CLINICO-PATHOLOGIC CASE CONFERENCE
CASE NO. 08 - SGD GROUP 03
LOGICAL IMPRESSION
Ampullary Carcinoma
PRACTICE ESSENTIALS
- Ampullary carcinoma is a rare malignant
tumor originating at the ampulla of Vater, in
the last centimeter of the common bile
duct, where it passes through the wall of
the duodenum and ampullary papilla.
- Patients typically present with symptoms
related to biliary obstruction.
- A high index of suspicion is paramount so
that the appropriate laboratory and
imaging studies may be obtained to
facilitate early diagnosis.
- Over the last decade, advances in
technology have allowed improvements in
the diagnosis and staging of this disease.
- Current imaging techniques enable more
accurate staging of these tumors and
permit preoperative determination of
which tumors are surgically resectable.
- Surgical resection with
pancreaticoduodenectomy remains the
gold standard for treatment, although local
excision is an option for patients who may
be unable to tolerate this.
- Several palliative options exist for patients
with unresectable or metastatic disease.
While certain features (eg, positive
resection margins and lymph node
positivity) portend poorer prognosis,
patients with ampullary cancer generally
have better overall survival than patients
with pancreatic cancer.
SIGNS AND SYMPTOMS
- The signs and symptoms of ampullary
carcinoma are largely related to
obstruction of the bile duct or pancreatic
duct. They include the following:
- Jaundice secondary to biliary
obstruction
- Most common clinical presentation
- Abdominal pain
- Dyspepsia
- Malaise
- Fever/chills
- Anorexia
- Pancreatitis
- May be the first clinical manifestation,
due to obstruction of the pancreatic
duct
- Pruritus - Secondary to biliary obstruction
- Nausea
- Vomiting
- Weight loss
- Diarrhea
- Upper GI bleed and Heme positive
stools
- Both may occur due to ulceration of
ampullary mass (less common)
- Courvoisier gallbladder (ie, a distended,
palpable gallbladder in a patient with
jaundice)
PRESENTATION OF AMPULLARY CARCINOMA
HISTORY
- The most common clinical manifestation of
ampullary carcinoma is jaundice, which
occurs due to obstruction of the biliary tract
by the tumor.
- Patients may also experience scleral icterus
and pruritus because of obstruction of the
bile duct.
- Other common complaints include
dyspepsia, anorexia, malaise, and weight
loss.
- Pancreatitis may sometimes be the initial
clinical presentation due to pancreatic
duct obstruction.
- Patients may therefore complain of
symptoms of pancreatitis, such as
epigastric/mid-abdominal pain, back pain,
nausea, and vomiting.
PHYSICAL EXAMINATION
- Physical examination sometimes reveals a
Courvoisier’s sign (ie, a distended,
palpable gallbladder in a patient with
jaundice).
- Fever can be present, particularly when the
biliary tract has been explored previously
(eg, after common duct exploration for
stones, or after endoscopic retrograde
cholangiopancreatography [ERCP]).
- Diarrhea, a common but not universal
symptom, might be associated with an
absence of lipase within the gut because
of pancreatic duct obstruction.
DIAGNOSIS
LABORATORY TESTS
- Routine laboratory studies include the
following:
- Complete blood count
- Electrolyte panel
- Liver function studies
- Prothrombin time, bilirubin (direct and
indirect), transaminases, and alkaline
phosphatase
- A rising bilirubin level due to obstructive
jaundice often is the sole presenting
sign.
- CA 19-9
- Serum tumor marker that is often
elevated in pancreatic malignancies
and may have a role in assessing
response to therapy and/or predicting
tumor recurrence.
 - CARCINOEMBRYONIC ANTIGEN (CEA)
- A nonspecific tumor marker that is
sometimes elevated in pancreatic
malignancies; it may have a role in
assessing response to treatment or
predicting tumor recurrence.
IMAGING STUDIES
ULTRASONOGRAPHY OF THE ABDOMEN
- Abdominal ultrasonography is the initial
study to evaluate the common bile duct or
pancreatic ducts.
- Dilatation of these ducts is essentially
diagnostic for extrahepatic obstruction
- Biliary or pancreatic ductal dilatation can
explain abdominal pain, even in patients
with localized and noninvasive disease.
- Ten (10) to 15% of patients with normal
common bile duct findings on
ultrasonography demonstrate extrahepatic
biliary obstruction on a computed
tomography (CT) scan.
- Ultrasonography and CT scanning can help
reveal metastatic disease in the liver or
regional lymph nodes.
CT SCANNING OF THE ABDOMEN AND/OR
PELVIS
- Obtain a CT scan to evaluate the local
region of interest and evaluate for possible
metastases.
- CT scanning often demonstrates a mass but
is not helpful in differentiating ampullary
carcinoma from tumors of the head of the
pancreas or periampullary region; if the
lesion is smaller than 2 cm, pancreatic or
bile duct dilation may be the only
abnormalities noted on the CT scan.
- Such findings are highly suggestive of
pancreatic malignancy and require further
evaluation, usually with endoscopic
retrograde cholangiopancreatography
(ERCP).
- Dynamic CT scanning (ie, high-speed scans
obtained during rapid intravenous
administration of iodinated contrast
material) can reveal tumor involvement of
the vasculature.
OTHER IMAGING STUDIES
ERCP
- Obtain ERCP to evaluate the ductal
architecture further.
CHEST RADIOGRAPHY
- Obtain a chest radiograph to complete the
workup (ie, for staging purposes).
POSITRON EMISSION TOMOGRAPHY (PET) OR
PET-CT SCANNING
- PET or PET-CT scans can detect metastases
that are too small to be reliably detected
on a CT scan
MANAGEMENT
- The standard surgical approach to the
treatment of ampullary carcinoma is
pancreaticoduodenal resection (Whipple
procedure).
- The procedure involves en bloc resection of
the gastric antrum and duodenum; a
segment of the first portion of the jejunum,
gallbladder, and distal common bile duct;
the head and often the neck of the
pancreas; and adjacent regional lymph
nodes.
- The operative mortality rate for
pancreaticoduodenectomy was at one
time reported to be approximately 20%, but
several hospital centers have since
reported large series with operative
mortality rates in the range of 5%.
BACKGROUND
- Carcinoma of the ampulla of Vater is a
malignant tumor arising in the last
centimeter of the common bile duct,
where it passes through the wall of the
duodenum and ampullary papilla.
- The pancreatic duct (of Wirsung) and
common bile duct merge and exit by way
of the ampulla into the duodenum.
- The ductal epithelium in these areas is
columnar and resembles that of the lower
common bile duct.
- Adenocarcinoma of the ampulla of Vater is
relatively uncommon, accounting for
approximately 0.2% of gastrointestinal tract
malignancies and approximately 7% of all
periampullary carcinomas.
PATHOPHYSIOLOGY
- The periampullary region is anatomically
complex, representing the junction of 3
different epithelia, pancreatic ducts, bile
ducts, and duodenal mucosa.
- Grossly, carcinomas originating in the
ampulla of Vater can arise from 1 of 4
epithelial types: (1) terminal common bile
duct, (2) duodenal mucosa, (3) pancreatic
duct, or (4) ampulla of Vater.
- Distinguishing between true ampullary
cancers and periampullary tumors is critical
to understanding the biology of these
lesions.
- Each type of mucosa produces a different
pattern of mucus secretion.
- In a complete histochemical study, Dawson
and Connolly divided acid mucins into
sulphomucins and sialomucins; in general,
ampullary cancers produce sialomucins,
 whereas periampullary tumors secrete
sulfated mucins.
- These researchers demonstrated that
ampullary tumors secreting sialomucins had
a better prognosis (100% vs 27% 5-y survival
rate).
- Other investigators have confirmed the
prognostic power of the pattern of mucin
secretion.
- Carter et al suggest that, histologically,
ampullary tumors can be classified as either
pancreaticobiliary or intestinal, and that
the clinical behavior of these tumors
reflects this classification; the course of
intestinal ampullary adenocarcinomas is
similar to that of their duodenal
counterparts, whereas pancreaticobiliary
tumors follow a more aggressive course,
similar to that of pancreatic
adenocarcinomas.
- Immunohistochemical stains for expressions
of carcinoembryonic antigen (CEA),
carbohydrate antigen (CA) 19-9, Ki-67, and
p53 have been studied for prognostic
power.
- In a series of 45 patients, expression of CA
19-9 labeling intensity and apical
localization both were statistically
significant predictors of poor prognosis. The
5-year survival rates were markedly
different between tumors that expressed
CA 19-9 and those that did not (36% vs
100%).
- CEA expression also might be a marker for
prognosis, but it is much weaker.
- Ki-67 and p53 were not demonstrated to
have an effect on outcome.
- Research along these avenues ultimately
might provide the rationale for
discriminative administration of adjuvant
therapy.
MORTALITY/MORBIDITY
- Pancreaticoduodenectomy is a formidable
operation, and the morbidity and mortality
rates associated with this procedure
historically have been high.
- Until recently, the operative mortality rate
was reported to be approximately 20%.
- In the past few years, several centers have
reported large series with an operative
mortality rate in the range of 5%.
- A review of the last 130
pancreaticoduodenectomies performed at
Stanford University Medical Center over the
previous 5 years revealed an operative
mortality rate of 3%.
- This improvement can be attributed to
increased surgical experience, improved
patient selection, improved anesthesia,
better preoperative imaging, and general
improvement in the management of ill
patients.
- The morbidity rate associated with the
surgery is approximately 65%. In some series,
13% of patients required a repeat
laparotomy for complications.
- Patients may experience fistula formation,
delayed intestinal function, pneumonitis,
intra-abdominal infection, abscess, or
thrombophlebitis.
- Marginal ulceration, diabetes, pancreatic
dysfunction (steatorrhea), and
gastrointestinal motility disorder all can
manifest as late complications of the
surgery.
RACE- AND SEX-RELATED DEMOGRAPHICS
- Because carcinoma of the ampulla of
Vater is relatively uncommon, studies of the
patterns of occurrence among different
ethnic groups have not been conducted.
- Ampullary cancer is more common in men,
according to the National Cancer
Institute’s SEER Program.
STAGING
- Over the years, multiple systems for staging
this tumor have been proposed. Martin
proposed a 4-stage system, as follows:
- Stage I - Vegetating tumor limited to the
epithelium with no involvement of the
sphincter of Oddi
- Stage II - Tumor localized in the
duodenal submucosa without
involvement of the duodenal muscularis
propria but possible involvement of the
sphincter of Oddi
- Stage III - Tumor of the duodenal
muscularis propria
- Stage IV - Tumor of the periduodenal
area or pancreas, with proximal or distal
lymph node involvement
- The classification system of Yamaguchi and
Enjoji is similar to the Martin classification.
- Talbot et al devised a system that scored
tumors according to the degree of
infiltration (from 1-4 according to increasing
infiltration) and according to tumor
differentiation (from 1-3 for well,
moderately, and poorly differentiated
tumors), the sum of which separated the
patients into 2 groups (scores 2-4 and
scores 5-7).
- The currently accepted American Joint
Committee on Cancer staging system (7th
edition) for ampullary carcinoma
emphasizes the importance of pancreatic
invasion and lymph node metastases (see
below and see Table 1, below).
- Size has little impact on tumor stage.
- The definition of primary tumor (T), regional
lymph node (N), and remote metastases
(M) for classification and staging of cancer
of the ampulla of Vater is provided below.
PRIMARY TUMOR IS DEFINED AS FOLLOWS:
STAGES (TABLE)
ADJUVANT THERAPY
SURGICAL CARE
- The standard surgical approach is
pancreaticoduodenal resection (Whipple
procedure). The procedure involves en
bloc resection of the following:
- The gastric antrum and duodenum
- A segment of the first portion of the
jejunum, gallbladder, and distal common
bile duct
- The head and often the neck of the
pancreas
- Adjacent regional lymph nodes
- In a review of 450 cases of surgical
resection of ampullary adenoma or
adenocarcinoma at Johns Hopkins, Winter
et al found that 96.7% of the patients had
undergone pancreaticoduodenectomy
rather than local excision.
- These researchers concluded that
pancreaticoduodenectomy should be the
preferred approach for most ampullary
neoplasms that require surgical resection,
given that nearly 30% of the Johns Hopkins
patients with T1 disease had lymph node
metastases.
- Factors associated with the presence of
lymph node metastasis included the
following:
- Tumor size ≥1 cm (odds ratio [OR] 2.1)
- Poor histologic grade (OR 4.8)
- Perineural invasion (OR 3.0)
- Microscopic vessel invasion (OR 6.6)
- Depth of invasion > pT1 (OR 4.3; all P <
0.05)
- Specifically, risk of lymph node metastasis
increased with T stage (T1, 28.0%; T2, 50.9%;
T3, 71.7%; T4, 77.3%; P < 0.001)
- Results after radical resection of ampullary
of Vater carcinoma have been improving.
- During recent decades, 5-year survival
rates have ranged from 20-61%, averaging
higher than 35%.
- The reported mortality rates from this
operation are decreasing. A summary
follows in Table 2, below.
- Because local and systemic failures remain
problematic, physicians continue to be
interested in offering adjuvant therapy.
- The relative rarity of this disease limits
research in this area.
- Willett and colleagues summarized their
experience with adjuvant radiotherapy for
high-risk tumors of the ampulla of Vater (risk
factors included invasion into the pancreas,
poorly differentiated histology, involved
lymph nodes, or positive resection margins).
- Twelve patients received adjuvant
radiotherapy (40-50.4 Gy) to the tumor bed
and some received concurrent 5-
fluorouracil (5-FU) as a radiosensitizer.
- Comparison of these patients with 17
patients who underwent surgical resection
alone showed a trend toward better
locoregional control with adjuvant
radiotherapy, but there was no advantage
in survival.
- Distant metastasis to the liver, peritoneum,
and pleura was the dominant failure
pattern in this group of patients.
- Barton and Copeland reported on the M.D.
Anderson Cancer Center experience of
using postoperative chemotherapy for
carcinoma of the ampulla of Vater.
- Seventeen patients received a variety of
chemotherapeutic regimens (5-FU was
used in combination with doxorubicin,
carmustine, vincristine, methyl-lomustine, or
mitomycin-C).
- Although no analysis was presented, the
authors concluded that "no combination of
drugs appeared to prolong life."
- Sikora and colleagues presented their
experience from a hospital in India in a
retrospective review.
 - Patients who underwent
pancreaticoduodenectomy with adjuvant
chemotherapy and radiation did not do
any better than the group treated with
surgery alone.
- Zhou et al reviewed the records of 111
patients at Johns Hopkins who underwent
curative surgery for ampullary
adenocarcinoma, 45% of whom also
received adjuvant chemotherapy and
radiation.
- In these patients, the improvement in
survival with adjuvant treatment was not
statistically significant (median overall
survival: 21.6 vs. 13.0 months, P=0.092).
- In a retrospective review, Chan and
colleagues reported that 13 patients who
received adjuvant chemotherapy
(predominantly involving 5-FU, mitomycin-
C, and doxorubicin) had a significantly
better survival than 16 patients who
underwent resection only.
- Yeung and colleagues used neoadjuvant
chemoradiotherapy for 20 patients with
presumed carcinoma of the head of the
pancreas, including 4 patients with
duodenal/ampullary carcinomas.
- Interestingly, no residual tumor was found in
pancreaticoduodenectomy specimens of
the 4 patients thought to have had
ampullary/duodenal carcinomas.
- At Stanford University, all cases of
periampullary carcinoma are discussed
and reviewed in detail by a multidisciplinary
team that includes surgical oncologists,
medical oncologists, radiation oncologists,
a pathologist, a gastroenterologist, and a
radiologist.
- All resected tumors are reviewed.
- Patients with tumors with poor prognostic
features (eg, involved surgical margins,
lymph nodes, invasion of the pancreas,
perineural invasion, or poor histologic
grade) are enrolled in a single-arm
investigational protocol to receive adjuvant
radiotherapy (45 Gy) and concurrent
protracted venous infusion of 5-FU (225
mg/m2/d) during the entire treatment
course.
TREATMENT OF UNRESECTABLE DISEASE
- For patients with unresectable ampillary
carcinoma, endoscopic stenting to
achieve biliary decompression is an
appropriate palliative procedure.
- Endoscopic palliation may also be
performed for duodenal obstruction with
expandable metal stents.
- Similarly, a palliative bypass may be
performed for tumors found to be
unresectable intraoperatively.
- No established answer exists to the question
of further therapy.
a - Very little has been published on adjuvant
treatment for locally advanced and
advanced ampullary carcinoma.
- Confining the therapeutic approach to
relief of symptoms is reasonable.
- Given the paucity of effective standard
treatment options, encourage patients to
enroll in clinical trials.
- Radiotherapy, chemotherapy, and
chemoradiotherapy have been tried, but
response rates probably are low, and an
effect on survival is questionable.
FURTHER OUTPATIENT CARE
- Follow-up guidelines are not well
established for ampullary carcinoma.
- Reasonable practice includes blood
studies, chest radiograph, and CT scan of
the abdomen and/or pelvis every 6 months.
- If treatment ultimately fails, it often does so
within 5 years.
- Unfortunately, good salvage therapies do
not yet exist.
- Palliative chemotherapeutic agents and
effective medications for pain relief exist.
SOURCE
Medscape
(https://emedicine.medscape.com/article/276
413-overview)
PANCREATIC CANCER
INTRODUCTION
- Pancreatic cancer is the fourth leading
cause of cancer death in the United States
and is associated with a poor prognosis.
- Endocrine tumors affecting the pancreas
are discussed in Chap. 113.
- Infiltrating ductal adenocarcinomas, the
subject of this Chapter, account for the
vast majority of cases and arise most
frequently in the head of pancreas.
- At the time of diagnosis, 85–90% of patients
have inoperable or metastatic disease,
which is reflected in the 5-year survival rate
of only 6% for all stages combined.
- An improved 5-year survival of up to 24%
may be achieved when the tumor is
detected at an early stage and when
complete surgical resection is
accomplished.
EPIDEMIOLOGY
- Pancreatic cancer represents 3% of all
newly diagnosed malignancies in the
United States. The most common age
group at diagnosis is 65–84 years for both
sexes.
- Pancreatic cancer was estimated to have
been diagnosed in approximately 45,220
patients and accounted for approximately
38,460 deaths in 2013.
 - Although survival rates have almost
doubled over the past 35 years for this
disease, overall survival remains low.
GLOBAL CONSIDERATION
- An estimated 278,684 cases of pancreatic
cancer occur annually worldwide (the
thirteenth most common cancer globally),
with up to 60% of these cases diagnosed in
more developed countries.
- It remains the eighth most common cause
of cancer death in men and the ninth most
common in women.
- The incidence is highest in the United States
and western Europe and lowest in parts of
Africa and South Central Asia.
- However, increasing rates of obesity,
diabetes, and tobacco use in addition to
access to diagnostic radiology in the
developing world are likely to increase
incidence rates in these countries.
- In this situation, consideration of the cost
implications of adoption of current
treatment paradigms in resource-
constrained environments will be
necessary.
- Primary prevention such as limiting tobacco
use and avoiding obesity may be more
cost effective than improvements in
treatment of preexisting disease.
RISK FACTORS
- Cigarette smoking may be the cause of up
to 20–25% of all pancreatic cancers and is
the most common environmental risk factor
for this disease.
- A longstanding history of type 1 or type 2
diabetes also appears to be a risk factor;
however, diabetes may also occur in
association with pancreatic cancer,
possibly confounding this interpretation.
- Other risk factors may include obesity,
chronic pancreatitis, and ABO blood group
status.
- Alcohol does not appear to be a risk factor
unless excess consumption gives rise to
chronic pancreatitis.
GENETIC AND MOLECULAR CONSIDERATIONS
- Pancreatic cancer is associated with a
number of well-defined molecular
hallmarks.
- The four genes most commonly mutated or
inactivated in pancreatic cancer are KRAS
(predominantly codon 12, in 60–75% of
pancreatic cancers), the tumor-suppressor
genes p16 (deleted in 95% of tumors), p53
(inactivated or mutated in 50–70% of
tumors), and SMAD4 (deleted in 55% of
tumors).
- The pancreatic cancer precursor lesion
pancreatic intraepithelial neoplasia (PanIN)
acquires these genetic abnormalities in a
progressive manner associated with
increasing dysplasia; initial KRAS mutations
are followed by p16 loss and finally p53 and
SMAD4 alterations.
- SMAD4 gene inactivation is associated with
a pattern of widespread metastatic disease
in advanced-stage patients and poorer
survival in patients with surgically resected
pancreatic adenocarcinoma.
- Up to 16% of pancreatic cancers may be
inherited.
- Germline mutations in the following genes
are associated with a significantly
increased risk of pancreatic cancer and
other cancers: (1) STK11 gene (Peutz-
Jeghers syndrome), which carries a 132-fold
increased lifetime risk of pancreatic cancer
above the general population; (2) BRCA2
(increased risk of breast, ovarian, and
pancreatic cancer); (3) p16/CDKN2A
(familial atypical multiple mole melanoma),
which carries an increased risk of
melanoma and pancreatic cancer; (4)
PALB2, which confers an increased risk of
breast and pancreatic cancer; (5) hMLH1
and MSH2 (Lynch syndrome), which carries
an increased risk of colon and pancreatic
cancer; and (6) ATM (ataxia-
telangiectasia), which carries an increased
risk of breast cancer, lymphoma, and
pancreatic cancer.
- Familial pancreatitis and an increased risk
of pancreatic cancer are associated with
mutations of the PRSS1 (serine protease 1)
gene.
- However, for most familial pancreatic
syndromes, the underlying genetic cause
remains unexplained.
- The absolute number of affected first-
degree relatives is also correlated with
increased cancer risk, and patients with at
least two first-degree relatives with
pancreatic cancer should be considered
to have familial pancreatic cancer until
proven otherwise.
- The desmoplastic stroma surrounding
pancreatic adenocarcinoma functions as
a mechanical barrier to chemotherapy
and secretes compounds essential for
tumor progression and metastasis.
- Key mediators of these functions include
the activated pancreatic stellate cell and
the glycoprotein SPARC (secreted protein
acidic and rich in cysteine), which is
expressed in 80% of pancreatic ductal
adenocarcinomas.
- Targeting this extracellular environment has
become increasingly important in the
treatment of advanced disease.
SCREENING AND PRECURSOR LESIONS
- Screening is not routinely recommended
because the incidence of pancreatic
cancer in the general population is low
(lifetime risk 1.3%), putative tumor markers
 such as carbohydrate antigen 19-9 (CA19-
9) and carcinoembryonic antigen (CEA)
have insufficient sensitivity, and computed
tomography (CT) has inadequate resolution
to detect pancreatic dysplasia.
- Endoscopic ultrasound (EUS) is a more
promising screening tool, and preclinical
efforts are focused on identifying
biomarkers that may detect pancreatic
cancer at an early stage.
- Consensus practice recommendations
based largely on expert opinion have
chosen a threshold of greater than fivefold
increased risk for developing pancreatic
cancer to select individuals who may
benefit from screening.
- This includes people with two or more first-
degree relatives with pancreatic cancer,
patients with Peutz-Jeghers syndrome, and
BRCA 2, p16, and hereditary nonpolyposis
colorectal cancer (HNPCC) mutation
carriers with one or more affected first-
degree relatives.
- PanIN represents a spectrum of small (<5
mm) neoplastic but noninvasive precursor
lesions of the pancreatic ductal epithelium
demonstrating mild, moderate, or severe
dysplasia (PanIN 1–3, respectively);
however, not all PanIN lesions will progress
to frank invasive malignancy.
- Cystic pancreatic tumors such as
intraductal mucinous papillary neoplasms
(IPMNs) and mucinous cystic neoplasms
(MCNs) are increasingly detected
radiologically and are frequently
asymptomatic.
- Main duct IPMNs are more likely to occur in
older persons and have higher malignant
potential than branched duct IPMNs
(invasive cancer in 45% vs 18% of resected
lesions, respectively).
- In contrast, MCNs are solitary lesions of the
distal pancreas that do not communicate
with the duct system.
- MCNs have an almost exclusive female
distribution (95%).
- The rate of invasive cancer in resected
MCNs is lower (<18%) with increased rates
associated with larger tumors or the
presence of nodules.
CLINICAL FEATURES
CLINICAL PRESENTATION
- Obstructive jaundice occurs frequently
when the cancer is located in the head of
the pancreas.
- This may be accompanied by symptoms of
abdominal discomfort, pruritus, lethargy,
and weight loss.
- Less common presenting features include
epigastric pain, backache, new-onset
diabetes mellitus, and acute pancreatitis
caused by pressure effects on the
pancreatic duct.
- Nausea and vomiting, resulting from
gastroduodenal obstruction, may also be a
symptom of this disease.
PHYSICAL SIGNS
- Patients can present with jaundice and
cachexia, and scratch marks may be
present.
- Of patients with operable tumors, 25% have
a palpable gallbladder (Courvoisier’s sign).
- Physical signs related to the development
of distant metastases include
hepatomegaly, ascites, left supraclavicular
lymphadenopathy (Virchow’s node), and
periumbilical nodules (Sister Mary Joseph’s
nodes).
DIAGNOSTIC IMAGING
- Patients who present with clinical features
suggestive of pancreatic cancer undergo
imaging to confirm the presence of a tumor
and to establish whether the mass is likely to
be inflammatory or malignant in nature.
- Other imaging objectives include the local
and distant staging of the tumor, which will
determine resectability and provide
prognostic information.
- Dual-phase, contrast-enhanced spiral CT is
the imaging modality of choice (Fig. 112-1).
- It provides accurate visualization of
surrounding viscera, vessels, and lymph
nodes, thus determining tumor resectability.
- Intestinal infiltration and liver and lung
metastases are also reliably depicted on
CT.
- There is no advantage of
magneticresonance imaging (MRI) over CT
in predicting tumor resectability, but
selected cases may benefit from MRI to
characterize the nature of small
indeterminate liver lesions and to evaluate
the cause of biliary dilatation when no
obvious mass is seen on CT.
- Endoscopic retrograde
cholangiopancreatography (ERCP) is useful
for revealing small pancreatic lesions,
identifying stricture or obstruction in
pancreatic or common bile ducts, and
facilitating stent placement; however, it is
associated with a risk of pancreatitis (Fig.
112-2).
- Magnetic resonance
cholangiopancreatography (MRCP) is a
noninvasive method for accurately
depicting the level and degree of bile and
pancreatic duct dilatation.
- EUS is highly sensitive in detecting lesions
less than 3 cm in size (more sensitive than
CT for lesions <2 cm) and is useful as a local
staging tool for assessing vascular invasion
and lymph node involvement.
 - Fluorodeoxyglucose positron emission
tomography (FDG-PET) should be
considered before surgery or radical
chemoradiotherapy (CRT), because it is
superior to conventional imaging in
detecting distant metastases.

TISSUE DIAGNOSIS AND CYTOLOGY

- Preoperative confirmation of malignancy is
not always necessary in patients with
radiologic appearances consistent with
operable pancreatic cancer.
- However, EUS-guided fine-needle aspiration
is the technique of choice when there is
any doubt, and also for use in patients who
require neoadjuvant treatment.
- It has an accuracy of approximately 90%
and has a smaller risk of intraperitoneal
dissemination compared with the
percutaneous route.
- Percutaneous biopsy of the pancreatic
primary or liver metastases is only
acceptable in patients with inoperable or
metastatic disease.
- ERCP is a useful method for obtaining
ductal brushings, but the sensitivity of ERCP
for diagnosis ranges from 35 to 70%.

SERUM MARKERS
- Tumor-associated CA19-9 is elevated in
approximately 70–80% of patients with
pancreatic carcinoma but is not
recommended as a routine diagnostic or
screening test because its sensitivity and
specificity are inadequate for accurate
diagnosis.
- Preoperative CA19-9 levels correlate with
tumor stage, and postresection CA19-9
level has prognostic value. It is an indicator
of asymptomatic recurrence in patients
with completely resected tumors and is
used as a biomarker of response in patients
with advanced disease undergoing
chemotherapy.
- A number of studies have established a
high pretreatment CA19-9 level as an
independent prognostic factor.

STAGING
- The American Joint Committee on Cancer
(AJCC) tumor-nodemetastasis (TNM)
staging of pancreatic cancer takes into
account the location and size of the tumor,
the involvement of lymph nodes, and
distant metastasis.
- This information is then combined to assign
a stage (Fig. 112-3). From a practical
standpoint, patients are grouped
according to whether the cancer is
resectable, locally advanced
(unresectable, but without distant spread),
or metastatic.

SOURCE
Harrison’s Principles of Internal Medicine
19TH Edition (Pages 554 to 557)
JAUNDICE
INTRODUCTION
- Jaundice, or icterus, is a yellowish
discoloration of tissue resulting from the
deposition of bilirubin.
- Tissue deposition of bilirubin occurs only in
the presence of serum hyperbilirubinemia
and is a sign of either liver disease or, less
often, a hemolytic disorder.
- The degree of serum bilirubin elevation can
be estimated by physical examination.
Slight increases in serum bilirubin level are
best detected by examining the sclerae,
which have a particular affinity for bilirubin
due to their high elastin content.
- The presence of scleral icterus indicates a
serum bilirubin level of at least 51 μmol/L (3
mg/dL).
- The ability to detect sclera icterus is made
more difficult if the examining room has
fluorescent lighting.
- If the examiner suspects scleral icterus, a
second site to examine is underneath the
tongue.
- As serum bilirubin levels rise, the skin will
eventually become yellow in light-skinned
patients and even green if the process is
long-standing; the green color is produced
by oxidation of bilirubin to biliverdin.
- The differential diagnosis for yellowing of
the skin is limited.
- In addition to jaundice, it includes
carotenoderma, the use of the drug
quinacrine, and excessive exposure to
phenols.
- Carotenoderma is the yellow color
imparted to the skin of healthy individuals
who ingest excessive amounts of
vegetables and fruits that contain
carotene, such as carrots, leafy vegetables,
squash, peaches, and oranges.
- In jaundice the yellow coloration of the skin
is uniformly distributed over the body,
whereas in carotenoderma the pigment is
concentrated on the palms, soles,
forehead, and nasolabial folds.
- Carotenoderma can be distinguished from
jaundice by the sparing of the sclerae.
- Quinacrine causes a yellow discoloration of
the skin in 4–37% of patients treated with it.
- Another sensitive indicator of increased
serum bilirubin is darkening of the urine,
which is due to the renal excretion of
conjugated bilirubin.
- Patients often describe their urine as tea- or
cola-colored.
- Bilirubinuria indicates an elevation of the
direct serum bilirubin fraction and,
therefore, the presence of liver disease.
- Serum bilirubin levels increase when an
imbalance exists between bilirubin
production and clearance.
- A logical evaluation of the patient who is
jaundiced requires an understanding of
bilirubin production and metabolism
PRODUCTION AND METABOLISM OF BILIRUBIN
- Bilirubin, a tetrapyrrole pigment, is a
breakdown product of heme
(ferroprotoporphyrin IX).
- About 70–80% of the 250–300 mg of bilirubin
produced each day is derived from the
breakdown of hemoglobin in senescent red
blood cells.
- The remainder comes from prematurely
destroyed erythroid cells in bone marrow
and from the turnover of hemoproteins
such as myoglobin and cytochromes found
in tissues throughout the body.
- The formation of bilirubin occurs in
reticuloendothelial cells, primarily in the
spleen and liver.
- The first reaction, catalyzed by the
microsomal enzyme heme oxygenase,
oxidatively cleaves the αlpha bridge of the
porphyrin group and opens the heme ring.
- The end products of this reaction are
biliverdin, carbon monoxide, and iron. The
second reaction, catalyzed by the
cytosolic enzyme biliverdin reductase,
reduces the central methylene bridge of
biliverdin and converts it to bilirubin.
- Bilirubin formed in the reticuloendothelial
cells is virtually insoluble in water due to
tight internal hydrogen bonding between
the water-soluble moieties of bilirubin—i.e.,
the bonding of the proprionic acid
 carboxyl groups of one dipyrrolic half of the
molecule with the imino and lactam groups
of the opposite half.
- This configuration blocks solvent access to
the polar residues of bilirubin and places
the hydrophobic residues on the outside.
- To be transported in blood, bilirubin must be
solubilized.
- Solubilization is accomplished by the
reversible, noncovalent binding of bilirubin
to albumin.
- Unconjugated bilirubin bound to albumin is
transported to the liver.
- There, the bilirubin—but not the albumin—is
taken up by hepatocytes via a process that
at least partly involves carrier-mediated
membrane transport.
- No specific bilirubin transporter has yet
been identified (Chap. 359, Fig. 359-1).
- After entering the hepatocyte,
unconjugated bilirubin is bound in the
cytosol to a number of proteins including
proteins in the glutathione-S-transferase
superfamily.
- These proteins serve both to reduce efflux
of bilirubin back into the serum and to
present the bilirubin for conjugation.
- In the endoplasmic reticulum, bilirubin is
solubilized by conjugation to glucuronic
acid, a process that disrupts the internal
hydrogen bonds and yields bilirubin
monoglucuronide and diglucuronide.
- The conjugation of glucuronic acid to
bilirubin is catalyzed by bilirubin uridine
diphosphate-glucuronosyl transferase
(UDPGT).
- The now-hydrophilic bilirubin conjugates
diffuse from the endoplasmic reticulum to
the canalicular membrane, where bilirubin
monoglucuronide and diglucuronide are
actively transported into canalicular bile by
an energy-dependent mechanism
involving the multidrug resistance–
associated protein 2 (MRP2).
- The conjugated bilirubin excreted into bile
drains into the duodenum and passes
unchanged through the proximal small
bowel.
- Conjugated bilirubin is not taken up by the
intestinal mucosa.
- When the conjugated bilirubin reaches the
distal ileum and colon, it is hydrolyzed to
unconjugated bilirubin by bacterial β-
glucuronidases.
- The unconjugated bilirubin is reduced by
normal gut bacteria to form a group of
colorless tetrapyrroles called urobilinogens.
- About 80–90% of these products are
excreted in feces, either unchanged or
oxidized to orange derivatives called
urobilins.
- The remaining 10–20% of the urobilinogens
are passively absorbed, enter the portal
venous blood, and are re-excreted by the
liver.
- A small fraction (usually <3 mg/dL) escapes
hepatic uptake, filters across the renal
glomerulus, and is excreted in urine.
MEASUREMENT OF SERUM BILIRUBIN
- The terms direct and indirect bilirubin—i.e.,
conjugated and unconjugated bilirubin,
respectively—are based on the original van
den Bergh reaction.
- This assay, or a variation of it, is still used in
most clinical chemistry laboratories to
determine the serum bilirubin level.
- In this assay, bilirubin is exposed to
diazotized sulfanilic acid and splits into two
relatively stable dipyrrylmethene
azopigments that absorb maximally at 540
nm, allowing photometric analysis.
- The direct fraction is that which reacts with
diazotized sulfanilic acid in the absence of
an accelerator substance such as alcohol.
- The direct fraction provides an
approximation of the conjugated bilirubin
level in serum.
- The total serum bilirubin is the amount that
reacts after the addition of alcohol.
- The indirect fraction is the difference
between the total and the direct bilirubin
levels and provides an estimate of the
unconjugated bilirubin in serum.
- With the van den Bergh method, the
normal serum bilirubin concentration usually
is 17 μmol/L (<1 mg/dL). Up to 30%, or 5.1
μmol/L (0.3 mg/dL), of the total may be
direct-reacting (conjugated) bilirubin.
- Total serum bilirubin concentrations are
between 3.4 and 15.4 μmol/L (0.2 and 0.9
mg/dL) in 95% of a normal population.
- Several new techniques, although less
convenient to perform, have added
considerably to our understanding of
bilirubin metabolism.
- First, studies using these methods
demonstrate that, in normal persons or
those with Gilbert’s syndrome, almost 100%
of the serum bilirubin is unconjugated; <3%
is monoconjugated bilirubin.
- Second, in jaundiced patients with
hepatobiliary disease, the total serum
bilirubin concentration measured by these
new, more accurate methods is lower than
the values found with diazo methods.
- This finding suggests that there are diazo-
positive compounds distinct from bilirubin in
the serum of patients with hepatobiliary
disease.
- Third, these studies indicate that, in
jaundiced patients with hepatobiliary
disease, monoglucuronides of bilirubin
predominate over diglucuronides.
- Fourth, part of the direct-reacting bilirubin
fraction includes conjugated bilirubin that is
covalently linked to albumin. This albumin-
 linked bilirubin fraction (delta fraction, or EVALUATION OF PATIENT WITH JAUNDICE
biliprotein) represents an important fraction
of total serum bilirubin in patients with
cholestasis and hepatobiliary disorders.
- The delta fraction (delta bilirubin) is formed
in serum when hepatic excretion of bilirubin
glucuronides is impaired and the
glucuronides accumulate in serum.
- By virtue of its tight binding to albumin, the
clearance rate of delta bilirubin from serum
approximates the half-life of albumin (12–14
days) rather than the short half-life of
bilirubin (about 4 h).
- The prolonged half-life of albumin-bound
conjugated bilirubin accounts for two
previously unexplained enigmas in
jaundiced patients with liver disease: (1)
that some patients with conjugated
hyperbilirubinemia do not exhibit
bilirubinuria during the recovery phase of
their disease because the bilirubin is
covalently bound to albumin and therefore
not filtered by the renal glomeruli, and (2)
that the elevated serum bilirubin level
declines more slowly than expected in
some patients who otherwise appear to be
recovering satisfactorily.
- Late in the recovery phase of hepatobiliary
disorders, all the conjugated bilirubin may SOURCE
be in the albumin-linked form. Harrison’s Principles of Internal Medicine
19TH Edition (Pages 279 to 281)
MEASUREMENT OF URINE BILIRUBIN
- Unconjugated bilirubin is always bound to
albumin in the serum, is not filtered by the
kidney, and is not found in the urine.
- Conjugated bilirubin is filtered at the
glomerulus, and the majority is reabsorbed
by the proximal tubules; a small fraction is
excreted in the urine.
- Any bilirubin found in the urine is
conjugated bilirubin.
- The presence of bilirubinuria implies the
presence of liver disease.
- A urine dipstick test (Ictotest) gives the
same information as fractionation of the
serum bilirubin and is very accurate.
- A false-negative result is possible in patients
with prolonged cholestasis due to the
predominance of delta bilirubin, which is
covalently bound to albumin and therefore
not filtered by the renal glomeruli.