The liver is one of the most common sites for cancer metastasis, accounting for nearly 25% of all cases. A variety of primary tumors may be the source for metastasis; however, colorectal adenocarcinomas are the most prominent topic of research in the literature, as they are the most common. Treatment strategies are rapidly evolving worldwide, with a movement towards an interprofessional approach for better outcomes.
Metastatic hepatic tumors are more prominent than primary hepatocellular or biliary tumors, although the majority of metastatic tumors are adenocarcinomas. Squamous cell carcinoma, neuroendocrine carcinoma, and other far less common subtypes such as lymphoma, sarcoma, and melanoma also exist. By in large, the vast majority of the literature centers on the management of colorectal adenocarcinoma, which is reportedly the third most common primary malignancy worldwide. Nearly 70% to 80% of cases with metastatic disease remain confined to the liver.
Nearly 20% to 25% of patients diagnosed with colorectal cancer will develop liver metastases, with 15% to 25% of these cases presenting with synchronous disease. Researchers conducted a large nationwide study of more than 23000 patients over ten years investigating the origin and incidence of confirmed hepatic metastases in the Netherlands. It demonstrated that the most common metastases originated from colorectal primaries, followed by pancreatic and breast. In females less than 50 years of age, metastatic hepatic disease originated more frequently from the breast, as those older than 70 years old were from a gastrointestinal source; 92% of metastatic hepatic lesions were carcinomas. Of these carcinoma lesions, 75% of them were adenocarcinomas. Overall, histologically confirmed hepatic metastases were more common in males than females, and the majority of patients were older than 50 years of age.
The anatomy of the liver reveals a dual vascular supply, arising from both systemic arterial and portal venous systems. Therefore, hematogenous spread of disease to the liver is common both from intra-abdominal and extra-abdominal sources. At presentation, patients may have a wide range of symptoms. Many will be asymptomatic, while others will present with symptoms such as weight loss, fatigue, hematochezia, jaundice, encephalopathy, and pain.
In patients with a liver biopsy, it is essential to understand the morphology and anatomic site of origin of the tumor cells to dictate targeted chemotherapy and an understanding of the disease prognosis. There is literature that states that a diagnosis can be determined upon morphology alone; however, a series of additional biomarkers such as cytokeratins, S100, and leukocyte-common antigen (LCA) may assist in further categorizing the specific organ of origin. CK19 has been associated with adenocarcinoma, thus differentiating it from hepatocellular carcinoma. Other tumors markers such as C-kit, CD34, and vimentin have correlations with GISTs. Malignant melanomas have demonstrated that the highest sensitivity with S100+, although HMB45, MelanA-positive, and MART-1 are other biomarkers. Neuroendocrine carcinomas require testing for synaptophysin, chromogranin, and CD56. The vast majority of tumors will be carcinomas, specifically adenocarcinomas that become further delineated via their differentiation, mitoses, immunohistochemical studies, and overall appearance. CK7 and CK20 have been used as initial differentiating markers for tumor origin, as well as estrogen receptors in the case of metastatic lobular breast carcinoma.
Patients require assessment with an interprofessional approach with medical oncologists, radiation oncologists, interventional and diagnostic radiologists, and surgical oncologists to address the patient’s condition thoroughly. As previously mentioned, there is no robust data on an asymptomatic versus symptomatic presentation from a patient’s history and physical, as there is a large variety of symptoms. Distention, early satiety, vague abdominal complaints, changes in bowel habits, hematochezia, weight loss, encephalopathy, jaundice, ascites, and metabolic disturbances should all raise suspicion for metastatic disease. Physical examination findings associated with classic findings of hepatic disease (caput medusa, hepatosplenomegaly, ascites) should also prompt the astute physician to look elsewhere for evidence of disease. It is essential to perform a rectal exam with a subsequent colonoscopy to check for masses and blood in the stool. Any patient with a strong family history of colon cancer or those who are past due for their colonoscopy should r3eceive screening. As hepatic disease may arise from elsewhere, a thorough physical exam auscultating for adequate breath sounds and palpation of lymphadenopathy are important in decision making for care.
Evaluation should begin with CT imaging with a hepatic protocol, colonoscopy, and EGD. A recent panel agreed that PET-CT is unnecessary with an adequate CT scan; however, it may be useful for the detection of extra-hepatic disease. Patients with an unknown primary or patients that have recurrent disease may benefit from additional imaging. MRI has also shown to be more sensitive than CT scans, although CT scans are equally as effective. They may be useful when there is underlying hepatic disease. It is critical to determine the potential resectability of liver tumors, as lesions near major vascular structures may be inoperable. CT imaging evaluates metastatic tumor size, morphology, degree of liver disease, and the predicted future liver remnant. Liver function tests, along with a complete blood count, should be ordered. A chest radiograph or CT scan should also be part of the evaluation to assess for potential metastatic disease.
Surgical resection of hepatic metastases with adjuvant chemotherapy is associated with improved survival outcomes and reduced morbidity and mortality. Because colorectal adenocarcinoma is the most common form of hepatic metastasis, the vast majority of the literature centers on this disease process. Other specific clinical scenarios receive treatment on a personalized basis.
Surgical resection remains the gold standard for anatomically resectable colorectal hepatic metastases. Clinical guidelines have indicated that the future liver remnant is at least 20% of its original volume in a healthy liver, 30% with mild to moderate hepatic dysfunction, and 40% with hepatic cirrhosis. Strategies to improve the chances of resection include neoadjuvant chemotherapy, portal vein embolization to increase the future liver remnant, or a two-stage resection versus a combined one-stage resection of the primary tumor, and hepatic lesions.
The goal of surgery should be the removal of all gross disease with negative microscopic margins of 1 mm. Studies have shown that the degree of the resection margin has not demonstrated a significant difference in survival, as long as tumor margins are negative. An open or laparoscopic approach to surgery is an option for hepatic resection. A recent meta-analysis supports the use of laparoscopy for similar cancer-specific long-term outcomes as compared to open procedures with the added benefit of less short-term complications. Simultaneous resection for synchronous colorectal carcinoma and hepatic metastases is acceptable when there is favorable anatomy for partial hepatic resection. One-stage versus a two-stage surgical resection of the primary colorectal tumor and hepatic metastasis have shown comparable efficacy. A one-stage approach reduces the overall length of hospital stay. Other aspects, such as morbidity and mortality, have been varied among studies. Delaying liver resection has shown not to decrease survival in patients in need of resection when neoadjuvant chemotherapy a consideration. It is important to distinguish between asymptomatic and symptomatic primary tumors, as patients who are anemic, obstructed, or actively ill from the primary tumor should have that resection first. Extra-hepatic disease, in addition to metastatic liver disease, has shown significantly lower five-year survival rates (28% versus 55%). Predictors of poor cancer-specific survival outcomes are extra-hepatic disease other than lung, extra-hepatic disease in addition to colorectal metastatic recurrence, carcinoembryonic antigen level (CEA) greater than 10 ng/mL, right-sided colon cancer, and more than six colorectal liver metastatic lesions.
If utilizing neo-adjuvant chemotherapy, in general, 4 to 6 months of therapy is delivered before surgery. Fluorouracil-based chemotherapy serves as the base treatment, as its administration is in addition to other agents in combinations such as FOLFOX and FOLFIRI. It works to decrease both the number and size of metastases pre-operatively, and it aims to reduce recurrence postoperatively. Although the standard of care is for surgery and perioperative chemotherapy, some studies have called into question the benefit of chemotherapy and surgery versus surgery alone. Some studies have shown no significant improvement in median overall survival; however, other groups have demonstrated an observed benefit in survival. Specifically, one observational study demonstrated preoperative chemotherapy compared to patients who underwent resection first followed by chemotherapy had a greater percentage of patients with three-year disease-free survival (31.7% to 20.4%, respectively).
Systemic chemotherapy has demonstrated objective response rates; however, a complete pathological response is rare. There is no consensus in the literature regarding the optimal duration of chemotherapy, but a minimum of three to six months on a select regimen is advocated before changing agents. When offering non-first line chemotherapy agents that include biologic medications, the morbidity of side effects must be weighed against the clinical status of the patient. Careful monitoring must be employed, as there have been mixed data on their success rates in treating hepatic metastases.
Some centers have demonstrated success using intra-arterial chemotherapy within the hepatic artery, as there is a local advantage of targeted therapy without systemic side effects. It has been used in adjuvant treatment and palliation. One study has demonstrated a longer overall survival of 22 months versus 15 months when comparing intra-arterial chemotherapy to systemic therapy. Also, transarterial chemoembolization (TACE procedure) helps to embolize branches perforating off the hepatic artery with chemotherapeutic agents. TACE has demonstrated effectiveness in palliative cases and resistant hepatic lesions. Radio-embolization and radiofrequency ablation have also been used as alternative liver-directed treatment options. Clinicians may use ablation intra-operatively to create a necrotic rim surrounding the tumor to lesions that are deemed unable to be resected.
The differential diagnosis for hepatic lesions remains broad. Imaging and history will help delineate and focus more common etiologies; however, some differential disease processes may be as follows: primary hepatocellular carcinoma, cholangiocarcinoma, adenoma, hemangioma, hematoma, focal nodular hyperplasia, abscess, or secondary masses from metastatic disease (carcinoma, lymphoma, sarcoma).
The majority of the literature has centered on colorectal metastases. The prognosis for patients without treatment for synchronous disease is significant. There is a 5% five-year survival rate with no treatment. The five-year survival after curative resection of hepatic lesions may be up to 58%, which is in contrast to a median of 6 months of survival with no treatment. Neuroendocrine liver metastases that can undergo partial hepatectomy have slightly higher survival rates than colorectal carcinoma, as survival rates are 61% at five years.
Patients may develop postoperative hepatectomy complications such as abscess formation, biliary leaks, recurrent disease, bleeding, sepsis, damage to surrounding structures, and need for further operative intervention. Other complications may relate to preoperative systemic chemotherapy and include steatohepatitis, sinusoidal obstruction, leukopenia, system infections, fever, fatigue, weight loss, poor wound healing, and all other potential side effects from chemotherapy.
The diagnosis of metastatic disease to the liver is difficult, as this constitutes stage IV disease from another primary site. Prognosis is poor without treatment, and it requires an interprofessional approach with medical, radiological, and surgical oncology to coordinate a patient-centered treatment plan with the hope of using chemotherapy and surgical resection to increase overall survival. There is a consensus on chemotherapy agents; however, surgery planning varies based on patient presentation. Although there is no way to prevent metastases from occurring, it is essential to see a primary provider annually for screening with physical exams, colonoscopies, and blood work.
Interprofessional team communication and proper care coordination are paramount when taking care of sick patients with liver metastases. A hepatobiliary and oncologic team should evaluate pre and postoperative imaging modalities, chemotherapy regimens, and surgical intervention tailored to the patient. Further studies into the histopathological diagnosis of the disease may help direct more targeted preoperative chemotherapy regimens for an easier and more functional hepatic resection. Oncology specialty nurses monitor patients, provide education, and report on the patient's status to the team. Board-certified oncology pharmacists assist in agent selection, dosing, and check for drug-drug interactions. With an interprofessional approach to care, patients can attain better outcomes in metastatic hepatic disease. [Level 5] Patients with significant disease should be treated within a larger hospital system with higher patient volumes with open access to patient information for better care.
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