Biliary Tract Cancer

This classification was developed to assess the extent of infiltration of the hepatic bifurcation and, consequently, surgical resectability. However, it refers only to the longitudinal extent of the lesion within the biliary tract system; see Table 2. This information alone is insufficient for assessing surgical resectability, which can only be evaluated in combination with contrast-enhanced cross-sectional imaging (CT/MRI).

With the currently available diagnostic methods (MRCP and ERC), the extent of the tumor is frequently underestimated, but may also be overestimated (20-30% in each case). Therefore, even a Type IV classification in cases of uncertain or borderline findings is not per se, a contraindication for exploration followed by surgical resection if indicated. Furthermore, thanks to modern surgical techniques, even Bismuth Type IV tumors can now be resected with R0 status in many cases, meaning that Bismuth Stage IV does not represent an absolute contraindication for surgery. Local contraindications most commonly result from involvement of arterial vessels.

Neither the TNM/UICC classification nor the Bismuth-Corlette classification are sufficiently suitable for conclusively assessing the surgical resectability of the extrahepatic bile ducts. In this context, the Memorial Sloan Kettering (MSK) classification of extrahepatic bile duct tumors developed by Jarnagin-Blumgart is more helpful. In this classification, MSK T3 tumors are considered unresectable; see Table 3.

Regional lymph nodes are defined

• for the right side of the liver: as hilar lymph nodes along the common bile duct, common hepatic artery, portal vein, and cystic duct, as well as periduodenal and peripancreatic lymph nodes

• for the left side of the liver: as hilar and gastrohepatic lymph nodes

Lymph node metastases in the celiac, paraaortic, and paracaval regions are considered as distant metastases.

Perihilar carcinomas of the bile ducts are located in the extrahepatic bile ducts up to the junction with the cystic duct.

The following are considered as regional lymph nodes

• hilar lymph nodes

• pericholedochal lymph nodes in the hepatoduodenal ligament

This category includes carcinomas of the bile ducts located distal to the junction with the cystic duct. Carcinomas of the cystic duct are classified under gallbladder carcinomas.

Regional lymph nodes are defined as

• lymph nodes along the common bile duct and the hepatic artery

• lymph nodes toward the celiac trunk

• anterior and posterior pancreaticoduodenal lymph nodes

• lymph nodes along the superior mesenteric vein and artery

The following are considered as regional lymph nodes

• hilar lymph nodes along the common bile duct, the cystic duct, the hepatic artery, and the portal vein

• celiac lymph nodes

• lymph nodes along the superior mesenteric artery

The most common histological subtype of BTC across all locations is adenocarcinoma with biliary differentiation (“biliary-type adenocarcinoma”). These tumors typically exhibit a ductal-tubular growth pattern with variable diameters of the neoplastic glands (see also below) and often significant stromal desmoplasia. Immunohistochemically, these tumors typically express MUC1, CK7, CK19, and CA19-9. Biliary adenocarcinomas are graded as well-, moderately-, or poorly-differentiated cholangiocarcinomas, though according to criteria that are not precisely defined and depend on their morphological similarity to normal cholangiolar cells or ducts.

In up to 40-50% of biliary carcinomas, molecular alterations can be detected that are potentially exploitable for therapeutic purposes (“targetable alterations”). Significant differences are observed depending on the location of the primary tumor, as well as across the corresponding, mostly retrospective case series. Intrahepatic BTC show the most promising profile for targeted therapies, with IDH mutations in approximately 15-20%, FGFR2 fusions in approximately 10-15% (small-duct type), and BRAF V6000E mutations in approximately 3-5%. In extrahepatic BTC and gallbladder carcinomas, alterations in classic oncogenes are predominant: HER2/neu (ERBB2) alterations and overexpression are found in approximately 5-10% of extrahepatic BTC and in 10-15% of gallbladder carcinomas; KRAS and TP53 mutations are found in up to 40%. This knowledge of the mutation spectrum can also be helpful in differential diagnosis, e.g., in case of a hepatic CUP (cancer of unknown primary) syndrome [20, 21].

MSI-H / dMMR (microsatellite instability / deficient mismatch repair) status is observed in 1-2%, and NTRK fusions in < 1%.

Intrahepatic BTC belong to the group of adenocarcinomas with a ductal “pancreatobiliary” phenotype. Two types are generally distinguished.

The large-duct type of intrahepatic BTC typically manifests near the hilum, originates from the larger bile ducts and peribiliary glands, and exhibits a somewhat more large-glandular ductal-tubular growth pattern. These tumors are frequently associated with BilINs or IPNBs (see chapter 2.4.1., Precancerous Lesions), often exhibit a periductal infiltration pattern, and occasionally contain mucin. These tumors are associated with parasitic bile duct diseases, hepatolithiasis, and primary sclerosing cholangitis. In this subtype, histological variants such as those described for the extrahepatic bile ducts also occur.

In contrast, there is the small-duct type of intrahepatic BTC, which manifests in the periphery and typically forms a coherent tumor mass. These tumors, at least according to current assumptions, arise from ductular hepatic structures or hepatic progenitor cells, exhibit a small-duct and ductular growth pattern, do not produce mucin, and are rarely associated with the common precursor lesions for cholangiocarcinomas. Associations with non-biliary cirrhosis and viral hepatitis may be present. Subtypes of the small-duct type include cholangiolocarcinoma, intrahepatic cholangiocarcinoma with a “ductal plate malformation pattern”, lymphoepithelioma-like carcinoma, and solid-tubulocystic carcinoma. Mixed forms may occur.

Extrahepatically, the vast majority of epithelial tumors are classified as adenocarcinomas; here, too, the biliary-differentiated subtype, the classic extrahepatic BTC, is by far the most common. Variants include intestinal, foveolar, mucinous, signet-ring cell, clear cell, pyloric glandular, hepatoid, and micropapillary adenocarcinomas, each of which is rare to very rare.

Mixed tumors have also been described here, particularly in the form of adenosquamous carcinomas, as well as undifferentiated and sarcomatoid variants. Non-epithelial tumors and neuroendocrine neoplasms (see chapter 5.3.2.4 Gallbladder) also may occur.

Histologically, the vast majority of gallbladder carcinomas are adenocarcinomas; the most common subtype and the typical gallbladder carcinoma sensu strictu is the biliary-differentiated adenocarcinoma with its characteristic small-duct “pancreatobiliary” morphology. In addition to biliary-type adenocarcinoma, intestinal-differentiated (with an intestinal-like cellular pattern; rare), mucinous (where more than 50% of the tumor consists of extracellular mucin), clear-cell, and poorly cohesive adenocarcinomas associated with signet-ring cells, as well as the very rare hepatoid carcinoma, have been described. These different morphologies sometimes have prognostic significance and are associated with varying degrees of aggressiveness (for example, poorly cohesive and mucinous tumors have a poor prognosis).

Mixed tumors, such as adenosquamous carcinoma, also occur in the gallbladder. Focal squamous differentiation is quite common in gallbladder adenocarcinomas; however, an adenosquamous carcinoma is diagnosed only when the squamous epithelial component accounts for at least 25%. Extremely rare mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN) have also been described, which exhibit a wide spectrum of aggressiveness depending on their differentiation.

In addition to adenocarcinoma, pure squamous cell carcinomas are also seen extremely rarely, as are “pure” neuroendocrine neoplasms. Finally, undifferentiated carcinomas (without lineage classification) and, among them, sarcomatoid carcinomas should also be mentioned as exceptionally rare tumor types of the gallbladder.

It should also be noted that mesenchymal tumors and lymphomas can occur as primary tumors at this site. These tumors, as well as neuroendocrine neoplasms, are not addressed by this guideline.

Complete surgical resection is the only potentially curative treatment approach. The goal of the procedure must be an R0 resection. Depending on the stage and patient selection, 5-year survival rates of 20-50% can be achieved [9]. Contraindications to surgical resection include bilateral or multifocal disease with a non-curative prognosis, as well as comorbidities. As a general rule, the decision regarding treatment should be made by a multidisciplinary tumor board, with the participation of an experienced hepatobiliary surgeon. Even though regional lymph node involvement is associated with a less favorable prognosis, it does not constitute a contraindication to resection per se.

Preoperative histological confirmation is not mandatory for resectable tumors with clinically and radiologically unambiguous findings. This is often difficult, particularly with perihilar tumors, as it results in a high rate of false-negative findings. However, differential diagnoses such as the rare IgG4-associated cholangitis must be considered.

The resectability of perihilar tumors is assessed based on biliary tract imaging (MRCP, or ERC if necessary) and the local findings on MRI/CT (vascular involvement, atrophy of a liver lobe).

Neither the UICC classification nor the Bismuth-Corlette classification is suitable for definitively assessing surgical resectability. In this regard, the Memorial Sloan Kettering (MSK) classification of extrahepatic bile duct tumors, developed by Janargin-Blumgart, is more practical. According to this classification, MSK T3 tumors are considered unresectable (see table 4)

The type and extent of the surgery, as well as the associated lymph node dissection, depend on the specific location of the tumor and any affected lymph nodes; see chapter 6.2.1 Treatment modalities - Resection [23].

• For intrahepatic tumors, partial liver resection via segmental resection, hemihepatectomy, or extended hemihepatectomy are the methods of choice. For extensive tumors whose resection would result in a significant reduction in the remaining liver volume, ipsilateral preoperative portal vein embolization may be necessary to augment the remaining liver tissue.

• For perihilar carcinomas, hemihepatectomy or extended hemihepatectomy are usually performed, often in combination with preoperative portal vein embolization. The exact extent of bile duct infiltration can often only be determined during surgery (via frozen-section analysis of the bile duct resection margin). However, histological clarification (R0 or R1) is often only possible at a stage when the resection has already been performed. If a re-resection of the bile duct is possible following an R1 resection, it should be made.

• For extrahepatic distal biliary carcinomas, the standard treatment is a pylorus-preserving pancreaticoduodenectomy (PPPD) or a conventional Kausch-Whipple procedure.

• In cases of incidental gallbladder carcinoma, oncological resection should be performed within the next 45 days for tumors at stage ≥ T1b [24]. This radical cholecystectomy involves a liver resection, typically a wedge resection of the gallbladder bed with a 3-cm safety margin in the liver or an anatomical resection of liver segments IVb/V, known as a bisegmentectomy. This technique is sufficiently radical, particularly for T1b and T2 tumors; for T3 tumors, larger resections are usually required. In addition, a dissection of the locoregional lymph nodes in the hepatoduodenal ligament must be performed. Before the oncological follow-up resection, a complete staging should be performed to rule out distant metastases.

In recent years, postoperative morbidity and mortality have been reduced to less than 5%. The main complications include the occurrence of bile fistulas, intra-abdominal abscesses, and liver failure.

Laparoscopic surgery has become increasingly important in hepatic resections in recent years due to comparable mortality rates and reduced hospital stays, transfusion rates, and complication rates [25]. This does not apply to surgical procedures on the pancreatic head or liver surgery requiring complex biliary tract reconstruction.

The role of preoperative bile drainage via ERC in cases of cholestasis has not been conclusively established, but it is often unavoidable, particularly in cases of perihilar tumor localization requiring an extended partial hepatectomy. This should be considered in cases of hyperbilirubinemia (> 10 mg/dl), secondary complications such as cholangitis, or when surgery cannot be performed promptly [1]. PTCD should only be performed in exceptional cases, in order to minimize the risk of tumor cell dissemination.

Based on the currently available data from the BILCAP study (see chapter 6.1.1.2.1), patients should be offered adjuvant therapy with capecitabine for 6 months following complete curative resection (R0/1) of BTC.

Neoadjuvant treatment strategies appear promising, are currently part of individualized treatment plans, and are being further investigated in clinical trials. Retrospective analyses have shown that preoperative chemotherapy enabled curative surgical resection in patients with initially unresectable or borderline resectable BTC. In a case series, 39 of 74 initially inoperable intrahepatic BTC (cM0) were resected following various preoperative therapies. The OS of this group did not differ from that of the initially resectable group [31].

In the Chinese GOLP study [32], the following risk factors for relapse were identified in patients with resectable intrahepatic cholangiocarcinoma: tumor size > 5 cm, vascular infiltration, multiple intrahepatic lesions, and CA 19-9 levels above the normal range. In this randomized phase II/III trial (n = 178), neoadjuvant systemic therapy with gemcitabine/oxaliplatin with or without the PD-1 antibody toripalimab, and lenvatinib for 9 weeks was compared with primary resection, followed by eight cycles of capecitabine in both groups. In the interim analysis (median follow-up of 16.9 months), event-free survival improved to 18.0 vs. 8.7 months (p<0.001); for OS at 24 months, there was a non-significant improvement (as defined in this study by p<0.0019) to 79% vs. 61% (HR 0.43; 95% CI 0.23-0.79; p = 0.005). In the Chinese ZSAB-TransGOLP single-arm phase II trial (n = 41 enrolled patients), an R0 resection rate of 63% was achieved over 9 weeks in patients with intrahepatic cholangiocarcinoma initially deemed unresectable or locally advanced through the use of gemcitabine/oxaliplatin, tislelizumab (a PD-1 antibody), and lenvatinib over 9 weeks, an R0 resection rate of 63% was achieved [33].

The data from the German GAIN study on perioperative (neoadjuvant/adjuvant, as appropriate) chemotherapy for gallbladder carcinoma and intra- and extrahepatic BTC (NCT03673072) are currently available only as a conference abstract. Recruitment was terminated early with n = 68 enrolled patients. [34]. Perioperative administration of 3 cycles of gemcitabine plus cisplatin was compared with primary resection followed by adjuvant therapy at the investigator’s discretion. Perioperative therapy was associated with improved overall survival: 27.8 vs. 14.6 months (HR 0.46 (0.22-0.96); p = 0.04).

Therefore, initial chemotherapy may be considered in appropriate cases; during chemotherapy, the response and the possibility of a secondary resection should be monitored regularly.

• Atypical resections/enucleations: These are guided solely by the pathological findings irrespective of anatomical boundaries. Thus, small superficial lesions can be resected in a parenchyma-sparing manner through wedge-shaped excisions, and peripheral tumors can be resected using wedge resections. The advantage of atypical resection is the minimal loss of functional liver parenchyma, making this technique suitable for small tumors and a pre-damaged liver.

• Anatomical resections: To resect areas where tumor cells could potentially spread into the associated segments, anatomical resections are considered the method of choice for malignant liver tumors. This refers to the complete removal of anatomically and functionally autonomous parenchymal regions supplied by an associated pedicle (a branch of the portal vein, the hepatic artery, or the hepatic duct). A distinction is made between sector-oriented resections (right or left hemihepatectomy, left-lateral and right-posterior sectorectomy, central sectorectomy, and right- or left-sided trisectorectomy) and segment resections (mono-, bi-, and polysegmentectomies, various combinations) [74].

Partial duodenopancreatectomy is the standard procedure for resectable carcinomas of the papilla, the distal common bile duct, and the pancreatic head.

The surgical procedures include the classic Kausch-Whipple surgery and the pylorus-preserving duodenopancreatectomy according to Traverso-Longmire (PPPD). The en-bloc resection includes the head of the pancreas together with the common bile duct and the gallbladder, the duodenum with the proximal 5 cm of the jejunum, as well as the peripancreatic lymph nodes, those along the ligamentum duodenale, and those on the right side of the superior mesenteric artery; in Kausch-Whipple surgery, the distal stomach is also included. For functional reasons, an initial cholecystectomy is performed.

An extended lymphadenectomy (paraaortic or on the left side of the superior mesenteric artery) has no positive effect on OS and does result in increased morbidity.

Both surgical procedures are considered equivalent in terms of oncological radicality, and thus the overall prognosis, as well as postoperative mortality and morbidity.

Advantages of pylorus preservation and thus, PPPD include

• a shorter surgical time and recovery period

• fewer postoperative functional symptoms such as dumping syndrome, diarrhea, and dyspepsia

In cases of large tumors with pyloric infiltration or when lymph nodes in the region of the greater or lesser curvature of the stomach are suspected of containing tumor cells (rare), Kausch-Whipple surgery is indicated; otherwise, PPPD is preferred for functional reasons.

The following criteria, which argue against resection of the primary tumor, should initially be evaluated by means of an exploratory laparotomy (which can be converted directly into the definitive procedure if resectability is confirmed):

• Distant metastases, particularly to the peritoneum and liver, as well as paraaortic lymph nodes

• Infiltration of the mesenteric root

• Encasement of the celiac trunk and/or the superior mesenteric artery

Suspicious findings should be clarified by means of a histological frozen-section examination. This does not apply to a biopsy of regional lymph nodes, as their involvement does not influence the surgical strategy or technique.

Liver transplantation is not a standard treatment of BTC [1]. A multidisciplinary approach based on the “Mayo Protocol” involves neoadjuvant chemoradiotherapy (fluoropyrimidine-based), a combination of external beam radiation therapy and internal brachytherapy, prior to liver transplantation for perihilar tumors. For patients with inoperable Klatskin tumors in UICC stages I and II, this approach resulted in a 5-year survival rate of 82% and a complete remission rate of 42% (16/38 patients). However, only approximately 50% of patients who received neoadjuvant treatment were ultimately able to undergo transplantation, with a significantly increased mortality rate [75].

When specific selection criteria were met (N0, cM0V0, tumor size < 3 cm, CA 19-9 < 1000 U/ml), comparable survival rates were demonstrated with liver transplantation alone without neoadjuvant therapy [76]. Data from randomized trials are still lacking, so that currently, within the Eurotransplant network, liver transplantation for BTC is only possible as part of clinical trials.

In Germany, patients with a non-resectable Klatskin tumor (tumor size < 3 cm, CA 19-9 < 1000 U/mL, exclusion of lymph node and distant metastases) have the option to participate in the pro-duct002 study (DRKS00013276).

Currently, there is no evidence-based proof of benefit for the resection of metastases from BTC. In individual cases of oligometastasis, it may be considered.

Carcinomas of the ampulla of Vater constitute a rare group of entities and are classified under the chapter on tumors of the duodenum and ampulla in the latest WHO classification [86].

Ampullary adenocarcinomas are by far the most common; other types of carcinomas (neuroendocrine, others - see below) are extremely rare in this location. Ampullary carcinomas are classified as

• (peri)ampullary duodenal adenocarcinomas, frequently associated with adenomatous precursors

• adenocarcinomas of ductal ampullary origin

• intraampullary adenocarcinomas arising from an intraampullary papillary/tubular neoplasm

• adenocarcinomas NOS, for which precise classification into one of the three aforementioned groups is not possible.

These tumors must be distinguished from extraampullary duodenal carcinomas, distal cholangiocarcinomas, and pancreatic carcinomas that involve the papillary region. The distinction is sometimes unclear and is then determined based on the punctum maximum of the tumor manifestation. Distinguishing carcinomas of the ampulla of Vater from the aforementioned carcinomas is, in principle, important due to a better prognosis and different treatment approaches. This is also reflected in a separate TNM classification (C24.1, carcinomas of the ampulla of Vater) [87, 88].

In patients with familial adenomatous polyposis coli (FAP), adenomas also occur in the duodenum or ampulla in 50-90% of cases. The risk of malignant transformation is increased by up to 200 times compared to the general population; the lifetime risk of developing periampullary carcinoma in individuals with FAP is 12% [89].

The regional lymph nodes correspond to those of the pancreatic head and are located at:

• common bile duct

• common hepatic artery and portal vein

• pyloric, infrapyloric, subpyloric

• proximal mesenteric, celiac

• posterior and anterior pancreaticoduodenal

• superior mesenteric vein

• right lateral wall of the superior mesenteric artery

Lymph nodes at the hilum of the spleen and at the tail of the pancreas are not considered regional and are classified as distant metastases.

The diagnosis is usually made early based on clinical symptoms (jaundice/cholestasis); approximately 50% of patients are at a surgically resectable stage at the time of diagnosis [87, 88].

The tumor entity is determined histologically, typically based on a biopsy specimen of the tumor. To differentiate between the pancreaticobiliary and intestinal subtypes within the predominant group of adenocarcinomas of the ampulla of Vater, additional immunohistochemical examinations are frequently used in addition to conventional histology (intestinal growth pattern and cellular appearance versus pancreaticobiliary growth pattern and cellular appearance). The gastric subtype - which is sometimes classified separately (characterized by gastric-like mucin production) - is closely related to the pancreaticobiliary type and is therefore frequently classified within this subgroup; the current WHO classification also follows this approach [86].

Typically, immunohistochemical detection of mucin-2 (MUC2) and caudal homeobox gene transcription factor-2 (CDX2), as well as cytokeratin 20 (CK20), supports the intestinal type, whereas the expression of mucin-1 (MUC1), mucin-5AC (MUC5AC), and cytokeratin 7 (CK7) is indicative of the pancreatobiliary subtype [90, 91]. Mixed intestinal-pancreatobiliary types are common (>30% of tumors). In addition, the very rare mucinous, poorly cohesive, medullary, adenosquamous, neuroendocrine, and undifferentiated (sometimes with osteoclastic giant cells or a rhabdoid phenotype) carcinomas of the ampullary region are distinguished. Mixed forms occur.

Predictive morphomolecular factors for this family of entities have not been established in routine diagnostics.

Figure 7 provides an overview of the treatment algorithm.

T1 carcinomas <1 cm pose only a minimal risk of metastasis, so local resection may be sufficient in these cases.

For resectable tumors ≥ 1 cm, pancreaticoduodenectomy is the treatment of choice; for information on the various surgical procedures, see “Treatment Modalities - Surgical Resection,” chapter 6.2.1 [88].

Data from the ESPAC-3 “periampullary trial” (difference of 8 months, p=0.25) [92] and the CONKO-001 study [93] indicate an improvement in survival with adjuvant chemotherapy using gemcitabine. Adjuvant radiotherapy does not improve survival (ESPAC-1) [94]. It appears reasonable to select adjuvant therapy based on the histological subtype, such that carcinomas of the intestinal subtype (CDX2-positive) should be treated in a manner analogous to adjuvant therapy for colon cancer, and carcinomas of the pancreaticobiliary subtype (MUC1-positive) should be treated in a manner analogous to therapy for BTC or pancreatic cancer.

For inoperable locally advanced and/or metastatic tumors, systemic therapy is the first-line treatment; this is in palliative intent and may be supplemented by local measures if necessary.

5% (n=20) of the patients in the ABC-02 study had periampullary carcinoma (“ampullary cancer”) [38]. Palliative chemotherapy with gemcitabine and cisplatin also resulted in a significant improvement in survival in these patients (see Systemic tumor therapy (in German language only) and chapter 6.1.2.1.1). Data are thus available from a subgroup analysis of a randomized phase III trial; however, no information is available regarding the respective histological subtypes.

In principle, even in cases of advanced, inoperable carcinomas of the ampulla of Vater, the choice of chemotherapy should be based on the histological subtype, such that carcinomas of the intestinal subtype (CDX2-positive) should be treated analogously to colorectal carcinoma (see the Onkopedia guideline on colon carcinoma) and carcinomas of the pancreaticobiliary subtype (CDX2-negative, MUC1-positive) should be treated in a manner analogous to BTCs (see figure 7) or pancreatic carcinoma.