Overview

Facing cancer is a daunting battle on its own. Now, consider the fact that the fight spreads to other territories within the body. Metastasis is where cancer cells migrate from an original site to invade other organs, creating new tumours. Identifying the common sites of metastasis can help us recognise symptoms early, aiding patients and their families to navigate this complex journey with knowledge and hope.

Metastasis

Metastasis is a critical concept in cancer biology. It describes the process by which cancer cells break off from the primary tumour (original tumour) and spread to other parts of the body. This process is a significant cause of cancer-related morbidity and mortality. Distant metastasis indicates the aggressive nature of primary tumours. Nearly all cancers have the potential to metastasise, but whether they do depends on various factors. This includes the type, size, and location of the primary tumour.¹

Most of the time, cancer cells die at some point during the spreading process. However, if conditions are favourable (for the cancer cells) at each step, it can survive and form new tumours in other parts of the body. Metastatic cancer cells can also remain dormant at a distant site for many years before they begin to grow again.¹ General symptoms of metastasis may include extreme fatigue, night sweats, and unexplained weight loss. Specific signs depend on the location of the primary tumour and where cancer cells have spread.

Ways of metastasis

Metastasis can happen in several ways:²

• Direct invasion: Cancer cells grow directly into the tissue surrounding the primary tumour
• Bloodstream travel: Cancer cells enter the bloodstream, allowing them to travel to distant locations such as other organs or bones
• Lymphatic System movement: Cancer cells move through the lymphatic system, spreading to nearby or distant lymph nodes

The journey of metastatic tumour cells involves numerous stages:¹

1. Cancer cells detach from the primary tumour
2. These cells enter and move through the walls of nearby lymph nodes or blood vessels
3. The cancer cells circulate through the bloodstream or lymphatic system to other parts of the body
4. Cancer cells stop in small blood vessels at a distant location, invade the blood vessel walls, and move into the surrounding tissue
5. Cancer cells grow in this new tissue until a tiny tumour forms
6. Cancer cells cause new blood vessels to grow, which creates a blood supply that allows the metastatic tumour to continue growing. They establish a new microenvironment at the secondary site that supports their growth and blood supply

Common sites of metastasis

The sites of metastasis from different primary tumour organs are listed below:¹

The most common sites of cancer metastases are lymph nodes, lung, liver, brain, and bone.

Lymph node metastasis

Lymphogenic metastasis represents a type of regional metastasis that is distinct from distant metastases such as those affecting the bones, liver, or brain, which can originate from any part of the body. Metastases form first in the lymph nodes closest to the primary tumour because the lymphatic fluid (lymph) from the cancerous organ flows to these nearby lymph nodes. This carries tumour cells that reach the nodes, proliferate, and cause them to enlarge. Malignant tumours of epithelial origin often metastasize to regional lymph nodes (RLNs).³ A common symptom in lymph node metastasis is lymphadenopathy (swollen lymph nodes). 

Malignant tumour cells can hijack the lymphatic system to spread throughout the body. Lymph nodes serve as major hubs for metastatic cell growth, secondary dissemination to other tissues, and modulation of antitumor immune responses. Lymph node metastasis is a critical consideration in cancer evaluation due to its implications for disease staging, clinical management, and prognostic outcomes.⁴

Lung metastasis

The lung ranks as the second most common site for metastasis, affecting 20 to 54% of individuals with malignant tumours originating elsewhere in the body. Hematogenous spread to the lungs is common in tumours with venous drainage into the pulmonary circulation (head and neck, thyroid, adrenals, kidneys, testes, melanoma, and osteosarcoma cancers). Lymphatic spread occurs through the diaphragm and pleural surfaces. It can also occur retrograde from hilar nodal metastasis (lung, stomach, breast, pancreas, uterus, rectum, and prostate cancers) Direct spread to the pleura happens via hematogenous spread, lymphatic spread, or from established hepatic (liver) metastases (lung, breast, pancreas, and stomach cancers).⁵

Multiple lung nodules often indicate metastatic lung cancer even though solitary nodules could also be metastatic or a primary lung tumour. Patients with lung metastasis may either have a known primary tumour or present initially with metastasis to the lung. These metastases can manifest with symptoms or remain asymptomatic and lung nodules can be incidentally discovered.⁵

Localised symptoms can include:⁵

• Pleurisy
• Cough, both productive and non-productive
• Dyspnea 
• Hemoptysis 
• Electrolyte disturbances
• Pancoast tumour (affecting the apex of the lung)
• Superior vena cava syndrome

Based on tumour pathology, different treatment options are available for lung metastasis. Chemotherapy is effective in some cases like testicular tumours and osteosarcomas. Immunotherapy (using one’s own immune system to fight cancer) is utilised for highly immunogenic cancers such as melanoma and renal cell carcinoma. Radiation is used mainly as palliative care for lung metastases. It helps in pain control and reducing relapses, particularly effective in cancers like Ewing's sarcoma and thyroid carcinoma using modalities like external beam and brachytherapy.⁵

Liver metastasis

Metastatic hepatic (liver) tumours are more prevalent than primary hepatocellular or biliary tumours, particularly adenocarcinomas. Accounting for approximately 25% of all metastatic cases, the liver is commonly affected by primary tumours such as colorectal adenocarcinomas, followed by pancreatic and breast cancers. Symptoms of liver metastasis vary widely depending on disease burden and location, including abdominal pain, hepatomegaly (enlarged liver), ascites, jaundice, weight loss, and fatigue.⁶

The liver, receiving dual blood supply from the hepatic artery and portal vein, is uniquely vulnerable to metastases from gastrointestinal cancers and accessible to interventional liver-targeted therapies. Moreover, the liver's remarkable ability to hypertrophy enables it to compensate for tissue loss following surgical resections. Up to 80% of the liver can be surgically removed, with the remaining portion hypertrophying to restore full hepatic function within weeks. This capacity supports aggressive surgical approaches for multiple metastases in suitable candidates. Other less invasive techniques include stereotactic body radiotherapy have been utilised, and embolisation techniques with either chemotherapy or radioactive isotopes.⁶

Bone metastasis

The third most common form of metastatic disease, following lung and liver metastases are bone metastases. Tumour cells reach the bones through hematogenous spread or direct invasion. The rich arterial supply to bones makes them susceptible to metastatic colonisation. Carcinoma is the primary cause of secondary bone cancer, manifesting as single bone lesions, oligometastatic disease, multiple bone metastases, or visceral plus bone metastases.

The commonly involved bone sites in metastasis are:⁷

1. Vertebra: The most commonly affected site due to the rich vascular supply and large bone marrow content. Metastases here can lead to spinal cord compression
2. Femur: Frequently affected, leading to pathological fractures and pain with weight-bearing
3. Pelvis: Metastases can cause localised pain, difficulty with walking, and pelvic instability
4. Ribs: Often involved, causing localised pain exacerbated by breathing or movement
5. Sternum: Metastases here can present with pain and sometimes palpable masses
6. Proximal Humerus: Metastases can lead to shoulder pain and weakness
7. Skull: Metastases in the skull may cause headaches, visual disturbances, or palpable masses

The other common symptoms are:⁷

1. Hypercalcemia: Nausea, anorexia, abdominal pain, and mental status changes due to increased bone resorption
2. Myelophthisis: Symptomatic anaemia and pancytopenia due to bone marrow infiltration by metastatic cells

Treatments of bone metastasis aim to manage pain, reduce skeletal-related events, and achieve local tumour control while preserving the quality of life in patients. The debilitating bone pain is treated with NSAIDs, narcotics and glucocorticoids. To reduce morbidity and mortality, osteoclast inhibitors like bisphosphonates and denosumab are used. A significant component of palliative care in bone metastasis is radiation therapy: External Beam Radiation Therapy (EBRT) and Stereotactic Body Radiation Therapy (SBRT). 

Bone-Targeted Radiopharmaceutical Therapy ( Strontium-89, Radium-223) is helpful to treat diffuse pain. When feasible, systemic chemotherapy targeting the primary tumour with an aim to shrink it and slow down its spread is recommended. Prophylactic or stabilisation surgery is indicated for fractures of long bones and spinal decompression and stabilisation is done to prevent spinal decompression. Local Ablation with Radiofrequency Ablation (RFA), cryoablation, and Focused Ultrasound (FUS) is indicated in patients with persistent or recurrent pain.⁷

Brain metastasis

Metastatic brain tumours are much more common than primary brain tumours, occurring about five times more frequently. These tumours can grow rapidly, displacing or damaging surrounding brain tissue. Patients even develop multiple metastatic tumours in different regions of the brain. Approximately one-third of patients with other types of cancer will eventually develop one or more metastatic brain tumours. The risk of metastatic brain tumours increases notably after the age of 45, with the highest incidence seen in individuals over 65 years old.⁸

Cancer cells typically spread to the brain from a primary tumour elsewhere in the body, often travelling through the bloodstream. They commonly localise in areas such as the cerebral hemispheres or the cerebellum, where they form distinct masses. The timeline for the development of metastatic brain tumours varies: some may appear many years after the primary cancer diagnosis, while others metastasize so quickly that they are identified before the primary tumour is detected.⁸

The symptoms of brain metastasis are:^8,9

• Headaches
• Drowsiness
• Seizures
• Weakness in the arms or legs on one side 
• Loss of balance
• Cognitive problems (short-term memory loss, mood changes)
• Speech problems
• Behaviour and personality changes
• Vision problems
• Numbness
• Hearing loss
• Problems with swallowing

Timely treatment improves prognosis and control of metastatic brain tumours significantly. Brain metastasis can be managed by surgery, stereotactic radiosurgery/gamma knife radiosurgery, whole brain radiotherapy, chemotherapy, medications (steroids to reduce edema and anticonvulsants to prevent seizures), and immunotherapy.^8,9

Summary 

Metastasis is the spread of cancer cells from the original tumours to distant sites in the body This significantly impacts cancer prognosis and treatment strategies. Common sites include the lymph nodes, lungs, liver, bones, and brain. Metastatic tumours often present with symptoms specific to the organs to which they have spread, such as respiratory distress in lung metastases, jaundice in liver involvement, bone pain in skeletal metastases, and neurological deficits in brain metastases. Understanding the metastatic patterns helps to improve diagnostic approaches and therapeutic decisions. Ultimately, this leads to targeted therapies and comprehensive patient management in oncology practice.