Definition and epidemiology
Cancer encompasses over 200 distinct diseases unified by unregulated cell proliferation, invasion of local tissues, and potential for distant metastasis. Benign tumors grow locally without invasion; malignant tumors (cancers) invade surrounding structures and can metastasize.
Epidemiology
Cancer is the second leading cause of death globally, accounting for approximately 10 million deaths annually. In the United States, lifetime cancer risk is roughly 40%, with about 1.9 million new cases diagnosed each year. The most common cancers worldwide are lung, breast, colorectal, prostate, and stomach cancers. Incidence increases exponentially with age, reflecting the accumulation of somatic mutations over time. Geographic variation exists due to differences in environmental exposures, lifestyle factors, and genetic susceptibility. Childhood cancers account for less than 1% of all cancers, with leukemias, brain tumors, and lymphomas predominating in pediatric populations.
- Cancer requires accumulated mutations in oncogenes (gain of function), tumor suppressor genes (loss of function, two-hit hypothesis), and DNA repair genes.
- p53 is the most commonly mutated gene in human cancers; it normally arrests cell cycle and triggers apoptosis in response to DNA damage.
- Six hallmarks of cancer: growth signal autonomy, insensitivity to anti-growth signals, apoptosis evasion, limitless replication, angiogenesis, invasion and metastasis.
- Small cell lung cancer is associated with ectopic ACTH (Cushing) and SIADH; squamous cell lung cancer with PTHrP and hypercalcemia.
- Tissue diagnosis with histopathology is mandatory before initiating cancer treatment in nearly all cases; grade describes differentiation, stage (TNM) describes extent.
- Tumor markers (PSA, CEA, CA-125, AFP) are useful for monitoring response and recurrence but not for initial diagnosis due to limited sensitivity and specificity.
- Chemotherapy targets rapidly dividing cells; common toxicities include myelosuppression, mucositis, and drug-specific effects (anthracycline cardiotoxicity, bleomycin pulmonary toxicity).
- Immunotherapy checkpoint inhibitors (anti-PD-1, anti-CTLA-4) cause immune-related adverse events: colitis, pneumonitis, hepatitis, thyroiditis, hypophysitis.
Etiology and risk factors
Cancer arises from the interplay of genetic, environmental, and lifestyle factors. Carcinogenesis is a multi-step process requiring multiple mutations in critical genes.
Major etiological categories
- Tobacco use: Responsible for approximately 25-30% of all cancer deaths; strongly linked to lung, head and neck, esophageal, bladder, pancreatic, and kidney cancers
- Infectious agents: Human papillomavirus (cervical, oropharyngeal), Hepatitis B and C (hepatocellular carcinoma), Helicobacter pylori (gastric cancer and MALT lymphoma), Epstein-Barr virus (nasopharyngeal carcinoma, Burkitt lymphoma), Human T-cell leukemia virus (adult T-cell leukemia), Schistosoma (bladder cancer), liver flukes (cholangiocarcinoma)
- Radiation: Ultraviolet radiation (melanoma, basal and squamous cell carcinoma), ionizing radiation (leukemia, thyroid cancer, breast cancer)
- Chemical carcinogens: Asbestos (mesothelioma, lung cancer), benzene (leukemia), vinyl chloride (hepatic angiosarcoma), aflatoxin (hepatocellular carcinoma), aromatic amines (bladder cancer)
- Diet and obesity: High red/processed meat consumption, low fiber intake, obesity (endometrial, esophageal adenocarcinoma, renal, postmenopausal breast, colorectal cancers)
- Alcohol: Increases risk of head and neck, esophageal, liver, breast, and colorectal cancers
- Hormonal factors: Prolonged estrogen exposure (early menarche, late menopause, nulliparity) increases breast and endometrial cancer risk
- Inherited cancer syndromes: BRCA1/2 mutations (breast, ovarian), Lynch syndrome (colorectal, endometrial), Li-Fraumeni syndrome (p53 mutations, multiple cancers), familial adenomatous polyposis (APC gene, colorectal), von Hippel-Lindau disease (renal cell carcinoma, pheochromocytoma), retinoblastoma (RB gene), neurofibromatosis
- Immunosuppression: HIV/AIDS, transplant recipients on immunosuppressive therapy have increased risk of Kaposi sarcoma, lymphomas, and various carcinomas
Approximately 5-10% of cancers are directly attributable to inherited germline mutations; the remainder result from acquired somatic mutations.
Pathophysiology
Cancer pathogenesis centers on the acquisition of mutations in three classes of genes: oncogenes, tumor suppressor genes, and DNA repair genes.
Hallmarks of cancer
Weinberg and Hanahan describe six essential alterations (with recent additions):
- Self-sufficiency in growth signals: Mutations in oncogenes (RAS, MYC, HER2/ERBB2) lead to constitutive activation of growth pathways
- Insensitivity to anti-growth signals: Loss of tumor suppressors (RB, p16) allows cells to bypass cell cycle checkpoints
- Evasion of apoptosis: p53 mutations (most common), BCL2 overexpression prevent programmed cell death
- Limitless replicative potential: Telomerase reactivation maintains telomere length, enabling immortalization
- Sustained angiogenesis: VEGF upregulation promotes new blood vessel formation to supply nutrients
- Tissue invasion and metastasis: Loss of E-cadherin, matrix metalloproteinase activation enable local invasion and distant spread
Emerging hallmarks include reprogramming energy metabolism (Warburg effect—aerobic glycolysis), evading immune destruction, genome instability, and tumor-promoting inflammation.
Genetic mechanisms
Oncogenes (gain-of-function mutations): Growth factor receptors (EGFR, HER2), signal transduction proteins (RAS, RAF, PI3K), transcription factors (MYC), anti-apoptotic proteins (BCL2). Only one mutated allele needed (dominant).
Tumor suppressor genes (loss-of-function mutations): Cell cycle regulators (RB, p16), DNA damage sensors (p53, BRCA1/2, ATM), growth inhibitors (APC, NF1, PTEN). Both alleles must be inactivated (Knudson two-hit hypothesis).
DNA repair genes: Mismatch repair genes (Lynch syndrome), nucleotide excision repair (xeroderma pigmentosum), BRCA1/2 (homologous recombination). Defects lead to genomic instability and accelerated mutation accumulation.
Metastatic cascade
Metastasis requires: invasion through basement membrane, intravasation into blood/lymph vessels, survival in circulation, extravasation at distant site, and colonization with establishment of micrometastases that progress to macrometastases. Most common metastatic sites are lung, liver, bone, and brain.
Clinical features
Cancer presents with diverse manifestations depending on primary site, stage, and presence of metastases. Clinical features can be categorized as local, systemic, or paraneoplastic.
Local effects
- Mass effect: Palpable lump (breast, thyroid, lymph nodes), organ enlargement
- Obstruction: Bowel obstruction (colorectal cancer), biliary obstruction and jaundice (pancreatic cancer), bronchial obstruction (lung cancer), urinary obstruction (prostate cancer)
- Bleeding: Hematuria (bladder/renal cancer), hemoptysis (lung cancer), hematochezia (colorectal cancer), abnormal vaginal bleeding (endometrial/cervical cancer)
- Pain: From mass effect, nerve invasion, bone metastases
- Ulceration: Skin cancers, oral cavity tumors, gastric cancer
- Neurological deficits: Brain tumors cause headache, seizures, focal deficits; spinal cord compression causes back pain, weakness, sensory loss
Systemic manifestations
- Constitutional symptoms: Unintentional weight loss (>10% body weight), anorexia, cachexia, fever, night sweats, fatigue
- Lymphadenopathy: Regional or generalized
- Hepatomegaly: Liver metastases
- Ascites: Peritoneal carcinomatosis
- Pleural effusion: Lung cancer, metastatic disease
Paraneoplastic syndromes
These result from remote effects of tumor products (hormones, cytokines, antibodies) rather than direct invasion:
- Endocrine: Cushing syndrome (ACTH from small cell lung cancer), SIADH (small cell lung cancer), hypercalcemia (PTHrP from squamous cell lung cancer, breast, renal), hypoglycemia (IGF-2 from mesenchymal tumors)
- Hematologic: Anemia of chronic disease, thrombocytosis, disseminated intravascular coagulation, Trousseau syndrome (migratory thrombophlebitis with pancreatic, lung adenocarcinoma)
- Neurologic: Lambert-Eaton myasthenic syndrome (small cell lung cancer), myasthenia gravis (thymoma), cerebellar degeneration, limbic encephalitis
- Dermatologic: Acanthosis nigricans (gastric adenocarcinoma), dermatomyositis (ovarian, lung, gastrointestinal cancers), erythema gyratum repens
- Renal: Membranous nephropathy (solid tumors), minimal change disease (Hodgkin lymphoma)
- Rheumatologic: Hypertrophic osteoarthropathy (lung cancer)
Warning signs (CAUTION acronym)
Change in bowel or bladder habits, A sore that does not heal, Unusual bleeding or discharge, Thickening or lump, Indigestion or difficulty swallowing, Obvious change in wart or mole, Nagging cough or hoarseness.
Diagnosis
Cancer diagnosis requires integration of clinical evaluation, imaging, laboratory tests, and histopathological confirmation.
Clinical evaluation
Comprehensive history including risk factors, family history, constitutional symptoms, and thorough physical examination focusing on lymph nodes, skin, breast, abdomen, and digital rectal examination.
Laboratory investigations
- Complete blood count: Anemia, thrombocytosis, leukocytosis or leukopenia
- Comprehensive metabolic panel: Hypercalcemia, elevated alkaline phosphatase (bone metastases), liver function abnormalities
- Tumor markers: Useful for monitoring, not diagnostic alone
- PSA (prostate cancer)
- CA-125 (ovarian cancer)
- CA 19-9 (pancreatic cancer)
- CEA (colorectal cancer)
- AFP (hepatocellular carcinoma, germ cell tumors)
- β-hCG (germ cell tumors, choriocarcinoma)
- Calcitonin (medullary thyroid cancer)
- LDH (lymphoma, germ cell tumors)
Imaging
- Radiography: Initial evaluation of lung masses, bone lesions
- Computed tomography (CT): Staging of chest, abdomen, pelvis; detection of metastases
- Magnetic resonance imaging (MRI): Superior soft tissue contrast; preferred for brain, spinal cord, pelvis, musculoskeletal tumors
- Positron emission tomography (PET-CT): Whole-body staging, particularly for lymphoma, lung cancer, melanoma; detects metabolically active disease
- Ultrasound: Thyroid nodules, abdominal masses, guidance for biopsy
- Mammography: Breast cancer screening and diagnosis
Histopathological diagnosis
Tissue diagnosis is essential before initiating treatment (except in emergencies). Methods include:
- Fine needle aspiration (FNA): Cytology; quick, minimally invasive but limited tissue architecture
- Core needle biopsy: Histology; provides tissue architecture, preferred for most solid tumors
- Excisional/incisional biopsy: Surgical removal of entire lesion or portion
- Endoscopic biopsy: Gastrointestinal, bronchial, bladder tumors
Pathology evaluation
- Histologic type: Adenocarcinoma, squamous cell carcinoma, small cell carcinoma, sarcoma, etc.
- Grade: Degree of differentiation (well, moderate, poor)
- Stage: TNM classification (Tumor size/invasion, lymph Node involvement, distant Metastases)
- Immunohistochemistry: Identifies cell origin, prognostic markers (ER, PR, HER2 in breast cancer; PD-L1 expression)
- Molecular/genetic testing: EGFR, ALK, ROS1, BRAF mutations guide targeted therapy
Staging
TNM staging (American Joint Committee on Cancer) guides prognosis and treatment. Stage groupings range from stage I (localized) to stage IV (distant metastases). Some cancers use alternative systems (Ann Arbor for lymphoma, FIGO for gynecologic cancers).
Differential diagnosis
Cancer mimics many conditions, and conversely, benign diseases can present with suspicious features.
Benign tumors
Benign neoplasms (lipomas, fibromas, leiomyomas, adenomas) lack invasion and metastatic potential. Imaging and histology differentiate benign from malignant.
Infections
- Tuberculosis: Lymphadenopathy, pulmonary masses, constitutional symptoms
- Fungal infections: Pulmonary nodules mimicking lung cancer
- Infectious mononucleosis: Lymphadenopathy may suggest lymphoma
- Abscess: Can present as mass lesion
Inflammatory and autoimmune diseases
- Sarcoidosis: Hilar lymphadenopathy, pulmonary nodules
- Inflammatory bowel disease: Can present with mass lesions, increased colorectal cancer risk
- Rheumatoid nodules: Subcutaneous masses
Vascular lesions
- Hemangioma: Hepatic lesions on imaging
- Arteriovenous malformations: Brain lesions
Cysts
Ovarian cysts, pancreatic cysts, renal cysts may appear as masses on imaging.
Hematologic disorders
- Reactive lymphadenopathy: From infection or immune response
- Benign hematologic conditions: Immune thrombocytopenic purpura, myelodysplastic syndromes (pre-malignant)
Site-specific differentials
For each anatomic site, specific benign conditions must be excluded (e.g., fibroadenoma vs breast cancer, benign prostatic hyperplasia vs prostate cancer, multinodular goiter vs thyroid cancer).
Management
Cancer management is multidisciplinary, involving medical oncology, surgical oncology, radiation oncology, pathology, radiology, and supportive care. Treatment depends on cancer type, stage, molecular characteristics, and patient factors.
Treatment modalities
Surgery
Surgical resection aims for complete removal with negative margins. It is curative for localized disease in many solid tumors. Procedures range from local excision to radical resections with lymph node dissection. Debulking surgery may improve outcomes even when complete resection is not achievable (e.g., ovarian cancer).
Radiation therapy
External beam radiation or brachytherapy (internal radiation) damages DNA, leading to tumor cell death. Used as:
- Primary curative treatment (e.g., early-stage laryngeal cancer, prostate cancer)
- Adjuvant therapy post-surgery to eliminate microscopic residual disease
- Neoadjuvant therapy to shrink tumors before surgery
- Palliative treatment for metastases (bone pain, brain metastases, spinal cord compression)
Chemotherapy
Systemic cytotoxic drugs target rapidly dividing cells. Classes include:
- Alkylating agents (cyclophosphamide, platinum compounds)
- Antimetabolites (methotrexate, fluorouracil, gemcitabine)
- Anthracyclines (doxorubicin)
- Taxanes (paclitaxel, docetaxel)
- Topoisomerase inhibitors (irinotecan, etoposide)
- Vinca alkaloids (vincristine, vinblastine)
Used for systemic disease, micrometastases, adjuvant/neoadjuvant settings, or as primary treatment for chemosensitive cancers (lymphomas, germ cell tumors, small cell lung cancer).
Targeted therapy
Drugs directed against specific molecular targets:
- Tyrosine kinase inhibitors: Imatinib (BCR-ABL in CML), erlotinib/gefitinib (EGFR mutations), crizotinib (ALK rearrangements), vemurafenib (BRAF V600E)
- Monoclonal antibodies: Trastuzumab (HER2-positive breast cancer), bevacizumab (anti-VEGF), rituximab (CD20-positive lymphomas), cetuximab (EGFR)
- mTOR inhibitors: Everolimus, temsirolimus
- PARP inhibitors: Olaparib (BRCA-mutated cancers)
Immunotherapy
Harnesses immune system to fight cancer:
- Checkpoint inhibitors: Pembrolizumab, nivolumab (anti-PD-1), ipilimumab (anti-CTLA-4); effective in melanoma, lung cancer, renal cell carcinoma, others
- CAR-T cell therapy: Genetically modified T cells targeting CD19 (B-cell lymphomas, leukemias)
- Cytokines: Interferon-alpha, interleukin-2 (melanoma, renal cell carcinoma, though less commonly used now)
Hormone therapy
For hormone-sensitive cancers:
- Breast cancer: Tamoxifen, aromatase inhibitors (letrozole, anastrozole), ovarian suppression
- Prostate cancer: Androgen deprivation therapy with GnRH agonists (leuprolide, goserelin), anti-androgens (bicalutamide, enzalutamide)
Treatment approach by stage
- Localized disease: Surgery and/or radiation with curative intent
- Locally advanced disease: Multimodality therapy—neoadjuvant chemotherapy or radiation, surgery, adjuvant therapy
- Metastatic disease: Systemic therapy (chemotherapy, targeted therapy, immunotherapy); local treatment for palliation; cure possible in select cancers (germ cell tumors, some lymphomas)
Supportive and palliative care
Integral throughout cancer care:
- Pain management: Opioids, non-opioid analgesics, radiation for bone pain
- Nausea control: Antiemetics (ondansetron, metoclopramide, dexamethasone, aprepitant)
- Nutritional support: Address cachexia, supplementation
- Psychosocial support: Counseling, support groups
- Management of complications: Neutropenic fever, tumor lysis syndrome, hypercalcemia, spinal cord compression, superior vena cava syndrome
- End-of-life care: Hospice services when curative treatment is no longer beneficial
Screening and prevention
Established screening programs reduce mortality:
- Cervical cancer: Pap smear, HPV testing
- Breast cancer: Mammography starting age 40-50
- Colorectal cancer: Colonoscopy starting age 45-50, fecal immunochemical test
- Lung cancer: Low-dose CT in high-risk smokers age 50-80
- Prostate cancer: PSA testing (individualized decision-making)
Prevention strategies include tobacco cessation, HPV vaccination, healthy diet, physical activity, alcohol moderation, sun protection, and treatment of precancerous lesions.
Complications and prognosis
Complications
Treatment-related
- Chemotherapy: Myelosuppression (neutropenia, anemia, thrombocytopenia), mucositis, neuropathy, cardiotoxicity (anthracyclines), pulmonary toxicity (bleomycin), hemorrhagic cystitis (cyclophosphamide), nephrotoxicity (platinum agents)
- Radiation: Skin reactions, mucositis, pneumonitis, enteritis, secondary malignancies
- Surgery: Bleeding, infection, lymphedema, functional impairment
- Immunotherapy: Immune-related adverse events (colitis, pneumonitis, hepatitis, endocrinopathies, dermatitis)
Disease-related
- Oncologic emergencies: Spinal cord compression, superior vena cava syndrome, tumor lysis syndrome, hypercalcemia of malignancy, neutropenic fever
- Metastases: Brain metastases (seizures, neurologic deficits), bone metastases (pain, fractures, hypercalcemia), liver metastases (hepatic failure), lung metastases (respiratory failure)
- Effusions: Pleural effusion, pericardial effusion (tamponade), ascites
- Thromboembolism: Increased risk of deep vein thrombosis and pulmonary embolism
- Cachexia: Progressive weight loss, muscle wasting, functional decline
- Paraneoplastic syndromes: As described above
Long-term survivorship issues
- Secondary malignancies from treatment
- Chronic organ damage (heart, lungs, kidneys)
- Infertility
- Cognitive impairment ("chemobrain")
- Psychosocial effects (anxiety, depression, fear of recurrence)
Prognosis
Prognosis varies enormously by cancer type, stage, molecular features, and patient factors. Key prognostic determinants:
- Stage at diagnosis: Most critical factor; five-year survival for localized disease generally far exceeds that for metastatic disease
- Histologic grade and type: Higher-grade tumors behave more aggressively
- Molecular markers: BRCA mutations in ovarian cancer (better response to platinum), microsatellite instability (better prognosis in colorectal cancer, predicts immunotherapy response)
- Performance status: Better functional status correlates with improved outcomes
- Age: Younger patients often tolerate aggressive treatment better
- Comorbidities: Impact treatment options and survival
Five-year survival examples (approximate, stage-dependent):
- Pancreatic cancer: 10%
- Lung cancer: 20%
- Colorectal cancer: 65%
- Breast cancer: 90%
- Prostate cancer: 98%
- Thyroid cancer: 98%
- Testicular cancer: 95%
Early detection through screening significantly improves survival for many cancers. Advances in targeted therapy and immunotherapy have dramatically improved outcomes for specific molecular subtypes (e.g., BCR-ABL-positive CML, BRAF-mutated melanoma, PD-L1-expressing lung cancer).
CAUTION for cancer warning signs: Change in bowel/bladder habits, A sore that doesn't heal, Unusual bleeding/discharge, Thickening or lump, Indigestion or dysphagia, Obvious change in wart/mole, Nagging cough/hoarseness.
Practice questions
1. A 58-year-old man with a 40-pack-year smoking history presents with persistent cough, weight loss, and hyponatremia (serum sodium 118 mEq/L). Chest X-ray shows a central lung mass. Laboratory studies reveal urine osmolality of 450 mOsm/kg with serum osmolality of 260 mOsm/kg. Which of the following is the most likely diagnosis?
2. A 35-year-old woman discovers a 2-cm breast lump. Core needle biopsy shows invasive ductal carcinoma that is estrogen receptor-positive, progesterone receptor-positive, and HER2-negative. Sentinel lymph node biopsy is negative. Which of the following treatment components is most appropriate?
3. A 28-year-old man presents with a painless testicular mass. Serum markers show elevated AFP and normal β-hCG. Radical orchiectomy confirms nonseminomatous germ cell tumor. CT chest, abdomen, and pelvis reveals retroperitoneal lymphadenopathy (3-cm nodes) with no visceral metastases. What is the most appropriate next step?
Frequently asked questions
What causes cancer?
Cancer results from accumulated mutations in genes that control cell growth, death, and DNA repair. These mutations can be caused by tobacco use (leading cause), infections (HPV, hepatitis B/C, H. pylori), radiation (UV and ionizing), chemical carcinogens (asbestos, benzene), obesity, alcohol, hormonal factors, and inherited genetic mutations (5-10% of cancers). Most cancers arise from multiple somatic mutations acquired over decades, which explains why cancer incidence increases dramatically with age.
What are the first symptoms of cancer?
Early cancer symptoms vary by location but often include a new lump or mass, unexplained weight loss, persistent fatigue, or localized symptoms like cough that doesn't resolve, changes in bowel or bladder habits, unusual bleeding, or a sore that doesn't heal. Many early-stage cancers are asymptomatic, which is why screening is important for certain cancers. Constitutional symptoms like fever, night sweats, and significant weight loss usually indicate more advanced disease. Pain is not typically an early symptom except in bone cancers or when tumors compress nerves.
How is cancer diagnosed?
Cancer diagnosis requires tissue biopsy with histopathological examination to confirm malignancy, determine cancer type, and grade. Imaging studies (CT, MRI, PET scan) help identify the primary tumor and detect metastases for staging. Laboratory tests include complete blood count, metabolic panel, and tumor markers (PSA, CEA, CA-125) which support diagnosis but are not definitive alone. Biopsy methods include fine needle aspiration, core needle biopsy, or surgical excision. Molecular testing on tumor tissue identifies genetic mutations that guide targeted therapy.
Is cancer curable?
Cure depends on cancer type and stage at diagnosis. Many localized cancers are curable with surgery, radiation, or chemotherapy—examples include early-stage breast, colorectal, prostate, and testicular cancers. Metastatic cancer is generally not curable but may be treatable as a chronic disease for years. Exceptions include some metastatic testicular cancers and lymphomas which remain curable even when advanced. Five-year survival rates vary from under 10% for pancreatic cancer to over 95% for thyroid and testicular cancers. Early detection through screening dramatically improves cure rates.
What is the difference between benign and malignant tumors?
Benign tumors grow slowly, remain localized, are well-differentiated (resemble normal tissue), have smooth borders, do not invade surrounding tissues, and never metastasize. Malignant tumors (cancers) grow rapidly, invade through basement membranes into adjacent structures, are poorly differentiated with abnormal cell features, have irregular borders, and can metastasize to distant organs via blood or lymphatics. Benign tumors are generally cured by simple excision, while malignant tumors often require multimodality treatment and carry risk of recurrence and metastasis.
Key drugs
Related conditions and differentials
Sources and further reading
StatPearls (NCBI Bookshelf)MedlinePlusWHO ICD-10: C00-C97
Educational content for medical students, prepared by the WhiteCoat Pro editorial team with AI assistance; every page is reviewed by a second AI model for factual errors. It is not medical advice and does not replace the product label, local guidelines or a clinician.