1

DISTAL
CHOLANGIOCARCINOMA (DCC)

Paxton V. Dickson, MD, Stephen W. Behrman, MD

 KEY POINTS
2

 DCC  a rare malignancy that often clinically presents similar to

pancreatic cancer.

 Primary sclerosing cholangitis (PSC)  increased risk for

cholangiocarcinoma(CC) and should undergo rigorous surveillance to
preempt malignant transformation.

 Patients with imaging & endoscopy suggesting only locoregional

disease, & of adequate performance status  exploration for
possible pancreaticoduodenectomy.
 KEY POINTS
3

 Positive resection margins & lymph node metastases have consistently

 poor prognosis after pancreaticoduodenectomy.

 There are limited data to support adjuvant chemotherapy after

potentially curative resection for DCC.

 Unresectable or metastatic disease, palliative systemic chemotherapy

 gemcitabine and cisplatin; however, median survival in these

patients is <1 year

4

 Cholangiocarcinoma (CC) involving the DCC  a periampullary

neoplasm less common than, but often difficult to distinguish from,
pancreatic adenocarcinoma (PDA).

 Prognosis & cure rate of DCC is improved over that of PDA, it

remains a highly lethal disease.

 Diagnostic and therapeutic management of DCC is not dissimilar

from PDA, the pathophysiology is, in many instances, distinctly
different.
 Epidemiology
5

 It is difficult to determine the exact incidence of DCC

 Extrahepatic CC (hilar and distal) is stable or in some
instances decreasing.
 Intrahepatic CC is rising in incidence worldwide.
 DCC is, in many aspects, a vastly different disorder than
hilar CC and gallbladder carcinoma.
 CC, regardless of anatomic location, is more common in Asia
than in Western countries.
 Risk Factors
6

 80% CC in any anatomic location have no identifiable risk factor

for the development of the disease

 Recent work has accelerated knowledge of the molecular

pathways and genetic aberrations that may contribute toward
the development of cholangiocarcinogenesis.

 Social  Smoking and alcohol consumption common among

patients with CC but no data . Recent : Diabetes  increase the
risk of CC including extrahepatic CC.
 Risk Factors
7

 Disease Specific
A. PSC
• Autoimmune disease  affect the entire biliary tree. Risk of PSC-
associated CC  in concomitant ulcerative colitis.
• CC with PSC : CA19-9 and/or CEA, the emergence of a dominant
stricture, clinical and biochemical deterioration of liver function,
weight loss, jaundice, and the presence of bile duct dysplasia on
brush cytology.
• Diagnostically: ERCP in conjunction with endoscopic intraductal
ultrasound and cholangioscopic biopsy
• Resected CC for a dominant stricture resulting from unsuspected PSC
in the absence of other objective criteria for the diagnosis remains
exceptional.
 Risk Factors
8

 Choledochal cysts
• Congenital cystic dilations of the intrahepatic and/or
extrahepatic biliary tree.
• Commonly : infancy, but unrecognized until adulthood
• Symptoms related to associated choledocholithiasis, such as
nausea, vomiting, and epigastric pain.
• Type I (solitary extrahepatic) & type IV (extrahepatic and
intrahepatic dilation involving the bile duct confluence) cysts have
the highest lifetime risk of CC with an incidence up to 30%.
 Risk Factors
9

 Parasitic Infections
• Biliary infestation with the liver flukes Opisthorchis
viverrini and Clonorchis sinensis  Chronic
inflammation : increase the susceptibility to
cholangiocarcinogenesis.
• Infestation is linked to poor sanitation, therapeutic
intervention has focused on prevention.
• Treatment  anthelmintic agents is important if
infection is documented.
 BIOLOGIC BASIS OF CHOLANGIOCARCINOGENESIS
10

 Inflammatory Mediators

• Cholestasis  results in abnormal exposure of the biliary

epithelium to bile acids.

• Deoxycholic acid activate epidermal growth factor receptor &

serve as a neoplastic stimulus by promoting cellular proliferation
and attenuating apoptosis in cholangiocytes.

• IL-6 is upregulated in CC relative to normal biliary tract cells. IL-6

 desensitize CC to normal apoptotic cell death.
 BIOLOGIC BASIS OF CHOLANGIOCARCINOGENESIS
11

 Growth Factors
• Human CC cell lines express high levels of vascular endothelial growth
factor leading to angiogenesis and cancer growth.

• Inhibition of vascular endothelial growth factor reduces cell proliferation

and leads to apoptosis in tumor tissue.

• Epidermal growth factor receptor is a mediator of cholangiocarcinogenesis

as previously noted.

• Epidermal growth factor receptor has been detected in more than one-third
of samples obtained from patients with CC
12

 Stromal Alterations

• CC exhibits an epithelial-mesenchymal transition that results in a

desmoplastic stroma predominantly composed of cancerassociated
fibroblasts surrounding glandular structures.

• As opposed to tumors with epithelial expression, those exhibiting the

mesenchymal phenotype have been associated with the development of
chemoresistance in pancreatic cancer and tumor progression in CC.

• CC is associated with increased levels of matrix metalloproteinases,

which break down the extracellular matrix to allow tumor spread.
 BIOLOGIC BASIS OF CHOLANGIOCARCINOGENESIS
13

 Inflammatory Mediators
• IL-6   progranulin in CC in contrast to nonmalignant
cholangiocytes.
• COX-2overexpressed in CC and premalignant
conditions, such as PSC.
• COX-2 accumulation results in cellular proliferation and
inhibition of apoptosis in CC, a process reversed by the
administration of the COX-2 inhibitor celecoxib.
 BIOLOGIC BASIS OF CHOLANGIOCARCINOGENESIS
14

 Genetic Aberrations
• A mutation of the p53 tumor suppressor gene : 20%-61%,
resulting in inhibition of the normal cellular apoptotic response.
• miRNAs are single-strand noncoding RNA products that may have
tumor suppressor or oncogenic activity.
• Aberrant regulation of miRNA has been described in CC resulting
in cancer cell proliferation and survival.
• Manipulation of dysregulated miRNA may offer a potential
avenue for CC treatment.
 CLINICAL PRESENTATION AND EVALUATION
15

 Painless jaundice
 Experience pruritus
 Clay colored stools
 Tea-colored urine
 Right upper quadrant discomfort
 A bloating sensation
 Lab : bilirubin, alkaline phosphatase, g-glutamyl
transpeptidase, elevation of hepatic transaminases.
 CLINICAL PRESENTATION AND EVALUATION
16

 Dx  radiographic and endoscopic studies  define the

local extent of disease, evaluate for potential metastases,
& obtain tissue confirmation if the diagnosis is unclear.

 Jaundice transabdominal ultrasound : very sensitive 

intrahepatic and extrahepatic ductal dilation, the presence
of a choledochal cyst, cholelithiasis or choledocholithiasis,
and potential mass lesions.
 CLINICAL PRESENTATION AND
17
EVALUATION
 CT / MRI  distended gallbladder with dilated
extrahepatic and intrahepatic ducts.

 Contrastenhanced triple-phase CTallows for evaluation of

critical vascular anatomy, regional lymph node basins, and
potentially identifies distant metastases.

 DCC may result in biliary dilation alone but not uncommonly

results in the classic double-duct sign found with PDA.
 CLINICAL PRESENTATION AND
18
EVALUATION
 Imaging findings  periampullary mass or distal bile duct
stricture

 Endoscopic  if the diagnosis is uncertain.

 Transampullary biopsy  higher sensitivity to diagnosis a tissue

 EUS is shown to have a with fine-needle aspiration biopsy 

biliary malignancy and, unlike ERCP, does not require
cannulation of the biliary tree
 CLINICAL PRESENTATION AND
19
EVALUATION
 Recently, peroral cholangioscopy  allows direct
visualization of biliary epithelium and accurate
targeting for biopsies
 Certainly, the endoscopic modality of choice is largely
driven by institutional expertise and the nature of individual
cases.
 The tumor markers CA 19-9 and CEA have been used in
patients with biliary tract malignancies
 PRINCIPLES OF SURGICAL TECHNIQUE
20

 Pancreaticoduodenectomy focus on meticulous medial perivascular dissection of

tissue off the superior mesenteric artery (SMA) and vein and a careful regional

lymphadenectomy

 Medial dissection of the pancreatic head/uncinate process is crucial  this

margin is typically closest to the epicenter of the tumor and most difficult to

maximize.

 Adequate extirpation requires completely skeletonizing the right anterolateral

aspect of the SMA down to the level of the adventitia and mobilization of the

uncinate process off this vessel. This enhances pancreatic tissue yield while

broadening the medial (retroperitoneal) margin relative to the carcinoma

 PRINCIPLES OF SURGICAL TECHNIQUE
21

 On evaluation of excised specimens in patients undergoing vein resection, only 60-

70% had histologic evidence of frank tumor involvement and R0 resections were
still not obtainable in 10%-30%.

 However, if an R0 resection is obtained with vein excision, longevity seems similar to

those with R0 resections without venous involvement, with no significant increase in
morbidity and mortality.

 Lymphadenectomy should include a thorough dissection of regional nodes. Specific

to DCC, all nodes surrounding the common bile duct and porta hepatis should be
carefully excised as potential draining basins from distal common bile duct cancers.

 Hepatic artery nodes should be considered for resection if there is clinical suspicion
of involvement because these basins have been shown to have prognostic
implications in PDA and possibly also could in CC
22
 PATHOLOGIC ANALYSIS
23

A. Specimen Orientation and Margin Assessment

The primary  the pathologic stage of the tumor by

evaluating the type, grade, size, and extent of the cancer.

Specimen orientation, margin identification, and inking 

helps ensure accurate assessment of the size and extent of
the tumor and proximity concerns of the malignancy to the
margins assessed.
 The National Comprehensive Cancer Network

24
 PATHOLOGIC ANALYSIS
25

B. SMA (Retroperitoneal/Uncinate) Margin

 The most important margin is the ragged, soft tissue
directly adjacent to the proximal 3 to 4 cm of the SMA.
 In common with other margins assessed, radial rather than

en face sections are recommended and more clearly

demonstrate how closely this margin is approached by
tumor.
 The simple step of palpating the specimen can help guide

the pathologist as to the best location along the SMA

margin to select for sampling.
 PATHOLOGIC ANALYSIS
26

C. Posterior (Retroperitoneal) Margin

 This margin is from the posterior caudad aspect of the
pancreatic head that merges with the uncinate margin
and that appears to be covered by loose connective
tissue.
 In some instances this margin can be included in the
same section as the SMA margin section
 PATHOLOGIC ANALYSIS
27

D. Portal Vein Groove Margin

 This is the smooth-surfaced groove on the posterior
surface of the pancreatic head that rests over the
portal vein.
 As is true for the posterior margin, in some instances this
margin can be included in the same section as the SMA
section.
 PATHOLOGIC ANALYSIS
28

E. Pancreatic Neck (Transection) Margin

 This is the en face section of the transected pancreatic neck. The section
should be placed into the cassette with true margin facing up so that the
initial section into the block represents the true surgical margin.
 For purposes of frozen section analysis in the operating room, the
authors recommend assessment 5 mm from the transected pancreatic
neck.
 This eliminates any cautery artifact that may impede the pathologist’s
assessment for cancer on frozen section.
 Furthermore, this ensures a minimum of a 5-mm clearance of tumor from
this particular margin.
 If tumor is found on microscopic assessment, resection of further pancreas
to achieve an R0 resection can be easily accomplished.
 PATHOLOGIC ANALYSIS
29

F. Bile Duct Margin

 When there is clinical suspicion or pathologic confirmation of DCC, the stump of the
distal common bile duct demands specific scrutiny. Specifically, the circumferential
soft tissue sheath or radial periductal margin around the distal common bile duct
should be assessed.

 Other margins analyzed in Whipple specimens include the proximal and distal
enteric margins (en face sections) and anterior surface (closest representative).

 The anterior surface is not a true margin, but identification and reporting of this
surface when positive may portend a risk of local recurrence, and so should be
reported in all cases.

 Collectively, these pancreatic tissue surfaces constitute the circumferential radial

margin. Designating the various specific margins with different colored inks allows
recognition on microscopy.
 PATHOLOGIC ANALYSIS
30

G. Specimen Grossing Technique and Extent of

Tissue Sampling

 Options include (1) axial slicing through a plane

perpendicular to the second portion of the duodenum; (2)
bivalve or multivalve sectioning, bisecting the pancreas
along probes placed in the bile and pancreatic ducts and
then serially section along each half of the pancreas; or
(3) breadloafing technique whereby the specimen is
sectioned perpendicular to the neck of the pancreas (Fig.
3).
 PATHOLOGIC ANALYSIS
31

 The bivalve technique does not allow a satisfactory three-dimensional

perspective of the carcinoma relative to the entire specimen. The
breadloafing technique becomes difficult in the region of the duodenum
and may distort the relationship of the tumor to the ampulla and the
insertion of the pancreatic and bile ducts.

 In contrast to other techniques, axial slicing (Fig. 4) provides an overall

assessment of the epicenter of the tumor relative to the ampulla, bile duct,
duodenum, and pancreas, and all of the pancreatic circumferential tissue
margins mentioned previously.

 In addition, axial slicing correlates with preoperative computed

tomography or magnetic resonance imaging.

 Achievement of a large number of thin slices (>12) is possible by this

technique allowing a dogmatic assessment of the primary tumor relative
to the margins of resection
 PATHOLOGIC ANALYSIS
32
 PATHOLOGIC ANALYSIS
33
 PATHOLOGIC ANALYSIS
34

 The NCCN Pancreatic Adenocarcinoma Panel currently

supports pathology synoptic reports from the College of
American Pathologists.

 The proposal included herein is an abbreviated minimum

analysis of pancreatic cancer specimens from the College of
American Pathologists recommendations that we believe
should be used for DCC (Table 1).

 In addition to the standard TNM staging, other variables are

included, all of which have prognostic implications in the
evolution of pancreatic carcinoma that might be important in
DCC.
 PATHOLOGIC ANALYSIS
35

Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines") for Pancreatic Adenocarcinoma V.1.2014. ! 2014 National Comprehensive Cancer Network,
Inc. All rights reserved. The NCCN Guidelines" and illustrations herein may not be reproduced
in any form for any purpose without the express written permission of the NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NATIONAL
COMPREHENSIVE CANCER NETWORK", NCCN", NCCN GUIDELINES", and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.
 STAGING AND PROGNOSIS
36

 The median survival of patients who undergo resection

for DCC is approximately 2 years with a 5-year
survival of 20% to 40% depending on the extent of
disease.
 The current staging classification schema is shown in
Table 2.
 DeOliveira and colleagues reported on more than 500
patients with CC treated at the Johns Hopkins hospital,
including 239 individuals with distal tumors.
 STAGING AND PROGNOSIS
37

 In this series, 5-year overall survival for patients with

DCC was 23%. On multivariate analysis, resection
margin status (R0 vs R1/R2), lymph node status (positive
vs negative), tumor size (< or >2 cm), and degree of
tumor differentiation were all found to significantly
impact survival among this group of patients.

 Similarly, Murakami and colleagues found margin status

and lymph node status to significantly impact survival in
patients who underwent resection for CC.
 STAGING AND PROGNOSIS
38

 In a follow-up series from this same institution, specifically

examining 43 patients with distal bile duct tumors, resection
margin status and lymph node status were again identified
as important prognostic factors for survival with 5-year
survivals of 8% and 60% for patients with positive and
negative margins, respectively, and 5-year survivals of
18% and 46% for patients with positive and negative
nodes, respectively.

 Other factors shown to be predictive of poor prognosis

include perineural invasion, lymphovascular invasion,
pancreatic invasion, and depth of tumor invasion.
 STAGING AND PROGNOSIS
39
 POSTOPERATIVE THERAPY FOR LOCOREGIONAL DISEASE
40

 The role of adjuvant therapy in patients with DCC after

potentially curative resection is ill defined.
 In a phase III trial evaluating surgery followed by
treatment with 5-FU and mitomycin-C versus surgery alone
in patients with bile duct, gallbladder, pancreatic, or
ampullary cancer, postoperative chemotherapy offered no
benefit in overall or disease-free survival in patients with
bile duct carcinoma, regardless of resection margin status.
 POSTOPERATIVE THERAPY FOR LOCOREGIONAL DISEASE
41

 The European Study Group for Pancreatic Cancer-3

periampullary trial, which randomized patients to
postoperative observation or 6 months of chemotherapy
with either 5-FU/leucovorin or gemcitabine, included 96
patients with bile duct carcinoma.

 Subset analysis of this group did not demonstrate any

improvement in median survival between those randomized
to 5-FU/leucovorin (18.3 months) or gemcitabine (19.5
months) versus observation (27.2 months). Given results
observed in these trials, there is a general lack of support
for the use of adjuvant chemotherapy after R0 resection of
bile duct carcinoma.
 POSTOPERATIVE THERAPY FOR LOCOREGIONAL DISEASE
42

 Hughes and colleagues reported on 34 patients with DCC treated with

pancreaticoduodenectomy and adjuvant chemoradiation at the Johns
Hopkins Hospital.

 Actuarial 5-year overall survival was 35% and local control was 70%.
When compared with historical control subjects from the same institution
(patients managed with surgery alone) the addition of chemoradiation
seemed to confer a survival benefit (36.9 vs 22 months; P<.05). Nelson
and colleagues70 reported similar 5-year actuarial survival (33%) and
local control rates (78%) among 45 patients with extrahepatic CC treated
at Duke University with surgery and either neoadjuvant or adjuvant
chemoradiation.

 In each of these institutional reviews, most patients had disease recurrence

at distant sites, leading investigators to conclude that chemoradiation
offers a local control benefit for resected extrahepatic CC.
POSTOPERATIVE THERAPY FOR LOCOREGIONAL DISEASE
43

 In a retrospective review of 65 patients from the M.D.

Anderson Cancer Center with extrahepatic CC, there was
no difference in locoregional recurrence or 5-year survival
rates between patients who underwent R0 resection and
had negative nodes (N0) and received no adjuvant
therapy and patients who had either R1 resection and/or
positive nodes (N1) and were treated with postoperative
chemoradiation.

 These results suggest a benefit of postoperative

chemoradiation in individuals with features that place them
at high risk of recurrence.
 POSTOPERATIVE THERAPY FOR LOCOREGIONAL DISEASE
44

 Finally, Lim and colleagues examined outcomes in 120 patients

with extrahepatic bile duct carcinoma treated with radical
resection followed by chemoradiation or chemoradiation and
subsequent systemic chemotherapy. In this study, postoperative
chemoradiation followed by systemic chemotherapy resulted in
significantly improved 3-year disease-free and overall survival
compared with patients treated with postoperative
chemoradiation alone.

 Although limited by small sample size and their retrospective

nature, collectively these data suggest that postoperative
chemoradiation with or without systemic chemotherapy may offer
improved local control and possible survival benefit after
resection for extrahepatic CC, particularly in patients with R1
resection and/or node-positive disease.
 POSTOPERATIVE THERAPY FOR LOCOREGIONAL DISEASE
45

 For patients who undergo R0 resection and have node-

negative disease, current NCCN Clinical Practice Guidelines in
Oncology (NCCN Guidelines") recommend observation,
enrollment in a clinical trial, consideration of chemoradiation,
or consideration of fluoropyrimidine or gemcitabine
chemotherapy.

 For patients with positive resection margins and/or node-

positive disease these guidelines recommend consideration of
chemoradiation followed by chemotherapy or chemotherapy
alone. Clearly, there is a need for randomized prospective
trials to better define the appropriate adjuvant therapy in
patients who undergo potentially curative resection for DCC.
PALLIATION FOR PATIENTS WITH UNRESECTABLE DISEASE AND/OR
DISTANT METASTASES
46

 For patients who have locally advanced, unresectable

disease or distant metastases, the prognosis is very
poor. Several chemotherapy regimens have been
evaluated in the management of these patients.

 An analysis of clinical trials evaluating chemotherapy

for patients with advanced biliary tract cancer
suggested that a combination of gemcitabine and
platinum-based agents confers the greatest survival
benefit.
PALLIATION FOR PATIENTS WITH UNRESECTABLE DISEASE
AND/OR DISTANT METASTASES
47

 The Advanced Biliary Cancer 02 Trial was a randomized,

controlled, phase 3 study comparing cisplatin plus gemcitabine
with gemcitabine alone in patients with metastatic or locally
advanced biliary tract malignancy.

 Patients randomized to receive cisplatin-gemcitabine

demonstrated a significant improvement in median overall (11.7
vs 8.1 months; P<.0001) and progression-free (8 vs 5 months)
survival. Based on these data, doublet chemotherapy with
cisplatin-gemcitabine is considered standard first-line
chemotherapy for patients with locally advanced unresectable
or metastatic CC (NCCN Guidelines"). Before initiation of
systemic therapy, a definitive tissue diagnosis should be
confirmed, and adequate biliary drainage should be achieved.
 SUMMARY
48

 DCC is a rare malignancy that often clinically presents similar to

pancreatic cancer; a distinct set of risk factors indicating a unique
pathophysiology relative to other periampullary neoplasms.

 In particular, patients with PSC have a markedly increased risk for CC

and should undergo rigorous surveillance to preempt malignant
transformation.

 Patients with imaging and endoscopy suggesting only locoregional

disease, and of adequate performance status, should undergo
exploration for possible pancreaticoduodenectomy.

 Once resected, surgeons and pathologists should work together to mark

the critical margins of the surgical specimen.
 SUMMARY
49

 Positive resection margins and lymph node metastases have consistently

been shown to lead toward poor prognosis after
pancreaticoduodenectomy.

 There are limited data to support adjuvant chemotherapy after

potentially curative resection for DCC. Institutional series suggest a
potential benefit from postoperative chemoradiation, particularly in
patients with R1 resection or positive nodes. For patients with
unresectable or Distal Cholangiocarcinoma metastatic disease, palliative
systemic chemotherapy usually includes gemcitabine and cisplatin;
however, median survival in these patients is less than 1 year.

 It is hoped that investigation into the biologic and genetic basis of this
disease will lead toward a targeted approach to treatment that might
offer improved survival.
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