Staging and assessment of hepatobiliary malignancies

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Staging and assessment of hepatobiliary malignancies

Steve M.M. de Castro, Otto M. van Delden, Dirk J. Gouma and Olivier R.C. Busch

Introduction

Selection in patients with hepato-pancreato-biliary (HPB) malignancy is of the utmost importance. Patient selection should ideally identify those who might benefit from surgery and those who will not. Palliation for the majority of patients with unresectable or incurable disease utilises minimally invasive techniques (i.e. endoscopic or percutaneous biliary stenting, radiochemotherapy). Technological advances have changed the approach to evaluate patients with suspected HPB disease. Modern state-of-the-art imaging now allows physicians to focus on two key questions in patients with suspected HPB tumours. Is there really a malignant tumour present? If so, can it be removed with an R0 resection?

This chapter focuses on the diagnostic work-up of patients with the most common HPB malignancies and discusses the staging and assessment of resectability.

Colorectal liver metastases

Imaging of colorectal liver metastases (CRLMs) is important in patient assessment in several aspects. Firstly, to detect as many liver metastases as possible with their exact location within the liver, in order to maximise the chance of achieving complete clearance of disease at surgery. Secondly, to characterise any benign liver lesions that may be present, so as to avoid unnecessary surgical procedures.

Ultrasound has a diagnostic sensitivity of 36–61% for detecting lesions measuring 1–2 cm, even when performed by experienced radiologists.¹ It is very useful in guiding fine-needle aspiration (FNA) to confirm unresectability by cytopathology. However, FNA has a risk of seeding metastases in up to10% of patients and a risk of a false-negative result, which does not justify its use in candidates for potentially curative therapy.²

A meta-analysis of the performance of ultrasound for CRLMs found a pooled sensitivity of 63% (95% confidence interval (CI) 56–70%; five studies) with a specificity of 97.6% (95% CI 95.6–99.5%; four studies).³

Ultrasound can be very useful as a problem-solving tool when computed tomography (CT) or magnetic resonance imaging (MRI) is uncertain. A targeted ultrasound of a suspicious lesion can often discriminate between a benign and malignant lesion.

MRI, though not as widely available as CT, is the preferred first-line modality for evaluating CRLM; it provides anatomical detail and has a high detection rate, even for lesions less than 10 mm in diameter. FDG-PET is valuable in the evaluation of extrahepatic disease.

Computed tomography and magnetic resonance imaging

Nowadays, CT is the most commonly used imaging modality for staging and follow-up of these patients. Current multidetector scanners allow for multiplanar reformatting with the same resolution as the original axial images. This may improve detection and characterisation of small lesions.³ Multiplanar reformatting also enables the demonstration of hepatic arterial, venous and portal anatomy, which can be useful in preoperative planning.⁴ CT allows for accurate volumetric assessment of tumour size, liver volume to be resected and future liver remnant volume.⁵

A multiphase contrast-enhanced CT should be performed to stage liver metastases. The study should include an unenhanced, arterial, portovenous and delayed phase. CRLMs may show an enhancing rim on arterial phase imaging and are hypodense on portovenous phase imaging (Fig. 3.1). A slice thickness of 2–4 mm is recommended for axial viewing.

Figure 3.1 Patient with liver metastases in segment 7 and small adjacent satellite lesion on CT.

A meta-analysis on the performance of CT found a pooled sensitivity of 74.8% (95% CI 71.2–78.3%; 12 studies) and specificity of 95.6% (95% CI 93.4–97.8%; seven studies).³

The standard MRI protocol includes T2-weighted, unenhanced T1-weighted and dynamic contrast-enhanced T1-weighted sequences. T2-weighted images are used for the detection and characterisation of lesions (haemangioma, cyst).⁶^,⁷

A meta-analysis on the performance of MRI found a pooled sensitivity of 81.1% (95% CI 76.0–86.1%; five studies) and specificity of 97.2% (95% CI 94.5–99.9%; two studies).³ On per lesion analysis, MRI appeared to be the modality showing higher sensitivities across individual studies compared to CT. Pooled data showed comparable results, with MRI having a combined sensitivity of 88% and accuracy of 87% compared to CT with sensitivity of 74% and accuracy of 78%. Therefore, most centres choose the imaging technique of their preference.

Subgroup analyses of these studies showed that MRI has better sensitivity at picking up the smaller lesions < 1 cm compared to CT and also positron emission tomography (PET)-CT.⁸ The majority of lesions missed by CT and PET-CT were micrometastases of < 1 cm. This meta-analysis concludes that MRI is preferred as a first-line modality for evaluating the liver. It has high overall sensitivity and specificity estimates and can accurately depict lesions smaller than 10 mm. Secondly, it provides excellent anatomical details.

Positron emission tomography

Fluorine-18-2-fluoro-2-deoxy-D-glucose (FDG)-PET is a well-established non-invasive functional scanning method, where a labelled glucose molecule is injected intravenously. The principle of FDG-PET is that malignant cells have a higher glucose uptake than regular cells. The scanner performs a rapid non-invasive interrogation of glycolytic activity throughout the whole body in a single imaging session. Besides being used for the detection of primary malignant tumours, it also can be used to detect regional and distant metastases, to differentiate benign from malignant disease or recurrent cancer from treatment-related scarring, and to evaluate response to therapy.

With the PET-CT combination it is possible to produce fusion images with high-resolution anatomical localisation of CT together with the functional data of FDG-PET. This combination of scanning characteristics is becoming more widely available (Fig. 3.2).

Figure 3.2 PET-CT of same patient with CRLMs showing two distinct lesions.

Kinkel et al.⁹ performed a meta-analysis and concluded that, at equivalent specificity, PET-CT is more sensitive than ultrasound (US), CT and MRI for the detection of hepatic metastases from gastrointestinal cancers.

Bipat et al.¹⁰ performed a meta-analysis and concluded that PET-CT is the most sensitive diagnostic tool for the detection of hepatic metastases from colorectal cancer on a per-patient basis, but not on a per-lesion basis. The authors suggest that in patients requiring further work-up, FDG-PET can be used as a second-line modality because both sensitivity and specificity were high and FDG-PET plays a role in detecting extrahepatic disease.

Mainenti et al.¹¹ found that PET-CT showed a trend to perform better than the other modalities. The pooled estimates of a meta-analysis for PET-CT was 93.8% (95% CI 90.0–97.7; six studies) and specificity per patient was 98.7% (95% CI 97.2–100%; six studies).³

Diagnostic laparoscopy and laparoscopic ultrasound

Diagnostic laparoscopy is used to detect small peritoneal metastases or subcapsular liver metastases, which can be missed on non-invasive imaging. The addition of laparoscopic ultrasound (LUS) may increase the detection of small intrahepatic metastases. There are not many prospective studies on these specific patients and most retrospective series also include patients with other liver tumours.

Recent prospective studies have reported a limited benefit and found that an unnecessary laparotomy can be prevented in 10–13% of patients with CRLMs,¹²^,¹³ which is considerably lower than in earlier reports, where the figure varies from 12% to 33%.^14–16

One reason for the lower yield might be that the indications for resection for metastases have changed towards a more aggressive approach for multiple lesions and bilobar disease. Furthermore, the use of local ablative techniques such as radiofrequency ablation (RFA) in combination with resection and downsizing with chemotherapy has extended the possibilities for surgical treatment. Currently the only absolute restrictions for curative resection include unresectable extrahepatic dissemination and limited function of the (future) liver remnant. The varying definition of unresectablility has a linear correlation with the yield of laparoscopy. In addition, improved cross-sectional imaging techniques in recent years have also decreased the yield of diagnostic laparoscopy.

Several centres favour the selective use of laparoscopy. Jarnagin et al.¹³ have described a clinical risk score (CRS) that predicted survival after hepatic resection and was also suitable in identifying high-risk patients most likely to benefit from laparoscopy. In a study of 103 patients, occult unresectable disease was found in 12% of patients with a low score versus 42% of patients with a high score.¹³^,¹⁷ Similarly, in a series of 200 patients, a detection rate of only 6% was reported in patients with the lowest CRS, whereas this was 75% for the highest CRS scores.¹⁴ Another study demonstrated a yield of 50% in a selected group of patients, while in the group of 49 patients selected for direct surgical exploration, 46 patients (94%) were eventually resected.¹⁵

Staging and assesment of resectability

Factors that have favourable impact on survival are tumour-free resection margin, low level of carcinoembryonic antigen (CEA), single metastatic deposit and node-negative disease.¹⁸

The significance of resection margins of less than 10 mm is not clear.¹⁹ The results of this meta-analysis demonstrate that a negative margin of 1 cm or more confers a survival advantage when compared with subcentimeter negative margins. The management of synchronous liver metastases and extrahepatic abnormalities (particularly the hilar lymph nodes) is also unclear. There is a huge variation in techniques for resection (anatomical vs. non-anatomical, vena cava reconstruction, etc.). Although promising, clear results on the effectiveness of combination treatments with (neo)adjuvant chemotherapy are still lacking.

The optimal selection of patients for hepatic resection is evolving, and the criteria for resectability differ among individual liver surgeons.

A consensus statement in 2005 defined resectability as absence of non-treatable extrahepatic disease, fitness for surgery, ability to leave 30% of residual liver parenchyma in healthy livers or disease in no more than six segments.²⁰

Modern multidisciplinary consensus defines resectable CRLM simply as tumours that can be resected completely, leaving an adequate liver remnant.²¹ Before surgical exploration, most surgeons would require that there was no radiographic evidence of involvement of the hepatic artery, major bile ducts, main portal vein, or coeliac/para-aortic lymph nodes, and an adequate predicted functional hepatic remnant.²²

Some centres with extensive expertise do perform resections directly adjacent to major vascular structures with margins less than 10 mm; however, a margin of 10 mm is still recommended.¹⁹

In the presence of a limited number of lesions in the lung, liver resection is generally performed first. After radical resection of liver metastases, resection of the lung can follow. There is no reason to refrain from liver resection in a patient with advanced age who has good general (cardiopulmonary) fitness. Risk scoring systems (such as the clinical risk score ²³ and others^24–26) to predict which patients with CRLMs are most likely to benefit from resection are of uncertain clinical utility, particularly since most patients undergo different neoadjuvant chemotherapy regimens. Some studies have shown that the risk scoring system needs refinement²⁷^,²⁸ and that the outcome in patients treated by neoadjuvant chemotherapy was not predicted by the traditional clinical scoring system, but rather by response to chemotherapy as evaluated by CT and PET-CT.²⁹

Resection of synchronous metastases should be considered in selected patients. Other strategies such as RFA, portal vein embolisation and isolated liver perfusion fall beyond the scope of this chapter.

Hepatocellular carcinoma

The diagnosis of hepatocellular carcinoma (HCC) is challenging as it has a variable imaging appearance and because lesion detection is difficult against the inhomogeneous background of liver cirrhosis with dysplastic and regenerating nodules mimicking HCC.

Transabdominal ultrasound

Transabdominal ultrasound is recommended by the European Associasion for the Study of the Liver (EASL), the American Association for the Study of Liver Disease (AASLC) and the Asian Pacific Association for the Study of Liver Disease (APASL) as a surveillance tool for patients at high risk of developing HCC. Meta-regression analysis has demonstrated a significantly higher sensitivity for early HCC with US every 6 months than with annual surveillance.³⁰

Computed tomography and magnetic resonance imaging

Multiphase contrast-enhanced CT or MRI should be performed when evaluating HCC. The hallmark of HCC on CT and MRI is strong arterial enhancement (Fig. 3.3) and washout of contrast agent in the delayed phase (Fig. 3.4).³¹ This feature in particular enables differentiation from intrahepatic cholangiocarcinoma, which shows delayed enhancement.³²

Figure 3.3 CT image of patient with HCC in the liver showing arterial enhancement of the lesion.

Figure 3.4 CT image of same patient with HCC in the liver showing venous washout of the lesion with enhancing rim.

HCC arising in a non-cirrhotic liver is often large, due to its long asymptomatic course and late presentation.³³ This contrasts with the multifocal tumours more commonly found in patients with chronic liver disease, who are often in surveillance programmes. Large HCCs may demonstrate a number of characteristic appearances on CT, which make differentiation from other causes of focal liver masses relatively straightforward. These features include mosaic appearance, with fibrous septa separating areas of variable attenuation which represent internal regions of haemorrhage, necrosis, fatty degeneration and fibrosis. The fibrous capsule has a low attenuation on unenhanced images and enhances on the portal venous phase.

A number of benign lesions, including haemangiomas, focal confluent fibrosis, peliosis, benign regenerative nodules and transient hepatic attenuation difference, can mimic small HCC lesions on CT.³⁴

On MRI, HCCs can have a variable appearance on unenhanced T1-weighted images and typically show an increased signal on T2-weighted images.³⁵ Following gadolinium administration, HCC demonstrates characteristic early enhancement on arterial phase imaging³⁶ and washout on delayed images, resulting in a hypo-intense lesion compared to the surrounding parenchyma.³⁷

Diagnostic laparoscopy and laparoscopic ultrasound

Laparoscopic evaluation can avoid exploratory laparotomy in 45–63% of patients with unresectable disease.³⁸^,³⁹ The procedure has been shown to be accurate in assessing the presence of advanced intrahepatic disease and the quality of the liver remnant, but it was less sensitive in determining the extent of local invasion, especially in large (> 10 cm) tumours. Another study clearly reported the value of LUS in detecting small HCCs; 134 new nodules were visualised with this technique in 64 of 186 (34%) patients in whom 28 nodules (in 23 patients) were histologically diagnosed as HCC.⁴⁰ Of these 23 patients, 18 were diagnosed as having a solitary HCC before laparoscopy. Similarly, new lesions of histologically proven HCC were found in 22% of patients.⁴¹ Even when preoperative staging includes a CT, LUS was superior in detecting additional tumours.⁴² Ultrasound confirmed all 201 tumours seen on CT and detected 21 additional tumours (9.5%) in 11 patients (20%).

Staging and assesment of resectability

Tumour staging to select a treatment regimen is complicated by the fact that many of the staging systems (including the TNM staging system of the American Joint Committee on Cancer (AJCC) – see Table 3.1) are based on surgical findings, while surgery is applicable to only about 5% of these patients. Others recommend the Barcelona Clinic Liver Cancer (BCLC) staging system.⁴³ The Barcelona algorithm does not address the value of resection for some subgroups of patients with HCC who may potentially benefit from this approach, including some patients defined as being ‘early stage’ (with a single tumour size > 2 cm or multiple nodules) and ‘intermediate stage’ (patients who have multinodular tumours but a good performance status). The Milano/Mazzaferro criteria for liver transplantation for HCC (i.e. solitary tumour ≤ 5 cm or up to three tumours all ≤ 3 cm) are widely accepted.⁴⁴ However, according to the Barcelona algorithm, only selected patients with three nodules ≤ 3 cm (those without ‘associated diseases’) should also undergo liver transplantation.⁴³ The American Hepato-Pancreato-Biliary Association (AHPBA)/American Joint Commission on Cancer (AJCC) Consensus Conference on HCC in 2002 concluded that no single staging system could be used to accurately stage patients across the spectrum of HCCs.⁴⁴^,⁴⁵

Table 3.1

TNM staging for hepatocellular cancer

Note: cTNM is the clinical classification, pTNM is the pathological classification.

^*The fibrosis score as defined by Ishak is recommended because of its prognostic value in overall survival. This scoring system uses a 0–6 scale.

^†Data from AJCC sixth edition.

Modified from the AJCC Cancer Staging Manual, seventh edition (2010), published by Springer, New York.

The ideal patient for resection has a solitary HCC confined to the liver that shows no radiographic evidence of invasion of the hepatic vasculature, no evidence of portal hypertension and well-preserved hepatic function. According to the current TNM/UICC staging system for HCC (Table 3.1), most consider stage IIIB, IIIC, IVA or IVB disease to be incurable by resection. However, hepatic resection for stage IIIB, IIIC and IVA disease may be considered in some centres of excellence as clinical benefits, and long-term survival can be achieved in a selected minority of patients.

Assessment of hepatic reserve is paramount to selection for resection. Postoperative mortality is twice as high in cirrhotic as in non-cirrhotic patients unless proper patient selection is applied. For patients with cirrhosis, surgical resection can safely be performed in those with Child–Pugh class A disease. These patients should undergo assessment of liver volumetry and remaining function. Other indications for therapies such as liver transplantation, RFA, ablation and arterial chemoembolisation are discussed elsewhere.

Interval US at 6 months is recommended as a screening tool, while CT and MRI are most useful to confirm the diagnosis. Laparoscopic staging is useful in these patients since these tumours tend to be at high risk of being unresectable. The value of laparoscopy is further increased due to its capacity to aid guided biopsies of the future liver remnant in patients with cirrhosis.

Pancreatic and periampullary carcinoma

Most pancreatic tumours are located in the head of the pancreas (60–65%), while 20% are present in the body and 10% in the tail region. Unfortunately only a minority (5–20%) of pancreatic tumours are resectable. Tumours in the pancreatic head often present earlier due to compression of the adjacent common bile duct causing obstructive jaundice. Therefore these tumours are often smaller at time of presentation and more often resectable. These smaller tumours (< 2 cm) without liver metastases have better 5-year survival.⁴⁶ Hence, by accurately detecting and staging smaller tumours, imaging has the potential to influence survival.

The goal of imaging for pancreatic tumours is twofold. The first is to accurately identify tumours with local invasion or distant metastasis to tailor the treatment strategy, and the second is to accurately image the anatomical variations prior to resection.

Transabdominal ultrasound

This is usually the first screening examination of the abdomen in patients with obstructive jaundice. It is a useful diagnostic modality with a reasonable sensitivity (> 90%) for detecting bile duct obstruction, determining the level of the obstruction (e.g. intrahepatic, proximal or distal) and identifying the presence of gallstone disease.⁴⁷ Transabdominal ultrasound is cost-effective, widely available but highly operator dependent and often limited by the inability to adequately visualise the pancreas due to bowel gas interference. The goal of ultrasound is therefore to primarily establish a differential diagnosis among the various causes of obstructive jaundice and in identifying liver metastases. Ultrasound is highly sensitive in detecting gallbladder stones (> 90%),⁴⁸ but this sensitivity drops to 50–75% for the detection of bile duct stones.⁴⁹ On ultrasound, a pancreatic tumour appears as a hypoechoic (poorly reflective) mass. A tell-tale sign suggestive of malignant obstruction is the combined presence of a dilated common bile duct and pancreatic duct (double duct sign).

Ultrasound is able to detect most pancreatic masses of at least 3 cm, as was shown in a meta-analysis of 14 studies.⁵⁰ Pancreatic tumours (irrespective of size) yielded a sensitivity of 76% and a specificity of 75%.

However, these results are from studies performed in centres with significant experience in the diagnostic work-up of patients with pancreatic cancer. Doppler ultrasound can show vascular involvement of portal and mesenteric veins.

Additionally, transabdominal ultrasound has a high sensitivity for detecting liver metastases and ascites, and an FNA can be performed. Sensitivity for liver lesions depends on the size of the lesion and is > 90% for lesions larger than 2 cm, 60% for lesions of 1–2 cm and 20% for lesions < 1 cm in diameter.¹

Computed tomography and magnetic resonance imaging

CT is the most widely used imaging modality for pancreatic disease and staging pancreatic tumours. Modern multidetector CT enables evaluation of the vascular and ductal structures, and mapping of the anatomy and anatomical variations. The most important goal of CT imaging, besides the detection of tumours, is the assessment of resectability.

Tumour conspicuity depends heavily on CT scanning phases. Currently, a combination of pancreatic and portal phase CT is the optimal technique for pancreatic lesions. The best oral contrast is water. The optimal CT section thickness is 2 mm.

The arterial phase optimally demonstrates the arterial vessels (superior mesenteric artery, coeliac artery and hepatic artery) and their relation to the pancreatic tumour (Fig. 3.5). The portal venous phase demonstrates the portal and superior mesenteric veins and the junction (the confluence) at the pancreatic neck (Fig. 3.6). The parenchymal phase is between these two phases and demonstrates pancreatic adenocarinoma as a hypovascular tumour compared to the rest of the parenchyma.

Figure 3.5 CT image of patient with pancreatic head mass with no vascular involvement.

Figure 3.6 CT image of patient with pancreatic head mass with portal vein contact of approximately 90 degrees.

Tumours in the head of the pancreas usually cause dilatation of the common bile duct (CBD). The double duct sign appears when both the CBD and the pancreatic duct are dilated. Smooth dilatation is more suggestive of malignancy, whereas irregular or beaded dilatation is more suggestive of pancreatitis. Tumours that extend beyond the contours of the pancreas with infiltration of the peripancreatic fat are seen as blurring of the normal dark peripancreatic fat. The sensitivity and specificity of CT for detection of a pancreatic head mass were 91% and 85%, respectively, versus 84% and 82% for MRI in a pooled meta-analysis.⁵⁰ The meta-analysis found that CT was significantly better than MRI and US.

CT has been reported to have a positive predictive value of 100%, negative predictive value of 56% and overall accuracy of 70% for unresectable pancreatic carcinoma.⁵¹ This ability to predict unresectability preoperatively is superior to the ability to predict resectability, particularly because the detection of small (< 5 mm) liver and peritoneal metastases is limited.

Endoscopic retrograde cholangiopancreatography (ERCP)

ERCP has been performed as an initial investigation in patients with obstructive jaundice for many years. However, the advent of improved non-invasive diagnostic modalities such as CT, MRI and endoscopic ultrasound (EUS) has led to less frequent use of invasive ERCP. Endoscopic retrograde cholangiopancreatography is associated with a morbidity of 5–10% and a mortality of 0.1–1%. The most common complications include pancreatitis (5–10%), bleeding (1–2%) and perforation (< 0.3%).⁵²

A recent randomised controlled trial showed that early surgery without preoperative biliary drainage did not increase the risk of complications after surgery, as compared with preoperative biliary drainage.⁵³

Magnetic resonance cholangiopancreaticography (MRCP) closely mimics the imaging capacity of ERCP but is non-invasive. One advantage of MRCP is that information regarding the tumour and its relation to surrounding structures is also obtained during the same examination. In addition, distant metastases can be detected with MRI. The results of MRCP in visualisation of the biliary system are similar to ERCP in clinical studies, with a sensitivity of 71–93% versus 81–86% and specificity of 92–94% versus 82–100%. When comparing ERCP with EUS, the sensitivity was 75–89% versus 85–89% and specificity was 65–92% versus 80–96%.⁵⁴ There are no known direct comparisons between ERCP and CT. If an ERCP is performed, it is possible to perform brush cytology, bile aspiration cytology and even intraductal biopsies. These examinations are highly sensitive but lack specificity.

The detection rate of malignancy was not significantly different for brush cytology compared to bile cytology (sensitivity of 33–100% versus specificity of 6–50%, respectively) and also not significantly different for FNA cytology compared to brush cytology (25–91% versus 8–56%, respectively). Forceps biopsy versus brush cytology was also not significantly different (43–81% versus 18–53%, respectively).⁵⁴ Other new modalities such as intraductal cholangiopancreaticoscopy and intraductal endosonography have yet to be proven in larger series.

Endoscopic ultrasound

EUS allows a sonographic transducer to be placed in close proximity to the pancreas. In doing so, interference from overlying bowel gas is eliminated and higher frequencies can be used, resulting in markedly improved resolution. EUS was considered superior to the other imaging modalities prior to the recent refinements made in CT,⁵⁵ because most current CT studies date from the period 1994–2000. EUS was considered more sensitive in one systematic review describing nine studies of EUS compared to CT for diagnostic effectiveness.⁵⁶ The most valuable role of EUS in these studies was in detecting small tumours (< 2 cm). The pooled sensitivity was 85% with a specificity of 94%, but heterogeneity was an issue in this pooled analysis. FNA can be performed when in doubt with a lower risk of causing peritoneal carcinomatosis than with transabdominal aspiration. A study in 62 patients with pancreatic cancer that compared EUS, CT and MRI with the gold standard of surgery found that a sequential approach consisting of helical CT as an initial test and EUS as a confirmatory technique when in doubt seemed to be the most reliable and cost-effective strategy.⁵⁷ Thus, EUS is not mandatory in the work-up of patients with pancreatic cancer. In those cases with potentially resectable tumours, an EUS-guided (FNA) biopsy has a pooled sensitivity for malignant cytology of 85% (95% CI 84–86%) and a pooled specificity of 98% (95% CI 97–99%).⁵⁸ The major limitations of this technology are operator dependence and a limited field of visualisation for the detection of distant metastases. This modality should be used on a selective basis (e.g. to obtain preoperative tissue biopsy for patients scheduled for neoadjuvant therapy) and in centres with experience.

Positron emission tomography

Preliminary reports indicate that FDG-PET may provide additional information regarding the M status of a patient and can change the therapeutic option in up to 16% of patients.⁵⁹ A meta-analysis of PET scanning in patients with a positive, negative and inconclusive CT found sensitivity and specificity of 92% and 68%, respectively, after a positive CT, 73% and 86%, respectively, after a negative CT, and 100% and 68%, respectively, after an inconclusive CT.⁶⁰ Its usefulness will vary depending upon the pretest probability of the patient and the results of CT. FDG-PET is most often used for response evaluation in neoadjuvant chemoradiotherapy trials.

Diagnostic laparoscopy and laparoscopic ultrasound

Despite best efforts, there are still unexpected occasions when the intraoperative findings are contrary to those reported by the preoperative investigations, especially with regard to resectability. These patients consequently undergo an unnecessary laparotomy, along with its accompanying risks, albeit small, of postoperative morbidity and mortality. The quality of life becomes further diminished in a patient population whose survival is already limited. The detection of small liver and peritoneal metastases (Fig. 3.7) is an important motivation for performing diagnostic laparoscopy, since this might avoid open exploration. CT has excellent accuracy in predicting unresectability; however, sensitivity for assessment of resectability remains much lower. This is due to its inability to detect very small liver lesions (< 1 cm) or peritoneal deposits.

Figure 3.7 Peritoneal metastases on the first part of the duodenum found during laparotomy in a patient with a periampullary carcinoma.

Despite the logical rationale behind its use, laparoscopy continues to provoke considerable debate. Advocates have reported that laparoscopy can identify occult metastases, which were not detected by a preceding CT, in 30% of patients.⁶¹ Consequently, the resection rates after laparoscopy have been reported to be 75–92%.⁶² Because of these results, some centres strongly recommend the use of diagnostic laparoscopy as a routine procedure.

Critics argue that routine laparoscopy is not cost-effective. With the newer generations of CT scanners, the incidence of missed hepatic or peritoneal metastases is less than 20%. The implication is that performing routine laparoscopy adds unnecessary surgical time and expense to the remaining 80% of patients with resectable disease or, if locally unresectable, precludes them from surgical palliation, which is considered superior.⁶³^,⁶⁴

The yield of additional laparoscopic staging is influenced greatly by the quality of the prelaparoscopic staging process. Incorrect staging with poor quality CT, for example, results in an overestimation in the yield of diagnostic laparoscopy and LUS. While the most important objective in laparoscopy is to prevent an unnecessary laparotomy, a number of patients do need a subsequent laparotomy for further palliation (e.g. bypass procedure for gastrointestinal obstruction). The limited detection rate for unresectable metastatic disease and the likely absence of a large gain after switching from surgical to endoscopic palliation prompted many centres not to routinely perform laparoscopy in patients with peripancreatic carcinoma.⁶⁴ In a study assessing 233 patients with upper gastrointestinal malignancy, of whom 114 patients had a periampullary tumour, laparotomy was avoided initially in 17 patients (15%), but five of these patients subsequently required laparotomy for duodenal obstruction.⁶¹ This reduced the overall efficacy of laparoscopy in preventing unnecessary laparotomies from 15% to 11%. In a more recent study of 297 patients, the laparoscopic yield decreased to 13% (39 patients), probably due to improved radiological staging techniques.⁶⁴ This, combined with an increasingly critical view of resectability and palliation, has resulted in a decreased benefit of laparoscopic staging.

Diagnostic laparoscopy is advised to identify true locally advanced disease when chemoradiation is considered to ‘downstage’ the tumour. This is important to exclude patients with metastases not seen on preoperative imaging.

Staging and assesment of resectability

Staging is according to the TNM atlas, seventh edition, 2009 (Tables 3.2–3.4). Most clinicians agree that a tumour is considered incurable if there are distant metastases (liver, lung, lymph nodes outside the (radical) lymph node dissection area as defined by Pedrazzoli et al.⁶⁵) or if there is local invasion into arterial structures such as superior mesenteric artery, coeliac trunk or common hepatic artery (Table 3.5).

Table 3.2

TNM staging system for exocrine and endocrine tumours of the pancreas

Note: cTNM is the clinical classification, pTNM is the pathological classification.

^*This includes lesions classified as PanIn III classification.

^†Data from AJCC sixth edition.

Modified from the AJCC Cancer Staging Manual, seventh edition (2010), published by Springer, New York.

Table 3.3

TNM staging for ampullary carcinoma

Note: cTNM is the clinical classification, pTNM is the pathological classification.

^*Data from AJCC sixth edition.

Modified from the AJCC Cancer Staging Manual, seventh edition (2010), published by Springer, New York.

Table 3.4

TNM staging system for distal cholangiocarcinoma

Note: cTNM is the clinical classification, pTNM is the pathological classification.

^*Data from AJCC sixth edition.

Modified from the AJCC Cancer Staging Manual, seventh edition (2010), published by Springer, New York.

Table 3.5

Resectability of pancreatic tumours

Resectable	Borderline	Unresectable
No tumour abutment with vessel	> 90° tumour abutment with PV of SMV	> 180° tumour abutment with PV or SMV
	> 5 mm length of PV or SMV contact	PV/SMV constriction or thrombus or teardrop deformation of SMV
		Any ingrowth in SMA
No distant metastasis		Distant metastasis

PV, portal vein; SMA, superior mesenteric artery; SMV, superior mesenteric vein.

Arterial resections with reconstruction have been described in small retrospective studies, with almost no survival benefit, but increased mortality and morbidity, 21–40% and 2–35%, respectively.⁶⁶

Criteria to assess vascular ingrowth on CT include tumour involvement of any of the major pancreatic vessels (coeliac artery, hepatic artery, superior mesenteric artery, superior mesenteric vein or portal vein) that exceeds one-half of the circumference of the vessels (Fig. 3.8). This is especially specific for the involved arteries. Contour deformity, obliteration and thrombosis of the veins is also highly suspicious of vascular involvement.⁶⁷ Additional radiological features that suggest vascular invasion include perivascular cuffing, described as increased attenuation of the normal perivascular fat, and the presence of dilated collateral veins. The ‘teardrop’ sign, which describes the deformity of the otherwise round shape of the superior mesenteric vein, suggests venous invasion. Nevertheless, there is much debate over the exact definition of vascular involvement.

Figure 3.8 CT image of patient with pancreatic head mass with portal contact of more than 180 degrees.

Successful resection of (a part of) the superior mesenteric vein or portal vein has been described and could be an advantage, provided that an R0/R1 resection can be achieved. In a review by Ramacciato et al.,⁶⁸ 12 series are described with a total of 399 patients; the morbidity rate was 16.7–54% and mortality rate 0–7.7%, with a median survival of 13–22 months and a 5-year survival of 9–18%. Muller et al.⁶⁹ also described 110 patients following resection of venous invasion with a morbidity rate of 41.8% and mortality rate of 3.6%. The survival was not increased by the addition of a venous resection with bypass, because earlier local recurrence and/or distant metastases arose in this group of patients compared to patients who had no invasion of the vein.

Glanemann et al.⁷⁰ reported morbidity rates of 21–42% and mortality rates of 0–5.9% when pooling a series of 1967 patients with simultaneous venous vessel resection described throughout the literature. The 5-year survival in this study ranged from 7% to 20%. The systematic review of Siriwardana and Siriwardena⁶⁶ found no benefit from resection of venous structures with invasion.

Size is the only characteristic of a pancreatic tumour that can be determined preoperatively. A review by Garcea et al.⁷¹ analysed studies and used the size measured at histopathology. In these studies the cut-off value varied, but most studies suggested 2 cm. In all these studies, the median survival of patients with tumours < 2 cm is 35.5 months versus 14 months for larger tumours. Although the studies varied in quality, this meta-analysis concluded that size (< 2 cm or > 2 cm) is an (independent) prognostic factor for median survival (odds ratio (OR) = 2.52, 95% CI 1.95–3, P < 0.001). One relatively small study used size of the tumour on preoperative imaging and found that prognosis correlated with the size determined on CT.⁷²

Staging and assessment of patients with pancreatic or periampullary tumours is important because distant metastasis and frank vascular ingrowth precludes a curative resection. A pancreas protocol CT is the most important factor in the staging and assessment of pancreatic cancer.

There is still some controversy over the degree of vascular ingrowth and tumour resectability. It is clear that obvious vascular involvement precludes a curative resection. Patients with borderline tumours could benefit from limited vascular resection and should undergo explorative laparotomy.

Proximal bile duct tumours

Patients with proximal bile duct tumours generally present with jaundice. Patients with jaundice and a hilar stricture will either have a benign biliary stricture or a malignancy that has obstructed the hepatic confluence.⁷³^,⁷⁴ The differential diagnosis includes benign biliary strictures (postoperative bile duct injury, primary sclerosing cholangitis, HIV cholangiopathy, Mirizzi syndrome) or another malignancy such as gallbladder cancer or lymphoma. Diagnosis of a hilar cholangiocarcinoma can be challenging, particularly in patients with primary sclerosing cholangitis, with multiple stenosis and mass lesions often identified on imaging without significant intrahepatic biliary dilation.

Transabdominal ultrasound

Abdominal ultrasound is often the first diagnostic study to confirm biliary duct dilatation, identify the level of obstruction and exclude gallstones.⁷⁵ Duplex ultrasound has also been useful to assess vascular involvement.⁷⁶

Computed tomography and magnetic resonance imaging

CT is used to establish the presence of a tumour, its location as well as local spread, vascular ingrowth and metastases. Magnetic resonance cholangiography is comparable to ERCP in the detection of biliary malignancy. An advantage offered by magnetic resonance cholangiography is that it can identify the luminal involvement and thus give a better staging of the tumour without cannulation of the bile ducts and risk of infection. It allows visualisation of both the obstructed and non-obstructed ducts, and gives important information such as the extent of tumour within the biliary tree and in periductal tissue, vascular and nodal involvement, lobar atrophy, invasion of adjacent liver parenchyma and distant metastases, without the risk of biliary intubation.⁷⁷ If imaging studies demonstrate a focal stenotic lesion of the bile duct in the absence of previous biliary tract surgery, an assumptive diagnosis of hilar cholangiocarcinoma is made until proven otherwise.⁷⁴

Endoscopic retrograde cholangiopancreatography

ERCP and percutaneous transhepatic cholangiography (PTC) both allow for the collection of tissue samples for pathology and bile for cytology. The value of cytology has recently been stressed.⁷⁸ Non-invasive imaging does not allow tissue diagnosis, but histological confirmation is not mandatory before surgical exploration. It is notable that, in patients that require biliary drainage preoperatively, PTC is preferable to ERCP, as it allows selective evaluation of the intrahepatic biliary tree much more clearly.

Positron emission tomography

PET has been shown to have a high sensitivity for diagnosing biliary malignancy. The limitation of the method is that patients with an inflammatory process of the biliary tree (as in primary sclerosing cholangitis) can have false-positive findings. In a prospective study by Kim et al.,⁷⁹ PET proved significantly more accurate in identifying distant metastases compared with CT (58% vs. 0%). Other studies have confirmed the usefulness of PET for detecting metastases not found by other imaging,⁸⁰ ultimately influencing clinical management in up to 25% of patients.⁸¹ The sensitivity of FDG-PET for detecting primary intrahepatic cholangiocarcinoma has been estimated at 78%.⁸¹ However, Petrowsky et al.⁸² found PET-CT to be more sensitive (93% vs. 55%) and specific (80% vs. 33%) in detecting intrahepatic compared to extrahepatic cholangiocarcinoma.⁷⁸ Another limitation reported by Kluge et al.⁸³ was a sensitivity of 92% in detecting hilarcholangiocarcinoma, but the rate of detection of extrahepatic tumours was dependent on the shape of the tumour.

Diagnostic laparoscopy and laparoscopic ultrasound

Information on the additional value of diagnostic laparoscopy for malignant proximal bile duct obstruction is limited.

In a pilot study, advanced disease was diagnosed in 19 of 47 patients (40%) by laparoscopy.⁸⁴

These results were explained by a change in diagnosis after laparoscopy from a primary bile duct tumour to locally invasive gallbladder cancer. Another study of 110 consecutive patients confirmed these data.⁸⁵ Laparoscopy revealed histologically proven incurable disease in 44 patients (41%). Of the 65 patients who underwent laparotomy, 35 patients (54%) were unresectable. Although laparotomy was avoided in 41% of cases, laparoscopy was unable to assess resectability correctly in 44% of patients. These findings are in agreement with the study from the Memorial Sloan Kettering Cancer Center involving 100 patients with carcinoma of the extrahepatic biliary tree.⁸⁶ Thirty-five patients (35%) were identified as having unresectable disease at laparoscopy. Of the 65 patients who underwent laparotomy, a further 34 tumours (52%) were unresectable, resulting in an overall accuracy of 51%. Finally, in a series of 401 patients with hepatobiliary cancer, the highest yield for laparoscopy was found in patients with biliary cancer, but the study emphasised that the surgeon’s preoperative impression of resectability was as important as the laparoscopic staging procedure itself.¹² Recently, a study found that the yield has decreased to 12% in recent years due to better preoperative imaging.⁸⁷

LUS has not been very useful in staging the local tumour spread of proximal bile duct cancer. A previous study confirmed that patients with unresectable disease most often had locally advanced tumours, but LUS did not contribute to the assessment of resectability in these patients.⁸⁶ Furthermore, extensive biliary and vascular involvement can be determined with high accuracy (91%) using external colour Doppler ultrasound, as well as thin-slice contrast-enhanced multislice CT.⁸⁸ The additional value of LUS is therefore too low for it to be performed routinely.

Staging and assesment of resectability

The American Joint Committee on Cancer (AJCC) TNM staging system is most commonly used to stage hilar cholangiocarcinoma (Table 3.6). However, this system is based on pathology criteria and does not provide information on the potential for resectability. Therefore, other staging systems have been used to predict resectability and to assess the extent of resection. The Bismuth–Corlette classification (Fig. 3.9) stratifies patients based on extent of biliary involvement by tumour. In brief: type I tumours are below the confluence of the left and right hepatic duct; type II tumours reach the confluence; type IIIa and IIIb tumours occlude the common hepatic duct and either the right or left hepatic duct, respectively; and type IV tumours involve the confluence and both the right and left hepatic ducts.

Table 3.6

TNM staging system for perihilar cholangiocarcinoma

Note: cTNM is the clinical classification, pTNM is the pathological classification.

Modified from the AJCC Cancer Staging Manual, seventh edition (2010), published by Springer, New York.

Figure 3.9 Classification of Klatskin tumours according to Bismuth–Corlette, types I, II, IIIa and IV. Type I and II tumours are limited to the confluence of the right and left hepatic duct. In type III tumours, the segmental branches of the right or left hepatic duct are involved (type IIIa or IIIb respectively). In type IV tumours, the tumour extends into the segmental branches of both right and left hepatic duct.

The preoperative clinical T staging system (Table 3.7) as proposed by Jarnagin and colleagues⁸⁹^,⁹⁰ defines both the radial and longitudinal extension of hilar cholangiocarcinoma, which are critical factors in the determination of resectability. This Memorial Sloan-Kettering Cancer Center (MSKCC) staging system incorporates three factors based on preoperative imaging studies: (1) location and extent of ductal involvement; (2) presence or absence of portal vein invasion; and (3) presence or absence of hepatic lobar atrophy. Criteria for unresectable disease include locally advanced tumour extending to secondary biliary radicles (i.e. sectional bile ducts (right anterior, right posterior, left lateral and left medial) bilaterally), to unilateral sectional bile ducts with contralateral portal vein branch involvement, encasement or occlusion of the main portal vein proximal to its bifurcation, atrophy of one hepatic lobe with contralateral portal vein involvement, or atrophy of one hepatic lobe with contralateral tumour extension to sectional bile ducts. A recently designed new system of staging incorporates the size of the tumour, the extent of the disease in the biliary system, the involvement of the hepatic artery and portal vein, the involvement of lymph nodes, distant metastases, and the volume of the putative remnant liver after resection (Table 3.8). These staging systems are relatively new and have to be proven in future studies.

Table 3.7

Jarnagin–Blumgart Clinical T staging system ⁸⁹