General oncology

Oncology is the science of tumors. This article explains basic concepts relevant to the development, progression, spread, complications, diagnosis, and management of cancer. Histological analysis helps to determine tumor type and grade, whereas the TNM classification system is used to assess staging. Because it is standardized and used internationally, the TNM classification helps unify oncological research and therapy protocols. Metastasis occurs via different pathways mainly by hematogenous or lymphatic spreading. Therapy can be curative (mostly in early tumor stages) or palliative (mostly later stages). In addition to surgically removing a tumor, it can be beneficial to perform neoadjuvant (before surgery) and/or adjuvant (after surgery) radiation, chemotherapy, or both. Response rates to these forms of treatment are highly variable.

In addition to local effects, such as compression or infiltration of neighboring structures, malignant tumors can also cause systemic complications such as paraneoplastic syndromes and cancer anorexia-cachexia syndrome. See “Paraneoplastic syndromes” article for more information.

For more details about tumor markers and immunohistochemical markers, see “Tumor markers”.

Terminology

Benign and malignant tumors

Tumor origin

In 2020, approximately 1.8 million people will be diagnosed with cancer in the United States. Cancer is the 2^nd leading cause of death; after heart disease. The most common type of cancer in both men and women is skin cancer, with basal cell carcinoma being more common than squamous cell carcinoma and melanoma. ^[1]

Epidemiology of common cancer types in 2020 ^[2]

The following numbers are an estimation of new cancer cases and their mortality in the United States (excluding skin cancer ).

• The most common types of cancer in men (excluding skin cancer)
  1. Prostate cancer
  2. Lung and bronchus cancer
  3. Colorectal cancer
• The most common cancer in women (excluding skin cancer)
  1. Breast cancer
  2. Lung and bronchus cancer
  3. Colorectal cancer
• The types of cancer with the highest mortality rate in both men and women (in descending order)
  1. Cancer of lung and bronchus
  2. Prostate cancer (men), breast cancer (women)
  3. Colorectal cancer
• The most common types of cancer that have the greatest mortality rate in children (< 15 years)
  1. Leukemia (ALL, AML)
  2. Brain and spinal cord tumors
  3. Neuroblastoma

Overview

• Definition: a multistep process by which normal cells develop and accumulate genetic mutations (inherited or acquired), resulting in a monoclonal expansion of mutated cells that can progress to the development of neoplasia
• Process
  1. Initiation: DNA damage
  2. Promotion: DNA damage passed on
  3. Latency: the time between promotion and progression
  4. Progression: proliferation of the neoplastic cell line with the acquired DNA damage, leading to malignant transformation

Properties of malignant cells

• Sustained proliferative signaling: due to mutation of genes regulating cell division and growth
  • (Proto‑)oncogene: See “Proto-oncogene” below.
  • Growth factor receptors; (e.g., HER2/neu, EGFR)
  • Signaling molecules; (e.g., Ras, B-Raf) ^[3]
  • Transcription factors; (e.g., MYC, TP53) ^[4]
  • Cell cycle regulators; (e.g., cyclins, CDKs)
• Evade growth suppressors ^[5]
  • Tumor suppressor genes: See “Tumor suppressor genes” below.
  • Loss of contact inhibition
    • Mutated or absent E-cadherin → loss of growth inhibitory signals and contact inhibition of proliferation → excessive cell proliferation
    • Due to mutations in genes that regulate contact inhibition (e.g., NF2 gene)
• Genome instability and mutations
  • Mutations: See “Gene mutations” and “Chromosomal translocation” in the “Basics of human genetics” article.
  • Gene amplification; : increased gene expression (e.g., overexpression of HER2/neu gene in several forms of breast cancer)
• Resist cell death
  • Occurs because of mutations in apoptosis regulatory genes
  • Loss of regulatory genes (e.g., Bax, TP53, BCL-2) leads to cell immortality and increased proliferation.
• Enable replicative immortality: telomerase reactivation → ↑ length of telomeres → ↑ number of possible cell replication cycles
• Deregulate cellular energetics: a shift in cellular metabolism from glycolysis and mitochondrial oxidative phosphorylation to glycolysis and preferential lactate generation, regardless of the oxygen supply (Warburg effect)
  • In differentiated, non-malignant cells, glycolysis converts glucose to pyruvate, which then undergoes mitochondrial oxidative phosphorylation under aerobic conditions, or anaerobic glycolysis to generate lactate under anaerobic conditions.
  • In malignant cells, the so-called Warburg effect occurs, in which pyruvate is preferentially converted to lactate, regardless of the cellular oxygen supply. This mechanism supplies rapidly dividing malignant cells with the necessary carbon to synthesize cellular structures. ^[6]
• Induce angiogenesis ^[5]
  • Angiogenesis helps maintain an adequate supply of oxygen and nutrients to the neoplastic cells.
  • Regulated by angiogenic (e.g., VEGF, FGF) and inhibitory factors that are produced by neoplastic or supporting cells
  • Occurs as:
    • Vasculogenesis: de novo formation of blood vessels from bone marrow-derived endothelial cells
    • Neoangiogenesis: formation of blood vessels from existing blood vessels and capillaries
  • Newly formed blood vessels may be dilated or leaky.
• Activate invasion and metastasis: See “Metastasis” below.
• Avoid immune detection: See “Defense mechanisms of malignant cells” below.
• Tumor-promoted inflammation

Defense mechanisms of malignant cells ^[7]

• Immune response modification
  • ↓ MHC class I expression on malignant cells → inability of cytotoxic T-cells to recognize and mount an immune response against these cells
  • Secretion of immunosuppressive molecules (e.g., TGF-β) → enhanced immune tolerance of malignant cells
  • Enhanced regulatory T-cell activity → limited immune response
• Immune checkpoints ^[8]
  • Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)
    • Upregulation of CTLA-4 → promotion of binding to B7 protein (surface receptor on antigen-presenting cells, also called CD80 or CD86) → T-cell inactivation and simultaneous reduction of costimulation by binding of CD28 to B7
    • CTLA-4 is inhibited by anti-CTLA-4 antibody ipilimumab.
  • Programmed death-ligand system
    • Expression of programmed death-ligand 1 (PD-L1) and PD-L2 on tumor cells surface or environment → binding to programmed cell death protein 1 (PD-1) on T-cells → T-cell dysfunction
    • PD-L1 and PD-L2 are inhibited by cancer immunotherapy agents atezolizumab, durvalumab, and avelumab.
    • PD-1 is inhibited by cancer immunotherapy agents nivolumab and pembrolizumab.

• Oncogene: the product of a gain-of-function mutation in a proto-oncogene which leads to overexpression of signaling proteins and growth factors, and thus, uncontrolled cellular proliferation (e.g., dysplasia, neoplasia)
  • Only one allele of the proto-oncogene requires damage to form an oncogene.
  • Often present in cancer cells
• Proto-oncogene: Genes that encode proteins that are important in normal cell division and cell differentiation. Examples include:
  • Protein kinases, e.g., protein kinase B (PKB)
    • PKB activates and inhibits various substrates, regulates apoptosis, activates translation and, indirectly, cell division.
    • PKB is activated by phosphatidylinositide 3-kinase (PI3K).
  • Ligand-directed transcription factors (intracellular hormone receptors)
  • GTP-binding proteins
    • G protein-coupled receptors
    • Small G-proteins such as Ras
  • Tyrosine kinase receptors
  • Growth factors and cytokines

“Adenocarcinoma of Lung Kinase”: Cancer (adenocarcinoma of lung) and the gene product (tyrosine kinase) are associated with ALK mutations.

L-myc is associated with lung cancer and n-myc with neuroblastoma.

c-KIT mutations affect CytoKIne recepTor production.

BCL-2 mutations are associated with diffuse large B-cell lymphoma.

• Tumor suppressor gene: a gene that normally controls and suppresses cell proliferation
  • Loss of function or inactivation leads to an increased risk of developing cancer.
  • Both alleles must be mutated in order for complete loss of function of the gene.

Mutations of the Rb (retinoblastoma) gene mutations cause Retinoblastomas and bone cancer (osteosarcoma).

PTEN mutation is associated with cancers of the Prostate, breasT, and ENdometrium.

Mutations in MEN 1 affect its gene product: MENin.

Chemical carcinogens

Radiation

Oncogenic infections

Tumor grading

• Definition: the process of classifying tumors based on their histological appearance (degree of cell differentiation)
• Indicators of poor differentiation
  • High-proliferation index
  • Presence of nucleoli
  • Giant cells with multiple nuclei
  • Hyperchromasia and heterogeneous chromatin distribution
  • Abnormal shape of cell or nucleus (nuclear atypia, enlarged nucleoli)
  • Different cell polarity
  • Different orientation of nuclei belonging to the same group of cells
  • Increase in mitotic figures
• Anaplasia: loss of morphological features of malignant cells so that resemblance to normal cells of a particular tissue where tumor cell originated from is lost

Grading systems

• AJCC grading system
  • Most commonly used grading system for nonhematological malignancies
  • Can be applied to a wide range of tumors

• Cancer-specific grading systems
  • Gleason score for prostate cancer
  • Nottingham grading system for breast cancer

Tumor staging ^[18]

• Definition: a method of determining and classifying a tumor according to its spread throughout the body
• Prognosis: The stage of the tumor is typically more important than the grade in determining the prognosis.

Spread determines Stage, and Stage determines Survival more than grade.

TNM classification

• T: size or direct extent of the primary tumor
  • Tcis: carcinoma in situ (no basement membrane penetration and no infiltration of submucosa)
  • T1–4 based on the size and/or extent of the primary tumor (T4 refers to the infiltration of neighboring organs)
• N: involvement of regional lymph nodes
  • N0: no lymph node involvement
  • N1–3 based on type of tumor and lymph node involvement
• M: presence of distant metastasis
  • M0: no distant metastasis
  • M1: present distant metastasis
  • Mx: unknown if distant metastasis present or not
• By adding a "C" to any category, it is possible to express the certainty of the diagnosis:
  • C1: routine procedure (clinical examination, x-ray)
  • C2: special procedure (e.g. ERCP, CT)
  • C3: based on biopsy, cytology or surgical exploration
  • C4: based on surgery and additional histopathological workup
  • C5: based on autopsy and histopathological workup
• By adding a prefix to TNM it is possible to indicate additional diagnostic or clinical information:
  • cTNM: staging based on clinical criteria
  • pTNM: histopathological staging

T, N, and M have independent prognostic values. N and M are typically the most important determinants of prognosis.

AJCC staging system

• Stage 0 (carcinoma-in-situ)
• Stage I–III: Tumor spread into nearby tissues.
• Stage IV: Tumor spread to distant parts of the body.

Cancer-specific staging systems

• Ann-Arbor staging system for Hodgkin lymphoma

Definition

• Metastasis: the spread of malignant cells to distant organs, tissues (e.g., colorectal cancer spreads to the liver)

Types of metastasis ^[19]

• Lymphatic metastasis
  • Dissemination of malignant cells via lymphatic vessels and lymph nodes
  • Most common route of metastasis for most carcinomas
• Hematogenous metastasis
  • Dissemination of malignant cells via blood vessels
  • Venous dissemination is more common than arterial dissemination because thin vein walls facilitate invasion.
  • Most common route of metastasis for most sarcomas
• Seeding (oncology): spillage of malignant cells to neighboring structures → implants at a site adjacent to the primary tumor and subsequent growth (e.g., after a biopsy of cancer the cancer cells spill and implant along the biopsy canal)
• Transcoelomic metastasis: spread of malignant cells into body cavities by penetration of surfaces such as the pleura, pericardium, and peritoneum (e.g., ovarian cancer spread to the liver via the peritoneal cavity)
• Canalicular metastasis: spread of malignant cells via canalicular system (e.g. bile ducts, lactiferous ducts, urinary tract, and the subarachnoid space)
• Cavitating pulmonary metastasis ^[20][21]
  • Spread of malignant cells that form cavitary lesions in the lungs (e.g., gastrointestinal adenocarcinomas, renal cell carcinoma)
  • Cavitary lesions are most commonly caused by squamous cell carcinoma (e.g., lung, head, and neck cancer)
• Cystic pulmonary metastasis: spread of malignant cells that form cystic lesions (contain a thin wall) in the lungs (e.g., colorectal cancer, soft tissue sarcomas, transitional cell carcinoma) ^[22][23]

“Four Carcinomas Route Hematogenously”: Follicular thyroid carcinoma, Choriocarcinoma, Renal cell carcinoma, and Hepatocellular carcinoma spread via the blood, compared to most carcinomas which spread lymphatically.

Mechanisms of metastasis

• Complex genetic changes are responsible for the selection of tumor subclones that are capable of metastasis.
• All metastases can be understood as arising from a two-part process: invasion of local extracellular tissue and dissemination and colonization.
  • Invasion of extracellular tissue: loss of adhesion to the basement membrane → invasion through basement membrane → passage through extracellular tissue
    • Loss of E-cadherin expression is associated with tumor metastatic potential.
    • Overproduction of proteases such as collagenase and matrix metalloproteinases degrade the basement membrane and interstitial matrix; . Neoplastic cells encounter various chemotactic and angiogenic factors in the newly exposed extracellular matrix.
    • Autocrine signaling via tumor-produced cytokines and paracrine signaling by cleaved matrix components and extracellular growth factors stimulate tumor cell locomotion towards vasculature or lymphatics.
  • Dissemination and colonization: encountering vascular or lymphatic routes → evasion of host defenses → implantation with distant tissue
    • Host defenses destroy the majority of circulating cancer cells. Mechanisms to avoid this include tumor cell aggregation, formation of platelet-tumor complexes, and binding of active coagulation factors to form malignant emboli.
    • Disruption of cellular adhesion molecules (laminins, cadherins) enables extravasation at distant tissues.

Common sites for cancer metastasis ^[24]

• The target organ for metastasis is usually the first capillary bed encountered by the neoplastic cells during spread.
• Certain types of cancer have a tendency to spread to particular organs (organ tropism; e.g., prostate cancer to bone, lung cancer to adrenal glands)

Approximately 50% of brain tumors and most bone tumors are not primary tumors but rather result from metastases.

“Cancers spread progressively to the liver”: Colon, Stomach, and Pancreas cancers metastasize to the liver.

“BLT with a kosher pickle and mayo on the bun”: Breast, Lung, Thyroid, Kidney, Prostate cancers, and Multiple myeloma metastasize to the bone.

• Definition: a syndrome characterized by progressive wasting of skeletal muscle mass with or without loss of body fat that occurs in patients with advanced cancer
• Pathophysiology: excess in proinflammatory cytokines (IL-1, IL-6, IFN-γ, and TNF-α) as a result of tumor growth → ↑ basal metabolic rate and catabolism
  • Negative nitrogen balance
  • Proteasomal activation and breakdown of myosin in skeletal muscle with loss of adipose tissue
• Clinical features: weight loss, poor appetite, decreased adipose tissue, muscle wasting, fatigue
• Diagnostics
  • There are no formal diagnostic criteria available.
  • Some features for diagnosis include:
    • Weight loss
    • Decreased appetite
    • Loss of subcutaneous fat
    • Muscle wasting (temporal, deltoid, and quadricep regions)
    • Edema (in the ankles, or around the sacrum)
    • Ascites
• Treatment
  • Progesterone analogs (e.g., megestrol acetate)
  • Corticosteroids (e.g., prednisolone)
  • The use of cannabinoids (e.g., dronabinol) in CACS remains controversial. ^[25][26]
  • Nutritional counseling ^[27][28]
• Prognosis: CACS is an indicator of poor prognosis.

Definitions

• Curative therapy: therapy with the intent of curing the disease
• Palliative therapy: therapy with the intent of relieving symptoms and improving quality of life
• Neoadjuvant therapy: chemotherapy and/or radiation before elective surgery (e.g., preoperative radiotherapy/chemotherapy in advanced rectal cancer)
• Adjuvant therapy: chemotherapy and/or radiation after surgery (e.g., postoperative chemotherapy in advanced colorectal cancer)

Modalities of antineoplastic therapy

• Surgery (e.g., hysterectomy, mastectomy, prostatectomy)
• Chemotherapeutic drugs (e.g., BEP regimen in seminoma testicular cancer)
  • Combinations of multiple classes of chemotherapy are often used to treat malignancy.
  • Cancers develop resistance by expressing multidrug resistance protein 1 (MDR1; also called P-glycoprotein). ^[29]
    • P-glycoproteins are transmembrane ATP-dependent efflux pump proteins that decrease intracellular concentrations of chemotherapeutics.
    • Expressed in adrenocortical carcinoma as well as cancers of the colon, liver, pancreas, kidney, ovary, and breast
• Radiotherapy
• Hormone therapy (e.g., antiandrogens in prostate cancer)
• Biological agents (e.g., CD20 antibodies in non-Hodgkin lymphoma)

Besides tumor grade and stage, it is important to consider the patient's performance status (Karnofsky score), general well-being, comorbidities, and personal wishes regarding treatment options.

Assessing resection

Assessing response

1. Lodish HF, Zipursky HF, Matsudaria HF, et al.. Molecular Cell Biology. Scientific American Library ; 2000
2. Assi T, Kattan J, Rassy E, et al. Targeting CDK4 (cyclin-dependent kinase) amplification in liposarcoma: A comprehensive review. Crit Rev Oncol Hematol. 2020; 153 : p.103029. doi: 10.1016/j.critrevonc.2020.103029 . | Open in Read by QxMD
3. Lee B, McArthur GA. CDK4 inhibitors an emerging strategy for the treatment of melanoma. Melanoma Management. 2015; 2 (3): p.255-266. doi: 10.2217/mmt.15.14 . | Open in Read by QxMD
4. Coleman WB. Molecular Pathogenesis of Prostate Cancer. Elsevier ; 2018 : p. 555-568
5. Skin Cancer. https://www.cdc.gov/cancer/skin/statistics/index.htm. . Accessed: December 17, 2020.
6. Cancer Stat Facts: Common Cancer Sites. https://seer.cancer.gov/statfacts/html/common.html. Updated: April 1, 2018. Accessed: June 18, 2018.
7. Mücke M, Weier M, Carter C, et al. Systematic review and meta-analysis of cannabinoids in palliative medicine. Journal of Cachexia, Sarcopenia and Muscle. 2018; 9 (2): p.220-234. doi: 10.1002/jcsm.12273 . | Open in Read by QxMD
8. Wang J, Wang Y, Tong M, Pan H, Li D. New Prospect for Cancer Cachexia: Medical Cannabinoid.. Journal of Cancer. 2019; 10 (3): p.716-720. doi: 10.7150/jca.28246 . | Open in Read by QxMD
9. R D-D. Impact of Nutritional Support in Patients with Gastrointestinal Malignancies - A Review. Journal of Nutritional Disorders & Therapy. 2012; 03 (01). doi: 10.4172/2161-0509.s11-001 . | Open in Read by QxMD
10. Gangadharan A, Choi SE, Hassan A, et al. Protein calorie malnutrition, nutritional intervention and personalized cancer care.. Oncotarget. 2017; 8 (14): p.24009-24030. doi: 10.18632/oncotarget.15103 . | Open in Read by QxMD
11. Flynn SD, Murren JR, Kirby WM, Honig J, Kan L, Kinder BK. P-glycoprotein expression and multidrug resistance in adrenocortical carcinoma.. Surgery. 1992; 112 (6): p.981-6.
12. Cell Signaling in Cancer. https://www.technologynetworks.com/cancer-research/articles/cell-signaling-in-cancer-313171. Updated: December 17, 2018. Accessed: March 6, 2020.
13. Bhagwat AS, Vakoc CR. Targeting Transcription Factors in Cancer. Trends in Cancer. 2015; 1 (1): p.53-65. doi: 10.1016/j.trecan.2015.07.001 . | Open in Read by QxMD
14. Mendonsa AM, Na T-Y, Gumbiner BM. E-cadherin in contact inhibition and cancer. Oncogene. 2018; 37 (35): p.4769-4780. doi: 10.1038/s41388-018-0304-2 . | Open in Read by QxMD
15. Liberti MV, Locasale JW. The Warburg Effect: How Does it Benefit Cancer Cells?. Trends Biochem Sci. 2016; 41 (3): p.211-218. doi: 10.1016/j.tibs.2015.12.001 . | Open in Read by QxMD
16. Rabinovich GA, Gabrilovich D, Sotomayor EM. Immunosuppressive Strategies that are Mediated by Tumor Cells. Annu Rev Immunol. 2007; 25 (1): p.267-296. doi: 10.1146/annurev.immunol.25.022106.141609 . | Open in Read by QxMD
17. Buchbinder EI, Desai A. CTLA-4 and PD-1 Pathways: Similarities, Differences, and Implications of Their Inhibition.. Am J Clin Oncol. 2016; 39 (1): p.98-106. doi: 10.1097/COC.0000000000000239 . | Open in Read by QxMD
18. Hecht SS, Hoffmann D. Tobacco-specific nitrosamines, an important group of carcinogens in tobacco and tobacco smoke. Carcinogenesis. 1988; 9 (6): p.875-884. doi: 10.1093/carcin/9.6.875 . | Open in Read by QxMD
19. What Causes Lung Cancer. https://www.lung.org/lung-health-and-diseases/lung-disease-lookup/lung-cancer/learn-about-lung-cancer/what-is-lung-cancer/what-causes-lung-cancer.html. Updated: November 24, 2017. Accessed: March 6, 2020.
20. Cooper R, Harrison A. The uses and adverse effects of beryllium on health. Indian Journal of Occupational and Environmental Medicine. 2009; 13 (2): p.65. doi: 10.4103/0019-5278.55122 . | Open in Read by QxMD
21. Beryllium Toxicity. https://www.atsdr.cdc.gov/csem/csem.asp?csem=5&po=6. . Accessed: December 17, 2020.
22. Deslauriers JR, Redlich CA. Silica Exposure, Silicosis, and the New Occupational Safety and Health Administration Silica Standard. What Pulmonologists Need to Know.. Annals of the American Thoracic Society. 2018; 15 (12): p.1391-1392. doi: 10.1513/AnnalsATS.201809-589ED . | Open in Read by QxMD
23. Cowherd SM. Tumor Staging and Grading: A Primer. Humana Press ; 2011 : p. 1-18
24. Kumar V, Abbas AK, Aster JC. Robbins & Cotran Pathologic Basis of Disease. Elsevier Saunders ; 2014
25. Yu X, Wang P, Liang Z. Cavitary Pulmonary Metastases: CT Features and Their Correlation with the Pathology of the Primary Malignancy. The Chinese-German Journal of Clinical Oncology. 2004; 3 (1). doi: 10.1007/s10330-004-0208-1 . | Open in Read by QxMD
26. Gunasekaran K, Baskaran B, Rahi MS, Rudolph D, Parekh J. Cavitating pulmonary metastases from a renal cell carcinoma. Clinics and Practice. 2020; 10 (1). doi: 10.4081/cp.2020.1234 . | Open in Read by QxMD
27. Sagar D, Adeni A. Unusual cystic lung metastasis. BMJ Case Reports. 2018 : p.bcr-2018-224648. doi: 10.1136/bcr-2018-224648 . | Open in Read by QxMD
28. Fielli M, Avila F, Saino A, Seimah D, Fernández Casares M. Diffuse cystic lung disease due to pulmonary metastasis of colorectal carcinoma. Respiratory Medicine Case Reports. 2016; 17 : p.83-85. doi: 10.1016/j.rmcr.2015.12.006 . | Open in Read by QxMD
29. Obenauf AC, Massagué J. Surviving at a Distance: Organ-Specific Metastasis. Trends in Cancer. 2015; 1 (1): p.76-91. doi: 10.1016/j.trecan.2015.07.009 . | Open in Read by QxMD
30. Chen C-Y, Peng H-C, Chen Y-Y, Chan C-C, Yu C-J. Association of environmental heavy metals exposure and lung cancer incidence and prognosis. 11.1 Lung Cancer. 2016 . doi: 10.1183/13993003.congress-2016.pa2805 . | Open in Read by QxMD