Neoplasm and Oncology Overview

Neoplasm

• Neoplasia means new growth; a new growth is called a neoplasm.
• Tumor originally referred to swelling caused by inflammation. Now, the term is synonymous with neoplasm.
• Oncology is the study of tumors or neoplasms (Greek oncos = tumor).
• An eminent British oncologist, Rupert A. Willis, defined neoplasm as "an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the normal tissues and persists in the same excessive manner after cessation of the stimuli which evoked the change."
• James Ewing defined neoplasm as a relatively autonomous growth of tissue.
• The persistence of tumours, even after the initial stimulus is gone, results from genetic alterations passed down to the progeny of the tumor cells.
• These genetic changes permit excessive and unregulated proliferation that becomes autonomous (independent of physiologic growth stimuli).
• Tumours generally remain dependent on the host for nutrition and blood supply.

Oncogenes

• Oncogenes are a group of genetic mutations that cause cancer.
• These mutated genes are a mutated form of genes that manage cell growth.
• Oncogenes cause uncontrolled cell growth and division when the genes change into oncogenes.
• Genes promoting autonomous cell growth in cancer cells are called oncogenes, while their unmutated counterparts are called proto-oncogenes.
• Oncogenes are created by mutations in proto-oncogenes and have the ability to promote cell growth even in the absence of normal growth-promoting signals.
• Examples of genes that can mutate into oncogenes include RAS (lung), HER2 (breast), and Cyclin D.

Proto-oncogenes

• Proto-oncogenes are genes that regulate normal cell growth and division.
• They can mutate into oncogenes, which cause cancer.
• Examples of proto-oncogenes include RAS, HER2, and Cyclin D.

Principles involved in the molecular basis of cancer

• Nonlethal genetic damage is the core of carcinogenesis (the development of cancer).
• Genetic damage (mutation) can be acquired through environmental factors (chemicals, radiation, viruses/bacteria) or inherited in the germ line.
• Environmental factors, in this context, comprise any acquired defect caused by exogenous agents or endogenous products of cell metabolism.

Tumours

• A tumour forms when a single precursor cell with genetic damage undergoes clonal expansion.
• Tumours are often monoclonal, and sometimes multiclonal.
• Tumours are abnormal tissue masses where cells proliferate excessively or do not die when they should.
• Tumours can develop in any part of the body, including organs, joints, and bones.

Classes of normal regulatory genes

• Five classes of normal regulatory genes are primary targets for genetic damage in cancer:
  • Growth-promoting proto-oncogenes
  • Growth-inhibiting tumor suppressor genes
  • Genes that regulate cell death (apoptosis)
  • Genes involved in DNA repair
  • Metastatic genes

Carcinogenesis

• Carcinogenesis is a multistep process that happens at both phenotypic and genetic levels.
• The process results from the accumulation of multiple mutations.

Neoplasm types

• Benign neoplasms: characterized by relatively innocent microscopic and macroscopic features.
• Benign tumours remain localized.
• Benign tumours are usually amenable to local surgical removal, and patients typically survive.
• However, benign tumours can sometimes be responsible for serious diseases.
• Examples of common benign neoplasms include fibroids, polyps, and sebaceous cysts.
• Malignant neoplasms are collectively known as cancers.
• Malignant tumours are characterized by a crab-like adherence to surrounding tissues.
• Malignant neoplasms can invade and destroy adjacent structures and spread to distant sites (metastasis), often leading to death.
• Examples of common malignant neoplasms include lung cancer, leukemia, and lymphoma.

Nomenclature

• Neoplasms are named based on their two factors: histological types (mesenchymal and epithelial) and behavioural patterns (benign and malignant).
• Benign mesenchymal neoplasms originating from muscle, bone, fat, blood vessels, nerves, and fibrous/cartilage tissues have names ending in -oma (e.g., Rhabdomyoma, osteoma, lipoma, hemangioma, neuroma, fibroma, chondroma).
• Adenoma (benign neoplasm of glandular epithelium), fibroadenoma (benign neoplasm of the breast), and leiomyoma (benign neoplasm of smooth muscle)
• Malignant Mesenchymal tumors are called Sarcomas (fleshy tumours), e.g., fibrosarcoma, liposarcoma, osteosarcoma, and hemangiosarcoma.
• Malignant epithelial tumors derived from any of the three germ cell layers are called carcinomas.

Mechanisms of tumor invasion and metastasis

• Carcinoma in situ is a group of abnormal cells confined to the original site of formation.
• Malignant cells bind to basement membrane components (e.g., laminin).
• Malignant cells break down the basement membrane by releasing collagenase type IV and other proteases.
• Cells invade the extracellular matrix.
• Cells detach from the primary tumour.
• Cells undergo embolization and survival in the circulation.
• Extravasation occurs in the secondary sites.
• Cells can evade the host defense.
• Progressive growth occurs.
• Metastasis happens.

Pathways of spread

• Seeding of body cavities and surfaces
• Lymphatic spread
• Hematogenous spread

Premalignant disorders

• Hereditary premalignant disorders include familial cancers (breast, ovarian, colon, brain).
• Some families have documented clustering of cancers.
• Autosomal recessive syndromes with defective DNA repair can also be included.
• Acquired preneoplastic disorders are also important causes of premalignant conditions.

Types of Carcinogenesis

• Many factors induce neoplastic transformation in cells.
• These include chemical, radiation, and viral carcinogens, including bacteria like H. pylori.

Effects of tumours on the host

• Local and hormonal effects:
  • Cancers in or metastatic to endocrine glands can lead to endocrine insufficiency by destroying the gland.
  • Neoplasms, both benign and malignant, can cause obstruction in the gut as they enlarge.

Cancer cachexia

• Cachexia is a common symptom of cancer, including progressive loss of body fat and lean body mass, weakness, anorexia, and anemia.
• Unlike malnutrition, weight loss in cachexia equally affects fat and muscle tissue.
• The level of cachexia is often correlated with the tumor burden.

Immunology

• Immunology is the study of the cells, molecules, organs, and systems that recognize and eliminate foreign materials.
• Immunity is the body's defense against pathogenic microorganisms.
• Innate and adaptive immunity are the two main types of immunity.

Innate Immunity

• Innate immunity provides a first line of defense against pathogens.
• It is always on.
• Physical barriers like skin, hair, mucous membranes (with acidic content in GIT, vagina) play a significant role.
• White blood cells—basophils, mast cells, monocytes, neutrophils, and macrophages—are also involved in the process and act quickly.

Adaptive Immunity

• Adaptive immunity steps in after innate defenses are compromised.
• Adaptive immunity is specific to pathogens.
• It develops over time, through encounter or vaccination with pathogens.
• Adaptive immunity involves T and B cells.
• T cells mediate cell-mediated immunity.
• B cells mediate humoral immunity, producing antibodies.

Host Defense against Tumours - Immune Surveillance

• Paul Ehrlich proposed that the immune system recognizes and eliminates tumor cells.
• Lewis Thomas and Macfarlane Burnet further developed this concept, referring to it as immune surveillance.
• The immune system monitors the body for emerging malignant cells.
• The immune system aims to destroy these emerging cells.

Anti-tumour Effector Mechanisms

• Cell-mediated immunity is the dominant anti-tumor mechanism in vivo.
• Antibodies are not effective in controlling physiological tumor conditions.
• Cytotoxic T lymphocytes (CD8+ CTLs) play a protective role against virus-associated tumors (like EBV and HPV tumors).
• Natural killer (NK) cells can destroy tumor cells without prior sensitization—they provide the first line of defense against tumor cells.
• Activated macrophages exhibit cytotoxicity against tumor cells in vitro (in test tubes); T cells and NK cells activate macrophages.
• Antibodies against tumor cells may have therapeutic benefits but there is limited evidence in spontaneous tumors.

Immune Surveillance and Escape Mechanism

• Most cancers arise in people without overt immunodeficiency.
• This suggests that tumor cells develop mechanisms to evade the immune system.
• The evasion involves strategies like:
  • Failure to produce tumor antigens
  • Antigen loss variants
  • MHC deficiency