Hepatopancreatoduodenectomy (HPD) represents the most complex abdominal operation comprising generally large resections of hepatic parenchyma combined with gastro-duodenum-pancreatectomy, in which its main indications include biliary tract neoplasia. Surgical resection is considered the only potential modality of cure in the treatment of malignant biliary tumors, including gallbladder cancer and cholangiocarcinomas. High morbidity and mortality rates still affect a large part of the patients submitted to this operation due to extensive resections of hepatic parenchyma associated with critical anastomoses of bile ducts and pancreatic gland.

In Brazil, there is only one relevant publication about HPD in biliary cancer and some isolated groups in Rio Grande do Sul, São Paulo, Maranhão and Rio de Janeiro have gained experience in this operation. In three different institutions in Rio de Janeiro, the Hospital Adventista Silvestre, Hospital São Lucas and Hospital Universitario Clementino Fraga Filho-UFRJ, 35 patients underwent HPD between 2004 and 2014, representing, in our knowledge, the largest worldwide experience outside of Japan. We report a multicenter retrospective study

Our group has pioneered the radical operations of biliary carcinoma with HPD in Brazil. However, the initial results were poor with high rates of pancreatic fistulas and hepatic failure with subsequent sepsis and death. The use of protocols from the accumulated experience of the Japanese school, such as the oral replacement of bile in jaundiced patients, routine portal embolization, immunonutrition and the greater use of centralectomies in gallbladder carcinomas instead of trisectionectomy have shown a significant improvement in the results. In the 35cases evaluated, the overall mortality was 34.2% and in 17patients (53%) vascular resections and reconstruction were applied.

HPD is a complex abdominal operation with a high mortality rate and a long learning curve. We emphasize that this operation should be limited to specialized centers with experience in liver transplantation background and advanced hepatobiliopancreatic surgery. Aggressive preoperative management with biliary drainage and portal vein embolization are crucial maneuvers to obtain satisfactory results. The HPDs for gallbladder cancer is feasible but requires a careful patient selection.

Keywords: hepatopancreatoduodenectomy, gallbladder cancer, radical surgery, klatskin, cholangiocarcinomas

PD: Pancreatoduodenectomy;  HLPD: Hepatoligamentopacreatoduodenectomy; HPD: Hepatopancreatoduodenectomy

Hepatopancreatoduodenectomy (HPD) is the most complex abdominal surgery and performed in only a few groups in Brazil. Gallbladder cancer remains a reserved prognosis disease and in selected cases, radical resection (R0) surgery allows survival even in advanced tumors. Cholangiocarcinomas represent the main indication for HPD with promising results.

Hepatopancreatoduodenectomy (HPD) represents the most complex abdominal operation comprising generally large resections of hepatic parenchyma combined with gastro-duodenum-pancreatectomy, in which its main indications include biliary tract neoplasia. Surgical resection is considered the only potential modality of cure in the treatment of malignant biliary tumors, including gallbladder cancer and cholangiocarcinomas. High morbidity and mortality rates still affect a large part of the patients submitted to this operation due to extensive resections of hepatic parenchyma associated with critical anastomoses of bile ducts and pancreatic gland.^1‒3

Biliary carcinoma can be divided between gallbladder carcinoma and cholangiocarcinomas, since they have distinct biological behavior, probably because they have very different histological characteristics. Gallbladder carcinoma often mimics "pseudo-klatskin" hilar cholangiocarcinomas. The rich submucosal layer of the gallbladder is connected to the large lymphatic chain of the hepatic and retroperitoneum wire, in addition to numerous cystic veins draining into the liver parenchyma. In this way, the carcinoma of the vesicle presents a more aggressive biological behavior, with distant metastatic potential. In contrast, cholangiocarcinomas present local and radial (superficial spread) infiltration and less frequent distant dissemination, probably due to their histology with scarce submucosal layer.⁴

Numerous potential postoperative problems may occur, in particular, hepatic insufficiency, which is still the main cause of failure of this procedure. Pancreatic fistulae occurring at high frequency are also prominent, since the caliber and consistency of the pancreatic gland are normal in these patients. Despite the recent advances in diagnostic methods and an increasing number of cases in early stages, most patients present advanced disease at the time of diagnosis, making R0 resections and curative surgeries difficult. However, the Japanese school demonstrated a significant improvement in the results of this operation through a rigorous preoperative preparation including routine portal embolizations for hypertrophy of the remaining hepatic lobe; systematic biliary drainage; endogenous bile replacement and thorough surgical technique.⁵

In Brazil, there is only one relevant publication about HPD in biliary cancer and some isolated groups in Rio Grande do Sul, São Paulo, Maranhão and Rio de Janeiro have gained experience in this operation. In three different institutions in Rio de Janeiro, the Hospital Adventista Silvestre, Hospital São Lucas and Hospital Universitario Clementino Fraga Filho-UFRJ, 35 patients underwent HPD between 2004 and 2014, representing, in our knowledge, the largest worldwide experience outside of Japan.⁶

The history of surgical treatment of biliary tract dates back 100years. The radical operations employed in the treatment of biliary cancer were born in Japan in the late 1970s, gaining popularity in various Japanese centers.⁷ Table 1 shows highlights of HPD surgery.

In 1954, Glenn et al.⁶ performed hepatopancreatoduodenectomy in a patient who achieved 5-year survival after surgery. The first successful challenge of hepatopancreatoduodenectomy in biliary carcinoma (right hepatectomy) occurred in 1976, in Japan, by Kasumi et al.⁸ In 1980, Takasaki et al.⁹ reported 5cases of HPD, 3 postoperative deaths and 2 patients survived 5 and 16months, respectively. Despite the questionable outcome, this group produced a wealth of knowledge of the surgical treatment of biliary cancer in subsequent years and extensive experience was accumulated by this group in the radical resection of biliary carcinoma.¹⁰ In 1986 Shinohara et al.¹¹ reported survival of 4years and 6months in a patient undergoing right lobectomy+pancreatoduodenectomy (PD).

Mizumoto et al.¹² in 1990 and Nakamura et al.¹³ in 1992 reported that the number of simultaneous liver and pancreas resections doubled, from 241 to 478, within 2years, demonstrating the high acceptance of this operation in Japan. Over the years efforts were made to prevent postoperative complications, particularly liver failure, highlighting preoperative portal embolization.¹⁴ In 1992, Nakamura et al.¹³ reported 478 cases of HPD in Japan, 320 of which were from gallbladder cancer, 111 from cholangiocarcinoma, and 47 from other causes. In the western world there are few HPD citations,¹⁵ with 22cases in biliary cancer.

Indications of HPD in biliary carcinoma

Despite advances in the management of obstructive jaundice, biliary tract infections and increasing radiological technology, early detection of biliary neoplasms remains a challenge in clinical practice worldwide. In Brazil, the epidemiology of biliary cancer is still little known and radical surgeries are still poorly disseminated and restricted to a few groups. Most of the biliary tumors present with obstructive jaundice and many of these already with tumor invasion to the hepatoduodenal ligament, duodenum, liver, and advanced lymph node involvement. As previously described, biliary carcinoma can be divided into gallbladder cancer and cholangiocarcinomas of the extra hepatic biliary tract, the latter being a better prognostic tumor and often tumors with locoregional growth, which allows radical resection more frequently.^16‒18 In this way, HPD is the only operation with the possibility of R0 resection in some types of biliary cancer and should be used in selected cases of gallbladder cancer with possibility of lymphatic dissemination to the posterior pancreatoduodenal lymph nodes and eventually of the anterior pancreatoduodenals and, obviously, in the cases of direct tumor infiltration in the duodenal wall and pancreatic head.^19‒21

Gallbladder carcinoma presents many peculiarities, with 75% of the tumors located in the vesicular fund and 25% in the infundibulum.²² Thus, due to the rich submucosal network of the infundibulum region, the tumors of this region are generally more aggressive, frequently present with advanced lymph node disease, hepatoduodenal ligament involvement and may mimic a hilar Pseudo-Klatskin cholangiocarcinoma. Tumors at the bottom of the gallbladder are more likely to be resected and their treatment should invariably comprise hepatic resection. The extent of the operation is still a matter of discussion in specialized centers but the degree of tumor infiltration into the liver parenchyma should always be taken into account, since tumors that invade more than 3cm in the liver may have tumor cells in every right medial sector and left as venous branches of the vesicle flow into the intrahepatic portal branches of the IVb, V and VIII segments.²³

The main indications of HPD or PD in patients with advanced bladder cancer are

1. Direct invasion of the pancreas, duodenum or both
2. Signs of hepatoduodenal ligament invasion

• Lymph node infiltration of peripancreatic lymph nodes

1. Chain lymph nodes 13 affected.

Discussion of PD indications is still very controversial (Figure 1).^18,24,25 However, advanced gallbladder carcinoma is associated with a high incidence of metastases to the hepatoduodenal ligament lymph nodes, posterior pancreatoduodenal lymph nodes, and the common hepatic artery.

Figure 1 Major indications for HPD

There are basically 3 schools that differ on PD for resection of peripancreatic lymph nodes

1. PD is not indicated even in the presence of metastases, unless the metastases for lymph node infiltrate the pancreas
2. PD is indicated only if metastasis involvement is confirmed for posterior pancreatoduodenal lymph node
3. PD is indicated for regardless of the presence or absence of macroscopic lymph node metastases.²¹

Potential indications of HPD in cholangiocarcinoma

1. Diffuse tumor infiltration for any extrahepatic biliary tract
2. Perihilar tumor exhibiting superficial distal dissemination
3. Distal tumor exhibiting proximal and superficial dissemination
4. Tumor infiltrating the right hepatic artery and head of the pancreas
5. Perihilar tumor with lymph node metastasis bulky of the pancreatoduodenal region
6. Multiple tumors in the bile duct. Table 2 resumes total indications of HPD in our series.

We report a multicenter retrospective study, with 35 patients, over 10 years (2004-2014) in three different institutions in Rio de Janeiro, the Hospital Adventista Silvestre, Hospital São Lucas and Hospital Universitario Clementino Fraga Filho-UFRJ.

Surgery is initiated preferentially by the duodenopancreatic approach with extensive dissection of the hepatic wire and identification of possible vascular invasions. We do not recommend excessive manipulations of the vessels next to the tumor to guarantee R0 resections. Venous and arterial reconstructions are safer when performed while evacuating the surgical specimen.

1. First, the common or right common hepatic artery, which will feed the remaining liver in the future, is carefully dissected and preserved. The left portal vein is released from the hilar plaque allowing inspection of tumor invasion into the duct. As these steps are essential for R0 resection, the earliest possible preparation is recommended. The right hepatic artery and the gastroduodenal artery are ligated and sectioned. The stomach is sectioned 2 cm proximal of the pylorus when it is desired to preserve the pylorus or of the classic form transects the stomach to the level of the den. The superior mesenteric vein is exposed above and below the cervix of the pancreas.
2. Second, the jejunum is sectioned 10-20 cm distally to the Treitz angle. The first jejunal branch is taken in the play. The superior jejunum and the fourth portion of the duodenum pass through the surgical field on the right. The pancreatic nerve plexus between the uncinate process and the superior mesenteric artery is divided step by step along the lateral border of the superior mesenteric border. The extensive exposure of the mesenteric plateau and ligation of the pancreatoduodenal arteries in their origin with lymphadenectomy of this chain are mandatory. Then the cervix of the pancreas is divided and a drainage tube is placed in the wirsung after rigorous hemostasis. At this point the PD phase is complete.
3. Third, lymphadenectomy of the hepatoduodenal ligament is cephalad. The portal vein is repaired and dissected widely in the cranial direction. At this time, the hepatic lobe to be resected, more commonly the right one, and with that the ligature of the main portal branch assist in the ischemic demarcation of the hepatic parenchyma. The portal branches of the caudate lobe are carefully sectioned as well as the arantius canal in its origin on the left door. The mobilization ends with the section of the duct of arantius in its cephalic limit. Hepatic transection begins following the demarcation of the ischemic line. The pringle maneuver may be helpful in controlling bleeding. Hepatic transection can be performed in a variety of ways and with various energy and aspiration devices. However, kellyclasia can also be used safely. At the end of the transection, the piece surgery will only be attached to the hepatic vein of the wolf to be resected.
4. Finally, the pancreas, the intrahepatic bile duct and the duodenum are reconstructed in roux Y. Several pancreatic reconstructions can be used, including pancreatojejunostomy and pancreato-gastrostomy. Closure of the pancreatic stump can also be performed.

In the 1990s, several Japanese centers published their initial results with HPD and there was an increase in indications for cholangiocarcinomas and a decreasing number of cases in the gallbladder carcinoma. In this way, more consistent results begin to be observed. Nimura et al.²³ in 1991 reported 24 HPD with 6 deaths (25%) especially related to postoperative liver failure and sepsis related to pancreatic fistula. Miyagawa et al. ²⁴ in 1996 demonstrated 0% mortality in HPD who underwent preoperative portal embolization and two-time pancreatic reconstruction. Table 3 shows the mortality rate worldwide.

Shirai et al.²⁵ reported a 5-year survival rate of 29% in patients with stage IVB gallbladder cancer undergoing HPD. The 5-year survival was 50% in R0 resection, in a group of 17 patients undergoing HPD. Of these, 5 patients were stage IVB and in them the survival was 29% and concludes that even with advanced disease there is benefit to the realization of HPD. 29% and conclude that even with advanced disease there is benefit to the performance of HPD. In the decade of 2000, numerous reports of HPD were reported with results superior to that of the previous decade and the experience accumulated in Japanese centers contributed to an important advance in the results of radical surgery of bile carcinoma.

Our group has pioneered the radical operations of biliary carcinoma with HPD in Brazil. However, the initial results were poor with high rates of pancreatic fistulas and hepatic failure with subsequent sepsis and death. The use of protocols from the accumulated experience of the Japanese school, such as the oral replacement of bile in jaundiced patients, routine portal embolization, immunonutrition and the greater use of centralectomies in gallbladder carcinomas instead of trisectionectomy have shown a significant improvement in the results. In the 35 cases evaluated, the overall mortality was 34.2% and in 17 patients (53%) vascular resections and reconstruction were applied. Figure 2 shows types of hepatectomy employed and Figure 3 specimen’s photos.

Figure 2 Types of Hepatectomies.

Figure 3 HPD cases.

HPD is a complex abdominal operation with a high mortality rate and a long learning curve. We emphasize that this operation should be limited to specialized centers with experience in liver transplantation background and advanced hepatobiliopancreatic surgery. Aggressive preoperative management with biliary drainage and portal vein embolization are crucial maneuvers to obtain satisfactory results. The HPDs for gallbladder cancer is feasible but requires a careful patient selection.

None.

The author declares that there is no conflict of interest.

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