Perihilar cholangiocarcinoma: Presurgical management

Diagnosing pCCA

Patients with pCCA typically present with painless jaundice (90%). Concomitant cholangitis is uncommon and occurs in 10% of patients. ^, pCCA rarely arises in the left or right hepatic duct without jaundice. Anorexia, fatigue, weight loss, and sarcopenia are each observed in about 50% of patients. ^, Physical examination of the abdomen may reveal a palpable mass in the upper abdomen indicative of unilateral hepatic lobe hypertrophy because of the concomitant contralateral lobar atrophy ( Fig. 51B.1 ). ^,

Blood analysis generally reflects cholestasis and sometimes cholangitis. Serum carbohydrate antigen (CA) 19-9 level is high in most patients, but elevated CA 19-9 may be partially attributable to biliary obstruction. Moreover, about 10% of patients do not produce CA 19-9 because of the lack of the Lewis antigen. ^, Determination of immunoglobulin G4 (IgG4) serum level can help in diagnosing eosinophilic cholangiopathy (i.e., lymphoplasmatic cholangiopathy, more commonly referred to as auto-immune cholangitis), which is one of the benign diagnoses that may present as a hilar biliary obstruction (see Chapters 47 and 48 ). However, IgG4 can be normal in patients with auto-immune cholangitis and IgG4 can be elevated in patients with pCCA. A 4-fold increase in IgG4 nearly excludes pCCA. The HISORt criteria predict the presence of IgG4-associated disease based on histology, imaging (typically smooth concentric biliary wall thickening with a visible lumen, absence of a mass, skip lesions, and involvement of the extrahepatic bile duct), serology, other organ manifestation, and response to steroid treatment. ^, Finally, liver fluke infestation ( Clonorchis sinensis and Opisthorchis viverrini ) can be ruled out with serology if in an endemic area (see Chapter 45 ).

High-quality prestenting imaging is a crucial step in the preoperative work-up of pCCA, enabling diagnosis, staging, liver volumetry, and determination of the extent of resection (see Chapters 16 and 102 ). High-resolution thin-slice computed tomography (CT) with multiphase scanning using intravenous (IV) contrast (i.e., arterial and portovenous phases) enables a diagnostic accuracy to detect arterial involvement up to 93% and portal vein involvement as high as 87%. However, sensitivity of detecting lymph node metastases is poor (54%) and the proximal biliary extent of the tumor is often underestimated. Magnetic resonance imaging (MRI) with magnetic resonance cholangiopancreatography (MRCP) is superior to CT in assessing the intrahepatic biliary extent of pCCA and to help discriminate benign etiologies from pCCA (e.g., Mirizzi syndrome, intrahepatic lithiasis, and primary sclerosing cholangitis [PSC]; Fig. 51B.2 ). The role of positron emission tomography (PET) scanning is limited because of false-positive results related to inflammation and is reflected by a specificity of 67% ^, (see Chapter 18 ). It is of utmost importance to realize that the diagnosis and staging after biliary stenting are considerably impaired because of decompression of the biliary system and imaging artefacts induced by stenting-related inflammation. Patients with a perihilar obstruction should be referred to an expert center before biliary drainage because high-quality imaging is essential before biliary drainage, not all patients with pCCA require biliary drainage, and drainage of the FLR is only possible after an expert team has determined the resection plan (see later).

Tissue diagnosis is challenging because of the low sensitivity (typically less than 40%) of an endoscopic or percutaneous brush. ^, A tissue diagnosis is not mandatory for surgical exploration. The application of fluorescent in situ hybridization (FISH) to determine polysomy in addition to conventional cytology typically doubles the sensitivity to detect a malignancy. In a study on PSC patients with a dominant stricture without visible mass and equivocal cytology undergoing routine endoscopic brushing, multivariable analysis revealed FISH to be the only significant predictor of malignancy (see Chapter 43 ). Once CA 19-9 was at least 129, a hazard ratio (HR) of 11 was found when combined with polysomy on FISH. Percutaneous biopsy of pCCA should be avoided in patients that may be eligible for a liver transplant (LT; see later). Biopsy may cause needle track metastases and LT is therefore contraindicated in many centers after any transperitoneal biopsy. Suspicious lymphadenopathy may be subjected to fine needle aspiration (FNA) through endoscopic ultrasound (EUS) or resection at staging laparoscopy.

The current expert consensus statements of the American Hepato-Pancreato-Biliary Association (AHPBA), the National Comprehensive Cancer Network (NCCN), and the European Network for the Study of Cholangiocarcinoma (ENS-CCA) on the initial evaluation of pCCA dictate ^, :

• The minimum diagnostic and staging work-up in suspected pCCA includes liver function, CA 19-9 level, and high-quality cross-sectional imaging (preferably before biliary stenting) of the chest, abdomen and pelvis, besides cholangiography.

• Early consultation of a multidisciplinary team includes a surgeon with expertise in pCCA.

• Pathologic confirmation is not required before surgical exploration for resection or initiation of an LT protocol, provided that benign etiologies have been excluded and a complete staging evaluation has been completed.

• Percutaneous or laparoscopic biopsy of the primary tumor is not recommended in patients who may be candidates for transplantation because of the risk of biopsy tract metastases.

• Imaging by fluorodeoxyglucose-PET lacks the sensitivity and specificity required to be a routine staging tool for patients with pCCA.

The diagnostic work-up for pCCA is imperfect because, after surgery for anticipated pCCA, approximately 10% of patients are diagnosed with benign disease at pathologic examination of the resected specimen. ^{, , ,}

Classification and staging

Clinical staging of pCCA should first rule out metastatic disease by means of chest and abdominal/pelvic CT. Patients with distant metastases (e.g., in lung and peritoneum) and lymph node involvement beyond the hepatoduodenal ligament (e.g., aortocaval) have Stage IV disease and should rarely be considered for upfront resection. ^,

Several tumor-staging systems aim to determine local disease extent, guide treatment decisions (i.e., determine resectability), and inform prognosis. Unfortunately, current staging of pCCA remains challenging and imperfect and most systems are based on surgical pathology and therefore not applicable to the majority of patients that do not undergo resection.

The Bismuth-Corlette system was the first tumor-staging system to classify pCCA based solely on the extent of involvement of the biliary tree ( Fig. 51B.3 ). However, this classification does not take into account the radial extent of pCCA into surrounding structures such as the liver, hilar soft tissue, and vasculature. Bismuth stage is insufficient to determine resectability; for example, a large study found excellent outcomes of resection for Bismuth IV pCCA. In addition to the biliary extent of the tumor, the Memorial Sloan-Kettering Cancer Center (MSKCC) staging system involves portal venous involvement and lobar atrophy ( Fig. 51B.3 ). However, both classification systems perform poorly in predicting resectability because in most series about 50% of patients undergoing surgical exploration with curative intent undergo a resection. ^,

The third staging-system is the AJCC/International Union Against Cancer (UICC) tumor-node-metastasis (TNM) system, which is currently in its eighth edition. The T-stage of pCCA relies heavily on vascular invasion (unilateral or bilateral of portal vein or hepatic artery) but does not describe how pathologic vascular invasion can be determined on imaging or what extent of vascular invasion is still potentially resectable. Evaluation of the current eighth edition compared with the seventh edition showed slightly improved prognostic accuracy for patients after resection but remained poor in patients with unresectable disease. ^, To inform prognosis after resection of pCCA, staging systems have been developed that perform better than the TNM staging.

Preoperative considerations to surgery for pCCA

The median OS of patients with pCCA without surgery is around 8 months compared with up to 40 months after resection with curative intent. Actual cure (i.e., 10-year OS) is rarely seen outside of patients with papillary or well-differentiated pCCA. The expected benefit of surgery should outweigh the substantial postoperative morbidity and mortality.