Distal cholangiocarcinoma - from novel biomarkers to clinical management and outcome

Cholangiocarcinoma is an aggressive malignacy arising from the biliary tree. Anatomical subtypes of
cholangiocarcinoma differs in tumor biology and clinical management. Distal cholangiocarcinoma (dCCA)
originates from the common bile duct. Radical resection is the only curative treatment, for dCCA it entails a
pancreatoduodenectomy (Whipple procedure). Other periampullary cancers treated with pancreatoduodenectomy
include pancreatic cancer (PC), ampullary cancer (AC) and duodenal cancer (DC). There is a high rate of
recurrence after resection for dCCA. This thesis aimed to evaluate the clinical management of dCCA but also
improve understanding of the tumor biology and identify novel biomarkers.
In paper I, the outcome and prognostic factors of patients treated with pancreatoduodenectomy for dCCA from
2008 through 2015 at Skane University Hospital were evaluated. We found the median survival to be 22 months
which was worse than most previous studies. The presence of lymph node metastasis was confirmed as an
important prognostic factor.
In paper II, the expression of secreted protein acidic and rich in cysteine (SPARC) in resected dCCA speciemns,
paired lymph node metastases and normal bile ducts were evaluated using immunohistochemistry (IHC). We
found SPARC to be expressed in the stromal compartment of dCCA in 80% of samples. Stromal expression was
retained in 68% of lymph node metastases. There was no significant correlation between SPARC expression and
survival.
In paper III, bottom-up mass spectrometry (MS) followed by verification using parallel reaction monitoring (PRM)
was used to identify differentially expressed proteins between dCCA samples and normal bile ducts. Bioinformatic
analysis highlighted stromal alterations in dCCA. Forty-six proteins were verified using PRM. Thrombospondin-2
(THBS2) was further validated using IHC. We found THBS2 to be upregulated in dCCA epithelial and stromal
compartments. Stromal THBS2 expression was present in 72% of paired lymph node metastases. There was a
correlation between stromal THBS2 expression and poor disease-free survival.
In paper IV, we studied the utility of serum THBS2 as a diagnostic biomarker for dCCA and PC. THBS2 levels
were similar in dCCA and PC. THBS2 + CA 19–9 had an area under the curve of 0.92 in differentiating dCCA +
PC from healthy donors. THBS2 did not provide utility is discriminating benign disease however, it was diagnosis
dependent.
In paper V, we used Swedish National Registry for Pancreatic and Periampullary Cancer to study national trends
in frequency of tumor origin, survival, histopathological evaluation and diagnostic accuracy for patients with
periampullary cancers. We found PC diagnosis to be more common in unresected patients. Survival was better for
AC and DC then dCCA or PC. Median survival was 33 months for dCCA. Regional differences in tumor origin
frequency and histopathological outcomes were identified. Clinical rate of misdiagnosis was 15 % for PC and 23%
for non-pancreatic periampullary cancers.