Cancer

Cancer encompasses a diverse category of diseases characterized by unregulated cellular proliferation, frequently manifesting as tumors capable of local invasion or distant metastasis. Malignant tumors, unlike their benign counterparts, possess this invasive and metastatic potential. Humanity is affected by more than 100 distinct forms of cancer.

Cancer is a group of diseases involving uncontrolled cell growth typically resulting in tumors with the potential to invade or spread to other parts of the body. These malignant tumors contrast with benign tumors, which do not spread. Over 100 types of cancers affect humans.

Approximately 33% of cancer-related mortalities are attributable to factors such as tobacco and alcohol consumption, obesity, insufficient dietary intake of fruits and vegetables, and physical inactivity. Additional contributing elements comprise specific infections, exposure to ionizing radiation, and various environmental pollutants. Globally, infections with particular viruses, bacteria, and parasites account for an estimated 16–18% of all cancers. Notable infectious agents include Helicobacter pylori, hepatitis B, hepatitis C, HPV, Epstein–Barr virus, Human T-lymphotropic virus 1, Kaposi's sarcoma-associated herpesvirus, and Merkel cell polyomavirus. While the Human Immunodeficiency Virus (HIV) does not directly induce oncogenesis, it precipitates immune deficiency, thereby significantly elevating the risk of cancers stemming from other infections, potentially by several thousandfold in instances like Kaposi's sarcoma. Crucially, successful vaccination against the hepatitis B virus and human papillomavirus prior to infection has demonstrated the capacity to nearly eradicate the risk of cancers associated with these viral agents.

These environmental determinants contribute, at least partially, to carcinogenesis through alterations in cellular genetic material. The development of cancer typically necessitates numerous genetic modifications. Inherited genetic predispositions account for approximately 5–10% of all cancer cases. Detection of cancer can occur via specific clinical signs and symptoms or through screening protocols. Subsequent investigation commonly involves medical imaging, with definitive diagnosis established through biopsy.

The incidence of specific cancers can be mitigated through various preventative measures, including abstinence from smoking, maintenance of a healthy body weight, moderation of alcohol consumption, a diet rich in vegetables, fruits, and whole grains, vaccination against particular infectious diseases, restricted intake of processed and red meats, and limited exposure to direct solar radiation. Early detection via screening proves beneficial for cervical and colorectal cancers, although the efficacy of breast cancer screening remains a subject of debate. Cancer treatment frequently involves a multimodal approach, combining radiation therapy, surgical intervention, chemotherapy, and targeted therapies. The burgeoning field of cancer immunotherapy is introducing more individualized treatments that leverage the patient's own immune system. Palliative care, a medical subspecialty, focuses on advanced pain and symptom management, which is especially critical for individuals with advanced-stage disease. Prognosis, specifically the likelihood of survival, is contingent upon the cancer type and the disease's stage at the commencement of treatment. Among children under 15 years diagnosed with cancer in developed nations, the average five-year survival rate is 80%. In the United States, the overall average five-year survival rate for cancer across all age groups is 66%.

Globally, approximately 90.5 million individuals were afflicted with cancer in 2015. By 2019, the annual incidence of cancer cases had increased by 23.6 million people, with 10 million deaths recorded worldwide. These figures represent a 26% and 21% increase, respectively, over the preceding decade.

Among males, the predominant cancer types include lung, prostate, colorectal, and stomach cancers. For females, breast, colorectal, lung, and cervical cancers are most prevalent. If non-melanoma skin cancer were incorporated into the annual total of new cancer diagnoses, it would constitute approximately 40% of all cases. In pediatric populations, acute lymphoblastic leukemia and brain tumors are the most frequently observed, with the notable exception of Africa, where non-Hodgkin lymphoma is more common. In 2012, approximately 165,000 children under the age of 15 received a cancer diagnosis. The propensity for cancer development escalates considerably with advancing age, and numerous cancer types exhibit higher incidence rates in developed nations. Current trends indicate rising rates, attributed to increased life expectancy and evolving lifestyle patterns in developing regions. As of 2010, the cumulative global economic burden of cancer was projected to be US$1.16 trillion annually (equivalent to $1.71 trillion in 2025).

Etymological Origins and Definitional Frameworks

The term 'cancer' originates from the ancient Greek word καρκίνος, which denotes both 'crab' and 'tumor'. Ancient Greek physicians, including Hippocrates and Galen, observed morphological resemblances between certain tumors characterized by distended veins and crabs. The modern medical application of this term in English emerged around the year 1600.

Cancer encompasses a broad category of diseases characterized by uncontrolled cellular proliferation and the capacity to infiltrate or disseminate to disparate bodily regions. These conditions constitute a subgroup of neoplasms. A neoplasm, or tumor, refers to an aggregation of cells exhibiting unregulated growth, frequently manifesting as a distinct mass or lump, though it can also present as a diffuse distribution.

All neoplastic cells exhibit the six defining hallmarks of cancer. These specific characteristics are essential for the development of a malignant tumor, and they encompass:

• Unregulated cellular proliferation and division, independent of appropriate signaling mechanisms.
• Sustained cellular growth and division, even in the presence of inhibitory signals.
• Evasion of programmed cellular demise (apoptosis).
• Acquisition of an indefinite replicative potential.
• Induction of angiogenesis, facilitating new blood vessel formation.
• Invasion of surrounding tissues and the establishment of metastatic lesions.

The transformation from healthy cells to those capable of forming a discernible mass, and subsequently to overt cancer, is a multi-stage process termed malignant progression.

Clinical Manifestations

Initially, cancer typically presents asymptomatically. Clinical signs and symptoms emerge as the neoplastic mass expands or ulcerates. The specific manifestations observed are contingent upon the cancer's histological type and anatomical location. Few symptoms are pathognomonic, and many are commonly associated with other medical conditions. Consequently, cancer can pose diagnostic challenges and is often referred to as a 'great imitator'.

Following a cancer diagnosis, individuals may experience heightened levels of anxiety or depression. The risk of suicide among cancer patients is approximately twofold higher than in the general population.

Localized Symptoms

Localized symptoms can arise from the physical presence of the tumor mass or its ulceration. For instance, the mass effect of lung cancer may obstruct a bronchus, leading to coughing or pneumonia. Esophageal cancer can induce luminal narrowing, resulting in dysphagia or odynophagia. Colorectal cancer may cause strictures or obstructions within the bowel, thereby altering bowel habits. Palpable lumps may indicate masses in the breasts or testicles. Ulceration can precipitate hemorrhage, manifesting as hemoptysis (lung cancer), anemia or rectal bleeding (colon cancer), hematuria (bladder cancer), or abnormal vaginal bleeding (endometrial or cervical cancer). While localized pain can be a feature of advanced cancer, the primary tumor is typically asymptomatic in its early stages. Furthermore, certain malignancies can lead to fluid accumulation within the thoracic or abdominal cavities.

Systemic Manifestations

Systemic symptoms can result from the body's physiological response to the malignancy. These may encompass fatigue, unintentional weight loss, or dermatological alterations. Certain cancers can induce a systemic inflammatory response, culminating in progressive muscle atrophy and weakness, a condition termed cachexia.

Specific malignancies, including Hodgkin's lymphoma, leukemias, and hepatic or renal cancers, are known to induce persistent pyrexia.

Dyspnea, or shortness of breath, represents a frequent symptom associated with both cancer and its therapeutic interventions. Etiologies of cancer-related dyspnea may involve intrathoracic or peripulmonary tumors, airway obstruction, pleural effusions, pneumonia, or adverse reactions to treatment, such as allergic responses. Management strategies for dyspnea in patients with advanced cancer may incorporate the use of fans, bilevel positive airway pressure ventilation, acupressure/reflexology, and comprehensive non-pharmacological approaches.

Certain systemic manifestations of cancer are attributable to hormones or other bioactive molecules secreted by the tumor, collectively referred to as paraneoplastic syndromes. Notable paraneoplastic syndromes include hypercalcemia, which can induce altered mental status, constipation, and dehydration, and hyponatremia, which may similarly lead to altered mental state, emesis, headaches, or seizures.

Metastasis

Metastasis denotes the dissemination of cancer cells from their primary site to distant anatomical locations within the body. The resulting secondary growths are termed metastatic tumors, while the initial malignancy is referred to as the primary tumor. The vast majority of cancers possess the capacity to metastasize, and most cancer-related mortalities are attributed to metastatic disease.

Metastasis frequently occurs in advanced stages of cancer and can transpire through hematogenous, lymphatic, or combined routes. The characteristic stages of metastatic progression include:

1. Local tissue invasion.
2. Intravasation into the circulatory or lymphatic systems.
3. Circulation within the systemic vasculature.
4. Extravasation into a novel tissue microenvironment.
5. Subsequent proliferation.
6. Angiogenesis.

Specific cancer types exhibit predilection for metastasis to particular organs. Globally, the most frequent sites for metastatic deposition include the lungs, liver, brain, and skeletal system.

Although certain cancers are curable with early detection, metastatic disease presents greater challenges in terms of treatment and control. Nonetheless, contemporary therapeutic advancements are yielding promising outcomes.

Etiology

The majority of cancer cases, approximately 90–95%, originate from genetic mutations influenced by environmental and lifestyle elements. The remaining 5–10% are attributable to inherited genetic predispositions. The term environmental encompasses non-inherited etiologies, including lifestyle choices, socioeconomic conditions, and behavioral patterns, extending beyond mere pollution. Key environmental contributors to cancer mortality include tobacco consumption (25–30%), dietary habits and obesity (30–35%), infectious agents (15–20%), various forms of radiation (both ionizing and non-ionizing, accounting for up to 10%), insufficient physical activity, and environmental pollutants. While psychological stress does not appear to be a primary risk factor for cancer initiation, it may exacerbate outcomes in individuals already diagnosed with the disease.

The specific environmental or lifestyle factors contributing to an individual's cancer development can be ascertained through the analysis of mutational signatures derived from genomic sequencing of tumor DNA. This analytical approach can, for instance, identify whether lung cancer resulted from tobacco smoke exposure, if skin cancer was induced by ultraviolet radiation, or if subsequent malignancies were a consequence of prior chemotherapy regimens.

Cancer is generally not considered a transmissible disease. Rare instances of transmission have been documented in cases involving pregnancy and occasional organ donation. Nevertheless, certain transmissible infectious diseases, including hepatitis B, Epstein–Barr virus, human papillomavirus (HPV), and AIDS, are recognized contributors to oncogenesis.

Chemicals

Exposure to specific substances has been correlated with particular cancer types. These agents are designated as carcinogens.

For instance, tobacco smoke is implicated in 90% of lung cancer diagnoses. Tobacco consumption can induce malignancies across various bodily systems, affecting sites such as the oral cavity, pharynx, larynx, esophagus, stomach, bladder, kidneys, cervix, colon/rectum, liver, and pancreas. Tobacco smoke comprises more than fifty identified carcinogens, notably nitrosamines and polycyclic aromatic hydrocarbons.

Globally, tobacco accounts for approximately one in five cancer-related fatalities, a proportion that rises to about one in three in developed nations. In the United States, lung cancer mortality rates have historically correlated with smoking prevalence: periods of increased smoking were succeeded by significant rises in lung cancer deaths, while reductions in smoking rates since the 1950s have subsequently led to a decline in lung cancer mortality among men since 1990.

Alcohol consumption elevates the risk of developing cancers of the breast (in women), pharynx, liver, esophagus, oral cavity, larynx, and colon. In Western Europe, alcohol exposure is implicated in 10% of male cancers and 3% of female cancers, particularly those affecting the liver and digestive tract. Occupational exposure to certain substances may contribute to 2–20% of cancer cases, resulting in a minimum of 200,000 deaths annually. Examples include lung cancer and mesothelioma, which can arise from inhaling tobacco smoke or asbestos fibers, respectively, and leukemia, which is associated with benzene exposure.

Exposure to perfluorooctanoic acid (PFOA), primarily utilized in Teflon manufacturing, is recognized as a causative factor for two distinct types of cancer.

Chemotherapeutic agents, including platinum-based compounds, are classified as carcinogens that elevate the propensity for developing secondary malignancies.

Azathioprine, an immunosuppressive drug, is identified as a carcinogen capable of inducing the formation of primary tumors.

Diet and exercise

Dietary patterns, physical inactivity, and obesity collectively contribute to an estimated 30–35% of cancer-related mortalities. In the United States, surplus body weight is linked to the etiology of numerous cancer types, accounting for 14–20% of cancer deaths. Research conducted in the UK, encompassing data from over 5 million individuals, demonstrated a correlation between elevated body mass index and at least 10 distinct cancer types, responsible for approximately 12,000 cases annually within that nation. Physical inactivity is posited to heighten cancer risk, not solely through its influence on body weight but also via adverse impacts on the immune and endocrine systems. A substantial portion, over half, of the dietary impact on cancer risk is attributed to overnutrition, rather than insufficient consumption of vegetables or other beneficial foods.

Specific dietary components and practices are associated with particular cancer types. For instance, a high-sodium diet correlates with an elevated risk of gastric cancer. Aflatoxin B1, a common food contaminant, is a known cause of hepatocellular carcinoma. The practice of betel nut chewing contributes to the development of oral cancer. Variations in national dietary habits may partially account for observed disparities in cancer incidence. For example, the higher prevalence of gastric cancer in Japan is attributed to its high-salt dietary patterns, whereas colorectal cancer is more prevalent in the United States. Immigrant populations often adopt the cancer incidence profiles of their new host countries, frequently within a single generation.

Infection

Globally, infectious diseases account for approximately 18% of cancer-related mortalities. This percentage varies significantly, reaching up to 25% in Africa but falling below 10% in industrialized nations. While viruses are the predominant infectious agents implicated in carcinogenesis, bacteria and parasites can also contribute to cancer development. Key oncoviruses, defined as viruses capable of inducing human cancer, encompass:

• Human papillomavirus (associated with cervical cancer),
• Epstein–Barr virus (linked to B-cell lymphoproliferative disease and nasopharyngeal carcinoma),
• Kaposi's sarcoma herpesvirus (implicated in Kaposi's sarcoma and primary effusion lymphomas),
• Hepatitis B and hepatitis C viruses (causes of hepatocellular carcinoma),
• Human T-cell leukemia virus-1 (contributing to T-cell leukemias).
• Merkel cell polyomavirus (associated with Merkel cell carcinoma).

Bacterial infections can similarly elevate cancer risk, exemplified by:

• Gastric carcinoma induced by Helicobacter pylori.
• Colibactin, a genotoxin linked to Escherichia coli infection, which is associated with colorectal cancer.

Parasitic infections that have been linked to cancer include:

• Schistosoma haematobium (causing squamous cell carcinoma of the bladder),
• The liver flukes, Opisthorchis viverrini and Clonorchis sinensis (implicated in cholangiocarcinoma).

Radiation

Exposure to radiation, including ultraviolet radiation and radioactive substances, constitutes a significant risk factor for cancer. A substantial proportion of non-melanoma skin cancers result from ultraviolet radiation, primarily originating from solar exposure. Ionizing radiation sources encompass medical imaging procedures and radon gas.

Ionizing radiation is not considered an exceptionally potent mutagen on its own. For instance, residential exposure to radon gas carries cancer risks comparable to those associated with passive smoking. However, radiation becomes a more formidable carcinogenic agent when synergistically combined with other carcinogens, such as radon alongside tobacco smoke. Radiation has the potential to induce cancer in most bodily tissues, across all animal species, and at any developmental stage. Children exhibit a twofold increased susceptibility to developing radiation-induced leukemia compared to adults; prenatal radiation exposure amplifies this effect tenfold.

The medical application of ionizing radiation represents a minor yet expanding contributor to radiation-induced cancers. While ionizing radiation is employed in the treatment of various cancers, it can, in certain instances, paradoxically induce a secondary malignancy. Furthermore, it is utilized in specific medical imaging modalities.

Extended exposure to solar ultraviolet radiation can result in melanoma and other cutaneous malignancies. Robust evidence unequivocally identifies ultraviolet radiation, particularly the non-ionizing medium-wave UVB, as the primary etiology for the majority of non-melanoma skin cancers, which constitute the most prevalent cancer types globally.

Non-ionizing radio frequency radiation, emanating from sources such as mobile phones, electric power transmission, and comparable technologies, has been classified as a possible carcinogen by the International Agency for Research on Cancer (IARC) of the World Health Organization. Nevertheless, the available evidence has not substantiated these concerns. Specifically, research has failed to establish a consistent correlation between mobile phone radiation and an elevated cancer risk.

Heredity

The overwhelming majority of cancer cases are non-hereditary, or sporadic, in nature. Hereditary cancers primarily arise from an inherited genetic defect. Fewer than 0.3% of individuals carry a genetic mutation that significantly impacts cancer risk, and these mutations account for less than 3–10% of all cancers. Notable examples of such syndromes include specific inherited mutations in the BRCA1 and BRCA2 genes, which confer a greater than 75% risk of developing breast and ovarian cancer. Another example is hereditary nonpolyposis colorectal cancer (HNPCC or Lynch syndrome), observed in approximately 3% of individuals diagnosed with colorectal cancer, among other conditions.

For cancers exhibiting high mortality, the relative risk of developing colorectal cancer is approximately 2 when a first-degree relative (parent, sibling, or child) has received such a diagnosis. Lung cancer demonstrates a corresponding relative risk of 1.5, while prostate cancer shows a relative risk of 1.9. In the context of breast cancer, the relative risk is 1.8 if a first-degree relative was diagnosed at 50 years of age or older, increasing to 3.3 if the relative's diagnosis occurred before the age of 50.

Individuals of greater stature exhibit an elevated risk of cancer, a phenomenon attributed to their larger cellular count compared to shorter individuals. Given the substantial genetic influence on height, this predisposition to cancer in taller individuals is considered heritable.

Physical Agents

Certain substances induce carcinogenesis predominantly through their physical rather than chemical properties. A salient illustration is protracted exposure to asbestos, a naturally occurring mineral fiber recognized as a primary etiology of mesothelioma, a malignancy affecting the serous membrane, typically that enveloping the lungs. Other materials within this classification, encompassing both natural and synthetic asbestos-like fibers such as wollastonite, attapulgite, glass wool, and rock wool, are hypothesized to exert comparable effects. Non-fibrous particulate carcinogens include powdered metallic cobalt and nickel, alongside crystalline silica (e.g., quartz, cristobalite, and tridymite). Typically, physical carcinogens necessitate internal bodily entry, often via inhalation, and prolonged exposure over several years to manifest cancerous outcomes.

The incidence of cancer directly attributable to physical trauma is comparatively infrequent. For instance, assertions linking bone fractures to bone cancer lack empirical substantiation. Likewise, physical trauma is not recognized as an etiological factor for cervical, breast, or brain cancers. An acknowledged exception involves the frequent, long-term application of heated objects to the body. Repeated thermal injuries to the same anatomical region, such as those inflicted by kanger and kairo heaters (charcoal hand warmers), may potentially induce skin cancer, particularly when co-occurring with carcinogenic chemical exposure. Similarly, regular ingestion of excessively hot tea has been associated with esophageal cancer. The prevailing hypothesis suggests that cancer initiation or progression of a pre-existing malignancy occurs during the healing process, rather than as a direct consequence of the trauma itself. Nevertheless, recurrent tissue injuries could foster excessive cellular proliferation, thereby elevating the probability of oncogenic mutations.

Chronic inflammation is hypothesized to directly induce genetic mutations. Furthermore, inflammation can facilitate the proliferation, survival, angiogenesis, and migration of neoplastic cells through its influence on the tumor microenvironment. Oncogenes are implicated in establishing an inflammatory, pro-tumorigenic microenvironment.

Hormones

Hormones are also implicated in cancer development by stimulating cellular proliferation. Insulin-like growth factors (IGFs) and their associated binding proteins are pivotal in regulating cancer cell proliferation, differentiation, and apoptosis, thereby suggesting their potential involvement in carcinogenesis.

Hormones serve as critical mediators in the pathogenesis of sex-related cancers, including those affecting the breast, endometrium, prostate, ovary, and testis, as well as thyroid and bone cancers. For instance, daughters of women diagnosed with breast cancer exhibit significantly elevated concentrations of estrogen and progesterone compared to daughters of unaffected women. These heightened hormonal levels may elucidate their increased susceptibility to breast cancer, even in the absence of a specific breast cancer gene. Analogously, men of African descent demonstrate notably higher testosterone levels than men of European descent, correlating with a greater incidence of prostate cancer. Conversely, men of Asian descent, possessing the lowest levels of testosterone-activating androstanediol glucuronide, exhibit the lowest rates of prostate cancer.

Several additional factors are pertinent: individuals with obesity exhibit elevated levels of certain cancer-associated hormones and a correspondingly higher incidence of these malignancies. Women undergoing hormone replacement therapy also face an increased risk of developing cancers linked to the administered hormones. Conversely, individuals engaging in significantly above-average physical activity tend to have reduced levels of these hormones and a diminished cancer risk. Growth hormones may also promote osteosarcoma. Certain therapeutic and preventative strategies exploit this etiological link by artificially lowering hormone levels, thereby inhibiting the progression of hormone-sensitive cancers.

Autoimmune Diseases

Celiac disease is associated with an elevated risk of various cancers. Individuals with untreated celiac disease face a higher risk, which subsequently diminishes following diagnosis and adherence to rigorous treatment protocols. This reduction in risk is potentially attributable to the adoption of a gluten-free diet, which appears to confer protection against malignancy development in celiac patients. Conversely, a delayed diagnosis and postponed initiation of a gluten-free diet seem to exacerbate the risk of malignancies. Furthermore, chronic inflammation in Crohn's disease and ulcerative colitis contributes to increased rates of gastrointestinal cancers. The immunomodulators and biologic agents employed in the treatment of these conditions may also foster the development of extra-intestinal malignancies.

Mechanism

Genetics

Cancer is fundamentally characterized as a disorder of tissue growth regulation. The transformation of a normal cell into a cancerous one necessitates alterations in the genes responsible for controlling cell growth and differentiation.

The genes implicated in cancer are broadly classified into two categories. Oncogenes are defined as genes that stimulate cellular proliferation and reproduction. Conversely, tumor suppressor genes function to inhibit cell division and promote cell survival. Malignant transformation can arise from the genesis of novel oncogenes, the aberrant overexpression of endogenous oncogenes, or the underexpression or inactivation of tumor suppressor genes. Generally, the conversion of a normal cell into a cancerous cell requires modifications across multiple genes.

Genetic alterations manifest at various levels and through diverse mechanisms. Errors during mitosis can lead to the gain or loss of an entire chromosome. More frequently, these alterations involve mutations, which represent changes in the nucleotide sequence of genomic DNA.

Large-scale mutations encompass the deletion or acquisition of chromosomal segments. Genomic amplification is characterized by a cell acquiring multiple copies (frequently 20 or more) of a confined chromosomal locus, typically containing one or more oncogenes and contiguous genetic material. Translocation describes the abnormal fusion of two distinct chromosomal regions, often at a specific site. A prominent illustration is the Philadelphia chromosome, involving a translocation between chromosomes 9 and 22, which is observed in chronic myelogenous leukemia and leads to the production of the BCR-abl fusion protein, an oncogenic tyrosine kinase.

Small-scale mutations comprise point mutations, deletions, and insertions. These can occur within a gene's promoter region, thereby influencing its expression, or within its coding sequence, altering the function or stability of its protein product. Furthermore, the disruption of a single gene can also arise from the integration of genomic material from a DNA virus or retrovirus, culminating in the expression of viral oncogenes within the affected cell and its progeny.

The replication of genetic information within the DNA of living cells inherently carries a probabilistic risk of errors, resulting in mutations. Intricate mechanisms for error correction and prevention are integral to this process, safeguarding the cell against oncogenesis. Should a substantial error arise, the compromised cell can undergo programmed cell death, known as apoptosis. However, if these error control processes become compromised, the mutations will persist and be transmitted to subsequent daughter cells.

Certain environmental conditions can elevate the likelihood of errors emerging and propagating. These conditions encompass exposure to disruptive substances termed carcinogens, recurrent physical injury, elevated temperatures, ionizing radiation, or hypoxia.

The errors contributing to cancer development are characterized by their self-amplifying and compounding nature; for instance:

• A mutation affecting a cell's error-correcting machinery could lead to an accelerated accumulation of errors in that cell and its progeny.
• An additional mutation within an oncogene could induce the cell to proliferate more rapidly and frequently compared to its normal counterparts.
• Another mutation might result in the loss of a tumor suppressor gene, thereby disrupting the apoptotic signaling pathway and conferring immortality upon the cell.
• A subsequent mutation in the cell's signaling apparatus could transmit error-inducing signals to adjacent cells.

The transformation of a normal cell into cancer is analogous to a chain reaction initiated by errors that progressively escalate into more significant aberrations, each allowing the cell to circumvent regulatory mechanisms that restrict normal tissue growth. This scenario, characterized by cellular dysregulation, represents a detrimental form of natural selection, where evolutionary forces subvert the body's inherent regulatory systems and structural integrity. Following cancer initiation, this ongoing process, termed clonal evolution, propels its advancement toward more aggressive stages. Clonal evolution results in intratumor heterogeneity, characterized by diverse mutations among cancer cells, thereby complicating the development of efficacious therapeutic strategies and necessitating an evolutionary perspective in treatment design.

The distinctive capabilities acquired by cancerous cells are classified into several categories: evasion of apoptosis, uncontrolled proliferation independent of external stimuli, resistance to growth-inhibitory signals, sustained angiogenesis, limitless replicative potential, metastasis (dissemination to distant sites), metabolic reprogramming, and immune evasion.

Epigenetics

Traditionally, cancer has been conceptualized as a collection of diseases primarily driven by cumulative genetic abnormalities, encompassing mutations in tumor-suppressor genes and oncogenes, as well as chromosomal aberrations. However, the significance of epigenetic alterations in carcinogenesis was recognized during the early 21st century.

Epigenetic alterations are functionally significant genomic modifications that do not involve alterations to the underlying nucleotide sequence. These modifications include changes in DNA methylation (e.g., hypermethylation and hypomethylation), histone modifications, and changes in chromosomal architecture, often resulting from the aberrant expression of proteins like HMGA2 or HMGA1. Crucially, these alterations modulate gene expression without modifying the primary DNA sequence. Such epigenetic modifications can persist across cell divisions, be transmitted through multiple generations, and are functionally comparable to genetic mutations.

Epigenetic modifications are commonly observed in various cancers. For instance, a particular study identified numerous protein-coding genes exhibiting frequent methylation alterations in the context of colon cancer. Specifically, 147 genes were found to be hypermethylated, while 27 were hypomethylated. Among the hypermethylated genes, 10 demonstrated hypermethylation in all colon cancer cases examined, with many additional genes showing hypermethylation in over 50% of cases.

Although epigenetic alterations are prevalent in malignancies, epigenetic modifications affecting DNA repair genes, which lead to diminished expression of DNA repair proteins, warrant particular attention. These specific alterations may manifest early during oncogenesis and are hypothesized to contribute to the genetic instability commonly observed in cancers.

Diminished expression of DNA repair genes compromises DNA repair mechanisms. Consequently, when DNA repair is deficient, DNA damage accumulates within cells at elevated levels, leading to increased frequencies of both mutations and epimutations. Cells exhibiting defects in DNA mismatch repair or homologous recombinational repair (HRR) demonstrate a substantial increase in mutation rates. Furthermore, chromosomal rearrangements and aneuploidy are also more prevalent in HRR-deficient cells.

Elevated levels of DNA damage promote an increase in both mutations and epimutations. Incompletely resolved repair sites, following the repair of DNA double-strand breaks or other forms of DNA damage, can induce epigenetic gene silencing.

Inherited mutations leading to deficient expression of DNA repair proteins can elevate an individual's susceptibility to cancer. Individuals harboring an inherited impairment in any of 34 identified DNA repair genes face an elevated cancer risk; certain defects, such as p53 mutations, can confer a 100% lifetime probability of developing cancer. Nevertheless, these germline mutations, which are responsible for highly penetrant cancer syndromes, account for approximately only 1 percent of all cancer cases.

In sporadic cancers, DNA repair deficiencies occasionally result from mutations in DNA repair genes, but more frequently stem from epigenetic alterations that diminish or silence the expression of these genes. Numerous studies on heavy metal-induced carcinogenesis demonstrate that such metals reduce the expression of DNA repair enzymes, sometimes through epigenetic mechanisms. The inhibition of DNA repair is posited as a primary mechanism in heavy metal-induced carcinogenicity. Furthermore, frequent epigenetic modifications occur in DNA sequences that encode small RNAs known as microRNAs (or miRNAs). miRNAs do not encode proteins; instead, they can "target" protein-coding genes and consequently reduce their expression.

Cancers typically develop from an accumulation of mutations and epimutations that confer a selective advantage, leading to clonal expansion. However, mutations may not be as prevalent in cancers as epigenetic alterations. An average breast or colon cancer can exhibit approximately 60 to 70 protein-altering mutations, of which about three or four are considered "driver" mutations, with the remainder classified as "passenger" mutations.

Metastasis

Metastasis refers to the dissemination of cancer cells to other anatomical sites within the body. The resulting disseminated tumors are termed metastatic tumors, while the original lesion is designated the primary tumor. Nearly all cancers possess the capacity to metastasize, and the majority of cancer-related fatalities are attributable to metastatic disease.

Metastasis is a common occurrence in advanced stages of cancer and can transpire via the bloodstream, the lymphatic system, or both. The characteristic stages of metastasis encompass local invasion, intravasation into the blood or lymph, systemic circulation, extravasation into new tissues, subsequent proliferation, and angiogenesis. While various cancer types exhibit a propensity to metastasize to specific organs, the most frequent sites for metastases generally include the lungs, liver, brain, and bones.

Metabolism

Normal cells typically derive approximately 30% of their energy from glycolysis, whereas most cancers predominantly rely on glycolysis for energy production, a phenomenon known as the Warburg effect. Nevertheless, a minority of cancer types, including lymphoma, leukemia, and endometrial cancer, primarily utilize oxidative phosphorylation as their main energy source. Even in these instances, the reliance on glycolysis for energy rarely surpasses 60%. A limited number of cancers employ glutamine as a principal energy source, partly due to its provision of nitrogen essential for nucleotide (DNA, RNA) synthesis. Cancer stem cells frequently depend on either oxidative phosphorylation or glutamine as their primary energy source.

Diagnosis

Most cancers are initially identified either through the manifestation of specific signs or symptoms or via screening protocols. Neither of these methods provides a definitive diagnosis, which necessitates the histopathological examination of a tissue sample by a pathologist. Individuals with suspected cancer undergo medical investigations, commonly involving blood tests, X-rays, (contrast) CT scans, and endoscopy.

The tissue diagnosis obtained from a biopsy provides crucial information regarding the proliferating cell type, its histological grade, genetic abnormalities, and other pertinent characteristics. Collectively, this information is instrumental in assessing the prognosis and determining the optimal treatment strategy.

Cytogenetics and immunohistochemistry represent additional categories of tissue-based diagnostic tests. These analyses yield insights into molecular alterations, such as mutations, fusion genes, and numerical chromosomal changes, thereby also informing prognosis and guiding therapeutic decisions.

A cancer diagnosis can induce significant psychological distress, and psychosocial interventions, such as talking therapy, may offer support to affected individuals. While some individuals opt for broad disclosure of their diagnosis, others prefer to maintain privacy, particularly soon after diagnosis, or to disclose the information only partially or to a select group of people.

Classification

Cancers are categorized based on the cellular morphology of the tumor cells, which is presumed to indicate their tissue of origin. These classifications include:

• Carcinoma: These cancers originate from epithelial cells. This extensive group encompasses many of the most prevalent cancers, including nearly all those affecting the breast, prostate, lung, pancreas, and colon. The majority of these are of the adenocarcinoma type, signifying that the cancer exhibits gland-like differentiation.
• Sarcomas constitute malignancies originating from connective tissues, such as bone, cartilage, fat, and nerve, with their cellular genesis traced to mesenchymal cells located external to the bone marrow.
• Lymphomas and leukemias are distinct categories of cancer that develop from hematopoietic (blood-forming) cells, which egress from the bone marrow and typically undergo maturation in the lymph nodes and bloodstream, respectively.
• Germ cell tumors are neoplasms originating from pluripotent cells, frequently manifesting in the testicles or ovaries, exemplified by seminomas and dysgerminomas, respectively.
• Blastomas are malignant tumors that originate from immature precursor cells or embryonic tissues.

Neoplasms are typically designated by appending the suffixes -carcinoma, -sarcoma, or -blastoma to a Latin or Greek root word that denotes the organ or tissue of origin. For instance, malignancies of the liver parenchyma derived from malignant epithelial cells are termed hepatocarcinoma, whereas a neoplasm originating from primitive liver precursor cells is designated a hepatoblastoma, and a cancer arising from adipocytes is known as a liposarcoma. In certain prevalent cancers, the English name of the organ is employed; for example, the predominant form of breast cancer is referred to as ductal carcinoma of the breast. In this context, the descriptor ductal characterizes the microscopic morphology of the cancer, indicating its genesis within the milk ducts.

Benign tumors, which are non-malignant growths, are typically named by attaching the suffix -oma to the root word representing the organ. For example, a benign neoplasm of smooth muscle cells is termed a leiomyoma; a common manifestation of this benign uterine tumor is known as a fibroid. A notable exception is that certain malignant tumors, such as melanoma and seminoma, paradoxically utilize the -noma suffix, which can lead to terminological ambiguity.

Certain cancer classifications are based on the cellular morphology observed microscopically, including designations such as giant cell carcinoma, spindle cell carcinoma, and small-cell carcinoma.

Prevention

Cancer prevention encompasses proactive interventions designed to mitigate cancer risk. A substantial proportion of cancer diagnoses are attributable to environmental risk factors, many of which are modifiable through lifestyle choices. Consequently, cancer is largely considered preventable. Estimates suggest that 70% to 90% of prevalent cancers stem from environmental determinants and are thus potentially avertable.

Over 30% of cancer-related mortalities are potentially avertable through the elimination of various risk factors, including tobacco use, excessive weight or obesity, inadequate diet, sedentary lifestyles, alcohol consumption, sexually transmitted infections, and air pollution. Additionally, socioeconomic deprivation, specifically poverty, may function as an indirect contributor to human carcinogenesis. However, not all environmental etiologies are subject to personal control, exemplified by naturally occurring background radiation and malignancies arising from hereditary genetic disorders, which are not preventable through individual behavioral modifications.

A systematic analysis conducted by the Global Burden of Disease (GBD) in 2019 indicated that approximately 44% of all cancer fatalities, equating to about 4.5 million deaths or 105 million disability-adjusted life years lost, were attributable to identifiable and preventable risk factors, predominantly smoking, alcohol consumption, and elevated body mass index.

Dietary Factors

Although numerous dietary guidelines have been advanced to mitigate cancer risks, the supporting empirical evidence remains inconclusive. The principal dietary contributors to increased cancer risk are obesity and alcohol intake. While diets deficient in fruits and vegetables and rich in red meat have been implicated, systematic reviews and meta-analyses have not yielded consistent conclusions. For instance, a 2014 meta-analysis identified no correlation between fruit and vegetable consumption and cancer incidence. Conversely, coffee consumption is associated with a diminished risk of liver cancer. Research has established a link between excessive intake of red or processed meat and an elevated risk of breast, colon, and pancreatic cancers, a correlation potentially explained by the presence of carcinogens formed during high-temperature cooking. In 2015, the International Agency for Research on Cancer (IARC) reported an association between the consumption of processed meats (e.g., bacon, ham, hot dogs, sausages) and, to a lesser extent, red meat, with certain types of cancer.

Standard dietary recommendations for cancer prophylaxis generally advocate for a diet rich in vegetables, fruits, whole grains, and fish, while advising against the consumption of processed and red meats (such as beef, pork, and lamb), animal fats, pickled items, and refined carbohydrates.

Pharmacological Interventions

Pharmacological interventions offer prophylactic potential against certain cancers under specific conditions. For the general population, nonsteroidal anti-inflammatory drugs (NSAIDs) have demonstrated efficacy in reducing colorectal cancer risk; however, their prophylactic application is generally contraindicated due to associated cardiovascular and gastrointestinal adverse effects, leading to a net negative health outcome. Aspirin has been observed to decrease cancer-related mortality by approximately 7%. COX-2 inhibitors may mitigate polyp development in individuals with familial adenomatous polyposis, though they share similar adverse effect profiles with NSAIDs. Daily administration of tamoxifen or raloxifene has been shown to reduce breast cancer incidence in high-risk female populations. The risk-benefit ratio for 5-alpha-reductase inhibitors, such as finasteride, remains inconclusive.

Vitamin supplementation generally lacks demonstrable efficacy in cancer prevention. Although a correlation exists between diminished circulating vitamin D levels and elevated cancer risk, the causality of this relationship and the protective potential of vitamin D supplementation remain unestablished. A 2014 systematic review indicated no statistically significant impact of general supplementation on cancer risk. Conversely, another review from 2014 suggested that vitamin D₃ might reduce cancer mortality (translating to one fewer death per 150 individuals treated over a five-year period), though reservations regarding data quality were concurrently expressed.

Beta-carotene supplementation has been linked to an elevated incidence of lung cancer in high-risk populations. Folic acid supplementation has not demonstrated efficacy in preventing colon cancer and may, in fact, promote the development of colon polyps. Evidence does not support a reduction in cancer risk through selenium supplementation.

Vaccination

Vaccines have been developed to prevent infections caused by specific oncogenic viruses. Human papillomavirus (HPV) vaccines, including Gardasil and Cervarix, effectively reduce the risk of cervical cancer development. Similarly, the hepatitis B vaccine confers protection against hepatitis B virus infection, thereby mitigating the risk of hepatocellular carcinoma. The implementation of both HPV and hepatitis B vaccination programs is advisable in contexts where resources permit.

Screening

In contrast to diagnostic procedures initiated by overt symptoms or clinical signs, cancer screening aims to identify malignancies in asymptomatic individuals following their formation but prior to symptomatic manifestation. Screening methodologies may encompass physical examinations, biochemical analyses of blood or urine, or medical imaging techniques.

Screening protocols are not universally available for all cancer types. Furthermore, even when screening tests exist, their application may not be universally recommended for all individuals. Universal screening, also known as mass screening, entails the systematic examination of an entire population. Conversely, selective screening targets individuals identified as having an elevated risk, such as those with a pertinent family history. The determination of whether screening benefits supersede associated risks and costs involves the consideration of multiple factors, including:

• Potential adverse effects directly attributable to the screening modality; for instance, radiographic imaging entails exposure to potentially deleterious ionizing radiation.
• The diagnostic accuracy of the test in correctly identifying malignancy.
• The prevalence of the target cancer within the screened population; screening is typically less effective for rare cancer types.
• Potential risks associated with subsequent diagnostic or interventional procedures.
• The availability of an effective therapeutic intervention for the detected cancer.
• The demonstrable impact of early detection on enhancing treatment prognoses.
• The potential for overdiagnosis, where detected cancers may never progress to require clinical intervention.
• Patient acceptability and adherence to the screening protocol; overly burdensome or painful tests may lead to low participation rates.
• Economic implications and resource allocation.

Recommendations

U.S. Preventive Services Task Force

The U.S. Preventive Services Task Force (USPSTF) provides guidelines concerning screening for various malignancies:

• Strongly advocates for cervical cancer screening in sexually active women with a cervix, continuing at least until 65 years of age.
• Recommends colorectal cancer screening for individuals aged 50 to 75 years, utilizing methods such as fecal occult blood testing, sigmoidoscopy, or colonoscopy.
• Insufficient evidence exists to endorse or contraindicate screening for skin cancer, oral cancer, lung cancer, or prostate cancer in men younger than 75 years.
• Routine screening is not advised for bladder cancer, testicular cancer, ovarian cancer, pancreatic cancer, or prostate cancer.
• Advocates for biennial mammography for breast cancer screening in women aged 50–74, while explicitly not recommending breast self-examination or clinical breast examination. However, a 2013 Cochrane review determined that mammographic breast cancer screening did not significantly reduce mortality, attributing this to issues of overdiagnosis and subsequent overtreatment.

Japan

In regions with a high incidence of gastric cancer, photofluorography is employed for screening purposes.

Genetic Testing

Unofficial organizations advocate for genetic testing in individuals identified as high-risk for specific cancers. Those found to be carriers of relevant mutations may subsequently undergo intensified surveillance, chemoprevention, or prophylactic surgery to mitigate their future cancer risk.

Management

A diverse array of treatment modalities is available for cancer. Key approaches encompass surgery, chemotherapy, radiation therapy, hormonal therapy, targeted therapy, and palliative care. The selection of specific treatments is contingent upon the cancer's type, anatomical location, and histological grade, in addition to the patient's overall health status and personal preferences. The objective of treatment may range from curative intent to symptom management.

Chemotherapy

Chemotherapy involves the administration of one or more cytotoxic antineoplastic agents, or chemotherapeutic drugs, within a structured regimen to treat cancer. This broad term covers various pharmacological agents, categorized into groups such as alkylating agents and antimetabolites. Conventional chemotherapeutic agents primarily function by targeting and eliminating rapidly dividing cells, a characteristic feature of most malignant cells.

Research indicates that the administration of combined cytotoxic drugs, known as combination therapy, offers advantages over single-agent regimens in terms of survival statistics, tumor response, and disease progression. A Cochrane review specifically determined that combination therapy demonstrated greater efficacy in managing metastatic breast cancer. Nevertheless, the overall superiority of combination chemotherapy in achieving improved health outcomes, when balancing both survival benefits and potential toxicity, remains generally uncertain.

Targeted therapy represents a specialized form of chemotherapy designed to exploit specific molecular distinctions between cancerous and healthy cells. Early targeted therapies, for instance, focused on blocking the estrogen receptor molecule, thereby impeding the proliferation of breast cancer cells. Another prominent illustration is the class of Bcr-Abl inhibitors, which are effectively utilized in the treatment of chronic myelogenous leukemia (CML). Presently, targeted therapeutic agents are available for numerous prevalent cancer types, including but not limited to bladder cancer, breast cancer, colorectal cancer, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, pancreatic cancer, prostate cancer, skin cancer, thyroid cancer, and various other malignancies.

The effectiveness of chemotherapy is contingent upon the specific cancer type and its stage. When combined with surgical intervention, chemotherapy has demonstrated utility in treating various malignancies, including breast cancer, colorectal cancer, pancreatic cancer, osteogenic sarcoma, testicular cancer, ovarian cancer, and certain lung cancers. While chemotherapy can be curative for some cancers, such as particular leukemias, it proves ineffective for certain brain tumors and is deemed unnecessary for others, like most non-melanoma skin cancers. A significant limitation to chemotherapy's efficacy is its inherent toxicity to healthy bodily tissues. Even in cases where a permanent cure is not achievable, chemotherapy can serve to alleviate symptoms, such as pain, or to reduce the dimensions of an inoperable tumor, potentially rendering surgical resection feasible at a later stage.

Radiation Therapy

Radiation therapy employs ionizing radiation with the objective of either curing cancer or ameliorating its symptoms. Its mechanism of action involves inflicting damage upon the DNA of malignant cells, leading to mitotic catastrophe and subsequent cellular demise. To safeguard healthy tissues, such as skin or internal organs through which radiation must traverse to reach the tumor, precisely shaped radiation beams are directed from multiple angles. These beams converge at the tumor site, delivering a substantially higher dose to the malignancy compared to the surrounding healthy tissue. Similar to chemotherapy, the responsiveness of different cancers to radiation therapy varies considerably.

Radiation therapy is utilized in approximately 50% of cancer cases. The radiation source can be either internal (brachytherapy) or external. Low-energy X-rays are most frequently employed for treating superficial skin cancers, whereas higher-energy X-rays are reserved for internal malignancies. Typically, radiation therapy is administered as an adjunct to surgery and/or chemotherapy. However, for specific cancer types, such as early-stage head and neck cancer, it may constitute the sole treatment modality. Studies have indicated that post-surgical radiation therapy for brain metastases does not enhance overall patient survival when compared to surgery alone. Conversely, for painful bone metastases, radiation therapy has demonstrated efficacy in approximately 70% of patients.

Surgery

Surgical intervention constitutes the principal therapeutic approach for the majority of isolated, solid malignancies, potentially contributing to both palliation and extended survival. This procedure is generally crucial for the definitive diagnosis and staging of tumors, given the frequent necessity of biopsies. For localized cancers, surgery typically aims to excise the entire tumor mass, occasionally including regional lymph nodes. In specific cancer types, this approach proves adequate for disease eradication.

Palliative Care

Palliative care encompasses therapeutic interventions designed to enhance patient well-being and can be administered concurrently with cancer-directed treatments. This form of care addresses the reduction of physical, emotional, spiritual, and psychosocial distress. Distinct from treatments focused on direct cancer cell eradication, the paramount objective of palliative care is to elevate the patient's quality of life.

Individuals undergoing any phase of cancer treatment commonly receive some form of palliative care. In specific scenarios, professional medical organizations advocate for palliative care as the sole therapeutic response to cancer for patients who meet the following criteria:

• Exhibit a diminished performance status, indicating a restricted capacity for self-care.
• Have not responded favorably to previous evidence-based therapies.
• Do not qualify for enrollment in any pertinent clinical trials.
• Lack robust evidence suggesting the potential efficacy of further treatment.

Palliative care is sometimes erroneously equated with hospice care, leading to the misconception that it is exclusively appropriate for individuals nearing the end of life. Similar to hospice, palliative care endeavors to assist patients in managing their immediate requirements and enhancing comfort. However, a key distinction is that palliative care does not necessitate the cessation of cancer-directed treatments.

Numerous national medical guidelines advocate for the early integration of palliative care for patients experiencing distressing cancer-related symptoms or requiring assistance in managing their illness. For individuals initially diagnosed with metastatic disease, palliative care may be warranted immediately. Furthermore, palliative care is indicated for patients with a life expectancy of less than 12 months, even when aggressive treatments are pursued.

Immunotherapy

Since 1997, a diverse array of immunotherapeutic interventions, designed to stimulate or augment the immune system's capacity to combat cancer, has been introduced into clinical practice. These approaches encompass:

• Monoclonal Antibody Therapy
• Checkpoint Therapy (a therapeutic modality targeting immune checkpoints, which are regulators of the immune system)
• Adoptive Cell Transfer
• Chimeric Antigen Receptor (CAR) T-Cell Therapy

Laser Therapy

Laser therapy employs high-intensity light to manage cancer by inducing the regression or destruction of tumors and precancerous lesions. This modality is predominantly applied to superficial malignancies located on the body's surface or within the lining of internal organs. Specific applications include the treatment of basal cell skin cancer and the nascent stages of other cancers, such as cervical, penile, vaginal, vulvar, and non-small cell lung cancer. It is frequently integrated with other therapeutic strategies, including surgery, chemotherapy, or radiation therapy. Laser-induced interstitial thermotherapy (LITT), also known as interstitial laser photocoagulation, utilizes lasers to treat certain cancers via hyperthermia, a process that employs heat to reduce tumor size by damaging or eradicating cancer cells. Lasers offer greater precision compared to conventional surgery, resulting in reduced tissue damage, pain, hemorrhage, edema, and scarring. A notable drawback is the requirement for specialized surgical training. Furthermore, this treatment may incur higher costs than alternative therapies.

Alternative Medicine

Complementary and alternative cancer treatments encompass a heterogeneous collection of therapies, practices, and products that operate outside the purview of conventional medical paradigms. "Complementary medicine" denotes methodologies and substances employed in conjunction with conventional medical care, whereas "alternative medicine" refers to agents utilized as substitutes for conventional treatments. The majority of complementary and alternative cancer interventions have not undergone rigorous investigation or validation through conventional methodologies, such as clinical trials. While some alternative treatments have been examined and demonstrated to be inefficacious, they persist in being marketed and promoted. Cancer researcher Andrew J. Vickers asserted, "The label 'unproven' is inappropriate for such therapies; it is time to assert that many alternative cancer therapies have been 'disproven'."

Prognosis

Survival rates exhibit considerable variability, contingent upon the specific cancer type and its diagnostic stage, spanning from a high probability of survival to complete mortality within five years post-diagnosis. The prognosis typically deteriorates significantly once a cancer has metastasized. Approximately half of all patients undergoing treatment for invasive cancer (excluding carcinoma in situ and non-melanoma skin cancers) succumb to either the disease itself or its therapeutic interventions. The predominant cause of cancer-related fatalities is the metastasis of the primary tumor.

Survival outcomes are generally poorer in developing nations, partly attributable to the prevalence of cancer types that present greater treatment challenges compared to those commonly observed in developed countries.

Individuals who survive cancer exhibit approximately double the incidence of developing a second primary cancer compared to those who have never received a cancer diagnosis. This elevated risk is hypothesized to stem from several factors: the inherent random probability of developing any cancer, the improved survival rates from initial cancer diagnoses, shared risk factors contributing to both the first and subsequent cancers, adverse effects of initial cancer treatments (especially radiation therapy), and enhanced adherence to screening protocols.

The prediction of both short-term and long-term survival is influenced by numerous variables. Paramount among these are the specific cancer type, the patient's age, and their overall health status. Individuals characterized by frailty and co-morbidities typically demonstrate diminished survival rates compared to their healthier counterparts. Centenarians, for instance, are improbable to achieve a five-year survival, even with successful treatment interventions. Conversely, patients who report a superior quality of life generally exhibit extended survival durations. A reduced quality of life may be associated with depression, other complications, or disease progression, all of which can detrimentally impact both the quality and length of life. Furthermore, patients facing a less favorable prognosis may experience depression or report a poorer quality of life due to their perception of a potentially fatal outcome.

Cancer patients face an elevated risk of developing venous blood clots, a condition that can be life-threatening. While anticoagulants like heparin can mitigate the risk of these clots, their administration has not been demonstrated to enhance overall survival in individuals with cancer. Furthermore, patients receiving anticoagulant therapy are subject to an increased propensity for bleeding.

Despite its extreme rarity, certain forms of cancer, even when in advanced stages, can undergo spontaneous resolution. This phenomenon is scientifically termed spontaneous remission.

Epidemiology

Global estimates for 2018 indicate approximately 18.1 million new cancer diagnoses and 9.6 million cancer-related deaths. Projections suggest that around 20% of males and 17% of females will develop cancer during their lifetime, with 13% of males and 9% of females succumbing to the disease.

In 2008, approximately 12.7 million cancer cases were diagnosed globally (excluding non-melanoma skin cancers and other non-invasive forms), leading to nearly 7.98 million deaths in 2010. Cancer is responsible for almost one in six fatalities worldwide. As of 2020, the leading causes of cancer-related mortality include lung cancer (1.8 million deaths), colorectal cancer (916,000), liver cancer (830,000), stomach cancer (769,000), and breast cancer (685,000). Consequently, invasive cancer represents the primary cause of death in developed nations and the second leading cause in developing countries, with over half of all cases originating in the latter.

Cancer-related deaths totaled 5.8 million in 1990. This mortality figure has subsequently risen, primarily attributed to increased life expectancies and evolving lifestyle patterns within the developing world. Age constitutes the most prominent risk factor for cancer development; while cancer can manifest at any age, the majority of patients with invasive forms are over 65. As noted by cancer researcher Robert A. Weinberg, "If we lived long enough, sooner or later we all would get cancer." The correlation between aging and cancer is partly explained by immunosenescence, the accumulation of DNA errors over a lifespan, and age-related alterations in the endocrine system. However, the impact of aging on cancer is complex, involving both promoting factors like DNA damage and inflammation, and inhibiting factors such as vascular aging and endocrine modifications.

Certain slow-growing cancers are notably prevalent yet frequently non-fatal. Post-mortem examinations conducted in Europe and Asia have revealed that up to 36% of individuals possess undiagnosed and seemingly benign thyroid cancer at the time of death, and that 80% of men develop prostate cancer by the age of 80. Given that these specific cancers do not contribute to patient mortality, their identification would constitute overdiagnosis rather than beneficial medical intervention.

Leukemia (34%), brain tumors (23%), and lymphomas (12%) constitute the three most prevalent forms of cancer observed in childhood. In the United States, approximately 1 in 285 children are affected by cancer. Between 1975 and 2002, the incidence of childhood cancer in the United States rose by an annual average of 0.6%, while in Europe, a 1.1% annual increase was recorded from 1978 to 1997. Conversely, mortality rates from childhood cancer in the United States declined by 50% between 1975 and 2010.

History

The presence of cancer spans the entirety of human history. The earliest documented account of cancer originates from the Egyptian Edwin Smith Papyrus, dating to approximately c. 1600 BC, which details breast cancer. Hippocrates (c. 460 BC – c. 370 BC) documented various forms of cancer, designating them with the Greek term καρκίνος karkinos, meaning 'crab' or 'crayfish'. This nomenclature arose from the visual characteristics of a sectioned solid malignant tumor, specifically its veins extending radially, akin to a crab's legs. Galen further elaborated, asserting that "cancer of the breast is so called because of the fancied resemblance to a crab given by the lateral prolongations of the tumor and the adjacent distended veins". Celsus (c. 25 BC – 50 AD) subsequently translated karkinos into the Latin word cancer, also signifying 'crab', and advocated for surgical intervention. In contrast, Galen (2nd century AD) opposed surgical treatment, instead proposing the use of purgatives. These therapeutic approaches remained largely influential for a millennium.

During the 15th, 16th, and 17th centuries, medical practitioners gained acceptance for conducting anatomical dissections to ascertain the etiology of death. Wilhelm Fabry, a German professor, posited that breast cancer resulted from a milk clot within a mammary duct. Concurrently, the Dutch professor Francois de la Boe Sylvius, influenced by Cartesian philosophy, theorized that all ailments stemmed from chemical processes, identifying acidic lymph fluid as the causative agent for cancer. Nicolaes Tulp, a contemporary of Sylvius, held the belief that cancer was a gradually disseminating poison and consequently deemed it contagious.

In 1761, physician John Hill identified tobacco sniffing as a causative factor for nasal cancer. Subsequently, in 1775, British surgeon Percivall Pott documented chimney sweeps' carcinoma, a scrotal cancer, as a prevalent condition among chimney sweeps. The widespread adoption of the microscope in the 18th century facilitated the discovery that the 'cancer poison' disseminated from the primary tumor via the lymph nodes to distant locations, a process termed 'metastasis'. This conceptualization of the disease was initially articulated by the English surgeon Campbell De Morgan between 1871 and 1874.

Society and culture

Despite the fact that numerous medical conditions, such as heart failure, often carry a more severe prognosis than the majority of cancer cases, cancer remains a subject of pervasive fear and societal taboos. The use of euphemisms like "a long illness" in obituaries to describe cancer-related deaths, rather than explicitly naming the disease, underscores a persistent stigma. Furthermore, cancer is frequently referred to euphemistically as "the C-word"; organizations like Macmillan Cancer Support employ this term in an effort to mitigate anxiety associated with the illness. In Nigeria, a local designation for cancer translates to "the disease that cannot be cured" in English. This deeply ingrained perception of cancer as an inherently challenging and frequently fatal condition is evident in the methodologies society employs for compiling cancer statistics: non-melanoma skin cancers, which represent approximately one-third of global cancer cases but result in very few fatalities, are specifically excluded from general cancer statistics due to their high curability, often achieved through a single, brief outpatient procedure.

In Western medical paradigms, patients' rights concerning cancer typically encompass the obligation to fully inform individuals about their medical condition and the prerogative to engage in shared decision-making that respects their personal values. Conversely, other cultures prioritize different rights and values. For instance, most African cultures emphasize familial well-being over individual autonomy. In certain African regions, a cancer diagnosis is frequently made at an advanced stage, rendering a cure impossible, and any available treatment would rapidly deplete family finances. Consequently, African healthcare providers often defer to family members regarding the timing and method of diagnosis disclosure, tending to proceed gradually and indirectly as the patient demonstrates readiness and capacity to process the severe news. Individuals from Asian and South American nations also generally favor a more gradual and less direct approach to disclosure than is commonly advocated in the United States and Western Europe, sometimes believing that withholding a cancer diagnosis is preferable. While diagnostic disclosure has become more prevalent than in the 20th century, comprehensive prognosis disclosure is still not universally offered to many patients globally.

In the United States and some other societies, cancer is conceptualized as a malady requiring a "fight" to quell a "civil insurrection," leading to the declaration of a "war on cancer" in the US. Military metaphors are frequently employed in describing the human impact of cancer, underscoring both the patient's health status and the imperative for immediate, decisive personal action, rather than procrastination, denial, or sole reliance on others. These military analogies also serve to rationalize radical and destructive therapeutic interventions. During the 1970s, a somewhat popular alternative cancer treatment in the US involved a specialized form of talk therapy, predicated on the notion that cancer originated from a negative disposition. Individuals exhibiting a "cancer personality"—characterized by depression, repression, self-loathing, and an inability to express emotions—were believed to have subconsciously willed their cancer into existence. Certain psychotherapists asserted that altering a patient's life outlook could cure the disease. Among other ramifications, this belief enabled society to assign blame to the victim for either causing the cancer (by "desiring" it) or impeding its cure (by failing to achieve sufficient happiness, fearlessness, and affection). It also exacerbated patient anxiety, as they erroneously believed that natural emotions such as sadness, anger, or fear would shorten their lives. This concept was critically derided by Susan Sontag, who published Illness as Metaphor in 1978 while recovering from breast cancer treatment. Although the original premise is now largely considered fallacious, a diluted version persists in the widespread, yet incorrect, conviction that deliberately cultivating positive thinking enhances survival, a notion particularly pronounced within breast cancer culture.

The just-world fallacy offers an explanation for the blame or stigmatization directed at individuals with cancer, positing that attributing the disease to a patient's actions or attitudes allows those assigning blame to reassert a sense of control. This perspective is rooted in the blamers' conviction that the world is inherently equitable, and consequently, any severe illness, such as cancer, must represent a form of retribution for poor choices, given that in a just world, adverse events would not befall virtuous individuals.

Economic Impact

The aggregate healthcare expenditure for cancer in the United States was projected to be $80.2 billion in 2015. Notwithstanding the absolute increase in cancer-related healthcare spending over recent decades, the proportion of total health expenditure allocated to cancer treatment remained consistently near 5% between the 1960s and 2004. A similar trend has been observed in Europe, where approximately 6% of all healthcare expenditure is dedicated to cancer treatment. Beyond direct healthcare costs and financial toxicity, cancer also incurs indirect costs, encompassing productivity losses due to sick days, permanent incapacity, disability, and premature mortality during working age. Furthermore, cancer generates costs associated with informal care. Indirect costs and informal care expenses are typically estimated to surpass or parallel the direct healthcare costs of cancer.

Effect on Divorce

Research indicates that women are approximately six times more prone to divorce following a cancer diagnosis than men. A separate study revealed correlations between separation rates among cancer survivors and factors such as race, age, income, and co-existing medical conditions. Conversely, a comprehensive review observed a slight reduction in divorce rates for the majority of cancer types, while also highlighting significant heterogeneity and methodological limitations across numerous studies examining cancer's impact on marital dissolution.

Research

Given that cancer encompasses a diverse class of diseases, the prospect of a singular "cure for cancer" is improbable, akin to the absence of a universal treatment for all infectious diseases. Historically, angiogenesis inhibitors were erroneously perceived as a potential "silver bullet" therapy applicable across numerous cancer types. Currently, these inhibitors, alongside other cancer therapeutics, are employed in combination strategies to mitigate cancer-related morbidity and mortality.

Experimental cancer treatments undergo rigorous evaluation in clinical trials, where their efficacy is benchmarked against the most effective current therapies. Successful treatments for one specific cancer type may subsequently be investigated for their applicability to other cancer classifications. Furthermore, advanced diagnostic tests are continually being developed to facilitate the precise targeting of appropriate therapies to individual patients, informed by their unique biological profiles.

Key areas of focus within cancer research include:

• Identifying agents, such as viruses, and events, such as mutations, that induce or promote genetic alterations in cells predisposed to malignant transformation.
• Elucidating the exact characteristics of genetic damage and the specific genes impacted by such alterations.
• Investigating the biological ramifications of these genetic changes within the cell, encompassing both the genesis of defining cancer cell properties and the facilitation of subsequent genetic events that drive further cancer progression.

Advances in molecular and cellular biology, largely propelled by cancer research, have facilitated the development of novel cancer treatments since U.S. President Richard Nixon initiated the "war on cancer" in 1971. Subsequently, the nation has allocated more than $200 billion to cancer research, drawing funds from both public and private sectors. Between 1950 and 2005, the age- and population-adjusted cancer mortality rate decreased by five percent.

Intense competition for financial resources within the research community seems to have stifled the creativity, collaborative efforts, risk-taking, and original thought essential for groundbreaking discoveries. This environment disproportionately favors low-risk research focused on incremental advancements over more innovative, high-risk investigations. Additional repercussions of this competitive landscape include a proliferation of studies presenting sensational claims that lack replicability, alongside perverse incentives that encourage grantee institutions to expand without adequately investing in their own faculty and infrastructure.

Virotherapy, which employs viruses, is currently under investigation.

Following the COVID-19 pandemic, concerns have emerged regarding a potential deceleration in the pace of cancer research and treatment.

Pregnancy

Cancer impacts approximately 1 in 1,000 pregnant women. The malignancies most frequently diagnosed during pregnancy mirror those prevalent among non-pregnant women of childbearing age, including breast cancer, cervical cancer, leukemia, lymphoma, melanoma, ovarian cancer, and colorectal cancer.

Diagnosing a novel cancer in a pregnant individual presents challenges, partly because symptoms are often misattributed to typical pregnancy-related discomforts. Consequently, cancer is generally identified at a more advanced stage than in the general population. Certain imaging modalities, including MRIs (magnetic resonance imaging), CT scans, ultrasounds, and mammograms with fetal shielding, are deemed safe during gestation; however, others, such as PET scans, are contraindicated.

Cancer treatment protocols for pregnant women generally align with those for non-pregnant individuals. Nevertheless, radiation therapy and radioactive pharmaceuticals are typically avoided during pregnancy, particularly if the estimated fetal dose could surpass 100 cGy. In specific scenarios, some or all therapeutic interventions may be deferred until after childbirth, especially if the cancer is diagnosed in the later stages of pregnancy. Expedited deliveries are frequently employed to facilitate an earlier commencement of treatment. Surgical procedures are generally considered safe, though pelvic surgeries performed during the first trimester carry an elevated risk of miscarriage. Certain treatments, notably specific chemotherapy agents administered during the first trimester, are associated with an increased likelihood of birth defects and pregnancy loss, including spontaneous abortions and stillbirths.

Elective abortions are generally not medically mandated and typically do not enhance maternal survival for most prevalent cancer types and stages. However, in specific scenarios, such as advanced uterine cancer, pregnancy continuation may be infeasible, or a patient might opt for pregnancy termination to facilitate the initiation of aggressive chemotherapy.

Certain therapeutic interventions can impede a mother's capacity for vaginal delivery or breastfeeding. For instance, cervical cancer may necessitate a Caesarean section. Breast radiation therapy diminishes milk production in the treated breast and elevates the susceptibility to mastitis. Furthermore, numerous chemotherapeutic agents administered postpartum can transfer into breast milk, potentially posing risks to the infant.

Cancer in Non-Human Animals

Veterinary oncology, primarily focused on companion animals like cats and dogs, represents an expanding specialized field in affluent nations, frequently employing therapeutic modalities akin to those used in human medicine, such as surgery and radiotherapy. While the predominant cancer types vary, the overall incidence of cancer in pets appears comparable to or even higher than that observed in humans. Rodents are commonly utilized in cancer research, and investigations into naturally occurring cancers in larger animal species can provide valuable insights for human cancer research.

Data concerning cancer prevalence in wild animal populations remain scarce. However, a 2022 study investigating cancer risk in 110,148 non-domesticated zoo mammals across 191 species revealed that cancer is a pervasive mammalian disease, capable of manifesting at any point within mammalian phylogeny. This research further indicated that cancer susceptibility is not uniformly distributed among mammals. For example, species within the order Carnivora exhibit a heightened predisposition to cancer, with over 25% of clouded leopards, bat-eared foxes, and red wolves succumbing to the disease, whereas ungulates, particularly even-toed ungulates, consistently demonstrate low cancer risks.

In non-human species, several forms of transmissible cancer have been identified, characterized by the direct transmission of tumor cells between individuals. Notable examples include Sticker's sarcoma, or canine transmissible venereal tumor, observed in dogs, and devil facial tumor disease (DFTD) affecting Tasmanian devils.

• Cancer screening
• Causes of cancer
• Occupational cancer
• Metabolic theory of cancer

References

• IARC Publications (World Health Organization)
• "On telling cancer patients to have a positive attitude" in The Atlantic
• World Health Organization fact sheet on cancer
• National Firefighter Registry (NFR) for Cancer, National Institute for Occupational Safety and Health (NIOSH), United States
• European Agency for Safety and Health at Work (EU OSHA) initiative to prevent occupational exposure to carcinogens, providing resources for workplace safety.
• Occupational Cancer resources from the National Institute for Occupational Safety and Health (NIOSH).
• National Institute for Occupational Safety and Health (NIOSH) Pocket Guide to Chemical Hazards, Appendix A: Potential Occupational Carcinogens.