The history of liver surgery: Achievements over the past 50 years

Abstract We reviewed the progress made in the field of liver surgery over the past 50 years. The widespread use and improved outcomes of the hepatectomy were, primarily, due to pioneer surgeons who were responsible for technological advances and rapid improvements in the safety of the procedure in the last century. These advances included the hepatic functional evaluation used to determine the safety limit of liver resections, the introduction of intraoperative ultrasonography, and the development of innovative techniques such as portal vein embolization to increase the remnant liver volume. Cadaveric liver transplantation has been attempted since 1963. However, the clinical outcomes only began improving and becoming acceptable in the 1970s‐1980s due to refinements in technology and the development of new immunosuppressants. Partial liver transplantation from living donors, which was first attempted in 1988, required further technological innovation and sophisticated perioperative management plans. Moreover, these developments allowed for further overall improvements to take place in the field of liver surgery. Since the turn of the century, advances in computation and imaging technology have made it possible for safer and more elaborate surgeries to be performed. In Japan, preoperative 3‐dimensional simulation technology has been covered by health insurance since 2012 and is now widely used. An urgent need for real‐time navigation tools will develop in the future. Indocyanine green (ICG) fluorescence imaging was first used in 2007 and has led to the creation of a new surgical concept known as fluorescence navigation surgery. Laparoscopic surgery and robotic surgery have solved the issue of large incisions, which used to be a major drawback of open liver surgery; however, further improvements are required in order to achieve the level of safety and accuracy observed during open liver resection when performing all minimally invasive procedures. In the near future, liver surgery will become more precise and less invasive due to substantial progress including the development of navigation surgery, cancer imaging, and minimally invasive surgery. This overview of the history of liver surgery over the past 50 years may provide useful insights for further innovation in the next 50 years.


| INTRODUC TI ON
Tremendous progress has been made in the field of liver surgery over the past 50 years. The safety and accuracy of performing liver resections have been improved dramatically, making it a current daily practice in many centers for the treatment of various liver diseases. Liver transplantation, the sole treatment option for patients with end-stage liver disease, has also become a widely used, accessible surgical treatment option with acceptable surgical outcomes.
Herein, we present an overview of the history of liver surgery over the last 50 years, highlighting the major pioneering events that took place, in order to provide insights which are useful for further innovation over the next 50 years. The first report of the successful resection of the right hepatic lobe is said to have been performed by Wendel in 1911. The patient was a 44-year-old housewife who underwent extended right lobe resection for hepatocellular carcinoma (HCC); the resected specimen weighed 940 g, and the patient survived for 9 years. However, the details of the procedure are unclear, and although the right hepatic artery and hepatic duct were ligated and resected, the portal vein was not treated individually due to fear of thrombus formation. In the 1950s, Lin (Taiwan) developed the so-called "finger fracture method" in which the fingertips are used to crush the liver parenchyma in order to expose vessels needing to be ligated and divided.

| PREHIS TORY OF LIVER SURG ERY
They reported having performed 48 cases of right hepatectomies and 34 cases of left hepatectomies using this method. Surgery-related mortality within 1 month was 12.1%, and the 5-year survival rate was 19%; outcomes which were considered excellent for that era. 5 As for the definition of S1, Couinaud simply named the Spiegelian lobe "S1" and did not mention the concept of the paracaval portion (of the caudate lobe of the liver), proposed by Kumon. In 1985, Kumon examined the detailed anatomy of 23 cast specimens of human livers and showed that S1 was composed of three elements, namely, the so-called Spiegelian lobe, the paracaval portion, and the caudate process, which in many cases have their own independent branches. 9 Identifying the concept of the paracaval portion had a particularly powerful impact on liver surgery and has allowed the establishment of the anatomical definitions necessary to surgically address hilar cholangiocarcinoma 10 as well as total caudate lobe resection for HCC. 11 per year and has led to the establishment of a valuable patient registry that is likely to be the largest in the world.

| HIS TORY OF HEPATEC TOMY IN JAPAN AND E S TAB LIS HMENT OF THE LIVER C AN CER S TUDY G ROUP OF JAPAN
According to the initial report published by Okuda et al, a total of 360 liver resections for liver cancer were performed in 155 facilities nationwide during the 10-year period from 1968-1977. 12 Their calculations showed that there were as few as 2.3 cases per facility per 10 years, and when the total number of cases (4031) was used as the denominator, the liver resection rate was only 9.0%. By comparison, the number of patients subjected to exploratory laparotomy during that same period was 518, which is indicative of the difficulty of obtaining a preoperative diagnosis. In 222 cases of resection due to HCC, the mortality rate within 1 month of surgery was as high as 27.4%, and the 3-year and 5-year survival rates were as poor as 19.6% and 11.8%, respectively. According to the aggregated data published by Arii, surgery-related mortality after liver cancer resection in Japan exceeded 15% in the 1970s, but decreased rapidly in the 1980s and reached a level as low as approximately 1% in the 1990s 13 ( Figure 1).

| 198 0 S -1990 S: THE ER A OF MODERN LIVER SURG ERY PI ONEER S
While several factors may have led to the rapid decrease in mortality in the 1980s, the establishment of safety limits for the extent of liver resection in injured livers played a major role. In Japan, when determining resectability, the severity of liver impairment is accurately assessed on the basis of the indocyanine green (ICG) tolerance test. The so-called "Makuuchi criteria" for hepatic resection, which include ICG clearance, are widely used in Japan and other Asian countries 14 ( Figure 2). The data accumulated using these criteria F I G U R E 1 Variations in hepatectomyrelated mortality, according to data from a nationwide follow-up study conducted by the Liver Cancer Study Group of Japan. In Japan, surgery-related mortality after liver cancer resection exceeded 15% in the 1970s, but decreased rapidly in the 1980s and reached a level as low as approximately 1% in the late 1990s 13 accounts for several hundred patients who underwent liver resection at the National Cancer Center until the 1980s, and although the criteria were developed empirically rather than using a formal statistical method, it has greatly contributed to the safety of liver resection. Other liver function tests using asialo-scintigraphy, 15 biliary scintigraphy, 16 and gadoxetic acid (Gd-EOB-DTPA) enhanced magnetic resonance imaging (EOB-MRI) 17 are currently available and used complementarily and sometimes as tools for the measurement of segmental liver function.
As for technological advances, intraoperative ultrasonography has had a great impact on the safety and quality of liver resections. Intraoperative ultrasonography has made it possible to visualize, in real time, the vascular anatomy of the portal and hepatic veins, which pass through the liver in a complex layout. Makuuchi et al quickly adopted the use of intraoperative ultrasonography and developed a systematic subsegmental resection, which ensured a balance between oncological curability and safety. 18 To carry out a systematic subsegmental resection, surgeons need to identify the areas perfused by the portal vein in the cancer-bearing subsegment; as such, an ultrasound-guided dye injection method (for indigoid dyes) was simultaneously reported. Although no reported randomized controlled study has shown the superiority of systematic liver resections for HCC, its usefulness has been demonstrated by a number of retrospective studies. 19,20 Portal vein embolization for the prevention of liver failure, after extended resection, was also developed in the 1980s. 21  In 2010, lateral sectionectomy and wedge liver resection were approved for social insurance coverage, and since then, have been attempted in many centers in Japan. According to the fourth report, which was released in 2011, the number of hospitals performing these procedures increased to 113, and the number of patients receiving laparoscopic liver resections increased to 2899. The number of patients treated using pure laparoscopic surgery, similarly, increased to 63%. It was anticipated that highly challenging liver resections, such as the hepatic lobectomy, would also be covered by health insurance, but issues arose due to multiple deaths following laparoscopic hepatectomy and pancreatectomy in some university hospitals. In 2016, highly challenging surgical procedures, such as subsegmentectomy and more extensive operations, were finally approved for insurance coverage under the condition that all patients would be registered prospectively. Since late 2017, 4095 patients have been registered, including 891 cases of subsegmentectomy and other more extensive procedures, and the mortality rate within 90 days has reportedly been 0.67%, which is much lower than that found in Western countries. However, according to the latest International Consensus Meeting, laparoscopic hepatic lobectomy is still considered an exploratory procedure and is not yet performed in routine surgical care, as it is a surgical procedure that requires significant expertise and has a steep learning curve. 27 Expectations are high regarding the application of minimally invasive robotic surgery to the field of hepatic surgery. However, due to issues such as expensive medical costs, limitations in the adjustment to patient posture or position, as well as differing opinions regarding the suitability of laparoscopic surgery for large organs like the liver, the procedure has only been attempted in a limited number of facilities. Nonetheless, the latest reports have shown that robotic surgery is better suited for performing the right hepatectomy than laparoscopic surgery in terms of surgery time (duration of surgery) and the rate of conversion to laparotomy; 28 thus, future progress is expected.

| PROG RE SS S IN CE 2 0 0 0 [2]: 3 -DIMENS IONAL S IMUL ATION AND NAVIG ATION TECHNOLOGY
Three-dimensional (3D) simulation technology differs from conventional 3D image display as it allows for the calculation of the volume of the areas perfused by intrahepatic blood vessels. Threedimensional simulation technology was developed in Germany in the early 2000s, 29 and immediately thereafter software based on an original algorithm was developed in Japan. This software has been widely used to assess the indicators for reconstruction of the middle hepatic vein branches in right liver grafts during livingdonor liver transplantations. 30 In 2008, the technology was recognized as part of advanced medicine and has since been applied to complex hepatectomies involving hepatic vein reconstruction as well as systematic subsegmental hepatectomies 31 (Figure 4). Its usefulness has been demonstrated in facilities specializing in liver surgery all over Japan, and, since 2012, it has been approved for insurance coverage. An analysis conducted by Mise et al, on more than 1000 cases of 3D simulation, has shown that the technology is essential for the determination of the appropriate surgical procedure to be performed on the donor in living-donor liver transplantations. Likewise, in the treatment of HCC, the number of cases in which systematic resection is indicated has increased, and findings have shown that 3D simulation may be excellent from F I G U R E 4 Typical case of liver navigation. In this patient, the treatment plan consisted of anatomic resection of the dorsal and ventral parts of S8 for the treatment of a small HCC an oncological perspective as well. In patients with multiple liver metastases, this has led to an increase in the number of patients undergoing surgery aimed at achieving R0 resection (complete resection) through complex procedures. 31 The next step after 3D simulation technology is advanced navigation technology that provides real-time intraoperative guidance during liver transection. Technology is currently being developed at many facilities in pursuit of this aim. 32 However, due to certain properties of the liver, such as liver plasticity and changes in liver position during surgery, there is still a large spatial navigation error of approximately 10 millimeters, 33 and many issues still need to be resolved, including a reduction in the time required for position adjustment.

| PROG RE SS S IN CE 2 0 0 0 [3]: ADVAN CE S IN INTR AOPER ATIVE IMAG ING
As mentioned above, significant progress was made due to intraoperative ultrasonography in the 1980s, and it has been widely used ever since. In the 1990s, the first-generation ultrasound contrast agents were released on the market, but were not widely used because there was no identified advantage to their application in intraoperative ultrasonography. In 2009, the second-generation contrast agent Sonazoid (perflubutane) displayed excellent results in the evaluation of tumor blood flow in the early phase of contrast enhancement and provided higher-definition images of tumors in the Kupffer phase of the delayed phase of contrast enhancement; thus, it rapidly became popular. In HCCs, as well as in metastatic liver cancers, intraoperative ultrasonography using Sonazoid has reportedly allowed for the detection of new lesions that were not identified preoperatively, 34,35 and, as a result, the procedure has become an essential modality in modern liver surgery.
Around the year 2007, ICG fluorescence imaging was first introduced as a completely new imaging technology. ICG is a green dye, which, for decades, has been used for the evaluation of liver function. When trace amounts of ICG are mixed with blood or bile and the mixture is excited with 750-810 nm near-infrared light, near-infrared fluorescence of approximately 840 nm is emitted. A camera designed to visualize near-infrared fluorescence was developed and, as a result, the procedure has been used for cholangiography 36,37 and for the evaluation of organ blood perfusion. It was found that HCCs that nest themselves became fluorescent, and findings revealed that ICG administered preoperatively for the purpose of conducting liver function tests was also absorbed by the cancer nests and retained there for some reason 38,39 ( Figure 5). In cases of metastatic liver cancer, findings have shown that ICG is not absorbed by the tumor itself, but is instead accumulated in a ringshaped manner in the liver parenchyma around the metastatic lesion and produces fluorescence. 38 stands out because of the absence of fluorescence. This is known as the negative staining method and has also been widely used. 42,43

| PROG RE SS S IN CE 2 0 0 0 [4]: B ROADENING OF THE IND IC ATI ON S FOR HEPATEC TOMY ( ALPPS)
As an additional measure to broaden the indications for hepatectomy, a new two-stage hepatectomy procedure was proposed in 2012. 44 In this procedure, only ligation of the right branch of the portal vein and transection of the liver are performed during the first surgery, and, approximately 9 days later, an extended right hepatectomy is performed during a second surgical procedure.
This method was named "associating liver partition and portal vein ligation for staged hepatectomy" (ALPPS) by Santibanez et al. 45 The procedure drew attention because of the accelerated speed of regeneration of the predicted residual liver, and because there were fewer dropouts during the waiting period. However, a notable disadvantage is the surgery-related mortality rate of 20% (or higher). Since the early development of this method, an international registry has been established, 46 and the procedure has been performed experimentally in many facilities worldwide. With transparency ensured, the number of registered cases has already exceeded 1100. Improvements have also been made with regard to partial hepatic transection, which already had a low mortality risk, and surgical safety has gradually improved. 47,48 Despite this, there have been recent questions regarding the oncological benefits of ALPPS. Olthof et al compared the long-term outcomes of ALPPS with those of systemic chemotherapy in the treatment of advanced colorectal cancers with multiple liver metastases and reported that there were no apparent differences between the two treatments. 49 In order for ALPPS to remain a valid surgical procedure in the future, additional careful studies will need to be executed.

| FIF T Y YE AR S OF LIVER TR AN S PL ANTATI ON
Liver transplantation is an extremely effective treatment for endstage liver failure. The world's first liver transplantation from a brain-  52 This success showed that living-donor liver transplantation could be considered a possible alternative to whole-liver transplantation from brain-dead donors, which was the only treatment option at the time for patients with liver failure in countries like Japan, where liver transplantation from brain-dead donors was almost impossible.
The first liver transplantation from a brain-dead donor in Japan was performed by Kawasaki et al from Shinshu University in 1999 after the "laws on organ transplantation" were enacted in 1997.
Initially, the donors themselves, while still alive, were required to express their willingness to donate their liver after death, and for this reason there were less than 10 cases per year in all of Japan. However, in 2009, the law was revised, and organ donations are now allowed upon consent from the donor's family. As a result, the number of cases has increased to more than 50 per year. According to the aggregated data published by the Japan Organ Transplant Network, the number of donations increased to 79 in 2017, bringing the total number to 499. However, even under these conditions, approximately 400 living-donor liver transplantations are currently needed every year, and the Japanese Society F I G U R E 6 ICG staining of hepatic segments. In this case, trace amounts of ICG is injected intraoperatively with ultrasound guidance into the portal vein branch, which perfuses the hepatic segment next to the one containing the tumor. The stained area is displayed with green fluorescence, and the boundaries between the hepatic segments are clearly visible for Transplantation and the Japan Organ Transplant Network are working on increasing awareness.
The so-called "Milan criteria," 53 which were proposed in 1994, have thus far been the gold standard for the applicability of liver transplantation in the treatment of HCC. Previous research papers suggested that the indications be broadened, and many additional criteria have been proposed. However, none have become widely used, with the exception of the University of California San Francisco (UCSF) criteria. 54 There were calls for the creation of Japanese criteria to broaden the indications for liver transplantation, most of which referred to living-donor liver transplantations, and recently, the 5-5-500 criteria were announced. 55 These criteria were statistically determined based on data from more than 1000 nationwide cases of living-donor liver transplantations for patients with liver cancer, including individuals that fulfilled certain conditions (maximum tumor size of 5 cm, a 70% or higher 5-year survival rate, and a 10% or lower 5-year incidence of recurrence), and were also based on the optimal criteria for alpha-fetoprotein (AFP) or protein induced by vitamin K absence or antagonist-II (PIVKA-II). These criteria, which require five or fewer tumors of 5 cm or less, as well as AFP levels of 500 ng/mL or lower (no extrahepatic metastasis, no vascular invasion), are already being used as the Japanese criteria for registration for liver transplantation from brain-dead donors and may potentially be used among other criteria for insurance coverage of living-donor liver transplantation.

| CON CLUS IONS
Tremendous progress in the field of liver surgery has been made over the past 50 years. The widespread use of hepatectomy and the improvement in outcomes have mainly been due to technological advances achieved by pioneers in the last century, as well as rapid improvements in safety. Whole-liver transplantation from brain-dead donors began being performed in the 1960s; however, acceptable outcomes were only achieved in the 1980s as a result of the development of novel immunosuppressants and technological progress. Partial liver transplantations from living donors, which began being performed in the 1990s, required further improvements in advanced technology and perioperative management, and technological development in that regard has contributed to overall improvements in the entire field of liver surgery. Since the turn of the century, safer and more extensive detailed surgeries have been made possible due to advances in computer and imaging technology. Laparoscopic surgery and robotic surgery have solved the issue of large incisional wounds, a major drawback of open liver surgery, but further innovation will be needed in order for safety and accuracy that is comparable to open abdominal surgery to be achieved in all surgical procedures. Liver surgery in the near future will be more precise and less invasive, supported by substantial progress in technologies surrounding liver surgery, including navigation surgery, cancer imaging, and minimally invasive surgery. This overview of the history of liver surgery over the last 50 years may provide useful insights for further innovation in the next 50 years.

D I SCLOS U R E
Authors declare no conflict of interests for this article.