Physical evidence of malignancy predates human civilization, with paleopathologists identifying osteosarcomas and other bone tumors in dinosaur fossils dating back 70 to 80 million years, as well as in human skeletal remains and mummies from ancient Egypt.¹⁵ The earliest known written record of the disease appears in the Edwin Smith Papyrus, an Egyptian medical text dated to approximately 1600 BCE and believed to copy treatises from as early as 3000 to 2500 BCE.¹⁶ The text describes eight cases of tumors or ulcers of the breast treated by cauterization with a fire drill, concluding with the observation that for this condition there is no treatment. Another ancient Egyptian text, the George Ebers Papyrus, outlines pharmacological, mechanical, and magical interventions for suspected malignancies.¹⁷

The terminology of modern oncology originated in classical antiquity. The Greek physician Hippocrates, practicing between 460 and 370 BCE, coined the terms karkinos and karkinoma—derived from the Greek word for crab—to describe non-ulcerforming and ulcer-forming tumors, likening the swollen blood vessels radiating from a solid tumor mass to the legs of a crab. Between 25 BCE and 50 CE, the Roman encyclopedist Aulus Cornelius Celsus translated the Greek term into the Latin cancer, also meaning crab. In the second century CE, the Greek physician Galen introduced the word oncos, meaning swelling, to describe tumors, establishing the root for the modern terms oncology and oncologist. For more than a millennium, following the humoral theory of Hippocrates and Galen, physicians attributed cancer to an excess of black bile within the body.

During the 17th and 18th centuries, anatomical and epidemiological observations began to displace humoral explanations.¹⁸ After Gaspare Aselli discovered the lymphatic system in the 17th century, theorists proposed that abnormalities in lymph fluid generated tumors. In 1775, the British surgeon Percivall Pott documented a high incidence of squamous cell carcinoma of the scrotum among London chimney sweeps, providing the first demonstration that an environmental exposure—chimney soot—could cause cancer. In the mid-19th century, the German pathologist Rudolf Virchow established cellular pathology, demonstrating that all cells, including tumor cells, arise from pre-existing cells.¹⁹ In 1863, Virchow identified white blood cells within tumor tissues, proposing a link between chronic inflammation and malignancy, and coined the term leukemia to describe blood disorders characterized by excessive leukocytes.

Oncologists classify cancers using two primary criteria: the anatomical primary site where the tumor first originated, such as the lung, breast, or colon, and the histological tissue type from which the malignant cells derive.²³ The international standard for coding and nomenclature is the World Health Organization's International Classification of Diseases for Oncology, Third Edition (ICD-O-3). Across more than 200 distinct clinical entities, malignancies are grouped into major histological categories.

Carcinomas are malignancies arising from epithelial cells, which cover external body surfaces and line internal organs, glands, and body cavities. Accounting for 80 to 90 percent of all human cancer diagnoses, carcinomas are subdivided primarily into adenocarcinomas and squamous cell carcinomas. Adenocarcinomas develop in glandular or secretory tissues and mucous membranes, representing the majority of cancers of the breast, prostate, colon, pancreas, and lung. Squamous cell carcinomas originate in the flat squamous epithelium lining structures such as the skin, esophagus, cervix, and airways. Other epithelial subtypes include basal cell carcinomas of the skin and transitional cell carcinomas of the urinary bladder.

Sarcomas originate in mesenchymal and connective tissues, including bone, cartilage, fat, muscle, tendons, and blood vessels. Considerably rarer than carcinomas and frequently observed in younger patients, sarcomas include bone malignancies such as osteosarcoma and Ewing sarcoma, cartilage tumors such as chondrosarcoma, and various soft tissue sarcomas.²⁴

Hematological malignancies, or blood cancers, arise in hematopoietic and lymphoid tissues rather than forming primary solid organ tumors. Leukemias originate in the blood-forming cells of the bone marrow, leading to the overproduction of abnormal white blood cells that crowd out healthy red blood cells and platelets; they represent the most common malignancy in children while also affecting adults. Lymphomas develop in the lymphocytes and lymph nodes of the immune system and are divided into Hodgkin lymphoma and non-Hodgkin lymphoma. Myeloma, most commonly presenting as multiple myeloma, arises in the bone marrow from plasma cells—specialized B lymphocytes that produce antibodies—causing bone lesions, anemia, and renal dysfunction.

Additional histological categories encompass tumors of the central nervous system, such as gliomas arising from glial cells of the brain and spinal cord; neuroectodermal tumors such as melanoma, which develops from pigment-producing melanocytes; germ cell tumors such as germinomas of the testes or ovaries; and mixed-type neoplasms. When a tumor spreads from its original site to a new organ, it retains the classification of its primary tissue of origin; for example, a breast adenocarcinoma that metastasizes to the lung is classified and treated as metastatic breast cancer rather than primary lung cancer.

Carcinogenesis is a multistep evolutionary process driven by the accumulation of genetic and epigenetic alterations within a lineage of cells.²⁵ While a single mutation rarely suffices to induce malignancy, most solid tumors harbor between 30 and 60 distinct somatic mutations that confer a selective growth advantage over neighboring healthy cells.²⁶²⁷ These alterations primarily affect two classes of regulatory genes: proto-oncogenes and tumor suppressor genes.

Proto-oncogenes code for proteins that stimulate normal cell division, such as growth factors, cell-surface receptors, intracellular signaling enzymes, and nuclear transcription factors. When mutated, amplified, or rearranged via chromosomal translocation, proto-oncogenes become active oncogenes that drive continuous proliferation even in the absence of normal growth signals. Examples include overexpression of the HER2 receptor gene in breast cancer and the BCR-ABL fusion gene generated by chromosomal translocation in chronic myelogenous leukemia, which produces a constitutively active tyrosine kinase enzyme.

Conversely, tumor suppressor genes encode proteins that inhibit cell division, repair damaged DNA, or trigger apoptosis (programmed cell death) when genetic damage is irreparable. Typically, both alleles of a tumor suppressor gene must be inactivated or lost—a phenomenon known as loss of heterozygosity—to eliminate their protective restraint.²⁸ The RB1 (retinoblastoma) gene and the TP53 gene are quintessential tumor suppressors. The p53 protein functions as a tetramer that halts the cell cycle in response to DNA damage; because a mutation in a single allele can poison the entire four-part protein complex, TP53 mutations are prevalent across diverse human malignancies.

In a foundational 2000 synthesis published in the journal Cell, and expanded in 2011 and 2022, researchers Douglas Hanahan and Robert Weinberg codified the functional capabilities acquired by cells during tumorigenesis as the "hallmarks of cancer". The core biological hallmarks include sustaining proliferative signaling, evading growth suppressors, resisting programmed cell death, enabling replicative immortality, inducing or accessing vasculature (angiogenesis) to supply nutrients, activating tissue invasion and metastasis, reprogramming cellular energy metabolism, and avoiding destruction by the immune system. These capabilities are facilitated by genomic instability, tumor-promoting inflammation, and an abetting tumor microenvironment. In 2022, Hanahan outlined four additional emerging and enabling features: unlocking phenotypic plasticity, non-mutational epigenetic reprogramming, polymorphic microbiomes, and senescent cells.

Epidemiological evidence demonstrates that while genetic alterations are the proximate mechanism of cancer, external environmental and lifestyle factors account for the majority of disease incidence. During a 1950 World Health Organization (WHO) symposium, researchers comparing international registries observed that migrant populations acquired the cancer incidence rates of their adoptive countries rather than retaining those of their homelands, establishing that environmental exposures predominate over inherited genetics at the population level.

According to the WHO, nearly one-quarter of all global cancer deaths are attributable to five modifiable behavioral and dietary risk factors: tobacco use, alcohol consumption, high body mass index (obesity), low intake of fruits and vegetables, and lack of physical activity. Tobacco smoking remains the single largest preventable cause of malignancy, introducing dozens of chemical carcinogens that form electrophilic centers capable of binding to and mutating cellular DNA. Outdoor and indoor air pollution also serves as a major environmental driver of lung cancer, alongside occupational chemical exposures and ultraviolet or ionizing radiation.²⁹

Infectious agents—including oncogenic viruses, bacteria, and parasites—represent another major etiological category. Globally, cancer-causing infections such as human papillomavirus (HPV), hepatitis B and C viruses, and Helicobacter pylori are responsible for approximately 30 percent of all cancer cases in low- and lower-middle-income countries. HPV infection is a primary driver of cervical and oropharyngeal carcinomas, while chronic viral hepatitis predisposes individuals to hepatocellular carcinoma.³⁰³¹

Inherited germline mutations passed from parent to offspring account for a smaller proportion of cases, creating hereditary cancer syndromes that markedly elevate individual lifetime risk. Beyond hereditary retinoblastoma, inherited defects in DNA repair genes or tumor suppressors predispose carriers to early-onset breast, ovarian, or colorectal malignancies.

Because early-stage tumors frequently produce no specific symptoms, clinical detection relies on both population-based screening of asymptomatic individuals and diagnostic evaluation of patients presenting with physical signs such as palpable lumps, unexplained weight loss, abnormal bleeding, or persistent pain.³² Established screening modalities—such as cervical cytology (the Pap smear) and HPV testing, mammography for breast cancer, and endoscopic or stool-based testing for colorectal cancer—aim to identify premalignant lesions or localized tumors when curative intervention is most feasible.³³

When a malignancy is suspected on physical examination or cross-sectional imaging (such as computed tomography, magnetic resonance imaging, or positron emission tomography), definitive diagnosis traditionally requires a tissue biopsy.³⁴ Pathologists examine the excised tissue microscopically to determine its histological type and cellular grade, utilizing immunohistochemistry—the application of antibody-linked stains—to identify specific protein markers, such as estrogen receptors in breast adenocarcinoma, that establish the tumor's origin and guide therapy.

Alongside conventional tissue pathology, liquid biopsy has become an increasingly integrated diagnostic tool in clinical oncology.³⁵ Performed on a standard blood draw, liquid biopsies detect circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and extracellular vesicles shed by tumors into the bloodstream. Because needle biopsies sample only a single site and may miss genetically distinct subregions within a heterogeneous tumor, blood-based genomic sequencing provides a broader molecular profile. Clinicians use liquid biopsies to identify actionable mutations for targeted therapy, monitor real-time treatment response, screen high-risk populations such as those with HPV-associated throat cancer, and detect molecular residual disease (MRD)—microscopic traces of cancer remaining after surgery that signal impending recurrence months before tumors become visible on imaging scans. Artificial intelligence and deep learning models are also increasingly deployed in diagnostic radiology and pathology to identify imaging biomarkers and predict patient responses to immunotherapy.³⁶

Once a diagnosis is confirmed, oncologists determine the anatomical extent of the disease through staging, which dictates prognosis and treatment selection. For most solid tumors, the international standard is the TNM staging system. In this framework, the letter T designates the size and local invasion of the primary tumor, N indicates whether and to what extent regional lymph nodes contain cancer cells, and M denotes the presence or absence of distant metastasis. These parameters are combined to assign an overall stage from Stage I (localized early disease) to Stage IV (metastatic disease); a patient's cancer retains its original diagnostic stage designation in medical registries even if the disease subsequently progresses. Brain tumors and hematological malignancies utilize specialized staging and risk-stratification systems tailored to their distinct anatomical behaviors.

Modern cancer care is organized around five primary therapeutic pillars: surgery, radiation therapy, cytotoxic chemotherapy, molecularly targeted therapy, and immunotherapy. Patients commonly receive multimodal treatment combining several approaches, administered either with curative intent or to prolong survival and control symptoms.³⁷

According to the GLOBOCAN estimates compiled by the International Agency for Research on Cancer (IARC) and the American Cancer Society covering 34 cancer types across 186 countries, approximately 20.6 million new cancer cases (19.5 million excluding non-melanoma skin cancer) and 9.8 million cancer deaths occurred worldwide in 2024. Globally, these figures correspond to a lifetime risk of approximately one in five people developing cancer, with roughly one in nine men and one in 13 women dying from the disease.

By incidence, lung cancer is the most frequently diagnosed malignancy worldwide, accounting for nearly 2.6 million new cases (12.8 percent of the global total), followed by female breast cancer (11.8 percent), colorectal cancer (9.9 percent), prostate cancer (7.5 percent), and stomach cancer (4.7 to 4.8 percent). Lung cancer is also the leading cause of cancer-related death globally, responsible for an estimated 1.9 million fatalities (19.1 percent of all cancer deaths), followed by colorectal cancer (9.4 percent), liver cancer (7.5 percent), female breast cancer (7.1 percent), and stomach cancer (6.6 percent).

Disease burden varies markedly by geographic region and socioeconomic development. Age-standardized incidence rates vary four- to five-fold across world regions, with the highest overall incidence recorded in Australia and New Zealand (477 cases per 100,000 men and 396 per 100,000 women).⁴³ Mortality rates vary two-fold internationally, with the highest male mortality rates observed in Eastern Europe (158 deaths per 100,000) and the highest female mortality rates in Melanesia (108 deaths per 100,000). In high-income nations such as the United States, overall age-adjusted cancer mortality rates have declined steadily due to reduced smoking prevalence, earlier detection, and therapeutic advances, resulting in a survivor population exceeding 20 million Americans. Globally, however, demographic aging and population growth are projected to drive annual global cancer incidence to 34.4 million new cases by 2050—a 67 percent increase over 2024 levels—with the largest proportional increases occurring in lower-income countries. Epidemiologists have also documented rising rates of early-onset colorectal and other cancers among younger adults across multiple countries.⁴⁴

Population-based cancer screening is the subject of ongoing scientific and policy debate regarding the balance between mortality reduction and the harms of overdiagnosis and overtreatment.⁴⁵ Overdiagnosis occurs when a screening test detects a histologically confirmed malignancy that grows so slowly—or not at all—that it would never have caused symptoms or death during the patient's remaining lifetime. Because clinicians generally cannot distinguish indolent screen-detected tumors from potentially lethal ones, overdiagnosed patients undergo surgery, radiation, or systemic therapy without clinical benefit. In prostate cancer, widespread prostate-specific antigen (PSA) blood testing sparked debate among urologists and public health task forces over the high rate of overtreatment of low-risk tumors versus the risk of missing aggressive disease if screening is curtailed.⁴⁶ Similarly, estimates of overdiagnosis in mammography screening for breast cancer have varied widely: while earlier observational studies and critiques by researchers at the Nordic Cochrane Centre suggested that 30 to 50 percent of screen-detected breast cancers represented overdiagnosis, subsequent biostatistical modeling by researchers at the Fred Hutchinson Cancer Center and a 2026 reanalysis of eight major randomized trials led by Sisse Helle Njor at the University of Southern Denmark indicated that true overdiagnosis rates, after accounting for follow-up time and lead-time bias, may be below 5 percent, though the risk remains elevated among frail women over age 70.⁴⁷⁴⁸

A second major challenge is the escalating cost of oncology care and its impact on patients, termed "financial toxicity".⁴⁹⁵⁰ Driven by the high prices of novel molecularly targeted drugs, immunotherapies, and diagnostic technologies, alongside high out-of-pocket insurance coinsurance and lost employment productivity, between 28 and 49 percent of cancer survivors in systematic reviews report significant financial distress, asset depletion, or medical debt. Longitudinal analyses of the United States Medical Expenditure Panel Survey demonstrate that a cancer diagnosis is associated with an average 14.4 percent reduction in income and a 15.9 percent reduction in personal wealth, with substantially steeper losses among Black and Hispanic survivors.⁵¹ Financial hardship directly compromises clinical outcomes by prompting patients to delay care or ration prescribed oral medications.⁵²

On a global scale, profound inequities persist in access to prevention, diagnostics, and treatment.⁵³ While high-income nations deploy precision genomics, AI-assisted imaging, and cellular immunotherapies, health systems in many low- and middle-income countries lack basic pathology infrastructure, radiotherapy equipment, essential cytotoxic medicines, and oral morphine for palliative pain relief. Addressing these structural disparities remains a central focus of international cancer control initiatives led by the World Health Organization.⁵⁴