A Two-Step Right Hepatic Lobectomy with Portal Vein Ligation for Large Hepatocellular Carcinoma: Rapid Induction of Left-Lobe Regeneration and Clinicopathologic Correlation

• Case Report
• Pathologic Findings
• Gross Examination of the Right Lobectomy Specimen
• Histological Examination of the Right Hepatic Lobectomy Specimen
• Pathological Changes of the Left Hepatic Lobes Following the Right Portal Vein Ligation and Right Lobectomy
• Discussion
• References

Abstract

The patient is a 56-year-old man with a long history of chronic hepatitis B, who developed multiple hepatocellular carcinomas in the right lobe with invasion of the right anterior portal vein. There was no evidence of tumor involvement in the left lobe or in extrahepatic organs. Given that the patient had advanced hepatocellular carcinoma associated with gross vascular invasion, a two-step liver resection procedure was performed with right portal vein ligation during the first operation and a subsequent right lobectomy of the liver. The stage I portal vein ligation induced a rapid growth of the left and caudate lobes of the liver with a volume increase from 201 to 405.2 mL in 9 days associated with a slight shrinkage of the tumor nodules. The subsequent right lobectomy was successfully done with a complete removal of tumor nodules and a well-compensated liver function. Postoperatively the patient was complicated with Staphylococcus aureus peritonitis, which was controlled eventually. Biopsy of the left lobe of liver revealed severe small- and medium- droplet steatosis, in addition to regenerative changes. In summary, right portal vein ligation with in situ splitting of the liver allows the surgeon to proceed with hepatic resection in cases where portal vein embolization is technically not possible. The increased risk of morbidity and mortality certainly must be weighed when contemplating this approach and is discussed in this report.

Case Report

The patient was a 56-year-old man with a long history of chronic hepatitis B. On initial evaluation (10/3/2012), he was found to have a slightly abnormal liver function with alanine aminotransferase (ALT) of 97 (normal 1–50 U/L), aspartate aminotransferase (AST) 70 (normal 1–53 U/L), total bilirubin 0.8 (normal 0.2–1.3 mg/dl), and serum α-fetoprotein of 7,264 (normal 0–9 ng/mL). An abdominal computed tomography (CT) study revealed that the liver was slightly small in size with mildly nodular contour, consistent with cirrhosis. Centrally in segment 8, there was a 4.6 × 3.4 × 3.2 cm hypervascular mass with associated washout. More peripherally in segment 8 was a 2.1 × 1.6 × 1.8 cm hypervascular nodule with washout. At the junction of segments 5 and 6, there was a 4.0 × 3.4 × 4.9 cm hypervascular mass with washout. A 1.5-cm hypervascular nodule was also noted in segment 7 in addition to multiple scattered subcentimeter hypervascular foci without associated washout in segments 5 and 8. These findings were consistent with multiple hepatocellular carcinomas with invasion of the right anterior portal vein. The main portal vein and hepatic veins were patent. There was no evidence of tumor in the left lobe or extrahepatic organs.

Given that the patient had advanced hepatocellular carcinoma associated with gross vascular invasion, he was not qualified for liver transplantation. In the presence of gross vascular invasion, transarterial chemoembolization was considered risky for hepatic necrosis. A right lobectomy was an option to remove the tumors, but hepatic functional decompensation was a major concern.

Generally, in cases where there is concern regarding the size of the remaining left lobe of liver, a right portal vein embolization is performed to allow for atrophy of the right lobe and hypertrophy of the left lobe prior to resection. In this particular case, the patient had invasion of a branch of the right portal system and it was unclear if portal vein embolization would be successful or if the patient would have progression of the tumor thrombus during the period waiting for left lobe hypertrophy. As such, a two-step liver resection procedure was attempted with a right portal vein ligation procedure first and a subsequent right lobectomy of the liver.

On October 9, 2012, the patient underwent a right portal vein ligation procedure. Following dividing the liver parenchyma between the right and the left lobe, the right portal vein was successfully divided. A successful right portal ligation was performed without interruption of the right hepatic artery. The patient tolerated the procedure well with stable postoperative condition. Subsequent laboratory results revealed a slight increase of ALT 213 U/L, AST 214 U/L, and total bilirubin 1.1 mg/dL. Nine days after the right portal vein ligation, a follow-up abdominal CT revealed a slight shrinkage of the tumor nodules with complete interruption of the right portal vein, while the other branches of the portal vein, hepatic vein, and hepatic artery were all patent. The combined volume of the left and caudate lobes of the liver was increased from 201 to 405.2 mL, more than doubling in size ([Fig. 1]).

On October 18, 2012, the patient underwent the second stage of the procedure, right lobectomy of the liver. Immediately following the procedure, the patient was uneventful with improving liver function. On postoperative day 5, the patient was complicated with Staphylococcus aureus peritonitis. This was treated with antibiotics and several surgeries for peritoneal lavage. A liver biopsy of the left lobe was performed during one the peritoneal lavages. On November 13, 2012, the abdominal infection was fully controlled and the patient was discharged with no evidence of infection. Three months following surgery, a follow-up CT imaging study demonstrated marked hypertrophy of the remaining left lobe and caudate lobe with no evidence of recurrent hepatocellular carcinoma ([Fig. 2]).

Pathologic Findings

Gross Examination of the Right Lobectomy Specimen

Nine days following the right portal vein ligation, a 578 g, 15.5 × 13.3 × 9.5 cm right lobectomy specimen was received and serially sectioned, revealing two tumors ([Fig. 3]). The first tumor was a well-delineated nodular tan/yellowish mass measuring 4.1 × 3.4 × 3.3 cm with extensive gross vascular invasion of portal vein branches. The tumor was located between segments 5 and 8, 0.6 cm from the resection margin. A 2.6-cm satellite nodule was also identified, 0.1 cm from the main tumor. The second tumor was nodular with bile stain, located between segments 5 and 6, measuring 4.3 × 3.8 × 3.4 cm with no gross vascular invasion. In addition, a 2.5 × 2 × 1.6 cm ill-defined fibrotic and hemorrhagic subcapsular tumor was recognized in segment 6, 0.7 cm from the second tumor. The uninvolved nonneoplastic liver was nodular and slightly firm, consistent with cirrhosis. Thrombotic materials were also identified in portal vein branches, consistent with postportal vein ligation procedure.

Histological Examination of the Right Hepatic Lobectomy Specimen

The first tumor located between segments 5 and 8 had irregular broad fibrotic septa giving rise to a nodular growth pattern ([Fig. 4A]). The tumor cells were arranged predominantly in solid areas with focal trabecular as well as pseudoglandular configuration ([Fig. 4B]). Scattered bile concretions were present in the lumen of the pseudoglands. Focal geographic tumor necrosis was noted, accounting for ∼15% of the tumor volume. There was extensive microscopic tumor invasion involving large caliber and small venous structures, and in portal tracts at a distance from the tumor. Cytologically, the neoplastic hepatocytes were enlarged, moderately pleomorphic, with large hyperchromatic nuclei, irregular nuclear contour and relatively basophilic cytoplasm, overall consistent with moderately differentiated hepatocellular carcinoma. Frequent mitoses were noted. The second tumor had more of the thick trabecular and pseudoglandular configuration, marked bile stasis in the pseudoglandular lumens, less tumor necrosis, but otherwise was morphologically similar to the first tumor ([Fig. 4C]).

The nonneoplastic background liver was cirrhotic composed of mixed large and small regenerative nodules surrounded by thin or thick fibrotic septa. Steatosis was absent ([Fig. 4D]). Lymphocytic infiltrates and scattered lymphoid aggregates were present in the fibrotic septa. Immunostains for hepatitis B surface antigen (HBsAg) and hepatitis core antigen (HBcAg) were performed in sections from the nonneoplastic liver, revealing few scattered positive hepatocytes for HBsAg and small groups of hepatocytes with positive cytoplasmic and nuclear staining for HBcAg, confirming the etiology of the underlying cirrhosis and also indicative of active viral replication ([Figs. 4E, 4F]).

Patchy necrosis and hemorrhage of the cirrhotic nodules were noted, which was particularly prominent corresponding to the fibrotic and hemorrhagic area in segment 6 as described in the gross examination, consistent with infarction, presumably as a consequence of the portal vein ligation procedure.

Pathological Changes of the Left Hepatic Lobes Following the Right Portal Vein Ligation and Right Lobectomy

Five days following the right lobectomy, a core biopsy of the left hepatic lobe was performed, revealing prominent regenerative changes of hepatocytes in the cirrhotic nodules, arranged in two-cell thick plates. There was no evidence of necrosis. Bile ducts are present in portal tracts. In addition, extensive (> 60%) small- and medium-droplet steatosis were present ([Fig. 5]), which was absent from the resected right lobe ([Fig. 4D]).

Discussion

Treatment of patients with well-preserved liver function and hepatocellular carcinoma with portal vein invasion remains a difficult therapeutic dilemma. Currently, the Barcelona Clinic Liver Cancer (BCLC) staging system classifies these patients as stage C and recommends sorafenib as treatment.[1] [2] The median survival of these patients treated with sorafenib has been reported at 8 months.[3]

Other therapeutic options including transcatheter arterial chemoembolization (TACE) and radioembolization using yttrium-90 have also been employed. When examining patients with Child A liver disease, Kim et al reported a median survival of 10.2 months for patients with branch invasion and 5.3 months for those with main portal invasion undergoing TACE.[4] Likewise, Sangro reported a median survival of 9.7 months in BCLC stage C patients with Child A liver disease who were treated with yttrium-90 radioembolization.[5] Multiple studies have been published regarding the outcomes with hepatic resection for these patients with median survivals ranging from 6 to 20 months. A recent study from our own institution revealed a median survival of 15 months for patients with involvement of a segmental branch of the portal vein such as this patient.

The utility of portal vein embolization in cirrhotic patients undergoing extended hepatic resections has been well described. However, its usefulness and safety in a patient with tumor invading a branch of the portal system is unclear. One can imagine that the tumor within the liver has the ability to grow during the period after embolization while waiting for contralateral hypertrophy, making resection impossible. In addition, the tumor thrombus within the portal vein can also grow and extend down the portal system, also making resection technically not possible.

Recently, an experience with right portal ligation and in situ splitting of the liver has been described.[6] The ligation of the portal vein with preservation of the right hepatic artery allows for hypertrophy of the left lobe and makes tumor extension down the portal system impossible. Likewise, transection of the hepatic parenchyma makes growth and extension of the tumor beyond the planned line of resection impossible. However, this procedure has been associated with significant morbidity and mortality.

It is unclear if the complication in this particular case was as a result of the two-staged procedure, exposing the patient to a second operation leading to an increased chance of infection from skin flora. Certainly, an extended hepatic resection alone in a cirrhotic can also be the sole explanation for this particular morbidity.

The extent of liver resection is largely restricted by the volume of the remnant liver, which is particularly problematic in patient with cirrhosis. Among different strategies, portal vein embolization is widely accepted to achieve the goal of presurgical liver compensation by inducing a hypertrophy of the remaining hepatic parenchyma.[7] It has been reported that clinically adequate liver hypertrophy occurs ∼2 to 3 weeks following portal embolization.[7] [8] Recently, portal vein ligation has been described for a rapid growth induction of the future liver remnant in two-stage liver resection.[9] In our case, portal vein ligation indeed resulted in a rapid growth induction of the left and caudate lobes of the liver with a volume increase from 201 to 405.2 mL in 9 days. The compensatory hypertrophy of the remnant liver was also evident histologically with prominent regenerative changes of hepatocytes, which were arranged in two-cell thick plates in the regenerative nodules.

Another remarkable pathological finding in the remnant liver was marked small- and medium-droplet steatosis. Surgical complication associated with systemic hypotension and decreased hepatic blood perfusion could contribute, at least partly to the steatosis. We also speculated that unbalanced arterial-portal perfusion in the left lobe of liver might play an important role in the development of postsurgical steatosis. The normal liver receives ∼75% of its blood through the hepatic portal vein, with the remainder coming from the hepatic artery proper. A significant increase in the portal blood flow to the left lobe is expected following right portal vein ligation that would lead to an increase in intrahepatic portal blood pressure. The outcome of this process is a decrease in the arterial blood flow to the remnant hepatic parenchyma, particularly in cirrhotic liver with well-known significant portal arterial shunting. With reduced arterial blood flow, a steatotic response could be rapidly initiated in the remnant liver,[10] as seen in our patient.

In conclusion, right portal vein ligation with in situ splitting of the liver allows the surgeon to proceed with hepatic resection in cases where portal vein embolization is technically not possible. The increased risk of morbidity and mortality certainly must be weighed when contemplating this approach.

• References

• 1 Bruix J, Sherman M. Practice Guidelines Committee, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma. Hepatology 2005; 42 (5) 1208-1236
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• 2 European Association For The Study Of The Liver; European Organisation For Research And Treatment Of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2012; 56 (4) 908-943
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• 5 Sangro B, Carpanese L, Cianni R , et al; European Network on Radioembolization with Yttrium-90 Resin Microspheres (ENRY). Survival after yttrium-90 resin microsphere radioembolization of hepatocellular carcinoma across Barcelona clinic liver cancer stages: a European evaluation. Hepatology 2011; 54 (3) 868-878
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• 6 Schnitzbauer AA, Lang SA, Goessmann H , et al. Right portal vein ligation combined with in situ splitting induces rapid left lateral liver lobe hypertrophy enabling 2-staged extended right hepatic resection in small-for-size settings. Ann Surg 2012; 255 (3) 405-414
  CrossrefPubMedSearch in Google Scholar
• 7 Madoff DC, Abdalla EK, Vauthey JN. Portal vein embolization in preparation for major hepatic resection: evolution of a new standard of care. J Vasc Interv Radiol 2005; 16 (6) 779-790
  CrossrefPubMedSearch in Google Scholar
• 8 Gulec SA, Pennington K, Hall M, Fong Y. Preoperative Y-90 microsphere selective internal radiation treatment for tumor downsizing and future liver remnant recruitment: a noval approach to improving the safety of major hepatic resections. World J Surg Oncol 2009; 7: 1-7
  CrossrefPubMedSearch in Google Scholar
• 9 Knoefel WT, Gabor I, Rehders A , et al. In situ liver transection with portal vein ligation for rapid growth of the future liver remnant in two-stage liver resection. Br J Surg 2013; 100 (3) 388-394
  CrossrefPubMedSearch in Google Scholar
• 10 Demetris AJ, Kelly DM, Eghtesad B , et al. Pathophysiologic observations and histopathologic recognition of the portal hyperperfusion or small-for-size syndrome. Am J Surg Pathol 2006; 30 (8) 986-993
  CrossrefPubMedSearch in Google Scholar

Address for correspondence

• References

• 1 Bruix J, Sherman M. Practice Guidelines Committee, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma. Hepatology 2005; 42 (5) 1208-1236
  CrossrefPubMedSearch in Google Scholar
• 2 European Association For The Study Of The Liver; European Organisation For Research And Treatment Of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2012; 56 (4) 908-943
  PubMedSearch in Google Scholar
• 3 Sherman M, Mazzaferro V, Amadori D , et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma and vascular invasion or extrahepatic spread: a subanalysis from the SHARP trial. J Clin Oncol 2008; 26 (15) Suppl 4584
  PubMedSearch in Google Scholar
• 4 Kim KM, Kim JH, Park IS , et al. Reappraisal of repeated transarterial chemoembolization in the treatment of hepatocellular carcinoma with portal vein invasion. J Gastroenterol Hepatol 2009; 24 (5) 806-814
  CrossrefPubMedSearch in Google Scholar
• 5 Sangro B, Carpanese L, Cianni R , et al; European Network on Radioembolization with Yttrium-90 Resin Microspheres (ENRY). Survival after yttrium-90 resin microsphere radioembolization of hepatocellular carcinoma across Barcelona clinic liver cancer stages: a European evaluation. Hepatology 2011; 54 (3) 868-878
  CrossrefPubMedSearch in Google Scholar
• 6 Schnitzbauer AA, Lang SA, Goessmann H , et al. Right portal vein ligation combined with in situ splitting induces rapid left lateral liver lobe hypertrophy enabling 2-staged extended right hepatic resection in small-for-size settings. Ann Surg 2012; 255 (3) 405-414
  CrossrefPubMedSearch in Google Scholar
• 7 Madoff DC, Abdalla EK, Vauthey JN. Portal vein embolization in preparation for major hepatic resection: evolution of a new standard of care. J Vasc Interv Radiol 2005; 16 (6) 779-790
  CrossrefPubMedSearch in Google Scholar
• 8 Gulec SA, Pennington K, Hall M, Fong Y. Preoperative Y-90 microsphere selective internal radiation treatment for tumor downsizing and future liver remnant recruitment: a noval approach to improving the safety of major hepatic resections. World J Surg Oncol 2009; 7: 1-7
  CrossrefPubMedSearch in Google Scholar
• 9 Knoefel WT, Gabor I, Rehders A , et al. In situ liver transection with portal vein ligation for rapid growth of the future liver remnant in two-stage liver resection. Br J Surg 2013; 100 (3) 388-394
  CrossrefPubMedSearch in Google Scholar
• 10 Demetris AJ, Kelly DM, Eghtesad B , et al. Pathophysiologic observations and histopathologic recognition of the portal hyperperfusion or small-for-size syndrome. Am J Surg Pathol 2006; 30 (8) 986-993
  CrossrefPubMedSearch in Google Scholar