97. Meyer CG, Penn I, James L. Liver transplantation for cholangiocarcinoma: results in 207 patients.

Transplantation 2000;69(8):1633–1637.

98. Robles R, Figueras J, Turrion VS, et al. Spanish experience in liver transplantation for hilar and

peripheral cholangiocarcinoma. Ann Surg 2004; 239(2):265–271.

99. Rea DJ, Munoz-Juarez M, Farnell MB, et al. Major hepatic resection for hilar cholangiocarcinoma:

analysis of 46 patients. Arch Surg 2004;139(5):514–523; discussion 523–525.

100. Sudan D, DeRoover A, Chinnakotla S, et al. Radiochemotherapy and transplantation allow longterm survival for nonresectable hilar cholangiocarcinoma. Am J Transplant 2002;2(8):774–779.

101. Kipp BR, Stadheim LM, Halling SA, et al. A comparison of routine cytology and fluorescence in situ

hybridization for the detection of malignant bile duct strictures. Am J Gastroenterol

2004;99(9):1675–1681.

102. McMasters KM, Tuttle TM, Leach SD, et al. Neoadjuvant chemoradiation for extrahepatic

cholangiocarcinoma. Am J Surg 1997;174(6):605–608.

103. Klempnauer J, Ridder GJ, von Wasielewski R, et al. Resectional surgery of hilar

cholangiocarcinoma: a multivariate analysis of prognostic factors. J Clin Oncol 1997;15(3):947–954.

104. Nagino M, Nimura Y, Kamiya J, et al. Segmental liver resections for hilar cholangiocarcinoma.

Hepatogastroenterology 1998;45(19):7–13.

105. Nakeeb A, Tran KQ, Black MJ, et al. Improved survival in resected biliary malignancies. Surgery

2002;132(4):555–563.

106. Jarnagin WR, Fong Y, DeMatteo RP, et al. Staging, resectability, and outcome in 225 patients with

hilar cholangiocarcinoma. Ann Surg 2000; 234(4):507–517.

107. Jang JY, Kim SW, Park DJ, et al. Actual long-term outcome of extrahepatic bile duct cancer after

surgical resection. Ann Surg 2005;241(1):77–84.

108. Konstadoulakis MM, Roayaie S, Gomatos IP, et al. Aggressive surgical resection for hilar

cholangiocarcinoma: is it justified? Audit of a single center’s experience. Am J Surg

2008;196(2):160–169.

109. Yubin L, Chihua F, Zhixiang J, et al. Surgical management and prognostic factors of hilar

cholangiocarcinoma: experience with 115 cases in China. Ann Surg Oncol 2008;15(8):2113–2119.

110. Blumgart LH, Hadjis NS, Benjamin IS, et al. Surgical approaches to cholangiocarcinoma at

confluence of hepatic ducts. Lancet 1984;1(8368):66–70.

111. Reding R, Buard JL, Lebeau G, et al. Surgical management of 552 carcinomas of the extrahepatic

bile ducts (gallbladder and periampullary tumors excluded). Results of the French Surgical

Association Survey. Ann Surg 1991;213(3):236–241.

112. Lieser MJ, Barry MK, Rowland C, et al. Surgical management of intrahepatic cholangiocarcinoma: a

31-year experience. J Hepatobiliary Pancreat Surg 1998;5(1):41–47.

113. Berdah SV, Delpero JR, Garcia S, et al. A western surgical experience of peripheral

cholangiocarcinoma. Br J Surg 1996;83(11):1517–1521.

114. Fong Y, Blumgart LH, Lin E, et al. Outcome of treatment for distal bile duct cancer. Br J Surg

1996;83(12):1712–1715.

115. Nakeeb A, Pitt HA, Sohn TA, et al. Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and

distal tumors. Ann Surg 1996;224(4):463–473; discussion 473–475.

116. Jarnagin WR, Burke E, Powers C, et al. Intrahepatic biliary enteric bypass provides effective

palliation in selected patients with malignant obstruction at the hepatic duct confluence. Am J Surg

1998;175(6):453–460.

117. Glattli A, Stain SC, Baer HU, et al. Unresectable malignant biliary obstruction: treatment by selfexpandable biliary endoprostheses. HPB Surg 1993;6(3):175–184.

1656

118. Kuvshinoff BW, Armstrong JG, Fong Y, et al. Palliation of irresectable hilar cholangiocarcinoma

with biliary drainage and radiotherapy. Br J Surg 1995;82(11):1522–1525.

119. Lee BH, Choe DH, Lee JH, et al. Metallic stents in malignant biliary obstruction: prospective longterm clinical results. AJR Am J Roentgenol 1997;168(3):741–745.

120. Rumalla A, Baron TH, Wang KK, et al. Endoscopic application of photodynamic therapy for

cholangiocarcinoma. Gastrointest Endosc 2001;53(4):500–504.

121. Yee K, Sheppard BC, Domreis J, et al. Cancers of the gallbladder and biliary ducts. Oncology

(Williston Park) 2002;16(7):939–946, 949; discussion 949–950, 952–953, 956–957.

122. Stemmler J, Heinemann V, Schalhorn A. Capecitabine as second-line treatment for metastatic

cholangiocarcinoma: a report of two cases. Onkologie 2002;25(2):182–184.

123. Meyerhardt JA, Zhu AX, Stuart K, et al. Phase-II study of gemcitabine and cisplatin in patients with

metastatic biliary and gallbladder cancer. Dig Dis Sci 2008;53(2):564–570.

124. Thongprasert S, Napapan S, Charoentum C, et al. Phase II study of gemcitabine and cisplatin as

first-line chemotherapy in inoperable biliary tract carcinoma. Ann Oncol 2005;16(2):279–281.

125. Oberfield RA, Rossi RL. The role of chemotherapy in the treatment of bile duct cancer. World J Surg

1988;12(1):105–108.

126. Borghero Y, Crane CH, Szklaruk J, et al. Extrahepatic bile duct adenocarcinoma: patients at high

risk for local recurrence treated with surgery and adjuvant chemoradiation have an equivalent

overall survival to patients with standard-risk treated with surgery alone. Ann Surg Oncol

2008;15(11):3147–3156.

127. Fletcher MS, Brinkley D, Dawson JL, et al. Treatment of high bileduct carcinoma by internal

radiotherapy with iridium-192 wire. Lancet 1981; 2(8239):172–174.

128. Iwasaki Y, Ohto M, Todoroki T, et al. Treatment of carcinoma of the biliary system. Surg Gynecol

Obstet 1977;144(2):219–224.

129. Kopelson G, Gunderson LL. Primary and adjuvant radiation therapy in gallbladder and extrahepatic

biliary tract carcinoma. J Clin Gastroenterol 1983;5(1):43–50.

130. Ikeda H, Kuroda C, Uchida H, et al. [Intraluminal irradiation with iridium-192 wires for

extrahepatic bile duct carcinoma–a preliminary report (author’s transl)]. Nihon Igaku Hoshasen

Gakkai Zasshi 1979; 39(12):1356–1358.

131. Todoroki T, Iwasaki Y, Okamura T, et al. Intraoperative radiotherapy for advanced carcinoma of

the biliary system. Cancer 1980;46(10):2179–2184.

132. Shiina T, Mikuriya S, Uno T, et al. Radiotherapy of cholangiocarcinoma: the roles for primary and

adjuvant therapies. Cancer Chemother Pharmacol 1992;31(suppl):S115–S118.

133. Koga A, Watanabe K, Fukuyama T, et al. Diagnosis and operative indications for polypoid lesions of

the gallbladder. Arch Surg 1988;123(1):26–29.

134. Furukawa H, Kosuge T, Shimada K, et al. Small polypoid lesions of the gallbladder: differential

diagnosis and surgical indications by helical computed tomography. Arch Surg 1998;133(7):735–

739.

135. Akiyama T, Sahara H, Seto K, et al. Gallbladder cancer associated with cholesterosis. J Gastroenterol

1996;31(3):470–474.

136. Kozuka S, Tsubone N, Yasui A, et al. Relation of adenoma to carcinoma in the gallbladder. Cancer

1982;50(10):2226–2234.

137. Aldridge MC, Gruffaz F, Castaing D, et al. Adenomyomatosis of the gallbladder. A premalignant

lesion? Surgery 1991;109(1):107–110.

138. Kurihara K, Mizuseki K, Ninomiya T, et al. Carcinoma of the gall-bladder arising in

adenomyomatosis. Acta Pathol Jpn 1993;43(1–2):82–85.

139. Aldridge MC, Bismuth H. Gallbladder cancer: the polyp-cancer sequence. Br J Surg 1990;77(4):363–

364.

140. Csendes A, Burgos AM, Csendes P, et al. Late follow-up of polypoid lesions of the gallbladder

smaller than 10 mm. Ann Surg 2001;234(5):657–660.

141. Farris KB, Faust BF. Granular cell tumors of biliary ducts. Report of two cases and review of the

literature. Arch Pathol Lab Med 1979;103(10):510–512.

142. Hadjis NS, Collier NA, Blumgart LH. Malignant masquerade at the hilum of the liver. Br J Surg

1657

1985;72(8):659–661.

143. Standfield NJ, Salisbury JR, Howard ER. Benign nontraumatic inflammatory strictures of the

extrahepatic biliary system. Br J Surg 1989;76(8):849–852.

144. Verbeek PC, van Leeuwen DJ, de Wit LT, et al. Benign fibrosing disease at the hepatic confluence

mimicking Klatskin tumors. Surgery 1992;112(5):866–871.

1658

SECTION I: COLON AND RECTUM

1659

Chapter 64

Colon and Rectal Anatomy and Physiology

Sandy H. Fang and Elizabeth C. Wick

Key Points

1 The mesorectum is invested by the fascia propria of the rectum.

2 The ileocolic branch of the superior mesenteric artery supplies the right colon and part of the

transverse colon.

3 The inferior mesenteric artery supplies part of the transverse colon, sigmoid colon, and rectum.

4 The inguinal lymph nodes drain the lymphatics from the anal canal below the dentate line.

5 The colon has 1013 bacteria, which promote mucosal immunity, help digest complex nutrients, and

protect against pathogenic organisms.

6 Alterations in the colonic flora have been associated with inflammatory bowel disease and colorectal

cancer.

7 Constipation is one of the most common conditions treated by physicians, but only rarely is it due to

colonic inertia.

8 During postoperative ileus, the stomach recovers after 1 to 2 days, the small bowel after 1 day, and

the colon after 3 days.

9 Thoracic epidural use after colorectal surgery can shorten postoperative ileus.

10 Sacral nerve stimulation is a newer and effective treatment for fecal incontinence.

INTRODUCTION

While the complex coordination of stool through the colon, rectum, and anus is the main function of the

colon, it also plays a role in the complex digestion and absorption of carbohydrate and protein residue,

creates a balanced environment for bacteria, and lubricates stool for transit. Understanding the anatomy

and physiology of the colon, rectum, and anus is important to treating the pathology associated with it.

EMBRYOLOGY OF THE COLON AND RECTUM

The primitive gut is derived from endoderm and begins to form during the third to fourth week of

gestation. It is divided into three segments: foregut, midgut, and hindgut. Embryologically, the colon is

derived from the midgut, which is supplied by the superior mesenteric artery, and the hindgut, which is

supplied by the inferior mesenteric artery.1 The midgut gives rise to the small intestine distal to the

ampulla of Vater, the cecum and appendix, the ascending colon, and the right half to two-thirds of the

transverse colon. During the sixth gestational week, the midgut herniates from the abdominal cavity

into the extraembryonic coelom, undergoes a 270-degree counterclockwise rotation around the superior

mesenteric artery, and then returns to the abdominal cavity at 10 weeks’ gestation. The hindgut gives

rise to the distal one-third of the transverse colon, descending and sigmoid colon, rectum, and upper

portion of the anal canal. The terminal end of the hindgut is the endoderm-lined pouch termed the

cloaca. During development, the cloaca is partitioned by the urorectal septum into the rectum and upper

anal canal and urogenital sinus. Ultimately, the distal anal canal arises from canalization of the

ectoderm. The pectineal or dentate line marks the junction between tissue derived from endoderm and

ectoderm in the anal canal.

ANATOMY OF THE COLON AND RECTUM

1660

The colon begins in the right lower quadrant of the abdomen as the cecum. The ileum enters the colon

at the posteromedial aspect at the ileocecal valve.1 Characteristics unique to the colon are (a) taeniae

coli, (b) haustra, and (c) appendices epiploicae, located on the antimesenteric surface of the colon.

There are three taeniae (anterior, posterior medial, and posterior lateral), which are condensations of

the outer longitudinal muscle layer in the colon. They are named according to their attachments: taenia

mesocolica (attached to the mesocolon), taenia omentalis (attached to the greater omentum), taenia

libera (no attachments). The taeniae originate at the base of the appendix, course along the length of

the colon, and then converge at the rectosigmoid junction.

On average, the colon is 150 cm long. The taenia are one-sixth shorter than the colon and are

believed to be responsible for pockets of the colon wall called sacculations or haustra.1 The epiploicae

appendices are fat appendages seen on the colonic serosa.

The colon consists of five layers: mucosa, submucosa, circular muscle layer, longitudinal muscle layer,

and serosa (Fig. 64-1). Microscopically, the colonic mucosa is a columnar epithelium marked by crypts

and goblet cells. Unlike the small intestine, the columnar epithelium of the colon and rectum does not

have villi. The submucosa is the strongest layer of bowel and contains Meissner plexus. The myenteric

plexus of Auerbach is on the external surface of the circular muscle layer. The outer longitudinal

muscles form the taeniae coli. Finally the serosa is not present in the lower portions of the rectum.

The colon begins in the right lower quadrant with the cecum. The cecum extends approximately 6 to

8 cm below the ileocecal valve (where the terminal ileum enters the posteromedial aspect of the cecum)

(Fig. 64-2). The angulation between the ileum and cecum via the superior and inferior ileocecal

ligaments is important in maintaining competence against reflux at the ileocecal junction.2 The cecum is

the widest portion of the colon (7.5 to 8.5 cm in diameter), has the thinnest wall, and is entirely

enveloped by peritoneum. The appendix originates from the lowest portion of the cecum and can be

readily identified by following the converging taeniae. In 85% to 95% of people, the appendix lies

posterior to the cecum, lateral and in line to the terminal ileum, but the position can vary, with the

most frequent variants being retrocecal (toward the psoas muscle), pelvic, and retroileal.3 During

colonoscopy, visualization of the appendiceal orifice and ileocecal valve are the landmarks required in a

complete colonic examination. From the cecum, the right colon ascends to the hepatic flexure

(approximately 15 cm). The hepatic flexure is anterior to the inferior pole of the right kidney and

overlies the second portion of the duodenum. The hepatic flexure is marked by medial, anterior, and

downward angulation of the colon. When the right colon and mesentery are mobilized during a

colectomy, care must be taken to avoid injury to the underlying duodenum. Only the anterior surface of

the right colon is invested with peritoneum; laterally, the white line of Toldt marks the extent of the

peritoneal covering and serves as an important landmark during surgical mobilization of the colon.

Figure 64-1. Layers of the colonic wall.

The transverse colon stretches from the hepatic flexure to the splenic flexure and is the longest

segment of colon (between 30 cm and 60 cm). The transverse colon is suspended by the transverse

mesocolon and is completely intraperitoneal. It is the most mobile portion of the colon and may descend

1661

to the level of the iliac crests or deep into the pelvis. The greater omentum descends from the greater

curve of the stomach in front of the transverse colon and then ascends to attach to the transverse colon

on its anterosuperior edge. To mobilize the transverse colon or enter the lesser sac, the fusion plane of

the omentum to the transverse colon must be dissected. The splenic flexure is situated high in the left

upper quadrant, more cephalad than the hepatic flexure, and lies anterior to the mid-left kidney and

abuts the lower pole of the spleen. There are attachments from the colon to the diaphragm at the level

of the 10th and 11th ribs and spleen (phrenocolic and splenocolic ligaments), and these must be

carefully divided during mobilization of the splenic flexure to avoid splenic injury.

The descending colon is approximately 25 cm long and courses from the splenic flexure to its junction

with the sigmoid colon at the pelvic brim. It lies anterior to the left kidney and, like the right colon, the

anterior, lateral, and medial portions of the descending colon are covered by peritoneum.

The sigmoid colon extends from the pelvic brim to the sacral promontory, where it continues as the

rectum and generally measures 15 to 50 cm in length. It is completely invested by peritoneum. The

rectosigmoid junction is marked by the convergence of the colonic taenia. The sigmoid colon is

extremely mobile and has a generous mesentery that extends along the pelvic brim from the iliac fossa

across the sacroiliac joint to the second or third sacral segment. Because of its mobile mesentery, the

sigmoid colon can twist and cause an obstruction, termed sigmoid volvulus. The left ureter runs in the

intersigmoid fossa, which is at the base of the mesosigmoid. When a high ligation of the inferior

mesenteric artery is performed during a cancer operation or the sigmoid colon is being mobilized along

the white line of Toldt, the left ureter should be identified to avoid inadvertent injury. Preoperative

placement of urinary stents can be useful for locating the ureter intraoperatively in complex,

reoperative pelvic surgery.

1 At the sacral promontory, the colon becomes the rectum. The outer layer of the rectal wall is

composed of the longitudinal muscle, where the three teniae splay. The rectum measures 12 to 15 cm in

length. It proceeds posterior and caudal along the curvature of the sacrum and coccyx, passing through

the levator ani muscles, at which point it turns abruptly caudal and posteriorly at the anorectal ring,

becoming the anal canal. Anterior to the rectum are the uterine cervix and posterior vaginal wall in

women, and the bladder and prostate in men. Posteriorly, the rectum occupies the sacral concavity

where the median sacral vessels, presacral veins, and sacral nerves run, all of which are invested in the

presacral fascia. The rectum is marked by three curves. The upper and lower curves are convex and to

the right, while the middle is convex and to the left. Within the lumen, these correspond to the valves

of Houston, which separate the lower third, middle third, and upper third of the rectum – important

landmarks when the location of a rectal abnormality is established endoscopically (the lower rectal

valve is at 7 to 8 cm from the anal verge, middle rectal valve at 9 to 11 cm, and upper rectal valve at

12 to 13 cm).4 The valves do not contain all layers of the bowel wall and thus biopsy at this location

carries minimal risk of perforation. The middle valve of Houston is the internal landmark corresponding

to the anterior peritoneal reflection. The anterior and lateral surfaces of the upper third of the rectum

are intraperitoneal, whereas only the anterior surface of the middle third of the rectum is

intraperitoneal in location. The lower third of the rectum is entirely extraperitoneal. The mesorectum is

the term used to describe the areolar tissue surrounding the rectum that contains nerves, lymphatics,

and terminal branches of the superior hemorrhoidal branch of the inferior mesenteric artery. Although it

invests the rectum circumferentially, the mesorectum is most prominent posterior to the rectum. It is

invested by the fascia propria of the rectum, a continuation of the parietal endopelvic fascia (Fig. 64-3).

The fascia propria (investing fascia) includes the distal two-thirds of the posterior rectum and the distal

one-third of the anterior rectum, where it is no longer intraperitoneal. A total mesorectal excision

entails removal of the entire rectum without violating the fascia propria of the rectum. This is

accomplished by mobilizing the rectum using the plane between the fascia propria of the rectum and the

presacral fascia. Anterior to the investing fascia (fascia propria) is a delicate layer of connective tissue

known as Denonvilliers fascia, which separates the rectum from its anterior structures. Waldeyer fascia

(rectosacral fascia) is the presacral fascia that is an extension of the parietal pelvic fascia from the

periosteum of sacral segment four to the posterior wall of the rectum. It contains branches of the sacral

splanchnic nerves. Below Waldeyer fascia is the supralevator or retrorectal space.

1662

Figure 64-2. General anatomic components of the colon.

Figure 64-3. Fascial relationships of the pelvis.

The surgical anal canal begins at the anorectal ring or levator ani muscles and extends to the anal

verge. It measures 2 to 4 cm and is usually longer in men than in women. The internal anal sphincter

(continuation of the circular smooth muscle of the rectum) and the external anal sphincter (continuation

of the puborectalis muscle) encircle the anal canal and control fecal continence. The internal anal

sphincter relies on autonomic innervation, while the external anal sphincter uses somatic innervation.

The median length and thickness of the female anterior external sphincter is 11 and 13 mm and thus a

small tear sustained during vaginal delivery may cause fecal incontinence.5 There are three layers of the

external sphincter – subcutaneous (traversed by the conjoined longitudinal muscle with some fiber

attachments to the skin), superficial (connective tissue attaches posteriorly, forming the anococcygeal

ligament), and deep (continues with the puborectalis muscle). Between the internal and external anal

sphincters, the longitudinal muscle of the rectum joins fibers of the levator ani and puborectalis muscles

to form the conjoined longitudinal muscle. The dentate line marks the transition between the columnar

epithelium of the intestine and the squamous epithelium of the anal canal. The transition between these

two epithelia is called the anal transitional zone. The Columns of Morgagni are the 6 to 14 longitudinal

folds located at the dentate line. Small pockets between these columns called anal crypts contain anal

glands, which may become obstructed with foreign material to cause an infection. Below the dentate

line is the anoderm, which extends to the anal verge and does not contain accessory skin structures,

such as hair, sebaceous and sweat glands. The autonomic nervous system innervates proximal to the

dentate line and the somatic nervous system supplies the anoderm and distally.

Pelvic Floor

The perineal body is the tendinous insertion of the external anal sphincter, bulbocavernosus, and

superficial and deep transverse perineal muscles. It supports the perineum and separates the vagina

1663

from the anus.

Three striated muscles that attach to the pubic bone make up the pelvic floor or levator ani muscles:

iliococcygeus, pubococcygeus, and puborectalis. The pelvic floor muscles are supplied by branches from

the third sacral nerve, while the external anal sphincter is supplied by nerve fibers traveling with the

pudendal nerve on the levators undersurface.

The puborectalis originates from the back of the symphysis pubis and forms a U-shaped sling as it

joins the opposite muscle posteriorly. The iliococygeus muscle arises from the ischial spine and posterior

part of the obturator fascia and travels inferiorly, posteriorly, and medially to insert into the last two

segments for the sacrum and coccyx. The pubococcygeus muscle arises from the anterior half of the

obturator fascia and the posterior pubis. Its fibers are directed backward, downward, and medially,

where they decussate with fibers of the opposite side. The decussation is called the anococcygeal raphe.

Anorectal Spaces

The perianal space surrounds the anal canal superficially and contains the external hemorrhoidal plexus.

The ischioanal space extends laterally and goes superiorly to the levator ani from the skin on the

perineum. The levator ani and external sphincter muscles form the medial boundary, while the lateral

wall is formed by the obturator fascia. The superficial postanal space connects the perianal spaces with

each other posteriorly below the anococcygeal ligament, while the deep postanal space lies above the

anococcygeal ligament. The ischioanal and perianal spaces make the ischioanal fossa. The deep postanal

and ischiorectal spaces form a horseshoe configuration that may be involved in a horseshoe abscess.

Below the perianal space between the sphincter muscles is the intersphincteric space. The submucosal

space contains the internal hemorrhoidal plexus and lies between the internal anal sphincter and the

mucosa distal to the dentate line. Proximally, it becomes the submucosa of the rectum. Above the

levator complex is the supralevator space, which extends superiorly to the peritoneum at the rectosacral

fascia. The retrorectal space extends above the rectosacral fascia and lies between the upper two-thirds

of the rectum and sacrum.

Arterial Blood Supply

2 3 The arterial blood supply to the colon, rectum, and anus is highly variable. The following

summarizes the general courses of the arterial blood supply. The superior mesenteric artery arises from

the aorta, runs posterior to the pancreas, and passes anterior to the third portion of the duodenum (Fig.

64-4). In addition to supplying the small bowel through jejunal and ileal branches, the superior

mesenteric artery gives rise to the ileocolic, right colic, and middle colic branches that supply the

cecum, ascending colon, and proximal transverse colon. The right colic arterial anatomy is particularly

variable and can be absent or arise from the ileocolic or the superior mesenteric artery. The middle colic

artery has a right branch that supplies the hepatic flexure and the right portion of the transverse colon,

while the left branch supplies the left portion of the transverse colon. The inferior mesenteric artery

arises from the anterior surface of the aorta, typically 3 to 4 cm above the aortic bifurcation, and

supplies the distal transverse colon, descending colon, sigmoid colon, and upper rectum. The inferior

mesenteric artery gives rise to the left colic artery and sigmoidal branches, then continues in the

sigmoid mesentery, and after crossing the left iliac vessels, is renamed the superior rectal/hemorrhoidal

artery. The inferior mesenteric artery may also function as an important collateral vessel to the lower

extremities during instances of distal aortic occlusion. The superior hemorrhoidal artery descends

behind the rectum and splits into right and left branches in the mesorectum. It is the main blood supply

of the rectum. The middle and inferior rectal/hemorrhoidal arteries arise from either the internal

pudendal arteries or the hypogastric arteries and supply the distal two-thirds of the rectum. The

presence of the middle rectal artery, in particular, can be variable. A series of arterial arcades along the

mesenteric border of the entire colon, known as the marginal artery of Drummond, connect the superior

mesenteric and inferior mesenteric arterial systems. The marginal artery may be attenuated or absent at

the distal transverse colon/splenic flexure, the delineation between the midgut and hindgut, and thus

ischemic colitis most commonly affects this region. The arc of Riolan (“meandering mesenteric artery”)

is a short loop connecting the left branch of the middle colic artery and the trunk of the inferior

mesenteric artery. The inferior rectal/hemorrhoidal arteries traverse the ischioanal fossa and supply the

anal canal and external anal sphincter muscles.

1664

Figure 64-4. Arterial blood supply of the colon.

Figure 64-5. Venous drainage of the colon by the portal vein.

VENOUS DRAINAGE

The veins that drain the large intestine bear the same terminology and follow a course similar to that of

their corresponding arteries (Fig. 64-5). The veins from the right colon and transverse colon, along with

the veins draining the small intestine, drain into the superior mesenteric vein. The superior mesenteric

vein runs slightly anterior to and to the right of the superior mesenteric artery. The superior mesenteric

vein courses beneath the neck of the pancreas, where it joins with the splenic vein to form the portal

vein. The inferior mesenteric vein is a continuation of the superior rectal vein and drains blood from the

1665

 

Follow-up After Resection of Cholangiocarcinoma

Recurrence following resection of ICC is within the liver in 60% of patients. While data are lacking,

there is some evidence to suggest that there is a role for reresection in highly selected patients. The

most likely site of recurrence after resection of hilar cholangiocarcinoma is locally within the bile duct,

regional lymph nodes, or liver. Therapy for recurrence is palliative. Surgical reexcision is usually

impossible because of the challenging anatomic location and the radical procedures that are required for

resection of the primary tumor. The main symptoms of recurrence that demand palliation are pruritus

or cholangitis associated with jaundice. For biliary drainage to relieve jaundice or cholangitis, either

surgical drainage or drainage by PTC can be effective. Endoscopic drainage has little role in the relief of

jaundice in patients who have had Roux-en-Y biliary reconstruction. For limited recurrences,

intraluminal brachytherapy or external beam radiotherapy may improve palliation and, potentially,

survival.132

Routine follow-up consists of office visits every 3 months with physical examination and

measurement of liver function tests. Although a rising alkaline phosphatase level is a reliable indicator

of evolving biliary obstruction, patients recovering from liver resection and biliary obstruction can have

persistent elevations of alkaline phosphatase. Up to 10% of patients with biliary surgical reconstruction,

however, may develop a benign anastomotic stricture. Most patients with recurrence or a benign

stricture will present with jaundice or cholangitis. Surveillance cross-sectional imaging is recommended

every 3 to 6 months for the first 2 years following resection and should be individualized thereafter.

Issues for the Future

Further studies are needed to develop effective adjuvant, and potentially neoadjuvant, therapies for

cholangiocarcinoma. Continued assessment of novel drugs and radiosensitizers, and biologic agents is

warranted. A better understanding of the molecular pathogenesis and genetics of bile duct cancers may

lead to new therapeutic strategies and possibly preventive strategies for high-risk populations.

BENIGN GALLBLADDER NEOPLASMS

Incidence

Benign tumors of the biliary tract are rare, but have been reported more frequently as imaging

modalities (e.g., ultrasound and CT scan) have come into widespread and frequent use. In patients

undergoing cholecystectomy, the reported incidence of benign gallbladder tumors is less than 3%.

Pathology

Polyps and Pseudotumors

Benign gallbladder tumors are most frequently polyps or polypoid lesions. The incidence of polyps in

asymptomatic patients is about 5%.3 Cholesterol polyps (cholesterolosis), accounting for half of all

gallbladder polypoid lesions, result from epithelium-covered, cholesterol-laden macrophages in the

lamina propria.133 These lesions are likely a result of an error in cholesterol metabolism. They extend

from the mucosa on a narrow stalk, grossly appearing as yellow spots on the mucosal surface. Nearly all

are multiple, and most are less than 10 mm in size.133,134 When a polyp is pedunculated, it is benign in

most cases; alternatively, sessile “polyps” are more often malignant (Fig. 63-10). Inflammatory polyps

result from chronic inflammation and extend by a narrow vascularized stalk into the gallbladder lumen.

None of these lesions are considered premalignant, although isolated cases of cholesterolosis associated

with in situ carcinoma have been reported.135

Adenomas

Gallbladder adenomas are found infrequently. They may be tubular or papillary, both arising from the

epithelial layer of the gallbladder. Multiple papillary adenomas, or papillomas, are called papillomatosis.

A direct association between benign adenoma, adenoma containing carcinoma in situ, and invasive

carcinoma has been demonstrated; thus these lesions are considered premalignant.136 Malignant

transformation, however, has only rarely been reported, primarily from large adenomas. In one series,

all benign adenomas were less than 12 mm in diameter, whereas the adenomas with cancerous foci

were greater than 12 mm.135

1649

Figure 63-10. T2-weighted magnetic resonance imaging scan showing a sessile polyp within the gallbladder (arrow) that was

malignant on histologic examination.

Adenomyomatosis

Adenomyomatosis of the gallbladder is characterized by localized or diffuse hyperplastic extensions of

the mucosa into, and often beyond, a hypertrophied gallbladder muscular layer. Hyperplasia occurs at

outpouchings of the mucosa of the gallbladder through the wall (Rokitansky–Aschoff sinuses) and

through the crypts of Luschka. This can result in focal thickening of the gallbladder wall, resembling

gallbladder adenocarcinoma. The etiology is unknown. This lesion may be premalignant, because cases

of adenocarcinoma arising in or near adenomyomatosis have been reported, but this relationship is

unclear.127,138

Other Benign Gallbladder Tumors

Other benign lesions include tumors arising from the tissue of the gallbladder wall, such as leiomyomas,

lipomas, hemangiomas, granular cell tumors, and heterotopic tissue, including gastric, pancreatic, or

intestinal epithelium.

Clinical Findings

Patients with benign gallbladder tumors typically present with symptoms consistent with

choledocholithiasis, including right upper quadrant pain, fatty food intolerance, and nausea. Many

benign gallbladder lesions are also discovered incidentally after elective cholecystectomy. Therefore,

symptoms caused by benign lesions are difficult to separate from those caused by gallstones. Most

lesions, however, are asymptomatic and are discovered incidentally during imaging for other abdominal

conditions.

Diagnosis

Diagnosis of benign gallbladder polyps is usually made when an ultrasound study is obtained to evaluate

a patient for symptoms consistent with gallstones. On ultrasound, a filling defect that does not change

with position is likely a polyp or carcinoma and not a gallstone. Cholesterol polyps are typically small,

submucosal, multiple, and hyperechoic on ultrasound because of their high cholesterol content. Other

than this typical appearance and the fact that malignant polyps are usually more than 1 cm in size, it is

difficult to differentiate benign from malignant polyps.

Both intravenous contrast-enhanced and unenhanced CT may be important in distinguishing benign

from malignant polyps. In a recent series examining 31 polypoid lesions of the gallbladder, contrastenhanced CT detected all of the lesions. Benign polyps were not visualized with unenhanced CT, unlike

neoplastic tumors, thus improving the ability to distinguish these lesions when both enhanced and

unenhanced CT scans were obtained.9 Endoscopic ultrasound has also been used to image these lesions,

and may be more accurate than transabdominal ultrasound in differentiating benign from malignant

tumors.22

Treatment

Large polyps, greater than 10 mm, have the greatest malignant potential.9,133,134 Without the evidence

of invasion or metastatic disease, however, no radiologic test can reliably differentiate benign from

1650

malignant lesions. Therefore, if large (>1 cm) polyps are present, even in asymptomatic patients

without stones, cholecystectomy is warranted.139 Additionally, resection is recommended for smaller

pedunculated lesions with evidence of a vascularized stalk. Small pedunculated lesions with the gross

characteristics of a benign cholesterol polyp may be observed and resected only if symptomatic.

Although these lesions have routinely been followed with ultrasound, a recent prospective study

suggested that polyps smaller than 1 cm do not progress to carcinoma.140 Cholecystectomy, however, is

still considered the standard of care if there is any increase in size.

BENIGN BILE DUCT NEOPLASMS

Incidence

Benign bile duct tumors, at times clinically resembling hilar cholangiocarcinoma, are less common,

occurring in less than 1% of patients.4

Pathology

Attesting to the rarity of these lesions, only two cases of benign extrahepatic bile duct disease occurred

in 4,200 biliary tract operations in one institution.141 The most common benign tumors of the

extrahepatic biliary tree arise from the glandular epithelium lining the ducts; about two-thirds of benign

tumors are polyps, adenomatous papilloma, or bile duct adenomas. Most are found in the periampullary

region, but they can be distributed throughout the entire biliary tree (Fig. 63-11). Multiple papillomas

also have been reported throughout the intrahepatic and extrahepatic biliary tree, termed multiple biliary

papillomatosis. Although local recurrence and progression to death from obstructive jaundice and

cholangitis occur frequently in these rare cases, these tumors have little, if any, malignant potential.

Other benign tumors (e.g., cystadenoma, granular cell myoblastoma, leiomyoma, and heterotopic

tissue) have also been reported.

One condition that deserves consideration is the case of “malignant masquerade,” an inflammatory,

fibrotic lesion clinically resembling hilar cholangiocarcinoma, but pathologically consisting only of

extensive fibrosis and inflammatory cells without evidence of dysplasia or preneoplastic change.142–144

In patients being considered for palliative treatment alone with presumed hilar cholangiocarcinoma, it is

essential to obtain a tissue diagnosis. It is inappropriate to treat benign lesions by percutaneous stenting

because of the excellent outcome after resection of these lesions.

Clinical Findings

Biliary obstruction, with resultant jaundice or cholangitis, is frequently the presenting symptom in

patients with benign bile duct tumors. Symptoms may also include epigastric pain or nausea. Because

these tumors are indolent, symptoms may be intermittent or gradually progressive.

Figure 63-11. Distribution of papillomas and adenomas of the biliary tree. The ampulla and common bile duct are the most

frequent sites.

Diagnosis

1651

Because of the presence of jaundice, benign bile duct tumors are usually initially evaluated with

ultrasound. Many patients then undergo ERCP or PTC and CT scan. A diagnosis of malignant

masquerade should be suspected in patients with mass lesions that resemble hilar cholangiocarcinomas,

but without lobar atrophy or portal vein involvement.

Treatment

Resection and reconstruction are performed to relieve jaundice and cholangitis. The preferred

reconstruction is a Roux-en-Y choledochojejunostomy to decrease the risk of postoperative biliary

stricture or recurrent cholangitis.

References

1. Siegel R, Ma J, Zou Z, et al. Cancer statistics, 2014. CA Cancer J Clin 2014; 64(1):9–29.

2. Wistuba II, Gazdar AF. Gallbladder cancer: lessons from a rare tumour. Nat Rev Cancer

2004;4(9):695–706.

3. Okamoto M, Okamoto H, Kitahara F, et al. Ultrasonographic evidence of association of polyps and

stones with gallbladder cancer. Am J Gastroenterol 1999;94(2):446–450.

4. Diehl AK. Epidemiology of gallbladder cancer: a synthesis of recent data. J Natl Cancer Inst

1980;65(6):1209–1214.

5. Piehler JM, Crichlow RW. Primary carcinoma of the gallbladder. Surg Gynecol Obstet

1978;147(6):929–942.

6. Hundal R, Shaffer EA. Gallbladder cancer: epidemiology and outcome. Clin Epidemiol 2014;6:99–

109.

7. Pitt SC, Jin LX, Hall BL, et al. Incidental gallbladder cancer at cholecystectomy: when should the

surgeon be suspicious? Ann Surg 2014;260(1):128–133.

8. Diehl AK. Gallstone size and the risk of gallbladder cancer. JAMA 1983; 250(17):2323–2326.

9. Shinkai H, Kimura W, Muto T. Surgical indications for small polypoid lesions of the gallbladder. Am

J Surg 1998;175(2):114–117.

10. Stephen AE, Berger DL. Carcinoma in the porcelain gallbladder: a relationship revisited. Surgery

2001;129(6):699–703.

11. Towfigh S, McFadden DW, Cortina GR, et al. Porcelain gallbladder is not associated with

gallbladder carcinoma. Am Surg 2001;67(1):7–10.

12. Henson DE, Albores-Saavedra J, Corle D. Carcinoma of the gallbladder. Histologic types, stage of

disease, grade, and survival rates. Cancer 1992;70(6):1493–1497.

13. Yamamoto M, Nakajo S, Tahara E. Carcinoma of the gallbladder: the correlation between

histogenesis and prognosis. Virchows Arch A Pathol Anat Histopathol 1989;414(2):83–90.

14. Bartlett DL, Fong Y, Fortner JG, et al. Long-term results after resection for gallbladder cancer.

Implications for staging and management. Ann Surg 1996;224(5):639–646.

15. Shirai Y, Yoshida K, Tsukada K, et al. Radical surgery for gallbladder carcinoma. Long-term results.

Ann Surg 1992;216(5):565–568.

16. Matsubara T, Sakurai Y, Sasayama Y, et al. K-ras point mutations in cancerous and noncancerous

biliary epithelium in patients with pancreaticobiliary maljunction. Cancer 1996;77(8 suppl):1752–

1757.

17. Wistuba II, Albores-Saavedra J. Genetic abnormalities involved in the pathogenesis of gallbladder

carcinoma. J Hepatobiliary Pancreat Surg 1999;6(3):237–244.

18. Wistuba II, Sugio K, Hung J, et al. Allele-specific mutations involved in the pathogenesis of

endemic gallbladder carcinoma in Chile. Cancer Res 1995;55(12):2511–2515.

19. Javle M, Rashid A, Churi C, et al. Molecular characterization of gallbladder cancer using somatic

mutation profiling. Hum Pathol 2014;45(4):701–708.

20. Jiao Y, Pawlik TM, Anders RA, et al. Exome sequencing identifies frequent inactivating mutations

in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas. Nat Genet 2013;45(12):1470–

1473.

21. Mizuguchi M, Kudo S, Fukahori T, et al. Endoscopic ultrasonography for demonstrating loss of

1652

multiple-layer pattern of the thickened gallbladder wall in the preoperative diagnosis of gallbladder

cancer. Eur Radiol 1997;7(8):1323–1327.

22. Sugiyama M, Xie XY, Atomi Y, et al. Differential diagnosis of small polypoid lesions of the

gallbladder: the value of endoscopic ultrasonography. Ann Surg 1999;229(4):498–504.

23. Bang SH, Lee JY, Woo H, et al. Differentiating between adenomyomatosis and gallbladder cancer:

revisiting a comparative study of high-resolution ultrasound, multidetector CT, and MR imaging.

Korean J Radiol 2014;15(2):226–234.

24. Ohtani T, Shirai Y, Tsukada K, et al. Spread of gallbladder carcinoma: CT evaluation with

pathologic correlation. Abdom Imaging 1996;21(3):195–201.

25. Demachi H, Matsui O, Hoshiba K, et al. Dynamic MRI using a surface coil in chronic cholecystitis

and gallbladder carcinoma: radiologic and histopathologic correlation. J Comput Assist Tomogr

1997;21(4):643–651.

26. Kang TW, Kim SH, Park HJ, et al. Differentiating xanthogranulomatous cholecystitis from wallthickening type of gallbladder cancer: added value of diffusion-weighted MRI. Clin Radiol

2013;68(10):992–1001.

27. Schwartz LH, Coakley FV, Sun Y, et al. Neoplastic pancreaticobiliary duct obstruction: evaluation

with breath-hold MR cholangiopancreatography. AJR Am J Roentgenol 1998;170(6):1491–1495.

28. Corvera CU, Blumgart LH, Akhurst T, et al. 18F-fluorodeoxyglucose positron emission tomography

influences management decisions in patients with biliary cancer. J Am Coll Surg 2008;206(1):57–65.

29. Fong Y, Brennan MF, Turnbull A, et al. Gallbladder cancer discovered during laparoscopic surgery.

Potential for iatrogenic tumor dissemination. Arch Surg 1993;128(9):1054–1056.

30. Barbot DJ, Marks JH, Feld RI, et al. Improved staging of liver tumors using laparoscopic

intraoperative ultrasound. J Surg Oncol 1997;64(1):63–67.

31. Bhargava DK, Sarin S, Verma K, et al. Laparoscopy in carcinoma of the gallbladder. Gastrointest

Endosc 1983;29(1):21–22.

32. Dagnini G, Marin G, Patella M, et al. Laparoscopy in the diagnosis of primary carcinoma of the

gallbladder. A study of 98 cases. Gastrointest Endosc 1984;30(5):289–291.

33. Weber SM, DeMatteo RP, Fong Y, et al. Staging laparoscopy in patients with extrahepatic biliary

carcinoma. Analysis of 100 patients. Ann Surg 2002;235(3):392–399.

34. Vollmer CM, Drebin JA, Middleton WD, et al. Utility of staging laparoscopy in subsets of

peripancreatic and biliary malignancies. Ann Surg 2002;235(1):1–7.

35. Weber SM, Jarnagin WR, Klimstra D, et al. Intrahepatic cholangiocarcinoma: resectability,

recurrence pattern, and outcomes. J Am Coll Surg 2001; 193(4):384–391.

36. Donohue JH, Nagorney DM, Grant CS, et al. Carcinoma of the gallbladder. Does radical resection

improve outcome? Arch Surg 1990;125(2):237–241.

37. Ogura Y, Mizumoto R, Isaji S, et al. Radical operations for carcinoma of the gallbladder: present

status in Japan. World J Surg 1991;15(3):337–343.

38. Ouchi K, Owada Y, Matsuno S, et al. Prognostic factors in the surgical treatment of gallbladder

carcinoma. Surgery 1987;101(6):731–737.

39. Wanebo HJ, Castle WN, Fechner RE. Is carcinoma of the gallbladder a curable lesion? Ann Surg

1982;195(5):624–631.

40. Nakamura S, Sakaguchi S, Suzuki S, et al. Aggressive surgery for carcinoma of the gallbladder.

Surgery 1989;106(3):467–473.

41. Fong Y, Jarnagin W, Blumgart LH. Gallbladder cancer: comparison of patients presenting initially

for definitive operation with those presenting after prior noncurative intervention. Ann Surg

2000;232(4):557–569.

42. Wakai T, Shirai Y, Yokoyama N, et al. Early gallbladder carcinoma does not warrant radical

resection. Br J Surg 2001;88(5):675–678.

43. Kai M, Chijiiwa K, Ohuchida J, et al. A curative resection improves the postoperative survival rate

even in patients with advanced gallbladder carcinoma. J Gastrointest Surg 2007;11(8):1025–1032.

44. Jensen EH, Abraham A, Habermann EB, et al. A critical analysis of the surgical management of

early-stage gallbladder cancer in the United States. J Gastrointest Surg 2009;13(4):722–727.

45. Mayo SC, Shore AD, Nathan H, et al. National trends in the management and survival of surgically

1653

managed gallbladder adenocarcinoma over 15 years: a population-based analysis. J Gastrointest Surg

2010;14(10):1578–1591.

46. Taner CB, Nagorney DM, Donohue JH. Surgical treatment of gallbladder cancer. J Gastrointest Surg

2004;8(1):83–89.

47. Yamaguchi K, Chijiiwa K, Saiki S, et al. Reliability of frozen section diagnosis of gallbladder tumor

for detecting carcinoma and depth of its invasion. J Surg Oncol 1997;65(2):132–136.

48. Yamaguchi K, Tsuneyoshi M. Subclinical gallbladder carcinoma. Am J Surg 1992;163(4):382–386.

49. Kelly KJ, Dukleska K, Kuk D, et al. Prognostic significance of the highest peripancreatic lymph

node in biliary tract adenocarcinoma. Ann Surg Oncol 2014;21(3):979–985.

50. Billingsley KG, Jarnagin WR, Fong Y, et al. Segment-oriented hepatic resection in the management

of malignant neoplasms of the liver. J Am Coll Surg 1998;187(5):471–481.

51. Shih SP, Schulick RD, Cameron JL, et al. Gallbladder cancer: the role of laparoscopy and radical

resection. Ann Surg 2007;245(6):893–901.

52. Shirai Y, Yoshida K, Tsukada K, et al. Inapparent carcinoma of the gallbladder. An appraisal of a

radical second operation after simple cholecystectomy. Ann Surg 1992;215(4):326–331.

53. Chijiiwa K, Tanaka M. Carcinoma of the gallbladder: an appraisal of surgical resection. Surgery

1994;115(6):751–756.

54. Butte JM, Kingham TP, Gonen M, et al. Residual disease predicts outcomes after definitive

resection for incidental gallbladder cancer. J Am Coll Surg 2014;219(3):416–429.

55. Dixon E, Vollmer CM Jr, Sahajpal A, et al. An aggressive surgical approach leads to improved

survival in patients with gallbladder cancer: a 12-year study at a North American Center. Ann Surg

2005;241(3):385–394.

56. Fuks D, Regimbeau JM, Le Treut YP, et al. Incidental gallbladder cancer by the AFC-GBC-2009

Study Group. World J Surg 2011;35(8):1887–1897.

57. Fuks D, Regimbeau JM, Pessaux P, et al. Is port-site resection necessary in the surgical

management of gallbladder cancer? J Visc Surg 2013;150(4):277–284.

58. Maker AV, Butte JM, Oxenberg J, et al. Is port site resection necessary in the surgical management

of gallbladder cancer? Ann Surg Oncol 2012;19(2):409–417.

59. Weiland ST, Mahvi DM, Niederhuber JE, et al. Should suspected early gallbladder cancer be treated

laparoscopically? J Gastrointest Surg 2002;6(1):50–56; discussion 56–57.

60. Takada T, Amano H, Yasuda H, et al. Is postoperative adjuvant chemotherapy useful for gallbladder

carcinoma? A phase III multicenter prospective randomized controlled trial in patients with

resected pancreaticobiliary carcinoma. Cancer 2002;95(8):1685–1695.

61. Wang SJ, Lemieux A, Kalpathy-Cramer J, et al. Nomogram for predicting the benefit of adjuvant

chemoradiotherapy for resected gallbladder cancer. J Clin Oncol 2011;29(35):4627–4632.

62. Ben-Josef E, Guthrie KA, El-Khoueiry AB, et al. SWOG 0809: a phase II intergroup trial of adjuvant

capecitabine and gencitabine followed by radiotherapy and concurrent capecitabine in extra hepatic

cholangiocarcinoma and gallbladder carcinoma. J Clin Oncol 2015;33(24):2617–2622.

63. Kim HJ, Kim MH, Myung SJ, et al. A new strategy for the application of CA19-9 in the

differentiation of pancreaticobiliary cancer: analysis using a receiver operating characteristic curve.

Am J Gastroenterol 1999;94(7):1941–1946.

64. Knox JJ, Hedley D, Oza A, et al. Combining gemcitabine and capecitabine in patients with

advanced biliary cancer: a phase II trial. J Clin Oncol 2005;23(10):2332–2338.

65. Iyer RV, Gibbs J, Kuvshinoff B, et al. A phase II study of gemcitabine and capecitabine in advanced

cholangiocarcinoma and carcinoma of the gallbladder: a single-institution prospective study. Ann

Surg Oncol 2007;14(11):3202–3209.

66. Lazcano-Ponce EC, Miquel JF, Munoz N, et al. Epidemiology and molecular pathology of

gallbladder cancer. CA Cancer J Clin 2001;51(6):349–364.

67. Patel T. Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the

United States. Hepatology 2001;33(6):1353–1357.

68. Pitt HA, Dooley WC, Yeo CJ, et al. Malignancies of the biliary tree. Curr Probl Surg 1995;32(1):1–

90.

69. Endo I, Gonen M, Yopp AC, et al. Intrahepatic cholangiocarcinoma: rising frequency, improved

1654

survival, and determinants of outcome after resection. Ann Surg 2008;248(1):84–96.

70. Welzel TM, Mellemkjaer L, Gloria G, et al. Risk factors for intrahepatic cholangiocarcinoma in a

low-risk population: a nationwide case-control study. Int J Cancer 2007;120(3):638–641.

71. de Groen PC, Gores GJ, LaRusso NF, et al. Biliary tract cancers. N Engl J Med 1999;341(18):1368–

1378.

72. Hakamada K, Sasaki M, Endoh M, et al. Late development of bile duct cancer after

sphincteroplasty: a ten- to twenty-two-year follow-up study. Surgery 1997;121(5):488–492.

73. Nathan H, Pawlik TM, Wolfgang CL, et al. Trends in survival after surgery for cholangiocarcinoma:

a 30-year population-based SEER database analysis. J Gastrointest Surg 2007;11(11):1488–1496;

discussion 1496–1497.

74. Burke EC, Jarnagin WR, Hochwald SN, et al. Hilar Cholangiocarcinoma: patterns of spread, the

importance of hepatic resection for curative operation, and a presurgical clinical staging system.

Ann Surg 1998;228(3):385–394.

75. Aloia TA, Charnsangavej C, Faria S, et al. High-resolution computed tomography accurately

predicts resectability in hilar cholangiocarcinoma. Am J Surg 2007;193(6):702–706.

76. Soto JA, Barish MA, Yucel EK, et al. Magnetic resonance cholangiography: comparison with

endoscopic retrograde cholangiopancreatography. Gastroenterology 1996;110(2):589–597.

77. Cameron JL, Pitt HA, Zinner MJ, et al. Management of proximal cholangiocarcinomas by surgical

resection and radiotherapy. Am J Surg 1990;159(1):91–97; discussion 97–98.

78. Nakayama T, Ikeda A, Okuda K. Percutaneous transhepatic drainage of the biliary tract: technique

and results in 104 cases. Gastroenterology 1978;74(3):554–559.

79. Hochwald SN, Burke EC, Jarnagin WR, et al. Association of preoperative biliary stenting with

increased postoperative infectious complications in proximal cholangiocarcinoma. Arch Surg

1999;134(3):261–266.

80. McPherson GA, Benjamin IS, Hodgson HJ, et al. Pre-operative percutaneous transhepatic biliary

drainage: the results of a controlled trial. Br J Surg 1984;71(5):371–375.

81. Pitt HA, Gomes AS, Lois JF, et al. Does preoperative percutaneous biliary drainage reduce

operative risk or increase hospital cost? Ann Surg 1985; 201(5):545–553.

82. Okuda K, Kubo Y, Okazaki N, et al. Clinical aspects of intrahepatic bile duct carcinoma including

hilar carcinoma: a study of 57 autopsy-proven cases. Cancer 1977;39(1):232–246.

83. Ottow RT, August DA, Sugarbaker PH. Treatment of proximal biliary tract carcinoma: an overview

of techniques and results. Surgery 1985; 97(3):251–262.

84. El Rassi ZE, Partensky C, Scoazec JY, et al. Peripheral cholangiocarcinoma: presentation, diagnosis,

pathology and management. Eur J Surg Oncol 1999;25(4):375–380.

85. Altaee MY, Johnson PJ, Farrant JM, et al. Etiologic and clinical characteristics of peripheral and

hilar cholangiocarcinoma. Cancer 1991;68(9):2051–2055.

86. Baer HU, Stain SC, Dennison AR, et al. Improvements in survival by aggressive resections of hilar

cholangiocarcinoma. Ann Surg 1993;217(1):20–27.

87. Bengmark S, Ekberg H, Evander A, et al. Major liver resection for hilar cholangiocarcinoma. Ann

Surg 1988;207(2):120–125.

88. Bismuth H, Nakache R, Diamond T. Management strategies in resection for hilar

cholangiocarcinoma. Ann Surg 1992;215(1):31–38.

89. Hadjis NS, Blenkharn JI, Alexander N, et al. Outcome of radical surgery in hilar

cholangiocarcinoma. Surgery 1990;107(6):597–604.

90. Nagorney DM, Donohue JH, Farnell MB, et al. Outcomes after curative resections of

cholangiocarcinoma. Arch Surg 1993;128(8):871–877; discussion 877–879.

91. Cameron JL, Broe P, Zuidema GD. Proximal bile duct tumors: surgical management with silastic

transhepatic biliary stents. Ann Surg 1982;196(4):412–419.

92. Ito K, Ito H, Allen PJ, et al. Adequate lymph node assessment for extrahepatic bile duct

adenocarcinoma. Ann Surg 2010;251(4):675–681.

93. de Jong MC, Nathan H, Sotiropoulos GC, et al. Intrahepatic cholangiocarcinoma: an international

multi-institutional analysis of prognostic factors and lymph node assessment. J Clin Oncol

2011;29(23):3140–3145.

1655

94. Ribero D, Pinna AD, Guglielmi A, et al. Surgical approach for long-term survival of patients with

intrahepatic cholangiocarcinoma: a multi-institutional analysis of 434 patients. Arch Surg

2012;147(12):1107–1113.

95. Edge SB, American Joint Committee on Cancer. AJCC Cancer Staging Manual. 7th ed. New York,

NY: Springer; 2010.

96. Brandsaeter B, Isoniemi H, Broome U, et al. Liver transplantation for primary sclerosing

cholangitis; predictors and consequences of hepatobiliary malignancy. J Hepatol 2004;40(5):815–

822.

 42

In most centers, direct cholangiography is used to evaluate the extent of biliary involvement and

provide palliation for jaundice. Endoscopic retrograde cholangiopancreatography (ERCP) has little role

to play in high biliary obstruction because opacification of the proximal biliary tree is difficult. ERCP,

however, can be effectively used to image more distal lesions. At the time cholangiography is

performed, some authors advocate the routine preoperative placement of biliary drainage catheters to

aid in intraoperative identification of the bile ducts.77,78 Others have found a higher incidence of

infectious complications and mortality, and a longer hospital stay, after preoperative placement of

biliary drainage catheters.79–81 The difficulty in making the decision regarding preoperative stenting is

that many patients are severely symptomatic because of jaundice and pruritus and require palliation,

thus if the operation is delayed, many patients require palliation.

Figure 63-5. Computed tomography scan in a patient with hilar cholangiocarcinoma, demonstrating dilated intrahepatic ducts in

the right lobe but inability to directly visualize tumor.

Figure 63-6. Coronal (A) and axial (B) magnetic resonance imaging in a patient with hilar cholangiocarcinoma. Dilated

intrahepatic ducts are present with a soft tissue density consistent with tumor (arrows).

Figure 63-7. Coronal (A) magnetic resonance imaging and magnetic resonance cholangiopancreatography (B) in a patient with

hilar cholangiocarcinoma, demonstrating dilated intrahepatic ducts narrowing at the area of obstruction.

1643

In many cases, it is difficult to obtain pathologic confirmation of cholangiocarcinoma except in very

advanced cases, even with the use of biliary brushings and cytology obtained at the time of direct

cholangiography. In most cases, patients are offered surgical therapy based on clinical suspicion and

radiographic appearance. In patients with ICC, cross-sectional imaging with CT scan is usually sufficient.

Tumors may be masslike or may have cystic areas.

Surgery

Untreated, most patients with bile duct cancers die within a year of diagnosis.81,82 Surgical excision is

the treatment of choice, with no other potentially curative therapy available. The immediate causes of

death are most commonly hepatic failure or cholangitis related to tumor growth and inadequate

drainage of the biliary tree.83 Therefore, the goals of surgery are complete removal of tumor with R0

margins while leaving a sufficient liver remnant, and establishing adequate biliary drainage. Patients

with ICC require additional consideration. Those patients with multifocal and especially bilobar

intrahepatic tumors, even if technically resectable with negative margins and adequate remnant liver,

should not be considered for resection. These patients have very poor prognosis indicating that bilobar

hepatic spread represents hematogenous metastasis.84 What remains controversial is whether

peritumoral satellite lesions also represent metastatic disease. Because this is unknown and surgery is

the only potentially curative therapy for these patients, satellite lesions are not currently considered a

contraindication to resection.

Hilar cholangiocarcinoma is often unresectable due to local factors. These include invasion of the

main portal vein or both the right and left portal veins and hepatic arteries and tumor extension into

second-order biliary radicals of both right and left hepatic lobes. By contrast, tumors extending into

second- or third-order biliary radicles on one side of the liver without vascular involvement can be

resected for cure. It has become clear over the last three decades that curative treatment for patients

with tumors of the hilum or those involving the upper half of the bile duct depends on aggressive

excision that often requires a major liver resection. Until as recently as one decade ago, treatment of

hilar cholangiocarcinomas was associated with mortality as high as 30%.85–89 Recently, major

improvements in the safety of these operations have been demonstrated, and resection of hilar tumors

now results in mortality of less than 10%, even when liver resections are required.85,86,88,90

Role of Staging Laparoscopy

Because of the potential morbidity of a laparotomy that has no therapeutic benefit, staging laparoscopy

has been advocated to save patients from unnecessary laparotomy. In patients with hilar

cholangiocarcinoma, up to 25% will benefit from staging laparoscopy because of detection of occult

extrahepatic disease.33,34 Laparoscopy is a very sensitive means to detect peritoneal metastases or

additional intrahepatic disease through the use of laparoscopic ultrasound but is less sensitive in

detecting nodal metastases or locally invasive tumors.

Partial Hepatectomy With or Without Bile Duct Resection

The extent of hepatectomy required for resection of cholangiocarcinoma is dependent on the tumor

location in relation to the portal inflow and venous outflow of the liver. Intraoperative ultrasound is a

useful adjunct for assessment of tumor extent and for small satellite lesions that may not be apparent on

cross-sectional imaging.

Small ICCs may be removed by segmentectomy or sectorectomy, but these tumors are often large and

require extended right or left hepatectomy. For hilar and proximal hepatic duct lesions, complete

resection usually requires combined biliary and hepatic resection with or without major vascular

reconstruction. Additionally, caudate resection is often required because of direct extension into caudate

biliary radicles or parenchyma.74,89,91 Resection of the extrahepatic bile duct with Roux-en-Y

hepaticojejunostomy to the remnant duct is required in these cases. Intraoperative assessment of the

bile duct resection margin should be performed if additional duct can potentially be taken. If not,

assessment on permanent sectioning is sufficient.

Lymphadenectomy

Regional lymphadenectomy is essential for accurate staging of cholangiocarcinoma, and may be

important for locoregional disease control, but has historically been underperformed for intrahepatic

and hilar tumors.73,92 Recent data have shown that lymph node metastases are present in 30% to 40% of

patients.73,92–94 Regional lymph nodes include those along the porta hepatis, the hepatoduodenal

1644

ligament, the hepatic artery for essentially all patients. In addition, for those with primary tumors of

the right hemiliver, retropancreatic nodes should be removed. For those with primary tumors of the left

hemiliver, perigastric lesser curve nodes (levels 1, 3, and 5) should be removed.95 As is true for

gallbladder cancer, there is currently no consensus on the minimum number of lymph nodes needed for

accurate staging of cholangiocarcinoma.

Pancreaticoduodenectomy

For cholangiocarcinoma of the lower half of the extrahepatic bile duct, pancreaticoduodenectomy is

requiring for complete tumor extirpation. The proximal bile duct margin should be assessed by frozen

section to ensure tumor clearance. Regional lymphadenectomy is inherent in this procedure.

Liver Transplantation for Hilar CC and the Mayo Protocol

Orthotopic liver transplantation (OLT) was thought to hold promise for patients with hilar CC, because

of the ability to achieve adequate margins by complete hepatectomy. Unfortunately, when used as a

single treatment modality, results have been poor. Three- and 5-year survival rates have been reported

at 25% to 30%.96–98 Because of this poor outcome, the Mayo Clinic developed a protocol combining

neoadjuvant therapy with liver transplant, based on a strategy initially developed by the University of

Nebraska. This protocol uses high-dose neoadjuvant 5-fluorouracil and brachytherapy followed by liver

transplantation.99,100 Inclusion criteria include (i) locally advanced unresectable disease with either

positive intraluminal brush cytology, positive intraluminal biopsy, or CA19-9 ≥100 in the setting of a

radiographic malignant stricture; (ii) primary sclerosing cholangitis with resectable disease; and (iii)

absence of medical contraindications for OLT. Since 2003, biliary aneuploidy as demonstrated by digital

image analysis (DIA)(77) and fluorescent in situ hybridization have been considered equivalent to

cytology.101 Exclusion criteria include (i) extrahepatic disease including regional lymph node

involvement; (ii) uncontrolled infection; (iii) prior attempt at resection; (iv) prior treatment with

radiation or chemotherapy; and (v) previous malignancy within 5 years. In this protocol, patients

receive external beam radiotherapy to a target dose of 4,500 cGy with concomitant fluorouracil (5-FU).

Following this, transcatheter iridium-192 brachytherapy with a target dose of 2,000 to 3,000 cGy is

administered. Thereafter, patients receive oral capecitabine as tolerated until transplantation. It is

important that, prior to transplantation, patients undergo a staging laparotomy, at which time biopsy of

perihilar lymph nodes as well as any lymph nodes or nodules suspicious for tumor is performed. Only

patients with negative staging operations remain eligible for transplantation.99

RESULTS

Table 63-7 Results after Resection for Hilar Cholangiocarcinoma

Patients eligible for OLT under this protocol have locally advanced tumors but no pathologic nodal

disease. The prolonged course of neoadjuvant therapy, staging laparotomy, and time on the OLT

waiting list provides an opportunity to exclude patients demonstrating disease progression. This highly

rigorous selection bias in favor of patients with biologically favorable disease is reflected in the early

outcomes published from the Mayo group. In a recent review of 71 patients enrolled in this transplant

1645

protocol, only 38 underwent transplantation (38%). These patients were compared to 26 patients (of 54

explored, 48%) who underwent successful resection. When compared to those undergoing resection

(some with node-positive disease), patients undergoing transplantation were younger (p < 0.001) and

more likely to have inflammatory bowel disease (p < 0.03) and PSC (p < 0.001). It is important that

only 58% of patients had histologically proven cancer. In these highly disparate groups, 5-year survival

was 82% after transplantation (38 patients) compared to 21% after resection of 26 patients (p =

0.022).97 There were also fewer recurrences in the transplant patients (13% vs. 27%), and recurrences

became apparent later after transplantation than after resection (mean 40 months vs. 21 months). Direct

comparisons are difficult with this study given the differences between groups.

At present, OLT cannot be considered a standard form of therapy for hilar cholangiocarcinoma for

patients with resectable disease, but it does offer a potential option for patients with underlying PSC or

those with unresectable tumors who fit the rigorous inclusion and exclusion criteria of the protocol.

Prognosis After Resection

Results of major studies on resection of hilar cholangiocarcinoma are summarized in Table 63-7. In

patients amenable to curative resection, the median survival is 35 months with a 5-year survival rate of

10% to 30%.79,87,88,96,100,110 Surgical resection provides both improved survival and improved quality of

life. The greatest risk factors for recurrence include the presence of positive margins, and node-positive

tumors.111

In patients with ICC, expected 3-year survival rates as high as 60% have been reported, with 5-year

survival rates of 30% to 45%.35,111,112 Patients with unresectable disease have a median survival of 12

months.35,113 Thus, completely resected ICC appears to have an improved prognosis over proximal

(hilar) cholangiocarcinoma. Patients with cholangiocarcinomas arising in the distal bile duct have both

an increased resectability rate and improved prognosis over those with hilar cholangiocarcinomas.90

Patients with resectable distal bile duct cancer have a 5-year survival rate of 30% to 50%, with a

decreased survival if nodes are involved with tumor.114,115

Unresectable Cholangiocarcinoma

6 For patients with unresectable hilar cholangiocarcinomas, significant improvement in quality of life

can be achieved with surgical bypass. Palliative bypass can be performed in several ways. A partial

excision of the left lateral segment and biliary-enteric anastomosis to the left hepatic duct (Longmire

procedure) was used commonly in the past, but more recently surgical techniques have become less

complicated and do not require hepatic parenchymal transection. One technique involves biliary

decompression through the left duct, approached through the round ligament, a segment III bypass (Fig.

63-8). Opening the bridge of tissue just beneath the ligamentum teres allows access to the duct. In this

position, a long anastomosis can be performed from the segment III duct to a jejunal limb because of

the horizontal course of the duct in this location. Although less commonly used, the right hepatic duct

can be approached at the base of the gallbladder fossa. This is technically more difficult and results in a

higher rate of late bypass failure.116

Nonoperative palliative biliary decompression can be accomplished with percutaneous or endoscopic

stenting, depending on the level of obstruction. Proximal lesions are usually approached percutaneously

with placement of expandable stents or drainage catheters (Fig. 63-9). Internal stents result in fewer

electrolyte abnormalities and improvement in patient comfort, although morbidity and mortality occurs

in up to 30% of patients and stent occlusion is common.117–119 There is a significant risk of cholangitis

with external and internal drainage, occurring in more than 90% of patients with metallic expandable

internal stents in one series.118 Bleeding and bile leaks are also frequent complications. More recent

techniques (e.g., photodynamic therapy) have been used to palliate patients with biliary obstruction and

may hold some promise for the future.120

Because patients with unresectable disease have a short median survival, those whose disease is

clearly unresectable on preoperative imaging should undergo percutaneous internal or external

drainage. In patients who undergo exploratory surgery and whose disease is found to be unresectable,

surgical bypass offers fewer episodes of cholangitis, with an improved quality of life. In some series,

surgical bypass for patients with unresectable disease is the only biliary drainage procedure ever

required by the patient.

1646

Figure 63-8. Surgical approach to segment III duct. A: The bridge of tissue present at the base of the liver is divided. B: The

ligamentum teres is held superiorly to expose the tissue overlying the segment III duct. C: The segment III duct is exposed. D: The

duct is opened in preparation for anastomosis with a Roux-en-Y jejunal limb. (Courtesy of Dr. L. H. Blumgart.)

In patients with unresectable distal cholangiocarcinomas, palliation can be achieved with surgical

bypass, percutaneous biliary drains, or ERCP-placed stents. The simplest and most effective way to

relieve jaundice is usually with an ERCP stent. Although surgical bypass offers improved patency and

fewer episodes of cholangitis, the morbidity of the procedure is not warranted in patients with these

aggressive tumors.

Adjuvant Therapy

To date, no chemotherapeutic regimen has consistently shown activity against cholangiocarcinoma.

Many of the issues that pertain to chemotherapy trials in gallbladder cancer are directly relevant to the

interpretation of trials for cholangiocarcinomas. Studies performed to date have typically been small,

single-institution trials, including patients with both gallbladder and bile duct cancers.121

Although 5-fluorouracil (5-FU)–based chemotherapy is often offered to patients with unresectable

disease, the likelihood of response is less than 10%. Capecitabine as a single agent may have some

modest activity in cholangiocarcinomas.122 When capecitabine was used in combination with

gemcitabine in a recent prospective study, overall survival was 14 months.65 Gemcitabine and cisplatin

combination therapy has also been tested in phase II studies of patients with advanced biliary tract

carcinoma.123,124 Results of these studies demonstrated response rates of 27% to 34.5%, and overall

survival of 9.7 to 11 months. The use of mitomycin C and doxorubicin (Adriamycin), in combination

with 5-FU, has resulted in combined response rates of less than 30%, with higher toxicity than 5-FU

alone.125

With the exception of extrahepatic disease, there is no clear role for adjuvant chemotherapy in the

treatment of cholangiocarcinoma. The previously mentioned phase II trial from 2015 showed a

promising 2 year survival for patients with extra hepatic cholangiocarinoma treated with adjuvant

capecitabine/gemcitabine and concurrent capecitabine and radiation therapy.62 Aside from this study,

however, previous data suggested no difference in overall survival (36% vs. 42%, p = 0.6) or loco

regional recurrence (38% vs. 37%, p = 0.13) in patients who underwent R0 resection alone versus

1647

those with high loco regional recurrence risk who received adjuvant chemoradiation therapy.126 Similar

to the recommendations for gallbladder cancer, patients with extra hepatic cholangiocarcinoma who

undergo R0 or R1 resection should be considered for adjuvant capecitabine/gemcitabine and concurrent

capecitabine and radiation therapy.

In cases of unresectable cholangiocarcinoma, the use of external beam radiation therapy has been

explored.91,127–130 To date, no study has clearly demonstrated efficacy for this modality. Anecdotal

reports of long-term survivors after external beam radiotherapy show that some individuals may benefit

from such treatment, but this must be weighed against the potential complications (e.g., duodenal or

bile duct stenosis and duodenitis). The most encouraging results involve use of intraoperative or

interstitial radiation.127,128,130,131 Our current practice is to use combined interstitial radiation and

external beam radiation in unresectable cases after palliative bypass. In patients whose disease is

resected and have node- or margin-positive disease, systemic therapy with gemcitabine or 5-FU, or 5-

FU–based chemoradiation, or enrollment in a clinical trial should be strongly encouraged.

Figure 63-9. A: Percutaneous transhepatic cholangiogram in a patient with hilar cholangiocarcinoma, demonstrating biliary

obstruction at the confluence. The patient has previously had placement of internal/external stents for biliary drainage. B: Film

demonstrates appearance of wall stents after deployment into the left and right biliary ducts. C: After stenting, the cholangiogram

demonstrates adequate biliary drainage, with contrast filling the duodenum.

1648

 

Tumor location may be important in determining the extent of resection. If the tumor arises in the

gallbladder infundibulum, the CBD is often involved with tumor, either by direct extension or external

invasion of the hepatoduodenal ligament. In this case, an extended liver resection and removal of a

portion of the CBD should be performed. Reconstruction is then performed by Roux-en-Y

hepaticojejunostomy. Tumor arising in the fundus of the gallbladder, however, can be treated with

limited hepatic resection without excision of the CBD. Complete regional lymphadenectomy should be

performed, skeletonizing the CBD, hepatic artery, and portal vein. Short-term postoperative outcomes

following resection of gallbladder cancer have remained relatively stable over time, with postoperative

morbidity occurring in 30% to 40% of patients, and mortality occurring in <5% (Table 63-4).

Incidentally or Laparoscopically Discovered Gallbladder Cancer

Gallbladder cancer is often discovered during pathologic examination after cholecystectomy for

presumed benign disease. Because of the popularization of laparoscopic cholecystectomy in the past

decade, an increasing number of patients with gallbladder cancer are found incidentally. Patients with

T1b or greater tumors and no signs of distant disease should be offered exploration and further

resection to eradicate all diseases. In a series of 135 patients who underwent reexploration following

laparoscopic cholecystectomy, 61% of all and 36% of those with T1b primary tumors were found to

have residual disease.54 In this study, survival following reresection of residual locoregional disease was

extremely poor and was not different from that of patients with metastatic disease. Improved survival

has been demonstrated following reresection to achieve negative margins, however, especially in

patients with T2 or T3 disease.51,55,56 While laparoscopic port-site recurrence has been reported, it is

associated with peritoneal-based disease. Port-site excision at the time of reexploration is no longer

recommended as recent data have shown that it is not associated with decreased recurrence or improved

survival.57,58

Reresection after recent cholecystectomy is often technically challenging. Postoperative inflammation

in the right upper quadrant often hinders distinction of tumor from normal tissue. Bile spillage at the

time of the initial operation may result in carcinomatosis.59 Determination of ductal or nodal

involvement by tumor is always difficult at the time of reoperation. In addition, postoperative fibrosis

often encases the right hepatic artery, which crosses behind the bile duct in most patients. Because of

this, during a second operation for incidentally discovered gallbladder cancer, an extended right

hepatectomy along with excision of the extrahepatic biliary tree and portal lymphadenectomy is often

necessary. This resection allows adequate exposure for lymphadenectomy and greater confidence of a

negative margin on the bile duct, and also permits biliary reconstruction to only one side of the liver.

The disadvantage is that a large portion of normal liver parenchyma is sacrificed, and consequently,

transient postoperative liver dysfunction is common. Although it may be more difficult to curatively

resect disease in patients with incidentally discovered gallbladder cancer after laparoscopic

cholecystectomy, there is no difference in overall survival between patients with incidentally discovered

gallbladder cancer who are submitted to curative resection and those patients who undergo initial

curative resection.50

When a patient presents with T1a gallbladder cancer discovered after simple cholecystectomy, the

pathology should be reviewed to determine if the entire gallbladder has been removed and if the cystic

duct margin is clear of tumor. If the cystic duct margin is positive, the patient requires bile duct

excision. If all margins are negative, no further therapy is warranted. If the tumor is proved to be T1b

or greater, complete staging should be performed. In the absence of metastatic disease, patients should

be counseled regarding reexcision to attempt complete resection, chemotherapy with or without

radiation, or observation. Patients with a known or suspected early gallbladder carcinoma should be

referred to an experienced center where curative-intent resection can be performed at the initial

operation.

Adjuvant Therapy

Adjuvant therapy for gallbladder cancer remains a controversial and unproved consideration and is

rarely utilized.45 Very few randomized trials have been completed, and the conclusions that can be

drawn from them are limited given the small sample sizes. Given the relative rarity of these

malignancies in the United States, large-scale, randomized trials are feasible only in the context of a

multi-institutional or cooperative group setting.

In 2002, a randomized phase III trial of adjuvant chemotherapy with 5-fluorouracil and mitomycin C

versus surgery alone for patients with pancreaticobiliary malignancies having resection found that in the

1638

subset of patients with gallbladder cancer (n = 112), the 5-year survival rate was significantly better in

the adjuvant group (26%) versus the control group (14%).60 Similarly, the 5-year disease-free survival

rate was 20.3% versus 11.6%, clearly favoring the adjuvant therapy group. A recent review of the SEER

database also reported an association between adjuvant chemoradiation therapy and improved survival

in patients with locoregionally advanced disease.61 This finding prompted a multi center phase II trial of

adjuvant capecitabine and gemcitabine followed by concurrent capecitabine and radiation therapy for

patients with resected gallbladder cancer or extra hepatic cholagiocarcinoma. The results of this study

were published in 2015 and showed promising findings of 65% two-year survival.62 These studies

suggest that patients with gallbladder cancer with high risk for recurrence (T2 or greater, node-positive,

or margin-positive) should be considered for adjuvant treatment with systemic chemotherapy or

chemoradiation.

Table 63-4 Complications Postoperative Morbidity Following Resection of

Gallbladder Cancer Over Time in the United States56

Prognosis

The 5-year survival rate for all patients with gallbladder cancer is less than 5% in most series, with a

median survival of 6 months. This is primarily because most patients present with unresectable disease.

Of those patients undergoing resection, survival is dependent on depth of penetration and nodal status.

Nearly 100% survival is reported after simple cholecystectomy for T1a disease, whereas patients with

T2 and T3 tumors without nodal disease have a 5-year survival greater than 50%.14,15,40,52 Node

positivity is an ominous finding, with few series reporting 5-year survivors.

Follow-up after Resection for Gallbladder Cancer

The most common sites of recurrence after resection of gallbladder cancer include carcinomatosis,

intrahepatic metastases, or nodal recurrence in the retroperitoneum. For most tumors, local recurrence

is found synchronously with diffuse intra-abdominal spread. Therefore, surgical treatment of recurrence

has little potential for cure. The main goal of surgery after recurrence of resected gallbladder cancer is

to provide palliation of symptoms such as pruritus or cholangitis associated with jaundice, or bowel

obstruction associated with carcinomatosis. When jaundice or cholangitis is the presenting symptom of

possible recurrence, a nonsurgical palliative approach using percutaneous transhepatic cholangiogram

(PTC) and stenting is usually favored unless a benign postsurgical stricture is suspected. Because of the

rapid growth of tumor in patients with recurrence, the hospitalization and recovery time from a surgical

bypass is usually not justified for recurrences resulting in biliary obstruction.

The routine follow-up of a patient after resection of gallbladder cancer includes office visits every 3

months with physical examination and measurement of liver function tests, and cross-sectional imaging

every 3 to 6 months for the first 2 years. In patients who remain free of disease at 2 years, follow-up

should be continued on an individualized basis. Although CA19-9 may be elevated in patients with

gallbladder cancer, the sensitivity and specificity are poor and, thus, should not be used for screening

patients for recurrence.63 If recurrence is identified, systemic therapy with gemcitabine and cisplatin

should be considered as it has been shown to prolong survival in the setting of metastatic disease.64 For

patients who cannot tolerate this regimen, alternatives include single-agent gemcitabine or gemcitabine

plus capecitabine.65

Issues for the Future

Clearly, improving our ability to recognize early gallbladder cancer in high-risk geographic areas would

have an important impact on outcome in these patients. This will likely require implementation of

screening programs in high-risk areas, which could result in prophylactic cholecystectomy.66

1639

Additionally, standardization of minimum pathologic assessment of gallbladder specimens in high-risk

areas is important to allow for accurate diagnosis, staging, and treatment of patients.

Further studies on characterization of molecular aberrations in gallbladder cancer by next generation

sequencing and other technologies may lead to the discovery of targetable mutations and lead to the

development of novel therapies. Additionally, there is a theoretical role for neoadjuvant therapy for

patients with locoregionally advanced gallbladder cancer given their poor prognosis following surgery.

Clinical trials in this area are needed.

BILE DUCT CARCINOMA

Bile duct carcinomas may arise within the liver (intrahepatic cholangiocarcinoma [ICC] or peripheral

cholangiocarcinoma), at the liver hilum (hilar cholangiocarcinoma or Klatskin tumor), or in the

extrahepatic bile duct (extrahepatic cholangiocarcioma [ECC]). While all arise from the biliary

epithelium, the location of these tumors affects prognosis as well as the potential for curative resection.

Resection of biliary neoplasms, particularly hilar cholangiocarcinoma, often requires radical

resections and complex biliary reconstructions that should be performed only at high-volume,

experienced centers. There is also a role for surgery in palliation for these cancers by providing biliary

bypass for jaundiced patients with unresectable tumors. Because disease is often diagnosed late in the

course and because complex operative techniques are required for potentially curative resection, these

tumors represent one of the greatest challenges for definitive treatment. Adding to this is that there are

no proven effective options for adjuvant therapy.

INCIDENCE

The incidence of ICC in the United States is approximately 0.7/100,000 with a similar mortality. During

the last 30 years, it appears that both the incidence and mortality in the United States are increasing.64

The overall incidence of hilar cholangiocarcinoma, the most common type, is 1.0/100,000 per year in

the United States, although rates are higher in other geographic regions such as Israel and Japan.68

Recent population studies have noted a trend toward a relative increased incidence of ICC compared to

ECC.4,69,70 Using the Surveillance, Epidemiology and End Results-Medicare databases, Welzel et al.70

noted HCV infection, chronic nonalcoholic liver disease and obesity, and smoking being associated only

with ICC and not ECC, possibly explaining the divergent trends in incidence. Cholangiocarcinomas arise

slightly more often in males, with a male-to-female ratio of 1.3:1 and an average age of 50 to 70 years.

Known risk factors for cholangiocarcinoma include primary sclerosing cholangitis, ulcerative colitis,

choledochal cysts, and biliary tract infection, either with Clonorchis or in chronic typhoid carriers.71

Some industrial chemicals (e.g., nitrosamines, dioxin, asbestos, and polychlorinated biphenyls) have also

been implicated in the pathogenesis of cholangiocarcinoma. Although there has been some suggestion of

an increased risk of cholangiocarcinoma arising after transduodenal sphincteroplasty,72 it is difficult to

determine if this is caused by the surgical intervention or the underlying disease leading to

sphincteroplasty.

Pathology and Staging

More than 90% of these bile duct cancers are adenocarcinomas. They are morphologically described as

nodular, which is the most common, scirrhous, diffusely infiltrating, or papillary. Histologic subtypes

include acinar, ductular, trabecular, alveolar, and papillary. Papillary tumors have an improved

outcome. Much less common types of bile duct tumors include cystadenocarcinomas,

hemangioendotheliomas, and mucoepidermoid carcinomas.

STAGING

Table 63-5 American Joint Committee on Cancer, 7th Edition, Staging System for

Perihilar Bile Duct Carcinoma

1640

In patients with ICC, negative prognostic signs include vascular invasion, multiple tumors, and lymph

node metastases, but not tumor size.73 These tumors can be sclerotic, masslike, or cystic lesions.

Historically, ECCs have been classified according to their location in the upper (60%), middle (15% to

20%), or lower third (15% to 20%) of the bile duct. Middle-third lesions arise between the cystic duct

and the superior border of the duodenum. Lower-third lesions are found below the superior border of

the duodenum but above the ampulla. The problem with this classification is that the anatomic

landmarks are somewhat arbitrary and not clinically useful. Most mid–bile duct malignant obstructions

are caused by gallbladder cancer. A more useful classification is to divide these lesions into upper-half

or lower-half tumors, based on the location of the cystic duct as it enters the common duct (in the case

of normal anatomy). The usefulness of this classification scheme is that it allows the surgeon to

delineate whether a hepatic or pancreatic resection will be required for clearance of tumor. The AJCC

TNM staging system (seventh edition) for bile duct cancers is described in Tables 63-5 and 63-6.

Other staging systems have been created that attempt to incorporate clinically important indicators of

resectability for hilar cholangiocarcinoma that are defined preoperatively, including hepatic lobe

atrophy or portal vein involvement.74 With the increasing acceptance of major hepatic resection for

these tumors, this preoperative staging system attempts to define whether there is ipsilateral

involvement alone, because tumors with bilateral extension past the primary biliary radicles are not

resectable.

STAGING

Table 63-6 American Joint Committee on Cancer, 7th Edition, Staging System for

Distal Bile Duct Carcinoma

1641

Clinical Findings and Diagnosis

The presentation of patients with cholangiocarcinoma is variable. Patients with hilar or extrahepatic

tumors most commonly present with painless jaundice. Symptoms of mild right upper quadrant pain,

pruritus, anorexia, malaise, and weight loss may also be reported. Cholangitis is the presenting

symptom in 10% to 30% of patients. Some patients, particularly those with ICC may be asymptomatic

and have their tumors discovered incidentally or on evaluation for elevations of alkaline phosphatase

and gamma-glutamyl transferase. Many of these patients will present to the surgeon with a biopsy

showing adenocarcinoma without a known primary tumor. The standard evaluation in these patients

should include tumor markers to rule out an elevated carcinoembryonic antigen (CEA) or α-fetoprotein

(AFP); upper and lower endoscopy to evaluate for a gastrointestinal source; CT scan to assess for a

primary tumor in the gastrointestinal tract or pancreas; and, in women, a mammogram. If no site of

primary disease is found, in most patients, the diagnosis is ICC.

Various imaging tests are available to assess patients with cholangiocarcinoma. Abdominal ultrasound

is noninvasive, easily available, and inexpensive, and thus is commonly used as a first imaging

modality. It can establish the level of biliary obstruction and rule out other etiologies, such as

choledocholithiasis. On CT, cholangiocarcinomas most often appear as hypodense masses with irregular

margins on precontrast phase images, with peripheral rim enhancement on arterial phase, followed by

progressive hyperattenuation on venous and delayed phases.75 Intrahepatic lesions often exhibit

associated capsular retraction and segmental/lobar atrophy and ductal dilatation. Hilar and proximal

extrahepatic lesions demonstrate dilated intrahepatic biliary ducts with a normal, collapsed gallbladder,

and, depending on the level of the tumor, a nondilated or partially dilated extrahepatic biliary tree (Fig.

63-5). While conventional CT is useful for assessment for extrahepatic, metastatic disease and perihilar

adenopathy, high-resolution CT and/or MRI are required for accurate assessment of the tumor and for

determination of respectability (Figs. 63-6 and 63-7).75 Portal vein patency can be determined with

ultrasound, CT, or MRI. Particularly for hilar tumors, signs of hepatic lobar atrophy should be carefully

sought, because this indicates ipsilateral portal vein involvement by tumor. MRCP offers the potential

of evaluating parenchymal, vascular, biliary, and nodal involvement with a single noninvasive

examination.25,27,76

16

 

mesenteric artery nodes. Nodal disease in the porta hepatis often causes common bile duct (CBD)

obstruction and resultant jaundice, which is the first clinical symptom in 30% of patients. Jaundice may

also be caused by tumors arising in the infundibulum, which may spread directly to the cystic duct and

common hepatic duct. Although peritoneal metastases are frequent, distant extraperitoneal metastases

are not.

Limited information exists regarding the genetic changes in gallbladder cancer. Recently reported

gene abnormalities associated with gallbladder cancer include p53, K-ras, CDKN2 (9p21), FGFR, and PI3

kinase pathway aberrations.16–20 The finding that patients with an anomalous pancreaticobiliary

junction have a greater frequency of K-ras mutations has led investigators to believe that reflux of

pancreatic enzymes into the biliary tree may contribute to the development of cancer.16 Because of our

limited knowledge of the sequence of molecular changes, there are no known detectors of early disease

or of risk assessment. Clearly, this is an area that needs improvement, particularly in endemic areas.

The American Joint Committee on Cancer’s (AJCC) seventh edition of its tumor, node, metastasis

(TNM) staging system (Table 63-1) reflects prognostic characteristics of tumor depth, regional nodal

disease, and distant spread. The gallbladder differs histologically from the rest of the gastrointestinal

tract in that it lacks a muscularis mucosa and submucosa. The gallbladder wall is composed of (a) a

single layer of columnar cells, the mucosa, and lamina propria; (b) a fibromuscular layer; (c) a

perimuscular, subserosal layer containing lymphatics and neurovascular structures; and (d) a serosal

surface, except where the gallbladder is embedded in the liver. Because lymphatics are present in the

subserosal layer only, tumors invading less than the full thickness of the muscular layer have minimal

risk of nodal spread. Thus, disease invading into, but not through, the muscular layer of the gallbladder

is T1b disease (stage I), whereas invasion into the perimuscular connective tissue is T2 (stage II). Stage

III disease includes tumors that have perforated the serosa or have directly invaded the liver or other

surrounding structures (T3), which are clearly more advanced but still potentially resectable. Tumors

that invade the main portal vein, hepatic artery, or two or more extrahepatic organs/structures are

classified as T4 (stage IVA) and are typically unresectable. Lymph node metastasis to regional,

periportal nodes are N1 whereas those to more distant nodes outside of what would be included in a

standard resection (celiac, periaortic, and superior mesenteric nodes) are N2. N1 nodal metastasis is

classified as stage IIIB and N2 as stage IVB. In line with other pancreaticobiliary malignancies, the stage

III grouping refers to locally advanced disease and stage IV indicates metastatic disease.

Clinical Findings and Diagnosis

Most patients are found to have gallbladder cancer during workup or treatment of cholelithiasis or

choledocholithiasis. In patients with symptoms, abdominal pain consistent with biliary colic or acute

cholecystitis is most common. Patients also present with jaundice, weight loss, anorexia, or an increase

in abdominal girth secondary to ascites. Physical findings may include right upper quadrant tenderness

or a palpable mass, hepatomegaly, and ascites. Laboratory investigation, if abnormal, is most often

consistent with biliary obstruction. Because of its nonspecific presentation and the lack of reliable

screening tests, gallbladder cancer is not diagnosed preoperatively in more than half the cases.

Imaging evaluation often reveals a thickened gallbladder wall or a mass within or replacing the

gallbladder on ultrasound examination. Because polyps, asymmetric wall thickening from cholecystitis

(especially xanthogranulomatous type), and carcinoma can have an echogenicity similar to the

gallbladder wall, these lesions are often difficult to distinguish. This is even more difficult when

inflammation is present from gallstones. At times, ultrasound can visualize invasion of the liver,

adjacent adenopathy, and a dilated biliary tree. The ability of ultrasound to differentiate benign from

neoplastic disease is enhanced using endoscopic ultrasound, and may be more specific than computed

tomography (CT) or magnetic resonance imaging (MRI).21–23

A dynamic contrast-enhanced CT scan may identify a gallbladder mass or invasion into the liver

parenchyma or adjacent organs. The classic finding in a patient with gallbladder cancer is asymmetric

thickening of the gallbladder wall. Staging of gallbladder carcinoma using CT, however, is limited by

poor sensitivity in identifying nodal spread.24

In patients who are jaundiced, direct cholangiography may be useful to delineate the extent of biliary

involvement as well as to palliate symptoms of biliary obstruction. A mid–bile duct obstruction not

caused by gallstones is gallbladder cancer until proved otherwise (Fig. 63-2). More recently, with

improvements in MRI technology, diffusion-weighted imaging and magnetic resonance

cholangiopancreatography (MRCP) have evolved into a single, noninvasive imaging modality that

allows complete assessment of biliary, vascular, hepatic parenchymal, and nodal involvement, as well as

1633

involvement of adjacent organs (Fig. 63-3).25–27

STAGING

Table 63-1 American Joint Committee on Cancer, 7th Edition, Staging System for

Gallbladder Carcinoma

In patients who present with incidentally discovered gallbladder cancer following cholecystectomy,

staging should be performed with high-quality CT or MRI of the chest, abdomen, and pelvis. There is no

clear role for PET/CT in this setting.28

Surgery

5 It is clear that the only curative option in patients with gallbladder cancer is complete surgical

resection. It is essential for optimal patient care that patients with gallbladder cancer be recognized

before laparoscopic cholecystectomy is performed, because of the risk of bile spillage, with its potential

for subsequent carcinomatosis.29

Role of Staging Laparoscopy

Because a large percentage of patients with gallbladder cancer are found to have occult, unresectable

disease at the time of surgical exploration, several authors have investigated the use of initial staging

laparoscopy for this disease.30–33 Because gallbladder cancer has such a propensity to spread intraabdominally, this tumor is ideal for detection of intra-abdominal metastases with laparoscopy. This is

demonstrated by the fact that up to 50% of patients are found to have unresectable disease at the time

1634

of laparoscopy.34,35 Patients who are found to have unresectable disease at laparoscopy can begin other

forms of systemic therapy earlier and may undergo the procedure as an outpatient. Particularly because

patients with unresectable disease have a median survival of only 6 months, the impact on quality of

life, including decreased length of stay in the hospital, cannot be overemphasized.

Figure 63-2. Endoscopic retrograde cholangiopancreatogram obtained from a patient with gallbladder cancer. Mid–bile duct

obstruction (arrow) is caused by direct extension of tumor to the cystic and common hepatic duct.

Cholecystectomy With or Without Partial Hepatectomy

Gallbladder cancer, if not completely surgically removed, results in rapid local progression and death. In

a collected review of 5,836 patients with gallbladder cancer, the overall mean survival was between 2

and 5 months, whereas the 5-year survival was 4%.5 The 5-year survival of patients undergoing

resection with curative intent was 17%. Of the 2,115 patients with unresectable disease, only a single

survivor was found at 5 years. Although surgical resection represents the treatment of choice and the

only potentially curative therapy available, resection is possible in only 25% of patients at presentation

because of the advanced nature of the disease.5

Figure 63-3. T1-weighted magnetic resonance imaging scan of a patient with gallbladder cancer (small arrows) with extension into

the duodenum and the hepatic flexure of colon (large arrows).

There is little doubt that the results of treatment, as well as the scope of operation, are related to

depth of tumor penetration (Table 63-2). For tumors limited to the muscular layer of the gallbladder

1635

(T1), there is near-universal agreement that simple cholecystectomy is adequate.15,36–38 T1 tumors have

not yet invaded the subserosal layer, which contains lymphatics, and therefore lymphadenectomy is not

required. Attesting to the fact that early gallbladder carcinoma is completely curable, simple

cholecystectomy has resulted in 90% to 100% survival when early cancer is an incidental finding after

elective cholecystectomy.15,47

RESULTS

Table 63-2 Five-Year Survival After Resection for Gallbladder Cancer

RESULTS

Table 63-3 Results After Radical Resection for Gallbladder Cancer

Difficulty can arise at the time of surgery in evaluating polypoid lesions of the gallbladder as either

benign or early gallbladder cancer. Although it appears that frozen section diagnosis is fairly reliable in

distinguishing whether lesions are malignant or benign (95% accurate), the accuracy in correctly

assessing depth of invasion is only 70%.47 Thus, it may be difficult at the time of surgery to determine

the extent of resection. Because of this, pursuing a more aggressive resection if the depth of invasion is

in doubt is important for adequate tumor clearance.

The extent of surgical resection for T2 or greater tumors is controversial, with recommendations

ranging from simple cholecystectomy to radical excision, including hepatectomy. For advanced local

disease, some groups have advocated radical resections, including hepatectomy and pancreatectomy.

Whereas it is clear that major hepatic resection can be performed safely with a mortality less than 5%

(Table 63-3) it has not been universally accepted that more aggressive resections, such as combined

hepatectomy and pancreaticoduodenectomy, improve survival.14,15,36,37,40,48

To understand the rationale for extensive resections, it is also important to understand the pattern of

spread of gallbladder cancer. Direct extension to the adjacent liver parenchyma often occurs first,

followed by adjacent organ involvement, including duodenum, colon, and stomach (Fig. 63-2).

Lymphatic spread of gallbladder cancer is routine, often involving nodes in the porta hepatis,

peripancreatic region, celiac axis, and the aortocaval nodal basins. There is currently no consensus on

the extent of lymphadenectomy that is appropriate for gallbladder cancer. Extensive lymphadenectomy

1636

including para-aortic nodes is advocated in the East, but is not universally accepted. Recently, a

technique of intraoperative nodal staging was proposed that entails sampling the highest peripancreatic

lymph node for frozen section. This is the lymph node situated between the N1 and N2 nodal stations at

the junction of the bile duct and the superior border of the head of the pancreas (Fig. 63-4). Metastatic

disease to this node has been shown to be a poor prognostic factor.49

Figure 63-4. Illustration of the highest peripancreatic lymph node.

Because the gallbladder is not surrounded by serosa where it is attached to the liver in the gallbladder

fossa, even T2 tumors (full-thickness invasion of the muscular layer into the perimuscular connective

tissue, no extension beyond serosa or into liver) can invade the normal plane of dissection in the

gallbladder fossa during simple cholecystectomy. Therefore, T2 tumors cannot be completely removed

with cholecystectomy alone, and a radical cholecystectomy, with resection of a 1- to 2-cm rim of normal

liver around the gallbladder fossa, is the minimal resection that is required. Many authors, however,

have found that segmental resection of segments IVb and V of the liver, which abut the gallbladder

fossa, results in a more anatomically controlled dissection with less blood loss.50 An additional part of

the definitive surgical treatment is regional lymphadenectomy, because about half the patients with T2

tumors are found to have nodal spread after resection.14 Dissection of lymph nodes should include all

tissues from the bifurcation of the hepatic ducts to the distal CBD. Proponents of this approach advocate

liver resection on the basis that it is the only way to obtain an adequate margin on the hepatic side of

the gallbladder and resection of the regional nodes allows the best chance for complete tumor clearance.

For all of these reasons, simple cholecystectomy is inadequate for T2 or greater tumors. When larger

anatomic hepatic resections have been performed in patients with T2 tumors, it has increased the 5-year

survival from 25% to 40% after simple cholecystectomy to 70% to 100% after radical

resection.14,36–38,39,43,44,51,52

For T3 and T4 lesions, there is a high likelihood of intraperitoneal and hematogenous spread and

significant morbidity from the radical procedures that are often necessary for excision of local disease.

Recent series, however, support an aggressive approach to resection of these large tumors, particularly

if no indication of nodal involvement is found (Table 63-3). For T3 and resectable T4 tumors, a minimal

resection includes segments IVb and V, and in many cases an extended right hepatectomy (segments IV,

V, VI, VII, and VIII) may be necessary to obtain complete resection. With aggressive resection, longterm survival can be achieved even for patients with these more advanced tumors.14,15,36,37,40,53

Surgical exploration should be performed for all patients without medical contraindications. If a T1

tumor is suspected, a cholecystectomy and biopsy of regional nodes should be performed after thorough

examination of the abdominal cavity for any signs of tumor dissemination. The pathology and depth of

penetration should be confirmed by frozen section, and the procedure terminated if a T1 tumor with

negative margins is confirmed. For T2 lesions, either a radical cholecystectomy (wedge resection of the

hepatic bed) or a segment IVb and V resection with lymphadenectomy should be performed.14 For T3

lesions, a segment IVb and V resection or extended right hepatectomy is performed. Finally, for T4

lesions, a more radical excision of the liver, such as extended right hepatectomy, usually must be

performed for adequate tumor clearance.

1637