PERSPECTIVE, PATTERNS OF SPREAD, AND PATHOLOGY
Painless jaundice suggests the head of the pancreas; pain in the back, worse at night, suggests the body of the pancreas. Invasion of the pancreas tail is usually silent.
PERSPECTIVE AND PATTERNS OF SPREAD
Cancer of the pancreas has been increasing in recent decades. There are >40,000 new patients annually, most of whom die within 1 to 2 years; there is a dismal 6% 5-year survival rate. The causative factors remain obscure; no dietary relationship is evident, and no high-risk group has been identified to receive more intensive screening of the pancreas. Painless jaundice suggests the head of the pancreas; pain in the back, worse at night, relieved by sitting up or rolling to the side, suggests the body of the pancreas is involved. Invasion of the pancreas tail is usually silent and invariably found postmortem in patients who died with severe cachexia. Cancer of the pancreas ranks as the fourth cause of cancer deaths. Patterns of spread for pancreatic cancer (Fig 28.1A) is contrasted with cancer of the Ampulla of Vater, which tends to be more confined (Fig. 28.1B; Table 28.1).
PATHOLOGY
The histogenesis of pancreatic cancers applies to its exocrine cell activities, not its endocrine activities, which relate to islands of Langerhans cells. The World Health Organization tabulation of carcinomas is long and varied (Fig. 28.2; Table 28.2).
Pancreatic cancer (PCC) is the second-most-common malignancy of the digestive system and one of the most lethal. Only 20% of patients live 1 year, and 5% live 5 years, making it the fourth-leading cause of cancer death.
• Hereditary pancreatitis has an abnormal trypsin gene, and the risk of patients for developing pancreatic cancer is 40%.
• Patients with chronic relapsing pancreatitis have an increased risk of 2% per decade.
• Patients with familial Peutz–Jeghers syndrome have a risk as high as 36%.
• New sudden-onset diabetes mellitus is very common (>50%) and is attributed to higher production of islet amyloid polypeptide (amylin) by the cancer.
• Three general genetic alterations occur in carcinogenesis of PCC: activation of oncogenes, inactivation of suppressor genes, and DNA mismatch repair genes. K-ras gene mutations are present in 90% of PCC and, in combination with suppressor gene CDK2A/p16, may be a “molecular signature” for PCC.
• Courvoisier sign is an acute palpable gallbladder dilation accompanied by jaundice due to obstruction of the common bile duct due to cancer of the head of the pancreas.
• Trousseau syndrome of migrating thrombophlebitis suggests PCC of body or tail of the pancreas and can occur in multiple veins due to tissue thromboplastin from tumor necrosis.
The major change in the seventh edition of the AJCC Cancer Staging Manual is the addition of neuroendocrine carcinoid tumors with a much improved outcome (55% 5-year survival) compared to adenocarcinomas.
Figure 28.1 | A. Patterns of spread for pancreas. Color coded for T stage: Tis, yellow; T1, green; T2, blue; T3, purple; T4, red. B. Patterns of spread for the ampulla of Vater. Color coded for T stage: Tis, yellow; T1, green; T2, blue; T3, purple; T4, red. The concept of visualizing patterns of spread to appreciate the surrounding anatomy is well demonstrated by the six-directional pattern, i.e., SIMLAP Table 28.1A. Pancreas, Table 28.1B. Ampulla of Vater.
Figure 28.2A-D | A. Carcinoma: A section of the tumor reveals malignant glands embedded in a dense fibrous stroma. A nerve (arrow) shows perineural invasion. B. Insulinoma: Nests of tumor cells are surrounded by numerous capillaries. C. Somatostatinoma: somatostatin in sparsely distributed delta cells. D. Glucagonoma: glucagon in alpha cells at the periphery of the islet. E. Secretory product and physiological action of neuroendocrine tumors.
Neuroendocrine tumors although uncommon are currently staged in a similar fashion as carcinomas, whether they are considered benign or malignant. Their secretary product and physiological action are noted in Fig. 28.1E. Because they are rare, factors other than T and N stage as age, degree of differentiation, impact of functional status on host are prognostic factors.
TNM STAGING CRITERIA
TNM STAGING CRITERIA
The pancreas is both intraperitoneal and retroperitoneal in location. Situated in the epigastrium, the cancer can and does invade adjacent structures. Size is the major factor in staging: T1, 2 cm and T2, >2 cm, limited to pancreas. Involvement of the celiac axis and superior mesenteric artery (SMA) renders the cancer T4 and nonresectable (Fig. 28.3A).
Each section of the pancreas has a critical adjacent structure that determines the clinical course as mentioned, but does not affect staging. Despite the intimate contact anteriorly with stomach, duodenum, colon, spleen, and kidneys, pancreatic cancers rarely invade these viscera; however, peritoneal seeding is common and can lead to massive ascites.
Generally, there is no overarching principle or context design for the digestive system (gastrointestinal tract) or major digestive glands (MDGs). Stages are frequently expanded to six by subdividing stages into A and B. The T and N categories are assigned to a stage grouping—specifically for division of a stage into more (a) versus less (b) favorable groupings. This occurs at different stages for different sites.
There is a direct relationship between N category and stage II progression with stage: IIA = N0 and IIB = N1.
The distinction between T3 and T4 reflects the border between resectable and unresectable cancers, respectively. M1 has been expanded to include positive peritoneal washings and ascites cells and for cancer seeding.
SUMMARY OF CHANGES SEVENTH EDITION AJCC
• Pancreatic neuroendocrine tumors (including carcinoid tumors) are now staged by a single pancreatic staging system.
• Survival tables and figures have been added for adenocarcinoma and neuroendocrine tumors.
• The definitions of TNM and the Anatomic Stage/Prognostic Groupings for this chapter have not changed from the sixth edition for exocrine tumors.
The TNM Staging Matrix is color coded for identification of Stage Group once T and N stages are determined (Table 28.3).
PANCREAS
Figure 28.3A | TNM staging diagram presents a vertical arrangement with color bars encompassing TN combinations showing progression. Pancreatic cancers are generally advanced, stage IIB (purple), and N1 borderline resectable. Stage III (red) are unresectable, and stage IV (black) are metastatic. Stage 0, yellow; I, green; IIA, blue; IIB, purple; III, red; and stage IV (metastatic), black. Definitions of TN on left and stage grouping on right.
AMPULLA OF VATER
Perspective and Patterns of Spread
Carcinomas of the ampulla of Vater reflect its complex anatomy although it is only 1.5 cm long. Remarkably, it has the highest rate of malignant transformation in the small intestine, likely due to interactions of bile, pancreatic enzymes, and duodenal content. Neoplastic transformation is similar to that of the colon, with transition of adenomas to adenocarcinomas with evidence of biassociation of 80% to 90%, that is, the adenocarcinoma is surrounded by benign adenoma. The average for adenomas is 50 years of age and of adenocarcinomas is 60 years of age, adding credence for the evolution to cancer.
Cancers in the distal portion of the bile duct at its confluens with the pancreatic duct are uncommon. The reason to be aware of these periampullary cancers is that they may offer a better chance for survival than that of the more common cancer in their neighborhood, cancer of the pancreas. The onset is insidious and unexplained persistent itching; slight alterations in the color of stool and urine are the precursors to frank jaundice. Mirizzi syndrome, idiopathic focal stenosis, or sclerosing cholangitis, referred as the “malignant masquerade,” is a hopeful entity in the differential diagnosis. Classically, Mirizzi syndrome is caused by a large gallstone impacted in the neck of the gallbladder causing biliary obstruction because of periductal inflammation.
• Familial adenomatous polyposis and Peutz–Jeghers syndrome have higher incidence of ampullary adenomas, ranging from 50% to 86%.
• Obstructive jaundice is seen in 80% of cases, and weight loss, abdominal pain, and occult bleeding occur.
• Silver stools are due to blood without bile.
Classification and Staging
Three distinct macroscopic subtypes occur: sclerosing, nodular, and papillary. With the sclerosing variety, diffuse or annular thickening or stricturing of the bile duct occurs, often associated with inflammatory disease. Nodular cancers project into the lumen, and papillary cancers are soft and friable but with a better prognosis because transmural invasion is less often seen. These tumors are more often encountered in the ductal part of the bile duct. Adenocarcinomas are most frequent at the site and have been referred to as periampullary or peripapillary, reflecting the normal anatomy (Fig. 28.2A; Table 28.2).
TNM Staging Criteria
The accuracy in staging is most often apparent after resection and dissection of the specimen. T1 is limited to the ampulla of Vater or the sphincter of Oddi, T2 invades the duodenal wall, T3 invades the pancreas, and T4 invades more extensively in peripancreatic tissues and adjacent organs and structures such as stomach, colon, and small intestines (Fig. 28.3B).
The nodal designation is simply N1, and the sentinel nodes are the pancreaticoduodenal lymph nodes. The regional nodes are in the porta hepatis region surrounding the hepatic artery and portal vein and juxtaregional paracaval and para-aortic nodes.
Summary of Changes Seventh Edition AJCC
• This staging system is the same for the seventh edition.
The TMN Staging Matrix is color coded for identification of Stage Group once T and N stages are determined (Table 28.3B).
T-ONCOANATOMY
The anatomic isocenter is at the L2 level surrounded by pancreas and duodenum. (i) The anterior bullet enters to right of the midline at the subcostal plane and (ii) the lateral bullet enters at the midcoronal plane anterior to the bodies of the upper lumbar vertebrae (Fig. 28.4).
The variation in the pancreatic duct and bile duct fusion are understandable if one reviews the developmental stages of this region (Fig. 28.4).
• Coronal: The gallbladder, bile duct, and ventral pancreas bud rotate when the duodenum rotates clockwise on its long axis during embryonic development. The fusion of the ventral and dorsal pancreatic buds results in numerous possible unions of the bile duct and pancreatic duct as it forms the ampulla of Vater.
• Transverse: The clockwise rotation is best appreciated in this view as the ventral pancreatic bud, which becomes the uncinate process, and the dorsal pancreatic bud forms the head, body, and tail of the pancreas.
• Sagittal: A variety of ampulla of Vater formations are shown, emphasizing the different fusions of the common bile duct and the main and accessory pancreatic ducts.
RULES FOR CLASSIFICATION AND STAGING
Clinical Staging and Imaging
The inability to evaluate the gallbladder, its ducts, and the ampulla of Vater has led the American Joint Committee on Cancer to simplify the staging so that both clinical and surgical criteria are the same. Imaging procedures include abdominal ultrasound, which is surpassed by computed tomography (CT) in defining biliary obstruction. Endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangiography define biliary tree anatomy. Magnetic resonance imaging with gadolinium is also useful (see Table 28.5).
AMPULLA OF VATER
Figure 28.3B | TNM staging diagram presents a vertical arrangement with color bars encompassing TN combinations showing progression. Ampulla of Vater cancers masquerade as pancreatic head cancers and are resectable as stage I and IIA, with stage IIB (purple) borderline resectable. Stage III (red) is often unresectable, and stage IV is metastatic (black). Stage 0, yellow; IA, green; IB, blue; IIB, purple; III, red; and IV (metastatic), black. Definitions of TN on left and stage grouping on right.
T-ONCOANATOMY
ORIENTATION OF THREE-PLANAR ONCOANATOMY
The anatomic isocenter for the three-planar oncoanatomy for the pancreas is at the L1/L2 level deep in the epigastrium (Fig. 28.4).
T-oncoanatomy
The T-oncoanatomy is displayed in three planar views. A. Coronal, B. Sagittal, C. Transverse axial (Fig. 28.5A).
Pancreas
• Coronal: The pancreas is a long, lobulated structure that lies transversely in the posterior abdomen, located retroperitoneally in the concavity of the duodenum on its right end and touching the spleen on its left end. The shape of the pancreas may be compared to the letter J placed sideways. It is divisible into a head with an uncinate process, a neck, a body, and a tail (Fig. 28.6A). The acinous glands of the pancreas secrete into a branching ductal network, which forms the main horizontal pancreatic duct that runs the length of the pancreas and terminates in the second portion of the duodenum after it creates a common junction with the hepatic duct at the ampulla of Vater. There is often a small accessory pancreatic duct, which has a separate opening into the duodenum. The uncinate process of the head wraps around the SMA and is hugged by the duodenum (Fig. 28.5B).
• Sagittal: The midsagittal plane shows the intimate relationship of the head of the pancreas to the SMA inferiorly. Note the retroperitoneal location of the pancreas posterior to the lesser omental bursa. However, the transverse mesocolon arising from its anterior surface allows pancreatic cancers to spread intraperitoneally and seed the peritoneal surface, once invaded.
• Transverse: The pancreas lies in the midcoronal plane and is at the divide of the retroperitoneum from the peritoneal cavity. The pancreas stretches from right kidney hilum to splenic and left renal hilum.
Figure 28.4 | Orientation and overview of oncoanatomy. The anatomic isocenter for the three-planar oncoanatomy for the pancreas and ampulla of Vater is at the L1/L2 level, deep in the epigastrium. A. Coronal. B. Sagittal. Same for ampulla of Vater.
Figure 28.5A | Pancreas T-oncoanatomy. Connecting the dots. Structures are color coded for cancer stage progression. The color code for the anatomic sites correlates with the color code for the stage group (Fig. 28.3A) and patterns of spread (Fig. 28.2A) and SIMLAP table (Table 28.2). Connecting the dots in similar colors will provide an appreciation for the 3D oncoanatomy.
Figure 28.5B | Ampulla of Vater T-oncoanatomy. Connecting the dots. Structures are color coded for cancer stage progression. The color code for the anatomic sites correlates with the color code for the stage group (Fig. 28.3B) and patterns of spread (Fig. 28.2B) and SIMLAP table (Table 28.2). Connecting the dots in similar colors will provide an appreciation for the 3D oncoanatomy.
N-ONCOANATOMY AND M-ONCOANATOMY
N-ONCOANATOMY
A rich lymphatic network surrounds the pancreas, with a left splenic and superior and inferior right-side truncal drainage. The first station nodes include the celiac, splenic, suprapancreatic, left gastropancreatic, and hepatic arteries, and inferior pancreatic, juxta-aortic, anterior pancreatic duodenal, and posterior pancreatic duodenal lymph nodes. Juxtaregional nodes include the inferior portion of the para-aortic nodal drainage and mediastinal and mesenteric nodes (Fig. 28.6A; Table 28.4).
Regional Lymph Nodes
A rich lymphatic network surrounds the pancreas, and accurate tumor staging requires that all lymph nodes that are removed be analyzed. Optimal histologic examination of a pancreaticoduodenectomy specimen should include analysis of a minimum of 12 lymph nodes. The standard regional lymph node basins and soft tissues resected for tumors located in the head and neck of the pancreas include lymph nodes along the common bile duct, common hepatic artery, portal vein, and posterior and anterior pancreaticoduodenal arcades and along the superior mesenteric vein and right lateral wall of the superior mesenteric artery. For cancers located in body and tail, regional lymph node basins include lymph nodes along the common hepatic artery, celiac axis, splenic artery, and splenic hilum. Anatomic division of regional lymph nodes is not necessary. However, separately submitted lymph nodes should be reported as labeled by the surgeon.*
*Preceding passage from Edge SB, Byrd DR, and Compton CC, et al., AJCC Cancer Staging Manual, 7th edition. New York. Springer, 2010, p. 242.
M-ONCOANATOMY
The rich venous anastomoses of pancreas and its juxtaposition to the liver make portal vein invasion and liver metastases the favored target organs. The entire portal circulation should be considered as a unit with regard to the venous anatomy of the gastrointestinal tract below the diaphragm (see Fig. 28.6B). The two major trunks are the inferior and superior mesenteric veins. The inferior mesenteric vein drains the left colon and sigmoid colon tributaries, which cover the vascular drainage to the left of the midline originating from the superior rectal veins. On the right side, the superior mesenteric vein originates from the tributaries draining the ileum, jejunum, and ileocolic and right middle colic veins. The inferior mesenteric vein usually joins the splenic vein, which coalesces with the superior mesenteric vein and forms the portal vein. The splenic vein, which is a major tributary of the portal system, also drains much of the stomach along its greater curvature and includes the short gastric veins and left and right gastroepiploic veins. The right gastroepiploic also flows into the superior mesenteric vein. The entire drainage of the lesser curvature of the stomach, including the left and right gastric veins, drains directly into the portal vein. Because the portal vein then drains directly into the liver, it is the target metastatic organ and the most commonly involved organ in the hematogenous spread pattern from the venous system of the gastrointestinal tract, as compared with other parts of the body, where the drainage is directly into the lung by way of the caval system.
The incidence of liver metastases exceeds that of other sites. According to a variety of reports in the literature, the range is 45% to 80% at autopsy. Other sites are mainly bone metastases (20% to 35%) and lung metastases (40% to 60%), with only occasional metastases to the brain.
The position of the pancreas often leads to direct invasion of the mesentery and omentum, with studding out of the peritoneal cavity with diffuse carcinomatosis and ascites.
Distant spread occurs mainly to liver and lungs, with a lesser degree of involvement of bones and brain, as well as to other anatomic sites.
Figure 28.6A | N-oncoanatomy. Sentinel nodes of the head of the pancreas and ampulla of Vater include the pancreatic duodenal nodes, as shown in a circle on the right, and those of the body and tail of the pancreas, as shown on the left.
Figure 28.6B | M-oncoanatomy. The venous drainage of the pancreas is complex in view of its length. The head of the pancreas drains into pancreatic to adrenal veins and then into the left gastroomental veins. The body and tail drain into the splenic vein along its superior border, and all of the venous drainage enters into the portal system ultimately, resulting in liver metastases.
STAGING WORKUP
RULES FOR CLASSIFICATION AND STAGING
Clinical Staging and Imaging
Clinical and pathologic classifications have been combined into a single staging system. It is important to distinguish resectable (T1, T2, and T3) from unresectable (T4). The critical feature is reliance on contrast-enhanced CT to assess whether the adjacent arterial structures—namely, the SMA or celiac axes—are involved. Portal vein involvement can also occur. Endoscopic ultrasound can be used for guiding needle biopsies. Laparoscopy is useful for detecting peritoneal seeding. ERCP is useful to place shunts when obstructions of bile ducts are present. Surgical pathologic staging requires definition of margins (Table 28.5; Fig. 28.7).
Pathologic Staging
Both partial and complete resections of pancreas and regional nodes, as well as of bile ducts and pancreatic ducts, need to be examined for margins and include the common bile duct, pancreatic neck, retroperitoneal margin, other soft tissue margins (such as posterior pancreatic), duodenum, and stomach. Special attention is required to the retroperitoneal margin adjacent to SMA. The uncinate process of head should be marked. The microscopic clearance of tumor should be recorded in millimeters. The completeness of resection depends on the clearing of the deepest point of invasion: R0, complete; R1, microscopic; and R2, macroscopic.
Oncoimaging Annotations
• When combined with needle biopsy, EUS is highly sensitive and specific. It yields the correct diagnosis with >95% accuracy.
• Multiplanar CT is highly effective in determining arterial and venous involvement and for staging. Unresectability is >76% accurate.
• Magnetic resonance imaging with gadolinium is excellent for defining extrapancreatic spread. Unresectability of >90% with gadolinium obviates the need for angiography.
• ERCP in combination with other imaging approaches is very valuable for distinguishing bile duct versus pancreatic cancer. Double duct strictures (bile duct/pancreatic duct) are associated with PCC.
• CT-guided biopsy is essential; sensitivity and specificity range from 57% to 96%; however, there are few to no false positives.
• Laparoscopy is advocated to ascertain peritoneal implants and seeding and obtain washings for cells and is essential to rule out M1.
• Staging is excellent with either CT or magnetic resonance imaging.
• Ultrasound initially reveals a dilated extrahepatic duct and intrahepatic duct system >90%.
• When direct cholangiograms are needed, a percutaneous transhepatic cholangiogram identifies the common bile duct cancer site and is preferred to ERCP.
Figure 28.7 | Axial CTs of L1 and L2 level correlate with the T-oncoanatomy transverse section (Figure 28.5A). Oncoimaging with CT is commonly applied to staging cancers, often combined with PET to determine true extent of primary cancer and involved lymph nodes. 1. Superior mesenteric vein. 2. Superior mesenteric art. 3. Left renal vein. 4. Right renal vein. 5. Inferior vena cava. 6. Pancreas. 7. Descending colon. 8. Ascending colon. 9. Duodenum. GB, gallbladder; J, jejunum; LK, left kidney; RK, right kidney.
PROGNOSIS AND CANCER SURVIVAL
PROGNOSIS
The limited number of prognostic factors are listed in Table 28.6. The prognostic factors for pancreas (Table 28.6A) differ from Ampulla of Vater (Table 28.6B).
CANCER STATISTICS AND SURVIVAL
The digestive system (gastrointestinal tract), which includes the MDG, accounts for 274,330 new patients annually, with colon and rectum responsible for >50%, with about 142,500 new diagnoses annually. Approximately half of these patients eventually die of these cancers. MDG cancers as a group are more lethal; only a handful of patients become long-term survivors. Fortunately, colon and rectal cancers are the most common, with the majority of patients becoming 5-year survivors (63%) responding to chemoradiation programs, often with the sparing of the rectal sphincter with conservative surgery. Anal cancers are the most responsive to chemoradiation (5-fluorouracil and cisplatin), eliminating the need for surgery. The 5-year survival rate is >90%, with anal sphincter preservation. This regimen has been proven to be very effective in clinical trials and to result in more long-term survivors, which is currently reflected in the literature. Liver, bile duct, and pancreatic cancers are among the poorest in terms of survival, which is often measured in months rather than years.
Specifically, the pancreas accounted for 43,140 new cancer cases and 36,800 cancer deaths (85%), with a survival (5-year) rate improvement over the last five decades of 3.4%. Currently, the 5 year survival for surgical resection vs. chemoradiation is: Stage IA, IB, 31-27% respectively vs. non-surgical Stage IA/B patients is a dismal 3-4% (Fig. 28.9A/B). More hopeful survival outcomes improves for neuroendocrine tumors if found in Stage I is 75.6%, especially islet cell and for Ampulla of Vater (Fig. 28.8 and Fig. 28.9C).
Figure 28.8 | Survival for patients with various peripancreatic tumors.
Figure 28.9 | A. Five-year survival for adenocarcinoma of the pancreas in surgical patients. B. Five-year survival for adeno-carcinoma of pancreas in nonsurgical patients. C. Five-year survival of pancreatic neuroendocrine tumor patients. (Data from Edge SB, Byrd DR, Compton CC, et al. AJCC Cancer Staging Manual, 7th ed. New York: Springer, 2010, p. 244.)