Makindo Medical Notes

Overview

Metastatic disease refers to the spread of cancer from the primary site to distant organs. Understanding the common primary cancers that metastasize, as well as their typical sites of metastasis, is crucial for diagnosis and management.

Key Steps in the Metastatic Process

1. Local Invasion: Cancer cells break through the basement membrane of the primary tumour and invade surrounding tissue. This is often facilitated by enzymes such as matrix metalloproteinases (MMPs), which degrade the extracellular matrix.
2. Intravasation: Cancer cells enter the bloodstream or lymphatic system. This requires them to penetrate the endothelial lining of blood vessels or lymphatic vessels.
3. Circulation: Once in circulation, cancer cells must survive in the bloodstream, where they are exposed to immune surveillance and shear forces. Some cancer cells form clusters with platelets to evade the immune system.
4. Extravasation: Cancer cells exit the bloodstream or lymphatic system and invade distant tissues. They adhere to the endothelium at distant sites and extravasate into the tissue.
5. Colonization and Growth: After reaching the distant site, cancer cells must adapt to the new microenvironment and establish a secondary tumour. The ability to proliferate in the new environment is crucial for successful metastasis.

Mechanisms of Metastasis

• Angiogenesis: For metastasis to occur, tumours need a blood supply to support their growth. Tumour cells secrete vascular endothelial growth factor (VEGF) to promote the formation of new blood vessels (angiogenesis).
• Epithelial-Mesenchymal Transition (EMT): EMT is a process in which epithelial cancer cells lose their polarity and cell-cell adhesion, becoming more migratory and invasive, similar to mesenchymal cells. This allows them to invade surrounding tissues and spread to distant sites.
• Immune Evasion: Cancer cells can evade immune detection through various mechanisms, such as downregulating MHC molecules, producing immunosuppressive cytokines, or expressing immune checkpoint proteins (e.g., PD-L1). This allows them to survive in the host immune environment during the metastatic process.
• Organotropism: Different cancers have a tendency to metastasize to specific organs, a phenomenon known as organotropism. For example, breast cancer frequently metastasizes to bone, while colorectal cancer often spreads to the liver. The "seed and soil" hypothesis suggests that certain organs provide a favorable microenvironment ("soil") for specific types of cancer cells ("seeds").

Common Sites of Metastasis

• Lymph nodes: One of the earliest and most common sites of metastasis, especially for solid tumours.
• Liver: Frequently affected by gastrointestinal cancers (e.g., colorectal cancer) and other tumours like breast and lung cancer.
• Lungs: Common site of metastasis for many cancers, including sarcomas, renal cell carcinoma, and breast cancer.
• Bone: Cancers such as breast, prostate, and lung often spread to bone, leading to complications like fractures and bone pain.
• Brain: Metastases to the brain are common in lung cancer, breast cancer, melanoma, and renal cell carcinoma.

Factors Influencing Metastasis

• Tumour Microenvironment: The local environment around the tumour can either promote or inhibit metastasis. Factors like oxygen availability, immune cells, and stromal cells play a role in shaping the metastatic potential of cancer cells.
• Genetic Mutations: Mutations in key genes (e.g., p53, BRCA1/2, KRAS) can enhance the ability of cancer cells to invade and metastasize.
• Immune System: While the immune system can suppress metastasis by targeting cancer cells, certain cancers develop mechanisms to evade immune surveillance, promoting metastasis.
• Extracellular Matrix (ECM) Components: The composition and stiffness of the ECM can influence cancer cell migration and invasion.

Diagnostic Tools for Detecting Metastasis

• Imaging: CT scans, MRI, PET scans, and bone scans are commonly used to detect the presence of metastases in organs such as the lungs, liver, bones, and brain.
• Biopsy: A biopsy of the metastatic site is often performed to confirm the diagnosis of metastatic cancer. Genetic testing of the biopsy can reveal mutations and inform targeted therapies.
• Tumour Markers: Blood tests for tumour markers (e.g., CEA, CA-125, PSA) can help monitor the spread of certain cancers and evaluate the effectiveness of treatment.

Causes of Metastatic Disease

Primary Cancer	Common Sites of Metastasis	Clinical Features	Diagnostic Approach
Breast Cancer	Bone Liver Lungs Brain	Bone pain (osteolytic lesions) Jaundice, hepatomegaly Dyspnea, cough (lung involvement) Headaches, seizures (brain metastasis)	Mammography and breast ultrasound for primary tumour Bone scan, liver function tests, chest X-ray, and brain MRI for metastasis Biopsy of metastatic site if unclear
Lung Cancer	Liver Brain Bone Adrenal glands	Cough, hemoptysis, chest pain (primary) Jaundice, liver dysfunction (liver metastasis) Seizures, headaches (brain metastasis) Bone pain, fractures (bone metastasis)	Chest X-ray, CT scan for primary tumour Liver function tests, bone scan, brain MRI PET scan to identify metastatic spread
Colorectal Cancer	Liver Lungs Peritoneum	Abdominal pain, rectal bleeding (primary) Jaundice, hepatomegaly (liver metastasis) Dyspnea, pleural effusion (lung metastasis) Abdominal distension, ascites (peritoneal metastasis)	Colonoscopy for primary tumour CT scan of abdomen and pelvis for staging Liver function tests, chest CT scan
Prostate Cancer	Bone Lungs Liver	Bone pain, fractures (bone metastasis) Dyspnea, cough (lung metastasis) Jaundice, hepatomegaly (liver metastasis)	PSA levels, digital rectal exam (DRE) for primary tumour Bone scan, chest X-ray, liver function tests MRI for more detailed metastatic assessment
Renal Cell Carcinoma	Lungs Bone Liver Brain	Hematuria, flank pain (primary) Dyspnea, pleural effusion (lung metastasis) Bone pain, pathological fractures Neurological symptoms (brain metastasis)	Abdominal CT scan for primary tumour Chest CT for lung metastasis, bone scan MRI of brain for neurological symptoms
Melanoma	Lungs Liver Brain Bone	Changes in skin lesions (primary) Dyspnea, chest pain (lung metastasis) Jaundice, hepatomegaly (liver metastasis) Seizures, headaches (brain metastasis)	Skin biopsy of primary lesion Chest X-ray, CT scan for lung metastasis Brain MRI, liver function tests

Management of Metastatic Disease

The management of metastatic disease is complex and involves multiple modalities:

• Surgery: Resection of the primary tumour or isolated metastases.
• Chemotherapy: Systemic treatment to target metastatic cancer cells.
• Radiation Therapy: Used for local control, especially in bone or brain metastases.
• Targeted Therapy: Drugs that specifically target molecular pathways in cancer cells (e.g., tyrosine kinase inhibitors).
• Immunotherapy: Immune checkpoint inhibitors for cancers such as melanoma and lung cancer.
• Palliative Care: Focuses on relieving symptoms and improving quality of life in advanced-stage disease.

Conclusion

Metastatic disease is a major cause of cancer-related mortality. Early detection and aggressive treatment of primary tumours, as well as advancements in systemic therapies, have improved outcomes for some patients with metastatic cancer.