Introduction
Liver cancer ranks as the fifth most common cancer in males and the ninth in females, with secondary liver cancer being more prevalent than primary cancer. It is the second leading cause of cancer-related mortality globally. The liver’s unique anatomy, with dual blood supply from the portal vein and hepatic artery, contributes to its susceptibility to metastasis, making it a frequent site for organ-specific spread.
Unlike primary liver cancer, liver metastases indicate a systemic condition that necessitates consideration in all patients before liver surgery. With the progress in chemotherapy for many gastrointestinal and some non-gastrointestinal cancers, there is a growing appeal for local treatments, either aiming for a cure or delaying systemic chemotherapy.
Liver metastases are conventionally categorized into three groups based on their biology and prognosis: colorectal liver metastases, metastases originating from endocrine tumors, and non-colorectal, non-endocrine metastases.
What Is Secondary Liver Cancer?
Secondary liver cancer or metastatic liver disease, stands out as the most prevalent malignant condition affecting the liver, posing significant cancer-related morbidity and mortality. Although colon cancer represents the primary culprit for liver metastases, other common primary tumors encompass lung and breast adenocarcinomas, neuroendocrine tumors, melanoma, and sarcomas.
Irrespective of the origin of the primary tumor, liver metastasis typically signals an advanced stage of disease, often associated with a bleak prognosis. While therapeutic goals at this juncture are frequently palliative, there is burgeoning interest in distinguishing between oligometastatic disease, characterized by limited metastases, and more widespread metastatic disease, as such distinctions may bear prognostic significance.
Curative treatment has been demonstrated in selected cases of oligometastatic disease, prompting aggressive local interventions in suitable candidates. Conventional management approaches for patients with liver metastases encompass surgical resection and systemic chemotherapy. However, the proportion of patients eligible for surgical intervention varies widely depending on the primary tumor, ranging from 25 to less than 10 percent. Despite significant advances in complex liver surgery, resections still entail considerable morbidity and mortality. Hence, the decision to pursue surgery must meticulously weigh the associated risks against the potential survival benefits, particularly in the context of metastatic disease.
How Does Secondary Liver Cancer Occur?
The liver receives blood supply from both the hepatic artery and the portal vein, with the latter collecting venous drainage from the pancreas, spleen, and nearly all of the gastrointestinal tract. This anatomical arrangement allows the liver to process newly digested and absorbed nutrients through first-pass metabolism. However, in the case of malignancy, it also renders the liver susceptible to metastasis from various abdominal and extra-abdominal malignancies. Liver metastasis can manifest with a range of symptoms, including abdominal pain, ascites, jaundice, weight loss, and fatigue.
While the portal vein primarily supplies hepatocytes, the cholangiocytes of the biliary system receive their blood supply from the hepatic artery. Metastatic liver tumors are believed to derive their blood supply predominantly from the hepatic artery. This unique vascular distribution offers opportunities for liver-directed therapies that selectively target tumor cells while preserving hepatocytes.
Furthermore, the liver possesses remarkable regenerative capacity, allowing it to hypertrophy to compensate for lost function. In cases where the vascular supply and biliary drainage remain intact, up to 80 percent of the liver can be surgically removed, with the remnant liver hypertrophying to restore full hepatic function within weeks. This capability enables more aggressive hepatic resections, even in multiple metastases.
Understanding the morphology and anatomical site of origin of tumor cells in patients undergoing liver biopsy is crucial for guiding targeted chemotherapy and assessing disease prognosis. While a diagnosis can often be made based on morphology alone, additional biomarkers such as cytokeratins, S100, and leukocyte-common antigen (LCA) may aid in further characterizing the specific organ of origin.
Various biomarkers, such as CK19 for adenocarcinomas, S100 for malignant melanomas, and synaptophysin and chromogranin for neuroendocrine carcinomas, help differentiate different types of tumors. Immunohistochemical studies and assessments of differentiation, mitotic activity, and overall appearance further refine the classification of tumors. Markers such as CK7, CK20, and estrogen receptors are commonly used to differentiate the origin of tumors, particularly in cases of metastatic lobular breast carcinoma.
How Is Secondary Liver Cancer Diagnosed?
Although no definitive data distinguish asymptomatic from symptomatic presentations in the patient’s history and physical examination, various symptoms such as abdominal distention, early satiety, vague abdominal complaints, changes in bowel habits, hematochezia, weight loss, encephalopathy, jaundice, ascites, and metabolic disturbances should raise suspicion for metastatic disease. However, there are no pathognomic findings specific to liver metastasis. Collaboration among medical oncologists, radiation oncologists, interventional and diagnostic radiologists, and surgical oncologists is imperative for effectively managing the patient’s condition.
Physical examination findings suggestive of hepatic diseases, such as caput medusa, hepatosplenomegaly, or ascites, warrant thorough evaluation. Rectal examination and subsequent colonoscopy are essential to identify masses and blood in the stool, particularly in patients with a strong family history of colon cancer or those overdue for colonoscopy. Given that hepatic disease may originate elsewhere, auscultation for adequate breath sounds and palpation for lymphadenopathy are crucial components of physical examination to guide decision-making regarding patient care.
High-quality imaging plays a pivotal role in suspected liver metastasis, facilitating confirmation of diagnosis and identification of the primary disease. Common imaging modalities include triple-phase CT and MRI scans. Triple-phase CT scans, comprising non-contrast, arterial, and venous phases, are particularly advantageous for tumor localization and planning liver-directed therapies. MRI can be utilized if characterizing a liver lesion proves challenging, with liver metastasis appearing hypo-intense on T1 weighted imaging and hyperintense on T2 imaging. Gadolinium-based contrast agents enhance sensitivity in MRI, although benign conditions may mimic liver metastasis on imaging.
FDG PET/CT can help detect hepatic metastasis and identify primary and extrahepatic metastasis, particularly in neuroendocrine carcinomas with gallium-68 DOTATATE PET imaging. However, PET/CT's lower anatomical resolution and insensitivity to lesions smaller than 1cm limit its utility. Ultrasonography, although less sensitive, may be used in diagnostic workups. Basic liver function tests, a complete blood count, esophagogastroduodenoscopy (EGD), and colonoscopy should also be included in the workup.
What Is the Treatment for Secondary Liver Cancer?
Although surgical resection remains the primary treatment modality, there are various approaches for managing liver metastasis in patients who are medically or surgically unfit for traditional surgery. While the bulk of available data pertains to colorectal malignancies, insights from neuroendocrine tumors and primary liver diseases have also proven valuable. Less invasive techniques, including stereotactic body radiotherapy, have been increasingly employed. Additionally, embolization techniques utilizing either chemotherapy or radioactive isotopes have demonstrated favorable outcomes with acceptable levels of toxicity.
Conclusion
Secondary liver cancer poses a significant challenge in oncology due to its high prevalence, diverse origins, and often advanced stage at presentation. While surgical resection remains the standard of care, advancements in less invasive techniques, such as stereotactic body radiotherapy and embolization therapies, offer promising alternatives for medically or surgically inoperable patients. Further research and clinical trials are needed to optimize treatment strategies, improve patient outcomes, and enhance the quality of life for individuals affected by secondary liver cancer.
