This classification was developed to assess the extent of infiltration of the hepatic bifurcation and thus resectability. However, it only refers to the longitudinal extent of the manifestation in the bile duct system, see Table 2. This information is not sufficient for the assessment of resectability, which can only be assessed in combination with contrast-based cross-sectional imaging (CT / MRI).

With the diagnostic methods currently available (MRCP and ERC), the extent of the tumor is often underestimated, but also overestimated (20-30% each). Therefore, even a type IV tumor with uncertain and borderline findings is not per se a contraindication for surgical exploration with subsequent resection if indicated. In addition, modern surgical procedures may allow R0 resection of Bismuth type IV tumors in many cases, so that stage Bismuth IV is not a contraindication to surgery. Local contraindications to curative surgery most frequently result from the involvement of arterial vessels.

Neither the TNM/UICC classification nor the Bismuth-Corlette classification are sufficient for conclusively assessing the resectability of extrahepatic bile ducts. The Memorial Sloan-Kettering (MSK) classification of extrahepatic bile duct tumors developed by Jarnagin-Blumgart is more practically useful here. In this classification, MSK T3 tumors are considered non-resectable, see Table 3.

Regional lymph nodes are

• for the right side of the liver: hilar lymph nodes along the choledochal Ductus choledochus, A. hepatica communis, V. portae and Ductus cysticus, periduodenal and peripancreatic lymph nodes

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

Celiac and/or paraaortic and paracaval lymph node metastases are considered distant metastases.

Regional lymph nodes are

• hilar lymph nodes along the Ductus choledochus, the Ductus cysticus, the hepatic artery, the portal vein

• celiac lymph nodes

• lymph nodes along the superior mesenteric artery.

Perihilar carcinomas of the bile ducts are localized in the extrahepatic bile ducts up to the junction of the Ductus cysticus.

Regional lymph nodes are

• hilar lymph nodes

• pericholedochal lymph nodes in the hepatoduodenal ligament

These include carcinomas of the bile ducts, which are located distal to the mouth of the Ductus cysticus. Carcinomas of the Ductus cysticus are classified as gallbladder carcinomas.

Regional lymph nodes are

• Lymph nodes along the Ductus choledochus and the A. hepatica,

• Lymph nodes in the direction of the celiac trunk

• Anterior and posterior pancreaticoduodenal lymph nodes

• Lymph nodes along the suspected and superior mesenteric artery

The regional lymph nodes correspond to those of the pancreatic head, located at

• Ductus choledochus

• A. hepatica communis and V. portae

• pyloric, infrapyloric, subpyloric

• proximal mesenteric, celiac

• posterior and anterior pancreatoduodenal

• V. mesenterica superior

• right lateral wall of the superior mesenteric artery

Lymph nodes of the splenic hilus and the tail of the pancreas are not considered regional and are classified as distant metastases.

The most common histological subtype of cholangiocarcinoma in all localizations is adenocarcinoma with biliary differentiation ("biliary-type cholangiocarcinoma"). These tumors usually show a ductal-tubular growth pattern with variable diameters of the neoplastic glands (see also below) and often considerable stromal dysplasia. Immunohistologically, these tumors usually express MUC1, CK7, CK19 and CA19-9. These tumors are graded as well, moderately or poorly differentiated cholangiocarcinomas - however, according to not exactly defined criteria depending on morphological proximity to normal cholangiolar cells/ducts.

Histologically, the vast majority of gallbladder carcinomas are adenocarcinomas; the most common subtype and the typical gallbladder carcinoma in particular is biliary-differentiated adenocarcinoma with its characteristic small ductal "pancreatobiliary" morphology. In addition, intestinal-differentiated adenocarcinomas (with intestinal-imposing cells, rare), mucinous adenocarcinomas (more than 50% of the tumor components form extracellular mucin), clear cell adenocarcinomas and the poorly cohesive adenocarcinoma associated with signet ring cells as well as the very rare hepatoid carcinoma have also been described. Partially, the different morphologies have prognostic relevance and are associated with different degrees of aggressiveness (for example, poorly cohesive and mucinous tumors are prognostically unfavorable).

Mixed tumors such as adenosquamous carcinoma also occur in the gallbladder. Focal squamous differentiation is quite common in adenocarcinomas of the gallbladder, but adenosquamous carcinoma is only diagnosed when 25% of the tumor is squamous. Also described are extremely rare mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN), which show a broad spectrum of aggressiveness depending on differentiation.

In addition to adenocarcinoma differentiation, pure squamous cell carcinomas and - also very rarely - "pure" neuroendocrine neoplasms are also seen extremely rarely. Finally, undifferentiated carcinomas (without lineage classification) and sarcomatoid carcinomas are also extremely rare tumor types of the gallbladder.

For the sake of completeness, it should also be mentioned that mesenchymal tumors and lymphomas can also occur as primary tumors in this location. However, these tumors - as well as neuroendocrine neoplasms - are not addressed in this guideline.

Extrahepatically, the vast majority of epithelial biliary tract tumors are adenocarcinomas; here too, the biliary differentiated subtype is the classic extrahepatic cholangiocarcinoma. Variants exist as intestinal, foveolar, mucinous, signet-ring cell, clear cell, pyloric-glandular, hepatoid and micropapillary adenocarcinomas, each being rare to very rare.

Mixed tumors are also described here, particularly in the sense of adenosquamous carcinomas as well as undifferentiated and sarcomatoid variants. Non-epithelial tumors and neuroendocrine neoplasms (see gallbladder) also occur.

By definition, carcinomas of the intrahepatic bile ducts only include "pure" cholangiocarcinomas. All other intrahepatic carcinomas, including mixed tumors with cholangiocellular-hepatocellular differentiation, undifferentiated carcinomas and neuroendocrine neoplasms, represent independent entities.

Intrahepatic cholangiocarcinomas belong to the group of adenocarcinomas with a ductal "pancreatobiliary" phenotype. There are basically two types.

The large duct type of intrahepatic cholangiocarcinoma usually manifests close to the hilus, originates from the larger bile ducts and peribiliary glands and shows a somewhat more large-glandular ductal-tubular growth pattern. These tumors are often associated with BilINs or IPNBs (see chapter 2.4.1., Precancerous lesions), often show a periductal infiltration pattern and sometimes contain mucin. These tumors are associated with parasitic bile duct diseases, hepatolithiasis and primary sclerosing cholangitis. Histological variants as described for the extrahepatic bile ducts also occur in this subtype.

In contrast, there is the small-duct type of intrahepatic cholangiocarcinoma, which manifests itself in the periphery and usually forms a coherent tumor mass. These tumors are thought to originate from ductal hepatic structures or hepatic progenitor cells, show a small ductal and ductal growth pattern, do not produce mucin and are rarely associated with the common precursor lesions for cholangiocarcinoma. Associations with non-biliary cirrhosis and viral hepatitis may be present. Subtypes of the small-duct type are cholangiolocarcinoma and intrahepatic cholangiocarcinoma with ductal plate malformation pattern. Mixed forms occur. IDH1/2 and BRAF mutations as well as FGFR2 fusions are typical for the small-duct type.

For carcinomas of the Ampulla Vateri, see chapter 6.3.1.

Complete surgical resection is the only potentially curative therapeutic approach. The aim of the procedure must be an R0 resection. Depending on the stage and selection, 5-year survival rates of 20-50% can be achieved [10]. Contraindications to surgical resection may include bilateral or multifocal manifestations with a non-curative approach and comorbidities. As a rule, the treatment decision should be made in a multidisciplinary tumor conference with the participation of an experienced hepatobiliary surgeon. Even if the involvement of regional lymph nodes is associated with a less favorable prognosis, this is not a contraindication for resection.

Preoperative histological confirmation is not necessary for resectable tumors with clear clinical and imaging findings. This is often difficult, especially in the case of perihilar tumors, as there is a high rate of false negative findings. However, differential diagnoses such as the rare IgG4-associated cholangitis must be taken into account.

The resectability of perihilar tumors is assessed on the basis of bile duct diagnostics (MRCP, ERC if necessary) and the local situation on MRI/CT (vascular involvement, atrophy of a liver lobe).

Neither the UICC classification nor the Bismuth-Corlette classification are suitable for conclusively assessing resectability. The Memorial Sloan-Kettering classification (MSK) of extrahepatic bile duct tumors developed by Janargin-Blumgart is more practicable here. In this classification, MSK T3 tumors are considered no longer resectable (see Table 4)

The type and extent of surgery and the associated lymph node dissection depend on the respective localization of the tumor and any affected lymph nodes, see chapter 6.2.1 Treatment modalities - Resection [20].

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

• In the case of perihilar carcinomas, hemihepatectomies or extended hemihepatectomies are usually performed, often in conjunction with preoperative portal vein embolization. The question of the exact extent of infiltration of the bile ducts can often only be clarified during the operation (by means of a frozen section examination of the bile duct incision margin). However, histological clarification (R0 or R1) is often only possible at a stage where resection has already taken place. If a subsequent resection is possible after R1 resection of the bile duct, this should be performed.

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

• In the case of incidental gallbladder carcinoma, an oncological resection should be performed within the next 45 days from stage ≥ T1b [21]. This radical cholecystectomy includes a liver resection, usually as a wedge resection of the gallbladder bed with a safety margin of 3 cm in the liver or an anatomical resection of liver segments IVb/V as a so-called bisegmentectomy. This technique is sufficiently radical, especially for T1b and T2 tumors; larger resections are usually required for T3 tumors. In addition, a dissection of the locoregional lymph nodes in the hepatoduodenal ligament must be performed. Complete staging to exclude distant metastases should be performed prior to oncological resection.

In recent years, postoperative morbidity and mortality have been reduced to less than 5%. The main complications may be biliary fistulas, intra-abdominal abscesses and hepatic insufficiency.

Laparoscopic surgery has become increasingly important for hepatic resections in recent years due to comparable mortality and reduced hospitalization time, transfusion frequency and complication rate [22]. This does not apply to surgical procedures on the pancreatic head and liver operations requiring complex bile duct reconstruction.

The value of preoperative bile drainage for cholestasis using ERC has not been conclusively clarified, but is often unavoidable, especially in the case of perihilar tumor localization, which then requires extended partial hepatectomy. This should be considered in cases of hyperbilirubinemia (> 10 mg/dl), secondary complications such as cholangitis or surgery that cannot be performed promptly [1]. PTCD should only be performed in exceptional cases in order to minimize the risk of tumor cell spread.

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 after complete curative resection (R0/1) of a biliary carcinoma.

Neoadjuvant treatment strategies are currently part of individual treatment concepts and are being further investigated as part of clinical trials. The German GAIN study on perioperative (neoadjuvant/adjuvant) chemotherapy for gallbladder carcinomas and intra- and extrahepatic biliary carcinomas is currently underway (NCT03673072). In retrospective evaluations, it was shown that preoperative chemotherapy enabled non-resectable or borderline resectable cases to undergo secondary curative resection. In the largest case series to date, 39 of 74 primarily non-resectable intrahepatic biliary carcinomas (cM0) could be resected after various preoperative therapies. The overall survival of this group did not differ from the primarily resectable group [31]. Therefore, in suitable cases, initial chemotherapy in the sense of conversion therapy can be considered, and the response and the possibility of secondary resection should be checked regularly during chemotherapy. This currently mainly concerns patients with borderline resectable tumor status, without a precise definition currently being available.

• Atypical resections/enucleations: these are based solely on the pathological findings without taking anatomical boundaries into account. For example, small superficial foci can be resected using wedge resections or marginal tumors can be resected using wedge resections to save parenchyma. The advantage of atypical resection is the minimal loss of functional liver parenchyma, so that this technique is used for small tumors and a previously damaged liver.

• Anatomical resections: Anatomical resections are the method of choice for liver malignancies in order to resect potential embolic spread of tumor cells into the associated segments. This refers to the complete removal of anatomically/functionally autonomous parenchymal districts that are supplied by an associated pedicle (branch of the V. portae, the hepatic artery and the D. hepaticus). A distinction is made between sector-oriented (right or left hemihepatectomy, left lateral and right posterior sectorectomy, central sectorectomy and right or left trisectorectomy) and segmental resections (mono-, bi- and polysegmentectomies, various combinations) [55].

Partial duodenopancreatectomy is the standard procedure for resectable carcinomas of the papilla or distal Ductus choledochus and pancreatic head.

The classic Kausch-Whipple operation and the Traverso-Longmire pylorus-preserving duodenopancreatectomy (PPPD) are available as surgical techniques. The en-bloc resection includes the pancreatic head together with the Ductus choledochus and the gallbladder, the duodenum with the proximal 5 cm of the jejunum as well as the peripancreatic lymph nodes, the duodenal ligament and the right side of the superior mesenteric artery and, in the case of the Kausch-Whipple operation, the distal stomach. An initial cholecystectomy is performed for functional reasons.

An extended lymphadenectomy (paraaortic or left side of the superior mesenteric artery) has no positive effect on overall survival, but increases morbidity.

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

The advantages of pylorus preservation and therefore PPPD are

• shortened operation time and convalescence

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

In the case of large tumors with invasion of the pylorus or tumor-sparing lymph nodes in the area of the large or small gastric curvature (rare), a Kausch-Whipple operation is indicated; otherwise, pylorus-preserving surgery is preferred for functional outcome.

The following criteria indicating non-resectability should initially be checked by means of an exploratory laparotomy (which can be extended directly to definitive surgery if resectability is confirmed):

• Distant metastases, especially to the peritoneum and liver as well as paraaortic lymph node involvement

• Invasion of the mesenteric root

• Encasement 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 affect the surgical tactics/technique.

Liver transplantation is not a standard therapy [1]. A multidisciplinary concept according to the so-called Mayo protocol includes neoadjuvant radiochemotherapy (fluoropyrimidine-based) as a combination of external radiotherapy and internal brachytherapy before liver transplantation for perihilar tumors. For patients with unresectable UICC stage I and II Klatskin tumors, a 5-year survival rate of 82% and a complete remission rate of 42% (16/38 patients) was observed. However, only about 50% of the patients treated preoperatively could also be transplanted, with a significantly increased mortality [56].

With appropriate selection criteria (N0, cM0V0, tumor size < 3 cm, CA 19-9 < 1000 U/ml), comparable survival rates have been shown with liver transplantation alone, even without neoadjuvant therapy [57]. Data from randomized studies are still lacking, so that liver transplantation for biliary tract cancer is currently only possible in the context of studies in the Eurotransplant area.

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

There is currently no evidence-based proof of benefit for the resection of metastases of biliary tract cancer. In individual cases, metastasectomy may be considered for oligometastasis.

Carcinomas of the Ampulla Vateri are a rare family of entities and are listed as a subgroup of tumors of the small intestine and ampulla in the latest WHO classification.

Ampullary adenocarcinomas are by far the most common; other types of carcinomas (neuroendocrine, others, see below) are extremely rare in this localization. The ampullary carcinomas are divided into

• (Peri)ampullary duodenal adenocarcinomas, often associated with adenomatous precursors

• Adenocarcinomas of ductal ampullary origin

• Intraampullary andenocarcinomas on the basis of an intraampullary papillary/tubular neoplasia

• Adenocarcinomas NOS for which an exact assignment to one of the three families mentioned is not possible

These tumors must be differentiated from duodenal carcinomas, distal bile duct carcinomas and pancreatic carcinomas that also affect the papilla region. The distinction is sometimes blurred and is then determined by the punctum maximum of the tumor manifestation. The differentiation of carcinomas of the Ampulla Vateri from the aforementioned carcinomas is important in principle due to a better prognosis and different treatment methods. This is also reflected in a separate TNM classification (C24.1, carcinoma of the Ampulla Vateri), see chapter 5.3.2.5.

In patients with familial adenomatous polyposis coli (FAP), adenomas also occur in the duodenum or ampulla in 50-90% of patients. The risk of malignant degeneration is increased up to 200-fold compared to the normal population, and the lifetime risk of developing periampullary carcinoma in people with FAP is 12% [66].

Diagnosis is usually made at a previous stage due to the clinical symptoms (jaundice/cholestasis), with approx. 50% of patients in a resectable stage at diagnosis [67, 68].

The tumor entity is determined histologically, usually on the basis of bioptic confirmation of the tumor. For the differential diagnosis between pancreaticobiliary and intestinal subtypes in the predominant group of adenocarcinomas of the Ampulla Vateri, additional immunohistologic examinations are often used in addition to conventional histology (intestinal growth form and cell image versus pancreaticobiliary growth form and cell image). The gastric subtype (with gastric-like mucin production), which is sometimes also classified separately, is closely related to the pancreatobiliary type and is therefore often classified in this subgroup, which is also followed by the current WHO classification.

Typically, immunohistochemical detection of mucin-2 (MUC2) and caudal homeobox gene transcription factor-2 (CDX2) as well as cytokeratin 20 is indicative of the intestinal type, while the expression of mucin-1 (MUC1), mucin-5AC (MUC5AC) and cytokeratin 7 is indicative of the pancreatobiliary subtype [69, 70]. Mixed intestinal-pancreatobiliary types are common (>30% of tumors). In addition, the very rare mucinous, poorly cohesive, medullary, adenosquamous, neuroendocrine and undifferentiated (sometimes with osteoclast giant cells or rhabdoid phenotype) carcinomas of the ampullary region are differentiated. Mixed forms occur.

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

Figure 8 provides a treatment algorithm.

T1 carcinomas <1 cm have only a minimal risk of metastasis, so that local resection may be sufficient.

For resectable tumors ≥ 1 cm, pancreaticoduodenectomy is the method of choice; for information on the various surgical procedures, see Treatment modalities – Surgical resection, chapter 6.2.1 [66].

Data from the ESPAC-3 "periampullary cancer" study (difference 8 months, p=0.25) [71] and the CONKO-001 study [72] indicate an improvement in survival with adjuvant chemotherapy with gemcitabine. Supplementary radiotherapy does not lead to any improvement in survival (ESPAC-1) [73].

A choice of adjuvant therapy according to the histological subtype appears to make sense, so that carcinomas of the intestinal subtype (CDX2 positive) should be treated in analogy to adjuvant therapy for colon cancer and carcinomas of the pancreaticobiliary subtype (MUC1 positive) in analogy to therapy for biliary tract cancer or pancreatic carcinoma.

In the case of inoperable locally advanced and/or metastatic tumors, systemic therapy is the first priority; this is palliative and can be supplemented by local measures if necessary.

5% (n=20) of the patients in the ABC-02 study had a periampullary carcinoma ("ampullary cancer") [32]. Palliative chemotherapy with gemcitabine and cisplatin also showed a significant improvement in survival in these patients (see Systemic tumor therapy, chapter 6.1.2.1.1) Data from a subgroup analysis of a randomized phase III trial are thus available, but no information on the respective histological subtypes.

In principle, the choice of chemotherapy for advanced inoperable carcinomas of the Ampulla Vateri should also be based on the histologic subtype, so that carcinomas of the intestinal subtype (CDX2 positive) should be treated in analogy to colorectal cancer (see Onkopedia guideline Colon cancer) and carcinomas of the pancreaticobiliary subtype (CDX2 negative, MUC1 positive) can be treated in analogy to biliary carcinomas (see Figure 8 of this LL) or pancreatic carcinoma (see Onkopedia guideline Pancreatic cancer).