Macroscopic portal vein tumor thrombi of liver metastasis from colorectal cancer

We present a case of multiple colorectal liver metastases with macroscopic portal vein thrombi. A 55-year-old woman presented to us with rectosigmoid cancer and presented with two liver metastases. The tumor in the posterior sector was associated with invasion of first order branches of the portal vein. We performed low anterior resection, hepatic posterior sectorectomy and partial left anterior sectorectomy. Both the colorectal cancer and liver tumors exhibited histological characteristics of moderately differentiated adenocarcinoma with a substantial amount of mucin production. The liver metastases were associated with prominent tumor thrombi in many branches of the portal vein. Stronger staining for endoglin (CD 105) than for Fas ligand (Fas L) and matrix metalloproteinase (MMP-2) was observed in both the colorectal cancer and metastatic liver tumor cells. Expression of the vascular endothelial growth factor within the tumor cells was seen in both the colorectal cancer as well as the metastatic liver tumor cells. Six months after the operation, she was diagnosed to have multiple, more than about 20 liver metastases, and in 9 months after the operation, the patient died. The colorectal cancer with liver metastases associated with portal vein tumor thrombosis was poor prognosis, found neoplastic microvessel formation.     

Intraperitoneal 5-fluorouracil infusion for treatment of both peritoneal and liver micrometastases

Pharmacokinetic studies indicate that intraperitoneal administration of 5-fluorouracil (5-FU) has the potential to reduce the locoregional recurrence rate of gastrointestinal cancer. We have tested this hypothesis in a rat model, in which liver and peritoneal micrometastases were induced by the injection of cultured colonic cancer spheroids into both the portal vein and peritoneal cavity, respectively. Sixty-seven tumor-bearing animals were randomized to receive either no treatment, superior mesenteric vein 5-FU, or intraperitoneal 5-FU. Infusions were begun 2 days after tumor inoculation at a dose of 45 mg/kg/day and continued for 5 days. All untreated animals had advanced liver and peritoneal metastases 1 month after tumor implantation. Intraperitoneal 5-FU totally prevented the development of macroscopic tumor on peritoneal surfaces in 57% of animals. Paradoxically, rats treated with portal vein 5-FU had significantly more tumor or peritoneal surfaces than did the untreated group (p = 0.038). Both intraperitoneal and portal vein chemotherapy resulted in approximately a 50% reduction in total liver metastases compared with untreated animals (p = 0.78). Comparison of hepatic tumor growth within different lobes or segments demonstrated that although intraperitoneal 5-FU produced a homogeneous reduction in liver metastases, the effect of portal vein chemotherapy was unevenly distributed. We conclude that intraperitoneal chemotherapy was not only effective in eradicating peritoneal micrometastases but also received the same overall reduction in liver metastases as did portal vein chemotherapy. Moreover, regional differences in hepatic tumor responses as a result of drug streaming during portal vein 5-FU infusion were not observed after intraperitoneal chemotherapy.     

结直肠癌肝转移与门静脉血K-ras基因突变的关系

目的 检测结直肠癌患者门静脉血液、原发癌组织及肝转移灶中K-ras基因突变,探讨K-ras突变与结直肠癌肝转移的关系.方法 采用实时荧光定量聚合酶链反应(PCR)技术和基因测序技术检测48例结直肠癌患者门静脉血液、原发肿瘤组织、相应的癌旁肠黏膜以及8例肝转移灶组织中K-ras基因突变.结果 48例结直肠癌组织中17例(35.4%)发现K-ras基因突变,48例癌旁黏膜中4例(8.3%)发现K-ras基因突变,明显低于癌组织的基因突变率(P＜0.05).48例结直肠癌患者中16例(33.3%)门静脉血中发现K-ras基因突变,与癌组织的基因突变率差异无统计学意义(P＞0.05).有肝转移患者门静脉血中K-ras基因突变率(7/10,70.0%)明显高于无肝转移者(9/38,23.7%,P＜0.05).16例门静脉血存在K-ras基因突变者,其相应的肿瘤组织中均发现K-ras突变.而结直肠癌组织中无K-ras基因突变者,患者门静脉血及癌旁黏膜无基因突变.8例同时性肝转移患者中5例门静脉血发现K-ras基因突变,且其相应的肝转移灶组织也发现相同的K-ras突变.2例异时性肝转移患者门静脉血检测到K-ras基因突变,手术时无肝转移,但分别于术后第6个月和第9个月经CT检查证实有肝转移.原发肿瘤组织K-ras基因突变类型与门静脉血、肝脏转移灶的K-ras基因突变一致,即K-ras基因12密码子GGT突变为GAT或GTT.结论 结直肠原发癌组织和患者门静脉血有K-ras基因的突变,预示着肿瘤可能有肝脏转移.

Abstract：

Objective To detect mutations of K-ras oncogene in portal vein blood of patients with colorectal cancer, and to find out the relationship between mutated K-ras oncogene and liver metastases in colorectal cancer. Methods Forty-eight patients with colorectal cancer were screened for the mutations of K-ras oncogene in tissue samples from their tumors, portal vein blood, proximally adjacent mucosa and 8metastatic liver biopsies by real-time fluorescence quantitative polymerase chain reaction (PCR) and DNA sequencing. The results were analyzed with their clinical data. Results Sixteen of the 48 patients with colorectal cancer had K-ras point mutations at codon 12 in their portal vein blood, and 17 of 48 patients had K-ras mutations in their primary tumors, but only 4 of 48 patients had K-ras mutations in proximally adjacent mucosa. There was no significant difference in rate of K-ras mutation between tumor tissues and portal vein blood (P ＞ 0. 05 ), but significant difference was found between the tumor tissue and the proximally adjacent mucosa ( P ＜0. 05 ). The rate of K-ras mutations in portal vein blood of colorectal cancer with liver metastases (70. 0% ) was higher than that of without liver metastases (23.7%). Sixteen cases of mutated K-ras in portal vein blood showed mutations in tumor tissues. Patients without mutated K-ras in tumor tissue had no mutations in their portal vein blood and proximally adjacent mucosa. In 5 of 8 patients with simultaneous liver metastasis, mutated K-ras oncogenes were detected in portal vein blood, and the type of K-ras mutation detected in the tumor tissue was accord with that in metastatic liver biopsies. Two patients with mutated K-ras detected in their portal vein blood had no liver metastases during perioperation, but liver metastases were diagnosed by CT at the postoperative month 6 and 9 respectively. The main types of K-ras mutations at codon 12 included GGT to GAT and GGT to GTT. No one had point mutation at codon 13. Conclusion Mutated K-ras detected in both cancer tissue and portal vein blood may indicate livermetastases from colorectal cancer.     

Murine portal vein catheterization to analyze liver-directed therapies

Background

Small interfering RNA (siRNA) provides a highly selective method to target mutated pathways; however, its use is complicated by specific delivery to tumor cells. The aims of the present study were to develop a novel murine model of portal vein catheterization for the chronic delivery of therapeutic agents to liver metastases, determine the benefits of local delivery of siRNA to liver metastases, and determine the utility of epithelial cell adhesion molecule (EpCAM) as a selective target for siRNA delivery to colorectal cancer (CRC) metastases.

Materials and methods

First, portal vein catheterization was performed through a midline laparotomy in 2 mo-old Balb/C mice. Second, the portal venous flow distribution and catheter patency were evaluated using fluorescent-labeled microspheres. Metastatic studies were performed by splenic injection of CT26 murine colon cancer cells. Uptake of DY-547-labeled siRNA was assessed by IVIS imaging, with delivery to the metastases confirmed using fluorescent microscopy. Finally, EpCAM expression was evaluated using immunohistochemical staining of human tissue microarrays.

Results

Successful portal vein catheterization was confirmed by saline injection and ultrasound. Fluorescent imaging of microspheres confirmed excellent distribution and catheter patency. Portal venous injection of DY547-labeled siRNA demonstrated a high level of fluorescence throughout the liver, with siRNA also identified within the liver metastases. Also, all primary CRCs and liver metastases stained strongly for EpCAM, with no expression in normal hepatocytes.

Conclusions

Liver-directed therapy can provide the selective delivery of siRNA to CRC metastases. EpCAM expression in CRC, but not normal liver, could further selectively target hepatic metastases of epithelial origin.     

Vascularization of small liver metastases

The portal vein contributes little to the blood supply of established liver metastases in the presence of a patent hepatic artery. However, its role in the perfusion of early metastatic liver disease remains controversial. We have quantified the relative contribution of the portal vein and hepatic artery to the internal circulation of small liver tumours. These studies were conducted in a new rat model of liver metastases generated by the intraportal injection of cultured tumour spheroids. A total of 633 lesions were studied in 18 animals using radioisotope tracer microspheres. Nodules ranged from 0.5 to 6.0 mm in diameter, 92 per cent being 3.0 mm or less. The ratio of radioactivity in tumour compared with normal tissue (T:N ratio) was determined after simultaneously injecting microspheres into the portal and arterial circulation of each animal. The mean hepatic artery T:N ratio was significantly greater than that of the portal vein for all tumour sizes studied (P less than 0.01). Nodules 0.5 mm in diameter had a mean (s.e.m.) hepatic artery T:N ratio of 1.50 (0.12) in comparison with a mean portal vein ratio of 0.13 (0.04). Tumour nodules 2.0 mm in diameter had a mean (s.e.m.) hepatic artery T:N ratio of 1.26 (0.11) in comparison with a mean portal vein ratio of 0.06 (0.01). The overall T:N ratio for both routes decreased with increasing tumour size. These results indicate that hepatic tumours as small as 0.5 mm already have an established internal vasculature perfused predominantly by the hepatic artery. In contrast, the portal vein contributes insignificantly to the internal perfusion of these lesions. These results have significant implications for adjuvant locoregional therapy in gastrointestinal cancer.     

Successful Living-Donor Liver Transplantation With Intraoperative Endovascular Recanalization via Transsplenic Access in a Recipient With Grade III Portal Vein Thrombosis: A Case Report

Extensive portosplenomesenteric thrombosis is regarded as a relative contraindication to liver transplantation because of the complexity of the surgical procedure. This report describes a case of living-donor liver transplantation (LDLT) for a patient with extensive portosplenomesenteric thrombosis, in whom portal flow was successfully restored by intraoperative transplenic portal vein and superior mesenteric vein stenting after surgical thrombectomy. The patient’s liver function remained normal with a patent portal vein stent 6 months after LDLT, and Doppler ultrasonography demonstrated a normal wave form for portal flow. To the best of our knowledge, this is the world’s first case of endovascular management of the portal vein via percutaneous transsplenic access during LDLT, demonstrating that transsplenic access can be an alternative approach without liver graft injury when the superior mesenteric vein branch and inferior mesenteric vein cannot be used as access routes.     

Impact of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) on growth of colorectal liver metastases

Background

Associating liver partition and portal vein ligation for staged hepatectomy induces an unprecedented liver hypertrophy and enables resection of otherwise unresectable liver tumors. The effect of associating liver partition and portal vein ligation for staged hepatectomy on tumor proliferation, however, remains a concern. This study investigated the impact of associating liver partition and portal vein ligation for staged hepatectomy on growth of colorectal metastases in mice and in humans.

Longer than 3-Year Survival Following Hepato-Ligamento-Pancreatoduodenectomy for Hilar Cholangiocarcinoma with Vascular Involvement: Report of a Case

A 70-year-old man presented with a mass-forming perihilar cholangiocarcinoma in his left liver, and both the portal trunk and proper hepatic artery were involved by the tumor. We performed a hepato-ligamento-pancreatoduodenectomy (HLPD), including an extended left lobectomy with a caudate lobectomy, and the external iliac vein graft was harvested for portal vein reconstruction while the right middle colic artery was anastomosed to the right posterior hepatic artery. Vascular involvement (portal vein and hepatic artery) and peripancreatic lymph node metastases were proven histologically. Although the liver abscess and pancreatic fistula both occurred postoperatively, the patient is now healthy and still alive 3 years 9 months after surgery without recurrence. We consider that the absence of para-aortic lymph node metastases and hepatic invasion which is not involved beyond the second order of the hepatic ducts in the future remnant liver might therefore have contributed to the satisfactory outcome after performing HLPD in this case.     

Selective portal clamping to minimize hepatic ischaemia-reperfusion damage and avoid accelerated outgrowth of experimental colorectal liver metastases

BACKGROUND: Temporary vascular clamping during local ablation for colorectal liver metastases increases destruction volumes. However, it also causes ischaemia-reperfusion (IR) injury to the liver parenchyma and accelerates the outgrowth of microscopic tumour deposits. The aim of this study was to investigate the effects of selective portal clamping on hepatocellular damage and tumour growth. METHODS: Mice carrying pre-established hepatic colorectal micrometastases underwent either simultaneous clamping of both the portal vein and the hepatic artery or selective clamping of the portal vein to the median and left liver lobes for 45 min. Sham-operated mice served as controls. Hepatic injury and tumour growth were assessed over time. RESULTS: Standard inflow occlusion resulted in a rise in liver enzymes, a local inflammatory response and hepatocellular necrosis. The outgrowth of pre-established micrometastases was accelerated three- to fourfold in clamped compared with non-clamped liver lobes (27.4 versus 7.8 per cent, P < 0.010). Conversely, selective portal clamping induced minimal liver injury, tissue inflammation or hepatocellular necrosis, and completely stopped the accelerated outgrowth of micrometastases. CONCLUSION: Selective portal clamping does not induce liver tissue damage or accelerate micrometastasis outgrowth and may therefore be the preferable clamping method during local ablative treatment of hepatic metastases.     

两种异位种植结肠癌肝转移动物模型的比较

目的建立并对比两种异位种植结肠癌肝转移小鼠模型。方法以1×106个/mL小鼠结肠癌细胞株(CT26)0.2mL对BALB/c小鼠分别行肝门静脉注射法,脾脏种植切除脾脏法构建结肠癌异位种植肝转移动物模型。术后待小鼠自然死亡,比较两种动物模型的肝转移率和成瘤效果、肺转移率以及小鼠生存期的差异。结果肝门静脉注射法与脾脏种植切除脾脏法相比,前者在肝转移率、肝脏成瘤效果和肺转移率方面高于后者,后者在小鼠生存时间和操作难易程度方面优于前者。结论本研究建立并对比了两种具有高转移率的结肠癌肝转移小鼠模型,肝门静脉法在肝转移率和肝脏成瘤效果方面更具优势,适合对肝转移率和取材要求较高的实验研究;而脾脏种植切除脾脏法则更适合验证周期较长的药物实验。     

Blood supply of metastatic liver tumors: an experimental study

Based on experiments with 18 female mice with induced secondary liver tumors, the entire liver metastasis blood circulation including characterization of efferent drainage system is described. The center of liver metastases is supplied from capillaries originated from branches of the hepatic artery. From the capillaries, blood is led to the superficial venous network of the metastases and further to intrahepatic veins. The portal vein system is essential for small metastases nutrition. The surface of large metastases is also nourished by the portal vein. Based on these findings, it is suggested that, in human surgery, the catheter for locoregional chemotherapy for liver tumors should be optimally implanted into both the hepatic artery and the portal vein at the same time. Thus, anticancer treatment can reach the whole tumor mass including its periphery, ie, its growth zone.     

The ALPPS technique for bilateral colorectal metastases: three “variations on a theme”

The aim of this study was to assess feasibility of technical variations of the associating liver partition and portal vein ligation for staged hepatectomy technique (ALPPS) with regard to three different ways of liver splitting. The ALPPS technique was applied in the classic form consisting in ligation of the right portal vein, limited resections on the left lobe and splitting along the umbilical fissure; the right lobe was removed 1 week later. The first variation was “left ALPPS”: ligation of the left portal vein, multiple resections on the right hemiliver and splitting along the main portal fissure. The second variation was “rescue ALPPS”, consisting in simple splitting of the liver along the main portal fissure several months after a radiological portal vein embolization that did not allow satisfactory liver hypertrophy. The third variation was “right ALPPS”, consisting in ligation of the posterolateral branch of right portal vein, left lateral sectionectomy, multiple resections on the right anterior and left medial section and splitting along the right portal fissure. In all cases auxiliary deportalized liver was removed 1 week later. 4 patients with colorectal metastases were included. Morbidity was defined according to the Clavien–Dindo classification: grade I (2 events), grade IIIb (1 event). Postoperative mortality was nil. Median follow-up was 4 months and to date all patients are still alive. ALPPS technique, in its “classical” and modified forms, is a good option for selected patients with bilateral colorectal metastases and represents a feasible alternative to classical two-stage hepatectomy.     

Una nueva estrategia quirúrgica para metástasis hepáticas bilobares múltiples: oclusión portal derecha y torniquete en la línea de sección parenquimatosa

Right portal vein occlusion plus «in situ split» has recently been reported as a new method to hypertrophy the functional remnant volume (FRV) in 7 days after two-stage liver resection. It is a complex procedure associated with the occlusion of the intrahepatic collaterals between both lobes. We present an original technique for hypertrophying the FRV by occluding the right portal vein and the intrahepatic collaterals: a case is presented of a 35-year-old woman with an intestinal stromal tumour, 14 bilobar metastases and an estimated 24% FRV. Once the lesions were removed from the left lobe, we performed a right portal vein transection and applied a tourniquet on the Cantlie line, using the hanging manoeuvre. A 57% hypertrophy of the FRV was achieved by day 7, and the right hepatectomy was performed on day 8. Our technique is effective and simple to perform and if corroborated in future studies, this technique would be of choice in 2-stage liver resection.     

Arterial, portal, or systemic chemotherapy for patients with hepatic metastasis of colorectal carcinoma

Hepatic metastases from colorectal carcinoma are common and may be resected for cure. The response of liver metastases to systemic chemotherapy is low. In contrast, hepatic arterial chemotherapy produces higher response rates than systemic chemotherapy, but randomized trials have not definitely proved a survival advantage because they allowed cross over. Most adjuvant portal vein chemotherapy studies have shown a survival advantage over the control group, but it is not clear whether this benefit is from the portal vein therapy or from immediate postoperative chemotherapy, since there is rarely a reduction in liver metastases. We describe the results of systemic, hepatic artery infusion, and portal therapy for patients with liver metastases of colorectal carcinoma. Received for publication on Aug. 30, 1998; accepted on Nov. 2, 1998     

结直肠癌肝转移的诊断和治疗

目的 探讨结直肠癌肝转移的诊断和治疗效果.方法 回顾性分析25 例结直肠癌肝转移的临床资料,其中原发盲升结肠癌9 例,横结肠癌3 例,降结肠癌2 例,乙状结肠癌8 例,直肠癌3 例.同时性肝转移癌9例,异时性肝转移癌16 例.肝左叶转移15 例,肝右叶转移4 例,左右叶转移6 例.单个转移15 例,多个转移10例.高分化腺癌13 例,中分化腺癌5 例,低分化腺癌6 例,未分化腺癌1 例.9 例同时性肝转移癌中施行肝左外叶切除7 例,其中加1 例门静脉插管埋泵化疗;右前叶切除2 例,1 例仅作门静脉和肝动脉双插管埋泵化疗.16例异时性肝转移癌中施行肝左外叶切除4 例,左半肝切除5 例,肝右前叶切除2 例,门静脉和肝动脉双插管埋泵化疗2 例,股动脉插管肝动脉介入治疗3 例.结果 全组均经3 年随访,同时性肝切除术8 例中5 例存活(62.5%),异时性肝切除术11 例中4 例存活(36.3%),仅作门静脉和肝动脉插管埋泵化疗或股动脉插管肝动脉介入化疗6 例中2 年内死亡5 例,3 年死亡1 例,3 年存活率仅16.6%.结论 同时性或异时性结直肠癌肝转移,只要全身情况和局部条件许可,均应首选手术切除治疗,以提高患者生存率.对不能切除的患者,可采用动、静脉插管埋泵或作股动脉插管肝动脉介入化疗,以延长患者生命.     

Surgical results for hepatocellular carcinoma with macroscopic portal vein tumor thrombosis

Background: The longterm results after liver resection for hepatocellular carcinoma with macroscopic tumor thrombus of the portal vein are unclear.

Study Design: The records of 47 HCC patients with tumor thrombus in the segmental portal branch (n = 33) and the first portal branch or portal vein trunk (n = 14) were reviewed in this study. Survival rates of the patients were calculated with regard to 14 clinicopathologic variables. A log-rank analysis was performed to identify which variables predicted the prognosis.

Results: Overall 1-, 3-, and 5-year survival rates were 53.9%, 33.2%, and 23.9%, respectively. The indicators of a favorable prognosis included curative liver resection, tumor size less than 10 cm in diameter, and absence of intrahepatic metastases.

Conclusions: Liver resection should be considered a therapeutic option for hepatocellular carcinoma with macroscopic portal vein tumor thrombus when the tumor is small and curative liver resection can be expected.     

原位肝移植术后门静脉并发症的诊治

目的 探讨原位肝移植术后门静脉并发症的诊断和治疗.方法 回顾性分析173例原位肝移植患者的临床资料.结果 本组原位肝移植术后有6例门静脉并发症(3.5%),门静脉狭窄发生率为1.2%,门静脉血栓发生率为2.3%,且术前3例有门静脉血栓,3例有门静脉高压症手术史.2例患者成功放置血管内支架,3例患者行套扎术或硬化剂治疗后好转出院,6例中无1例死亡.结论 术前存在门静脉高压症手术治疗史和门静脉血栓是门静脉并发症的高危因素.彩色多普勒超声检查是监测门静脉并发症的有效方法 ,确诊门静脉并发症则要依据门静脉CT血管成像.晚期门静脉血栓溶栓治疗效果不佳,对单纯性门静脉狭窄行介入治疗是安全可行的.     

Chemotherapy does not impair hypertrophy of the left liver after right portal vein obstruction

In patients with multiple colorectal liver metastases, the technical limits of curative surgery can be overcome by both reducing tumor volume with preoperative chemotherapy and by increasing the future remnant liver with portal vein embolization. Chemotherapy is generally discontinued before the embolization because it is alleged to impair hypertrophy of the future remnant liver. We have tested this assumption by comparing two groups of patients who had undergone right portal vein obstruction: 10 patients in whom chemotherapy was maintained until surgery and 10 patients in whom it was interrupted at least 1 month prior to portal obstruction. The two groups, with and without chemotherapy, were comparable for patient’s age (60 ± 9 versus 61 ± 9 years), number of metastases (7.7 ± 3 versus 6.2 ± 3), and future remnant liver volume (25 ± 9% versus 23 ± 5% of the total liver). After right portal vein obstruction, the increase of the future remnant liver was comparable in the two groups (33 ± 26% versus 25 ± 7%). Liver resection was performed in 14 patients (7 in each group) with a similar morbidity rate (57% in each group). In conclusion, continuing chemotherapy while portal vein obstruction is performed did not impair the hypertrophy of the future remnant volume nor the postoperative course after liver resection. Therefore, chemotherapy can be safely continued until liver surgery, when portal vein obstruction is indicated.     

门静脉栓塞术在二期精准肝切除中的应用

目的: 探讨门静脉栓塞术在二期精准肝切除的应用。方法: 分析7例在超声扫描及X线数字减影血管造影引导下,经皮经肝穿刺门静脉栓塞术后,行二期精准肝切除术的肝癌病人临床资料。分成肝硬化组3例和无肝硬化组4例,分别检测门静脉栓塞术前和术后肝功能指标及肝体积变化,总结二期手术切除。结果: 7例病人均成功实施经皮经肝穿刺门静脉栓塞术,其中6例病人达到肝脏体积代偿增大的预期效果,顺利完成二期精准肝切除术。1例结肠直肠癌肝转移病人在门静脉栓塞8周后,未栓塞肝脏代偿性增大体积未达到精准肝切除的条件,转外院顺利行拯救性联合肝脏离断和门静脉结扎的二步肝切除术。两组经皮经肝穿刺门静脉栓塞术后1 d,肝功能指标较术前升高（P<0.05）,予护肝治疗3~7 d后降至术前水平。未发生严重并发症。结论: 门静脉栓塞技术成功率高、安全可行。剩余肝脏代偿性增大明显,可显著提高二期精准肝切除手术率。     

Two-stage hepatectomy procedure to treat initially unresectable multiple bilobar colorectal liver metastases: technical aspects

A two-stage hepatectomy procedure is a therapeutic strategy for patients presenting with initially unresectable multiple and bilobar colorectal liver metastases in order to achieve a curative R0 resection. The main goal of this approach is to minimize the risk of postoperative liver failure resulting from a too small remnant liver after completing a curative resection. This procedure combines two sequential liver resections that involve perioperative chemotherapy and portal vein embolization. This article describes our standardized strategy of two-stage hepatectomy combined with portal vein embolization used over the last 15 years and discusses the alternative procedures as well as their respective advantages and drawbacks.