Malignant hepatic vascular tumors in adults: Characteristics,diagnostic difficulties and current management

Malignant vascular tumors of the liver include rare primary hepatic mesenchymal tumors developed in the background of a normal liver parenchyma. Most of them are detected incidentally by the increased use of performing imaging techniques. Their diagnosis is challenging, involving clinical and imaging criteria, with final confirmation by histology and immunohistochemistry. Surgery represents the mainstay of treatment. Liver transplantation (LT) has improved substantially the prognosis of hepatic epithelioid hemangioendothelioma (HEHE), with 5-year patient survival rates of up to 81%, based on the European Liver Intestine Transplantation Association-European Liver Transplant Registry study. Unfortunately, the results of surgery and LT are dismal in cases of hepatic angiosarcoma (HAS). Due to the disappointing results of very short survival periods of approximately 6-7 mo after LT, because of tumor recurrence and rapid progression of the disease, HAS is considered an absolute contraindication to LT. Recurrences after surgical resection are high in cases of HEHE and invariably present in cases of HAS. The discovery of reliable prognostic markers and the elaboration of prognostic scores following LT are needed to provide the best therapeutic choice for each patient. Studies on a few patients have demonstrated the stabilization of the disease in a proportion of patients with hepatic vascular tumors using novel targeted antiangiogenic agents, cytokines or immunotherapy. These new approaches, alone or in combination with other therapeutic modalities, such as surgery and classical chemotherapy, need further investigation to assess their role in prolonging patient survival. Personalized therapeutic algorithms according to the histopathological features, behavior, molecular biology and genetics of the tumors should be elaborated in the near future for the management of patients diagnosed with primary malignant vascular tumors of the liver.     

The role of radiotherapy in the treatment of liver metastases

Radiotherapy has historically played a minor role in the treatment of patients with unresectable liver metastases from colorectal cancer and other malignancies. This can be attributed chiefly to the low tolerance of the whole liver to radiation. High-precision radiotherapy planning techniques have allowed much higher doses of radiation to be delivered safely to focal liver metastases, while sparing most of the normal liver. When combined with hepatic arterial fluorodeoxyuridine, high-dose focal liver radiotherapy is associated with excellent response rates, local control, and survival in patients with unresectable liver metastases from colorectal cancer. Radiotherapy, with and without concurrent systemic chemotherapy, has also been used with encouraging outcomes for patients with liver metastases from colorectal cancer and other cancers. There appears to be a radiation dose response for liver metastases; tumors treated with doses of 70 Gy or greater are likelier to have durable local control. Advancements in tumor imaging, in radiotherapy techniques that will allow the safe delivery of higher doses of radiation, and in novel tumor radiation sensitizers and normal tissue radioprotectors should substantially improve the outcome of patients with unresectable liver metastases treated with radiotherapy.     

Conversion therapy for intrahepatic cholangiocarcinoma and tumor downsizing to increase resection rates: A systematic review

Intrahepatic cholangiocarcinoma (ICC) is a devastating malignant neoplasm with dismal outcomes. Several therapeutic modalities have been used with variable success to downsize these tumors for resection. Neoadjuvant therapy such as chemoembolization and radioembolization offer promising options to manage tumor burden prior to resection. A systematic review of the literature was performed with a focus on conversion therapy for ICC and tumor downsizing to increase resection rates among patients who have an initially unresectable tumor. Of 132 patients with initially unresectable ICC, we identified 27 who underwent conversion therapy with surgical resection. Adequate tumor downsizing was achieved with chemotherapy, chemoembolization, radioembolization, or combination thereof. Although negative tumor margins were possible in some patients, recurrence rates and survival outcomes were inconsistently reported. Twenty-three of 27 patients were alive at last reported follow-up. Conversion therapy for initially unresectable ICC may offer adequate tumor downsizing for resection.     

VEGF-VEGFR pathway seems to be the best target in hepatic epithelioid hemangioendothelioma: A case series with review of the literature

Epithelioid hemangioendothelioma (EHE) is a rare vascular tumor originating from endothelial cells. Clinical aspect of the disease covers a wide spectrum from a low-grade tumor to a fatal cancer. Most common sites of EHE are reported as lung, liver and bone. Hepatic EHE (HEHE) is a clinical form with an incidence of less than 1 person in a million. Due to rarity of the disease, there is no standard therapy established. Surgery and liver transplantation still seem to be the best approach if possible. However, most of the patients present with unresectable or metastatic disease. Many conventional chemotherapeutic agents and antiangiogenic drugs have been reported previously in the literature with inconsistent outcomes. Here we report 4 cases of HEHE, who benefit distinctly from anti-VEGF treatments in different settings. While combination of paclitaxel and bevacizumab resulted in partial response in 3 patients, one of them also achieved long-term disease stabilization with bevacizumab maintenance with no adverse event. Two of the patients had clear benefit from pazopanib during the course of disease. One patient was treated with thalidomide for 18 months with stable disease, and is still being followed without any treatment. Although targeting VEGF-VEGFR pathway seems to be the best approach in HEHE, randomized studies are urgently needed to support these findings.     

The Evolving Use of Prognostic Factors After Resection of Colorectal Liver Metastases

The expanding use of surgical therapy for patients with colorectal liver metastases (CRLM) and developments in chemotherapeutic regimens have led to a significant improvement in survival. However, outcomes can vary substantially and criteria for determining the prognosis of individual patients are lacking. Traditionally, clinicopathologic factors, for example primary tumor stage, number and size of liver metastases, preoperative carcinoembryonic antigen levels, presence of extrahepatic disease, and others, have been used to determine which patients are more likely to experience recurrence and poor survival. However, these factors, both separately and as part of scoring systems, have been inconsistent and conflicting in determining prognosis. Recently, molecular and biological indicators have emerged as potential prognosticators for CRLM patients undergoing hepatic resection. Tumor response to chemotherapy, both on imaging and on pathology, mutation status of such oncogenes as KRAS and BRAF, and expression patterns of proliferative markers including MACC1 and Ki-67, have all furnished promising results in prediction of patient outcomes. Moreover, circulating tumor cells and tumor DNA may not only be a useful prognostic instrument but also an excellent means of screening for early detection of recurrence.     

Non-surgical treatment of hilar cholangiocarcinoma

Cancer of the biliary confluence also known as hilar cholangiocarcinoma (HC) or Klatskin tumor, is a rare type of neoplastic disease constituting approximately 40%-60% of intrahepatic malignancies, and 2% of all cancers. The prognosis is extremely poor and the majority of Klatskin tumors are deemed unresectable upon diagnosis. Most patients with unresectable bile duct cancer die within the first year after diagnosis, due to hepatic failure, and/or infectious complications secondary to biliary obstruction. Curative treatments include surgical resection and liver transplantation in highly selected patients. Nevertheless, very few patients are eligible for surgery or transplant at the time of diagnosis. For patients with unresectable HC, radiotherapy, chemotherapy, photodynamic therapy, and liver-directed minimally invasive procedures such as percutaneous image-guided ablation and intra-arterial chemoembolization are recommended treatment options. This review focuses on currently available treatment options for unresectable HC and discusses future perspectives that could optimize outcomes.     

A contemporary systematic review on liver transplantation for unresectable liver metastases of colorectal cancer

The 5-year overall survival rate of a patient with unresectable metastatic colorectal cancer is poor at approximately 14%. Similarly, historical data on liver transplantation (LT) in those with colorectal liver metastases (CRLM) showed poor outcomes, with 5-year survival rates between 12% and 21%. More recently, limited data have shown improved outcomes in select patients with 5-year overall survival rates of approximately 60%. Despite these reported survival improvements, there is no significant improvement in disease-free survival. Given the uncertain benefit with this therapeutic approach and a renewed investigational interest, we aimed to conduct a contemporary systematic review on LT for CRLM. A systematic review of the literature was performed according to the preferred reporting items for systematic reviews and meta-analysis statement. English articles reporting on data regarding LT for CRLM were identified through the MEDLINE (via PubMed), Cochrane Library, and ClinicalTrials.gov databases (last search date: December 16th, 2021) by 2 researchers independently. A total of 58 studies (45 published and 13 ongoing) were included. Although early retrospective studies suggest the possibility that some carefully selected patients may benefit from LT, there is minimal prospective data on the topic and LT remains exploratory in the setting of CRLM. Additionally, several other challenges, such as the limited availability of deceased donor organs and defining appropriate selection criteria, remain when considering the implementation of LT for these patients. Further evidence from ongoing prospective trials is needed to determine if and to what extent there is a role for LT in patients with surgically unresectable CRLM.     

Current therapeutic strategies for childhood hepatic malignant tumors

The two main malignant hepatic tumors in children are hepatoblastomas (HBLs) and hepatocellular carcinomas (HCCs). The past two decades have brought significant improvement to the outcomes of children diagnosed with malignant hepatic tumors, especially HBL, due to improvements in diagnosis and treatment. Histological diagnosis is essential for differential diagnosis of these tumors. In surgery, liver resection has become a safe and secure technique because of progress in anatomical knowledge and surgical dissection; also liver transplantation has become widely used for unresectable tumors. Moreover, the introduction of effective chemotherapeutic regimens has significantly improved the survival of children with HBL due to an increase in the number of patients ultimately undergoing tumor resection, and a reduction in the incidence of post-surgical recurrence. These improvements are the result of multicenter cooperative trials conducted by the Japanese Study Group for Pediatric Liver Tumor, the Children’s Oncology Group, and the International Childhood Liver Tumor Strategy Group, including work of the German Association of Pediatric Hematology and Oncology. This paper summarizes the results of these studies and calls on the current international collaboration study called the Children’s Hepatic Tumors International Collaboration Project to establish global clinical research on childhood hepatic malignant tumors.     

Isolation perfusion of the liver

Thousands of patients die annually from unresectable metastatic or primary hepatic cancers confined to liver. Isolated hepatic perfusion (IHP) is a regional treatment strategy in which the vascular supply to the liver is isolated and perfused with a therapeutic regimen using an extracorporeal circuit consisting of a reservoir, heat exchanger, and oxygenator. Drug doses that would cause severe toxicities if delivered systemically can be confined to the liver by isolated hepatic perfusion, resulting in the ability to intensify treatment to the cancer-burdened region of the body. Agents and mechanisms commonly used in IHP include melphaIan, hyperthermia, and tumor necrosis factor. IHP appears to be efficacious for patients with advanced disease, as reflected by large tumor size, high number of lesions, or significant overall tumor burden in the liver. In addition, responses are observed for patients whose cancer is refractory to systemic and hepatic arterial infusion chemotherapy. Recent clinical trials have demonstrated that IHP has anti-tumor efficacy against primary hepatic neoplasms and metastases from various primary tumors, such as colorectal carcinoma, ocular melanoma, and neuroendocrine tumors. Current studies demonstrate that combining hepatic arterial infusion with floxuridine after IHP for patients with colorectal cancer metastases is associated with significant and durable response rates. Continued clinical evaluation is warranted for the use of IHP in the treatment of unresectable liver metastases.     

A pilot study of multimodality therapy for initially unresectable liver metastases from colorectal carcinoma: hepatic resection after hepatic arterial infusion chemotherapy and portal embolization

The prognosis of patients with unresectable liver metastases is poor, even if hepatic arterial infusion chemotherapy (HAI) or systemic chemotherapy is administered. A pilot study was performed to evaluate the feasibility and efficacy of multimodality therapy with hepatectomy after HAI and portal embolization for such patients. Eight patients with colorectal carcinoma and synchronous unresectable liver metastases underwent resection of the primary tumor and placement of a pump, followed by HAI with 5-fluorouracil and mitomycin C. Owing to shrinkage of the liver metastases, two patients could undergo extended right hepatic lobectomy after portal embolization, which was deemed to be essential to prevent post-operative hepatic failure. The median survival time of the eight patients was 30 months, with a response rate of 75%. Complications including sclerosing cholangitis and duodenal ulcer were observed in five patients (63%). Additional hepatectomy could be performed successfully after portal embolization without morbidity in two patients. These two patients are still alive more than 6 years after initiation of HAI and have been free of disease for more than 5 years after hepatectomy. Hepatectomy after HAI and portal embolization is feasible and may be an option to cure selected patients with initially unresectable liver metastases.      

Management of hepatic epithelioid haemangio-endothelioma in children: what option?

Hepatic epithelioid haemangio-endothelioma (HEHE) is an endothelium-derived tumour of low-to-medium grade malignancy. It is predominantly seen in adults and is unresponsive to chemotherapy. Liver transplantation is an accepted indication when the tumour is unresectable. Hepatic epithelioid haemangio-endothelioma is very rare in children and results after transplantation are not reported. The aim of this study is to review the experience of three European centres in the management of HEHE in children. A retrospective review of all paediatric patients with HEHE managed in three European centres is presented. Five children were identified. Four had unresectable tumours. The first had successful resection followed by chemotherapy and is alive, without disease 3 years after diagnosis. One child died of sepsis and one of tumour recurrence in the graft and lungs 2 and 5 months, respectively, after transplant. Two children who had progressive disease with ifosfamide-based chemotherapy have had a reduction in clinical symptoms and stabilisation of disease up to 18 and 24 months after the use of platinum-based chemotherapy. HEHE seems more aggressive in children than reported in adults and the curative role of transplantation must be questioned. Ifosfamide-based chemotherapy was not effective. Further studies are necessary to confirm if HEHE progression in children may be influenced by platinum-based chemotherapy.     

Surgical resection after preoperative chemoradiotherapy benefits selected patients with unresectable pancreatic cancer

Simultaneous chemoradiation is used in unresectable pancreatic cancer for palliation. It is not known if the use of adjuvant surgery will benefit this group of patients. From November 1991 to September 1998, 47 patients with unresectable pancreatic cancer were treated with simultaneous preoperative radiation therapy (45 Gy) and chemotherapy. Chemotherapy followed three different protocols: cisplatin, 5-fluorouracil +/- paclitaxel; cisplatin, 5-fluorouracil (protracted infusion); and docetaxel and gemcitabine. Whipple pancreatoduodenectomy was performed 1 month after the end of radiation in patients selected for resection. Twenty-three unresectable tumors after preoperative treatment (47%) received an additional dose (10-12 Gy) of radiotherapy using intraoperative or external radiation therapy. Twelve patients (26%) were considered to have clinically resectable tumors after the preoperative treatment. Nine patients had surgery (19% of the total number of patients), and 2 of them had complete pathologic response. After chemoradiation, two patients died of pneumonia and gastrointestinal bleeding, respectively, and another two patients died in the postoperative period. Local recurrence was observed in 22% of the patients and 57% had distant metastases. Three-year survival rates for patients with unresectable and resectable tumors was 0% (median survival 10 months) and 48% (median survival 23 months), respectively (p = 0.0004). Preoperative treatment with chemotherapy and radiotherapy in patients with unresectable pancreatic cancer is feasible. In some patients, the tumor can be resected, and in addition some cases of complete pathologic response were found. Long-term survivors were observed in the group of resected tumors. More effective chemotherapy regimens are needed because the majority of the patients died of metastatic disease.     

Liver transplantation for malignancy

Liver transplantation for hepatic malignancies has emerged from an exotic and desperate approach to a well-documented and proven treatment modality for these unfortunate patients. However, early unsatisfactory results emphasized that only a highly selected patient population would benefit from transplantation. Currently, <10% of all liver transplants performed are for hepatocellular cancer (HCC). There is no controversy that hepatoblastoma is an excellent indication in pediatric patients with unresectable tumors. Similarly, liver transplantation for HCC in the adult population yields good results for patients whose tumor masses do not exceed the Milan criteria. It remains to be determined whether patients with more extensive tumors can be reliably selected to benefit from the procedure. Adjunctive procedures like radiofrequency ablation, chemoembolization, or cryotherapy might be indicated to limit tumor progression for patients on waiting lists. Epitheloid hemangioendothelioma is also an appropriate indication for liver transplantation, unlike angiosarcoma. Metastatic liver disease is not an indication for liver transplantation, with the exception of cases in which the primary is a neuroendocrine tumor, for which liver transplantation can result in long-term survival and even cure in a number of patients. And finally, while gallbladder cancers are never an indication for liver transplantation, rare cases of cholangiocellular cancer might qualify if aggressive combination therapies, including chemotherapy and radiotherapy followed by OLT, are carried through. Survival in these selected patients can approach that for patients with cholestatic liver disease.     

Liver-directed therapies in colorectal cancer

The liver is the most common site of metastatic colorectal cancer (CRC) and the status of this organ is an important determinant of overall survival in patients with advanced disease. Complete resection of hepatic CRC metastases can provide a long-term cure for some patients, but the majority of liver metastases are not amenable to such surgery. Furthermore, most patients after curative resection ultimately suffer from recurrence, and the majority of such failures occur in the liver. Various ablative techniques can achieve local control of tumor after incomplete resection or for palliation. Tumor ablation currently has a secondary therapeutic role, as there is no evidence that it can achieve long-term survival comparable to surgical resection. Regional chemotherapy delivers tumoricidal agents in a selective fashion, minimizing systemic toxicity and damage to normal liver cells. Chemotherapy agents delivered through the hepatic artery can extend time to liver recurrence after curative resection and may prolong survival both in the adjuvant setting and when given to patients with unresectable disease. Molecular-based therapies, such as gene delivery and oncolytic viruses, provide promise for curative outcomes in patients with advanced disease.     

Surgical approaches to liver metastases

Metastases confined to the liver from tumors arising in the gastrointestinal tract or other sites represent a significant clinical problem. Although the majority of patients present with disease that is not amenable to resection based on the size, number, or anatomic distribution of tumors, for selected patients with limited extent of disease surgical resection can result in long-term survival. In patients with colorectal cancer, a number of adverse prognostic factors have been identified that are associated with shortened survival following hepatic resection. The role of adjuvant hepatic artery infusion and systemic chemotherapyfollowing resection in this patient population has been the topic of several prospective random assignment trials. For patients with unresectable metastases confined to liver, a number of regional therapies are in clinical development and share the advantages of intensifying therapy at the site of tumor while minimizing or eliminating unnecessary systemic exposure and toxicity. One such approach is vascular isolation and perfusion, also known as isolated hepatic perfusion or IHP, in which the liver is treated with high dose chemotherapy and/or biological agents under hyperthermic conditions. Although only a limited number of centers have reported substantial experience with this procedure, it appears to have significant efficacy even in patients with advanced tumor burden orthose with tumors refractory to other types of therapy. The status of IHP is presented.     

Hepatic resection following systemic chemotherapy for metastatic colorectal carcinoma.

Increasingly effective systemic chemotherapy has improved responses in patients with previously unresectable colorectal hepatic metastases. In the future, response to chemotherapy may define a new population of patients that may benefit from hepatic resection. A retrospective review to determine the safety and effectiveness of potentially curative hepatic resection of metastatic colorectal carcinoma after systemic chemotherapy identified 11 such patients with resections between July 1987 and October 1991. Five patients had unresectable disease confined to the liver, two had hepatic and limited extrahepatic metastases, two had hepatic recurrences after previous hepatic metastasectomy, and two had initially resectable liver metastases. These patients were resected after a mean of 8 months of systemic chemotherapy. Complications, usually minor, occurred in five patients (45%). There were no deaths. Three patients are disease free at 15, 18, and 31 months (mean 21) after hepatic resection. Eight patients have recurred with a median time to recurrence of 8 months. Five patients have subsequently died of recurrent disease. This study suggests that hepatic resection following systemic chemotherapy can be performed safely and may benefit selected patients.     

Role of liver transplantation in the management of colorectal liver metastases: Challenges and opportunities

The liver is the most common site of colorectal cancer metastasis. Complete resection of the metastatic tumor is currently the only treatment modality available with a potential for cure. However, only 20% of colorectal liver metastases (CRLM) are considered resectable at the time of presentation. Liver transplantation (LT) has been proposed as an alternative oncologic treatment for patients with unresectable CRLM. This review summarizes the published experiences of LT in the setting of unresectable CRLM from the previous decades and discusses the challenges and future horizons in the field. Contemporary experiences that come mostly from countries with broader access to liver grafts are also explored and their promising findings in terms of overall survival (OS) and disease-free survival (DFS) are outlined along with their study design and methods. The rationale of establishing specific patient selection criteria and the dilemmas around immunosuppressive regimens in patients undergoing LT for CRLM are also highlighted. Additionally, this review describes the findings of studies comparing LT vs chemotherapy alone and LT vs portal vein embolization plus resection for CRLM in terms of OS and DFS. Last but not least, we present current perspectives and ongoing prospective trials that try to elucidate the role of LT for CRLM.     

Hepatic artery infusion pumps

The preferential blood supply from the hepatic artery to liver tumors allows for the regional delivery of chemotherapy, commonly referred to as hepatic artery infusion chemotherapy via a subcutaneous pump. Hepatic artery infusion chemotherapy has been demonstrated to improve overall survival in select patients with colorectal liver metastasis and is a promising treatment for unresectable intrahepatic cholangiocarcinoma. This review focuses on the technical aspects of hepatic artery infusion pump placement.     

Exploring the role of resection of extrahepatic metastases from hepatocellular carcinoma

The role of hepatic resection, taking into consideration the functional status of the liver, for localized hepatocellular carcinoma (HCC) is an established curative treatment. In advance disease, a variety of interventional-based liver-directed therapies and more recently systemic therapy with sorafenib are available to treat unresectable tumors. Extrahepatic Metastasis (EHM) of HCC may occur at initial diagnosis or during recurrence following treatment. This may occur with or without concurrent intrahepatic disease. We reviewed the published works on surgical metastasectomy for common sites of EHM of HCC metastases. It appears from the studies reported in the literature that from selected cases reported, long-term survival may be achieved from resecting metastasis at sites of the abdominal lymph node, adrenal gland, lung, and peritoneum. The encouraging results presented demonstrate that highly selected fit patients may be suitable candidates for these radical curative pursuits. It is likely that indications for resection of EHM HCC may benefit patients with limited isolated metastasis, who have a preserved liver function, and whose primary tumor has been adequately controlled. A registry study to pull the results of case reports and institutional experiences may be useful in cumulating evidence of this practice.