scanning. The patients receive 240 to 280 mL of water or 2% barium sulfate suspension (Readi-CAT; E-Z-EM Inc, Westbury, NY) to opacify the stomach and small bowel. Non-contrastenhanced CT scans are obtained through the liver and pancreas at 10-ram slice thickness and 10-mm scan interval to identify liver metastases and localize the pancreas. Intravenous (IV) contrast enhancement is achieved with nonionic contrast material (300 to 320 mg of iodine/mL) administered by an automatic injector at a rate of three to five millileters per second for a total of 150 mL. At least two phases of helical scanning are performed. The pancreatic parenchyma phase starts at 30 to 40 seconds after delivery of the IV contrast material, with a scan time of 20 seconds to cover the liver and pancreas. This phase is done at 2.5- to five-millimeter slice thickness and is the best phase for detecting pancreatic neoplasms. The second phase, for metastatic screening of the liver and abdomen, begins 60 to 65 seconds after the start of IV injection to cover the entire liver and upper abdomen; this phase is done at five- to seven-millimeter slice thickness.

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Duod~

7 Contrast-enhanced CT scan (A) and illustration (B) showing adenocarcinoma of the pancreatic head with focal tumor extension to the lateral wall of the SMV (large arrow). In this case, pancreatoduodenectomy will likely require resection and reconstruction of the SMV. On the CT image, the area of low density tumor extends to the SMVjust inferior to the large arrow; the small arrow points to the SMA. A normal fat plane lies between the low-density tumor and the SMA. The intrapancreatic portion of the common bile duct contains a stent which was endoscopically placed for biliary drainage. (IVC, inferior vena cava; LRV, left renal vein.)

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Pancreatic and Periampullary Neoplasms

SMV Vein Involved

B

SMA

Artery Involved

8 Contrast-enhanced CT scan (A) and illustration (B) demonstrating an unresectable adenocarcinoma of the head and uncinate process of the pancreas. On the CT image, the low-density tumor is inseparable from the posterior wall of the SMA (open arrow), and a tumor thrombus can be seen in the adjacent SMV. This patient does not require laparotomy to confirm these findings on CT.

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Evans and Erickson

margin

:lenal artery

9 Operative illustration (A), specimen photograph (B), and specimen illustration (C) of the retroperitoneal margin as defined at the time of tumor resection. (A) Medial retraction of the SMV and PV facilitates dissection of the soft tissues adjacent to the lateral wall of the proximal SMA; this site represents the retroperitoneal margin. Complete permanent section analysis of the pancreatoduodenectomy specimen necessitates orienting it to enable the pathologist to accurately assess the retroperitoneal margin of excision and other standard pathologic variables. Because we advocate removing all tissue to the right of the SMA, further resection at the retroperitoneal margin is not possible. But this margin must be identified and inked by the pathologist and cannot be assessed retrospectively. A grossly positive retroperitoneal margin should not occur if high-quality preoperative CT is performed. A microscopically positive retroperitoneal margin occurs in 10% to 20% of cases.

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Pancreatic and Periampullary Neoplasms

gin

P~

•• :~

Q-tip applicator lying on indentation of SMV-PV confluence

C

9 (continued The specimen photograph (B) and illustration (C) show how the retroperitoneal margin (tissue adjacent to the SMA) is inked for evaluation of margin status on permanent section histologic evaluation. A small probe is in the bile duct; just inferior to the small probe, a slightly larger probe lies within the pancreatic duct. A white cotton-tipped applicator stick lies over the indentation from the SMV-PV confluence. Complete permanent section analysis of the pancreatoduodenectomy specimen necessitates orienting it to enable the pathologist to accurately assess the retroperitoneal margin of the excision and other standard pathologic variables.

16 Summary

CT remains the initial study of choice for determining whether a patient has potentially resectable, locally advanced, or metastatic pancreatic cancer; such clinical staging is critical for accurate treatment planning. EUS has become the preferred method of tissue acquisition through the use of EUS-guided FNA biopsy. ERCP remains an important diagnostic tool, and endobiliary stenting is the preferred initial therapy for biliary obstruction. The extent to which laparoscopy should be used remains controversial. Laparoscopy is reasonable to consider before laparotomy (during the same anesthesia induction) in patients with biopsy-proven or suspected potentially resectable pancreatic cancer in whom a decision has been made to proceed with pancreatoduodenectomy. Pancreatoduodenectomy should be considered only in those patients whose tumors appear to be resectable based on high-quality CT and who have a good performance status. Furthermore, pancreatoduodenectomy should be part of a muhimodality treatment program that includes preoperative or postoperative chemoradiation. Because of the modest survival rates associated with current treatments, the enrollment of all patients into clinical trials of new combinations of surgery, chemoradiation, and newly developed systemic drugs is strongly encouraged. Future progress in the treatment of pancreatic cancer will involve techniques for early diagnosis and effective systemic therapy. For now, the best results can be achieved by careful attention to patient selection, preoperative assessment of resectability, surgical technique, and postoperative care. Acknowledgment The authors thank Kathleen Wagner for preparation of all illustrations.

Evans and Erickson

RECOMMENDED

READINGS

1. Espat NJ, Brennan MF, Conlon KC: Patients with laparoscopically

staged unresectable pancreatic adenocarcinoma do not require subsequent surgical biliary or gastric bypass. J Am Coll Surg 188: 649-655, 1999 2. Evans DB, Abbruzzese JL, Willett CG: Cancer of the pancreas, in

DeVita VT, Hellman S, Rosenberg SA (eds): Cancer, Principles and Practice of Oncology (ed 6). Philadelphia, PA, Lippincott 3. Evans DB, Lee JE, Pisters PWT: Pancreaticoduodenectomy (Whipple operation) and total pancreatectomy for cancer, in Nyhus LM, Baker RJ, Fischer JF (eds): Mastery of Surgery (ed 3). Boston, MA, Little, Brown, 1997, pp 1233-1249 4. Fuhrman GM, Charnsangavej C, Abbruzzese JL, et al: Thin-section contrast enhanced computed tomography accurately predicts resectability of malignant pancreatic neoplasms. Am J Surg 167: 104-111, 1994 5. Pisters PWT, Hudec WA, Lee JE, et al: Preoperative chemoradia-

tion for patients with pancreatic cancer: Toxicity of endobiliary stents. J Clin Oncol 18:860-867, 2000 6. Pisters PWT, Hudec WA, Hess KR, et al: Effect of preoperative biliary decompression on pancreaticoduodenectomy-associated morbidity in 300 consecutive patients. Ann Surg 7. Robinson EK, Lee JE, Lowy AM, et al: Reoperative pancreaticoduodenectomy for periampullary carcinoma. Am J Surg 172: 432-437, 1996 8. Suits J, Frazee R, Erickson RA: Endoscopic ultrasound and fine

needle aspiration for the valuation of pancreatic masses. Arch Surg 134:639-643, 1999 9. Tyler DS, Evans DB: Reoperative pancreaticoduodenectomy. Ann Surg 219:211-221, 1994 10. WiUett C, Lewandrowski K, Warshaw A, et al: Resection margins

in carcinoma of the head of the pancreas. Implications for radiation therapy. Ann Surg 217:144-148, 1993 11. Whipple AO, Parsons WW, Mullin CR: Treatment of carcinoma of the ampulla of Vater. Ann Surg 102:763-269, 1935