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Due to our environmental change, neoplasia is much more common worldwide. And nowadays some well-developed modalities of cancer diagnosis are available. That is why we have to learn about neoplasia. Neoplasia is defined as a genetic disorientation of cell growth that is triggered by acquired or less commonly inherited mutations affecting a single cell and its clonal progeny. Nonlethal genetic damage lies at the heart of carcinogenesis. Genetic damage may be acquired or inherited. Mainly four types of cellular genes are involved in molecular carcinogenesis: 1. Growth-promoting proto-oncogenes, 2. Growth-inhibiting tumor suppressor genes, 3. Genes that regulate apoptosis, and 4. Genes involved in DNA repair. Carcinogenesis is a multistep process. Each cancer must result from accumulation of multiple mutations. Besides this carcinogens like chemicals, microbial and radiation can cause genetic damage or mutations that initiate cancer. Initiation of carcinogenesis is started with mutations and promotion of tumor growth is in involved cell. Due to the advanced tumor diagnosis, it helps in early tumor detection. We can identify a malignant cell by cell criteria. This property helps us to treat cancer early and help us to cure it. Therefore, nowadays tumor pathology or neoplasia is a topic of the time.
Dr. Sirajul Islam Medical College and Hospital, Dhaka, Bangladesh
*Address all correspondence to: ajmiree.flora2020@gmail.com
1. Introduction
Neoplasia → new growth
Oncology → study of tumors or neoplasm.
(‘Oncos’ means Tumor)
Definition → Neoplasia is defined as a genetic disorientation of cell growth that is triggered by acquired or less commonly inherited mutations affecting a single cell or its clonal progeny [1].
These mutations give the neoplastic cells a survival and growth advantage, resulting in excessive proliferation that is independent of physiological growth signals and control.
1.1 Salient features of neoplasia
Origin: Neoplasms arise from cells that normally maintain a proliferative capacity.
Genetic disorder: Cancer is due to permanent genetic changes in the cell, known as mutations. These mutations may occur in genes that regulate cell growth, apoptosis, or DNA repair.
Heritable: The genetic alterations are passed down to the daughter tumor cells.
Monoclonal: All the neoplastic cells within an individual tumor originate from a single cell or clone of cells that have undergone a genetic change. Thus, tumors are said to be monoclonal.
Carcinogenic stimulus: The stimulus responsible for the uncontrolled cell proliferation may not be identified or is not known.
Autonomy: In neoplasia, there is excessive and unregulated proliferation of cells that do not obey the normal regulatory control. The cell proliferation is independent of physiologic growth stimuli. But tumors are dependent on the host for their nutrition and blood supply.
Irreversible: Neoplasm is irreversible and persists even after the inciting stimulus is withdrawn or gone.
Differentiation: It refers to the extent to which the tumor cells resemble the cell of origin.
A tumor may show varying degrees of differentiation ranging from relatively mature structures that mimic normal tissues (well-differentiated) to cells, so primitive that the the cell of origin cannot be identified (poorly differentiated).
Persists even after withdrawal of stimulus (autonomous).
Permanent genetic change in the cell.
1.3 Components of neoplasms
Tumors (both benign and malignant) consist of two basic components:
Microscopic:
Parenchyma: It is made up of neoplastic cells. The nomenclature and biological behavior of tumors are based primarily on the parenchymal component of tumor.
Stroma: It is the supporting, nonneoplastic tissue derived from the host.
Components: Connective tissue, blood vessels, and inflammatory cells (e.g., macrophages and lymphocytes).
Inflammatory reaction: Stroma may show inflammatory reactions in and around the tumors. It may be due to ulceration and secondary infection in the tumors, especially on the surface of the body.
This type of inflammatory reaction may be acute, chronic, or rarely granulomatous reaction. Some tumors show inflammatory reactions even in the absence of ulceration. It is due to cell-mediated immunologic response of the host against the tumor in an attempt to destroy the tumor. For example, lymphocytes in the stroma are seen in seminoma testis and medullary carcinoma of the breast.
Importance of stroma: It is required for growth, survival, and replication of tumor (through blood supply) cells [1].
Tumor consistency depends on amount of stroma:
Soft and fleshy: These tumors have scanty stroma.
Desmoplasia: Parenchymal tumor cells may stimulate the formation of an abundant collagenous stroma.
referred to as desmoplasia. For example, some carcinomas in female breasts have stony hard consistency (or scirrhous) [1].
Tumors are classified as benign and malignant, depending on the biological behavior of a tumor.
Benign tumors: They have relatively innocent microscopic and gross characteristics
Remain localized without invasion or metastasis.
Well-differentiated: Their cells closely resemble their tissue of origin.
Prognosis: It is very good, can be cured by surgical removal in most patients and the patient generally survives [1].
Malignant tumors: Cancer is the general term used for malignant tumors. The term “cancer” is derived from the Latin word for crab, because similar to a crab, malignant tumors adhere to any part that they seize on, in an obstinate manner.
Invasion: Malignant tumors invade or infiltrate into the adjacent tissues or structures.
Metastasis: Cancers spread to distant sites metastasize), where the malignant cells reside, grow, and again invade.
Exception: Basal cell carcinoma of the skin, which is histologically malignant (i.e., it invades aggressively), rarely metastasizes to distant sites. Glioma is a malignant tumor of CNS.
Genetic predisposing and interactions between environmental and inherited factors.
3.1 Global impact of cancer
2018 → 9.5 million deaths were caused by cancer worldwide, one in six deaths.
No of cancer cause
No of cancer related deaths
↓
↓
Increase to 21.4 million
Increase to 13.2 million
M/C cancer in men → prostate, lung, colon, rectum.
M/C cancer in women → breast, lung, colon/rectum.
Environmental factors although both genetic and environmental factors contribute, Environmental influences are the dominant risk factors for most cancers. Incidence of cancer increases with age due to according of somatic mutations and decrease in immune competence in older individual [2, 3, 4, 5].
3.2 Age
Age was an important implication of the risk of cancer.
Most carcinomas occur in adults older than 55 years of age.
Mean age range for cancer in women – 40 to 79 years and in men – 60 to 79 years.
3.3 Infectious agents
15% cancers worldwide are caused directly/indirectly by infectious agents.
Risk is three times higher in developing countries.
E.g. Role of HPV → Cervical Carcinoma, Head and neck carcinoma.
3.4 Smoking
Implicated in cancers of the mouth, larynx, Pharynx, esophagus, Pancreas, bladder, and lung cancers (90%).
3.5 Alcohol consumption
Increased risk of carcinoma of oropharynx (excluding lip); larynx and esophagus.
Increases risk of cirrhosis and hepatocellular carcinoma.
(2) + (3) ace synergistically.
3.6 Diet
Diet Plays important role in cancers of prostate breast and colorectal cancer.
3.7 Obesity
Associated with increased cancer risk 14% cancer death in men and 20% cancer death in women. [Risk Associated with obesity]
3.8 Reproductive history
Lifelong exposure of estrogen increase risk (unopposed by progesterone) of carcinoma of tissue exposed to the hormones. For example-carcinoma of breast and endometrium.
3.9 Environmental carcinogens
For example, U-V- rays from sun, well water (Arsenic) medications (Methotrexate) work place (Asbestos) Home (Grilled meat; High-fat diet, alcohol) (Table 3) [2, 3, 4, 5].
Pathologic condition
Associated neoplasm(s)
Etiologic agent
Asbestosis, silicosis
Mesothelioma, lung carcinoma
Asbestos fibers, silica particles
Inflammatory bowel disease
Colorectal carcinoma
Lichen sclerosis
Vulvar squamous cell carcinoma
Pancreatitis
Pancreatic carcinoma
Alcoholism, germline mutations (e.g., in the trypsinogen gene)
Chronic cholecystitis
Gallbladder cancer
Bile acids, bacteria, gallbladder stones
Reflux esophagitis, Barrett esophagus
Esophageal carcinoma
Gastric acid
Sjogren syndrome, Hashimoto thyroiditis
MALT lymphoma
Opisthorchis, cholangitis
Cholangiocarcinoma, colon carcinoma
Liver flukes (Opisthorchis viverrinl)
Gastritis/ulcers
Gastric adenocarcinoma, MALT lymphoma
Helicobacter pylori
Hepatitis
Hepatocellular carcinoma
Hepatitis B and/or C virus
Osteomyelitis
Carcinoma in draining sinuses
Bacterial infection
Chronic cervicitis
Cervical carcinoma
Human papillomavirus
Chronic cystitis
Bladder carcinoma
Schistosomiasis
Table 3.
Chronic inflammatory states and cancer.
3.10 Precancerous conditions
Certain non-neoplastic disorders have association with cancer, termed precancerous conditions.
They are important to recognize because some precursor lesions can be detected by screening procedures, thereby reducing the risk of developing cancer.
Examples:
Skin: Solar actinic keratosis, Marjolin ulcer, Dysplastic nevi, Leukoplakia, Radio dermatitis.
Oral cavity: Leukoplakia of the oral cavity.
Female genital tract: Cervical dysplasia, leukoplakia of vulva, endometrial hyperplasia.
All cancers display eight fundamental changes in cell physiology, which are considered the hallmarks of cancer.
These changes are:
Self-sufficiency in growth signals: Tumors have the capacity to proliferate without external stimuli, usually as a consequence of oncogene activation.
Insensitivity to growth-inhibitory signals: Tumors may not respond to molecules that are inhibitory to the proliferation of normal cells such as cyclin-dependent kinases (CDKIs).
Altered cellular metabolism: Tumor cells undergo a metabolic switch to aerobic glycolysis, which enables the synthesis of the macromolecules and organelles that are needed for rapid cell growth – called the Warburg effect.
Evasion of apoptosis: Tumors are resistant to programmed cell death.
Limitless replicative potential (immortality): Tumors have unrestricted proliferative capacity to avoid cellular senescence.
Sustained angiogenesis: Tumor cells are not able to grow without vascular supply to bring nutrients, oxygen and remove waste products. So, tumors must induce angiogenesis.
Ability to invade and metastasize: Tumor metastases are the cause of the vast majority of cancer deaths [6].
Ability to evade the host immune response – cancer cells exhibit a number of alterations (in the innate and adaptive immune system) that allow them to evade the immune response.
Protooncogenes: Proto oncogenes have multiple roles but all participate at some level in signaling pathways that drive proliferation.
Normal cellular genes, whose products promote cell proliferation.
Unmutated version.
Proto-oncogenes may encode growth factors, growth factor receptors, signal transducers, transcription factors, or cell cycle components (Table 4).
Oncogenes:
Genes that promote autonomous cell growth in cancer cells are called oncogenes.
Mutant versions of proto-oncogenes.
Encode proteins called oncoproteins.
Have the ability to promote cell growth in the absence of normal growth promoting signal (Table 5) [7, 8, 9, 10].
Tumor suppressor gene:
Genes negatively regulate proliferation. Apply brakes or arrest cell cycle to cell proliferation.
Abnormalities in these genes lead to failure of growth inhibition.
Effect on the regulation of the cell cycle on promote apoptosis, and sometimes do both.
Mutation in tumor suppressor gene causes unregulated cell growth.
First tumor-suppressor protein discovered was the Retinoblastoma protein (pRb) in retinoblastoma (Table 6) [11, 12, 13, 14].
Category
Prolo-onicogene
Mode of activation in tumor
Associated human tumor
Growth factors
PDGFB chain
PDGFB
Overexpression
Astrocytoma
Fibroblast growth factors
HST1
Overexpression
Osteosarcoma stomach cancer bladder
FGF3
Amplification
Cancer breast cancer melanoma
TGF-a
TGFA
Overexpression
Astrocytomas
HGF
HGF
Overexpression
Hepatocellular carcionmas, thyroid cancer
Growth factor receptors
EGF-receptor family
ERBB1 (EGFR)
Mutation amplification
Adenocarinoma of lung
ERBB2 (EGFR)
Breast carcinoma
FMS-like tyrosin kinase 3
FLT3
Point mutation
Leukemia
Receptor for neurotrophic factors
RET
Point mutation
Multiple endocrine neoplasia 2A and B, familial medullary thyroid carcinomas
Selected oncogenes, their mode of activation, and associated human tumors.
Cell cycle component
Main function
Cyclins and cyclin-dependent kinases
CDK4; D cyclins
Form a complex that phosporylates RB, allowing the cell to progress througe the G, regtriction point
Cell cycle inhibitors
CIP/KIP family: p21, p27 (CDKN1A-D)
Block the cell cycle by binding to cyclin-CDK complexes
p21 Is induced by the tumor suppressor p53
p27 responds to growth suppressors such as TGF-B
INK4/ARF familly (CDKN2A-C)
p16/ink4A and promotes the inhibitory effects of RB
p14ARF increases p53 levels by inhibiting MDM2 activity
Cell cycle checkpoint components
RB
Tumor suppressive “pocket” protein that binds E2F transcription factors in its hypophosphorylated state, preventing G,/S transition; also interacts with several transcription factors that regulate differentiation
p53
Tumor suppressor altered in the majority of cancers; causes cell cycle arrest and apoptosis. Acts mainly through p21 to cause cell cycle arrest. Causes apoptosis by inducing the transcription of pro-apoptotic genes such as BAX. Levels of p53 are negatively regulated by MDM2 through a feedback loop. p53 is required for the G1/S checkpoint and is a main component of the G2/M checkpoint.
Table 5.
Cell cycle components and inhibitors that are frequently mutated in cancer.
Gene
Protein
Function
Familial syndromes
Sporadic cancers
Inhibitors of mitogenic signaling pathways
APC
Adenomatous polyposis coli protein
Inhibitor of WNT signating
Familial colonic polyps and carcinomas
Carcinomas of stomach, colon, pancreas; melanoma
NF1
Neurofibromin-1
Inhibitor of RAS/MAPK signaling
Neurofibromatosis type 1 (neurofibromas and malignant peripheral nerve
5. Altered cellular metabolism in canter cells (Warburg effect)
Cancer cells have different needs than their normal counterpart. Their proliferative rate generally exceeds that of normal cells. Cancer cells must quickly synthesize the structural components (e.g., protein, lipid, etc.) that are required for rapid cell growth (that is to sustain their mitotic activity).
With adequate oxygen supply, cancer cells undergo a metabolic switch to aerobic glycolysis. They develop a distinctive form of cellular metabolism characterized by increased amount of glucose uptake and increased conversion of glucose to lactose (fermentation) via the glycolytic pathway. This aerobic glycolysis is called the Warburg effect. It was described in 1930 by Otto Warburg and is not cancer-specific but observed in growing cells and it becomes “fixed” in cancer cells. It is seen because tumor cells have M2 isoform of pyruvate kinase enzyme.
Aerobic glycolysis provides metabolic intermediates that are needed for the synthesis of cellular components in rapidly dividing tumor cells. This cannot be met with normal mitochondrial oxidative phosphorylation.
Clinical utility: The “glucose-hunger” of tumors is made for visualization of tumors in positron emission tomography (PET) scanning. In PET scanning, patients are injected with 18F-fluorodeoxyglucose (a8-FDG- a non-metabolizable derivative of glucose) which is preferentially taken up into tumor cells (and also actively dividing normal cells, for example., bone marrow cells). Most tumors are PET-positive, and markedly positive are the rapidly growing tumors [15].
Definition: The malignant tumors that are locally invasive but show little or no tendency to metastasize are called locally malignant tumors.
Examples:
Basal cell carcinoma of skin.
Glioma/glial cell carcinoma of central nervous system.
Giant cell tumor of bone.
Ameloblastoma.
Craniopharyngioma.
Local Invasion:
Benign tumor:
Grow as cohesive expansile masses.
Remain localized to their site of origin.
Do not have the capacity to infiltrate, invade, or metastasize to distant sites.
Sometimes they develop a fibrous capsule.
Malignant Tumor:
Invasive and can be expected to penetrate the wall.
Such invasiveness makes their surgical resection difficult.
Mechanism of tumor invasion:
It involves following steps:
Detachment (“loosening up”) of the tumor cells from each other
Tumor cells remain attached to each other by several adhesion molecules, such as cadherins.
In several carcinomas, including adenocarcinoma.
Degradation of extracellular matrix
By elaborating protease enzymes-matrix metalloproteinases (MMPs), cathepsin D, and urokinase plasminogen activator.
Attachment to novel extracellular matrix components: Tumor cells bind to laminin and fibronectin via cell surface receptors.
Migration of tumor cells:
It is the final step of invasion, propelling tumor cells through the degraded basement membranes and zones of matrix proteolysis.
Stimulated and directed by tumor cell-derived cytokines, such as autocrine motility factors [16, 17].
6.2 Metastasis
Definition: Metastasis is defined by the spread of a tumor to sites that are physically discontinuous with the primary tumor. Or, tumor implant away from primary site to a distant place, without any communication with primary site, is known as metastasis.
Benign tumor: do not metastasize.
Malignant tumor: few exceptions, all cancers can metastasize.
The most common sites of cancer metastasis are the lungs, liver, bones, and brain.
Although most cancers have the ability to spread in many different parts of the body.
Exception: Locally invasive cancer. Approximately 30% of newly diagnosed solid tumors (excluding skin cancers other than melanomas) present with metastases.
Metastatic spread strongly reduces the possibility of cure.
6.3 Pathways of spread
Direct seeding of body cavities or surfaces,
Lymphatic spread, and
Hematogenous spread.
6.4 Direct seeding of body cavities or surfaces
Most often involved is the peritoneal cavity, but any other cavity—pleural, pericardial, subarachnoid, and joint space—may be affected.
Example: In the female, gastric carcinoma may metastasize through peritoneal cavity to one or both ovaries producing secondary tumors termed krukenberg tumors.
Sometimes mucus-secreting appendiceal carcinomas or ovarian carcinomas fill the peritoneal cavity with a gelatinous neoplastic mass referred to as pseudomyxoma peritonei.
6.5 Lymphatic spread
Transport through lymphatics is the most common pathway for the initial dissemination of carcinomas but sarcomas may also use this route.
Examples: a. Carcinomas of the upper outer quadrant of the breast usually spread first to axillary lymph nodes and those of the inner quadrants to the nodes along the internal mammary arteries then the infra-clavicular and supraclavicular may become involved.
Bronchogenic carcinoma first metastasizes first to the hilar and mediastinal lymph nodes.
6.6 Hematogenous spread
Hematogenous spread is typical of large masses but is also seen with carcinomas.
Because ultimately there are numerous interconnections between the vascular and the lymphatic systems.
Arteries are less (due to thicker wall) easily penetrated than veins.
Sentinel lymph node:
Definition: A “sentinel lymph node” is the first regional lymph node that reaches lymph flow from a primary tumor.
Sentinel node mapping can be done by injection of radio-labeled tracers or colored dyes.
Biopsy of sentinel nodes is often used to assess the presence or absence of metastatic lesions in the lymph nodes.
Examples: In breast cancer, determining the involvement of axillary lymph nodes is important for assessing the future course of the disease and for selecting suitable therapeutic strategies.
Skip metastasis:
Usually cancers metastasize along the natural lymphatic drainage of that tissue.
However local lymph node may be bypassed, which is known as skip metastasis.
Cause:
Lymphangitis.
Radiation.
Surgical intervention.
Developmental anomalies.
6.7 Mechanism of metastasis of malignant tumor
Metastasis is a multistep process that allows tumor cells to move from one site to another.
These steps include:
Detachment of invasive cells from the main tumor mass.
Invasion of the basement membrane and the connective tissue.
Intravasation (i.e., entry of tumor cells into the vessel).
Dissemination of tumor cells in the intravascular fluid (blood or lymph).
Anchorage (i.e., attachment of tumor cells to endothelial cells at a distant site).
Extravasation (i.e., emigration of tumor cells through the vessel wall).
Autophagy (“self- eating”) is the process in which lysosomal enzymes digest the own components of the cell during stress. It is a survival mechanism that occurs during a state of severe nutrient deficiency. By this mechanism, the starved cell can live by eating its own contents (e.g., organelles, proteins, and membranes) and by recycling these contents to provide nutrients and energy.
If this adaptive mechanism fails, the cells die.
Autophagy in cancer: Role of autophagy in the development and progression of cancer is complex and represents a double-edged sword. Several autophagy genes (e.g., Beclin-1 and some Atg genes) that promote autophagy, act as tumor suppressors and are deleted or mutated in many cancers. Tumor cells may accumulate mutations that deranges the pathways that induce autophagy and allows the cancer cells to grow without triggering autophagy. Tumor cells may corrupt the autophagy process to provide nutrients for continued growth and survival. On the other hand, autophagy can protect cancer cells if they are deprived of nutrients or oxygen because of therapy or insufficient blood supply [18, 19].
6.8.2 Several mechanisms may be operative by which tumor cells escape or evade the immune system:
Selective outgrowth of antigen-negative variants: During tumor progression, strongly immunogenic subclones may be eliminated.
Loss or reduced expression of MHC molecules: Tumor cells may fail to express normal levels of HLA class I molecules, thereby escaping attack by cytotoxic T cells. Such cells, however, may trigger NK cells.
Lack of co-stimulation: Sensitization of T cells requires two signals, one by a foreign peptide presented by MHC molecules and the other by co-stimulatory molecules. Although tumor cells may express peptide antigens with class I molecules, they often do not express co-stimulatory molecules.
Immunosuppression: Many oncogenic agents (e.g., chemicals and ionizing radiation) suppress host immune responses.
Antigen masking: The cell surface antigens of tumors may be hidden, or masked, from the immune system by glycocalyx molecules, such as sialic acid-containing mucopolysaccharides.
Apoptosis of cytotoxic T cells: Some melanomas and hepatocellular carcinomas express FasL which kills T lymphocytes that come in contact with tumor cells (Figure 1) [20].
Sir Percival Pott (London surgeon) first related scrotum skin cancer in the chimney sweeps to a specific chronic chemical exposure to soot. Based on this, a rule was made that chimney sweep members must bathe daily and this public health measure controlled scrotal skin cancer. Japanese investigators (Yamagiva and Ichikawa) experimentally produced skin cancers in rabbits by using coal tar. Subsequently, hundreds of chemical carcinogens were discovered (Table 7).
Direct-acting carcinogens
Alkylating agents
B-Propiolactone
Dimethyl sulfate
Diepoxybutane
Anticancer drugs (cyclophosphamide, chlorambucil, nitrosoureas, and other)
Acylating agents
1-acetyl-imidazole
Dimethylcarbamyl chloride
Procarcinogens that require metabolic activation
Polycyclic and heterocyclic aromatic hydrocarbons
Benz[a] anthracene
Benzo[a] pyrene
Dibenz[a,h]anthracene
3-Methylcholanthrene
7,12-Dimethylbenz[a]anthracene
Aromatic amines, amides, azo dyes
2-Naphthylamine (B-naphthylamine)
Benzidine
2-Acetylaminofluorene
Dimethylaminoazobenzene (Butter yellow)
Natural plant and microblal products
Aflatoxin B,
Griseofulvin
Cycasin
Safrole
Betel nuts
Others
Nitrosamine and amldes
Vinyl chloride, nickel, chromium
Insecticides, funglcides
Polychlorinated blphenyls
Table 7.
Major chemical carcinogens.
7.2 Direct-acting agents
Direct-acting chemical agents do not require metabolic conversion to become carcinogenic, but most of them are weak carcinogens. Some of the drugs (e.g., alkylating agents) are used to cure, control, or delay recurrence of some cancer (e.g., leukemia, lymphoma) and may produce a second form of cancer (e.g., acute myeloid leukemia) later.
7.3 Alkylating agents
Source: many cancer chemotherapeutic drugs (e.g. Cyclophosphamide, cisplatin, and busulfan) are alkylating agents.
Mechanism of action: alkylating agents contain electron-deficient atoms that react with electron-rich atoms in DNA. These drugs not only destroy cancer cells by damaging DNA but also injure normal cells.
Cancers produced: Solid and hematological malignancies (Table 8 and Figure 2) [21, 22].
Agents or groups of agents
Human cancers for which reasonable evidence is available
Typical use or occurrence
Arsenic and arsenic compounds
Lung carcinoma, skin carcinoma
By-product of metal smelting; component of alloys, electrical and semiconductor devices, medications and herbicides, fungicides, and animal dips
Asbestos
Lung, esophageal, gastric, and colon carcinoma; mesothelioma
Formerly used for many applications because of fire, heat, and friction resistance; still found in existing construction as well as fire-resistant textiles, friction materials (i.e., brake linings), underlayment and roofing papers, and floor tiles
Benzene
Acute myeloid leukemia
Principal component of light oil; despite known risk, many applications exist in printing and lithography, paint, rubber, dry cleaning, adhesives and coatings, and detergents; formerly widely used as solvent and fumigant
Beryllium and beryllium compounds
Lung carcinoma
Missile fuel and space vehicles; hardener for lightweight metal alloys, particularly in aerospace applications and nuclear reactors
Cadmlum and cadmium compounds
Prostate carcinoma
Uses include yellow pigments and phosphors; found in solders; used in batteries and as alloy and in metal platings and coatings
Chromium compounds
Lung carcinoma
Component of metal alloys, paints, pigments, and preservatives
Nickel compounds
Lung and oropharyngeal carcinoma
Nickel plating; component of ferrous alloys, ceramics, and batteries; by-product of stainless-steel arc welding
Radon and its decay products
Lung carcinoma
From decay of minerals containing uranium; potentially serious hazard in quarries and underground mines
Vinyl chloride
Hapatic angiosarcoma
Refrigerant; monomer for vinyl polymers; adhesive for plastics; formerly inert aerosol propellant in pressurized containers
Table 8.
Occupational cancers.
Figure 2.
Multistep theory of chemical carcinogenesis.
7.4 Radiation carcinogenesis
Radiation is a well-known carcinogen.
Latency: Extremely long latent period is common and It has a cumulative effect. Radiation has also additive or synergistic effects with other potential carcinogenic agents.
Types of radiation: They are divided into two types, namely:
Ultraviolet (UV) rays of sunlight, and
Ionizing electromagnetic and particulate radiation.
Ultraviolet rays:-.
They are derived from the sunlight.
Tumors caused: Skin cancer, namely.
Squamous cell carcinoma,
Basal cell carcinoma, and
Malignant melanoma.
They are more common on parts of the body regularly exposed to sunlight and ultraviolet light (UVL).
Risk factors.
The amount of damage incurred depends on:
Type of UV rays.
Intensity of exposure.
Protective mantle of melanin.
Melanin absorbs UV radiation and has a protective effect.
Skin cancers are more common in fair-skinned people and those living in a geographic location receiving a greater amount of sunlight (e.g., Queensland, Australia, close to the equator).
# Pathogenesis.
UV radiation leads to formation of pyrimidine dimers in DNA, which is a type of DNA damage that is responsible for carcinogenicity.
DNA damage that is responsible for carcinogenicity.
DNA damage is repaired by the nucleotide excision repair pathway.
With excessive sun exposure, the DNA damage exceeds the capacity of the nucleotide excision repair pathway and genomic injury becomes mutagenic and carcinogenic.
Xeroderma pigmentosum: It is a rare hereditary autosomal recessive disorder characterized by congenital deficiency of nucleotide excision repair DNA. These individuals develop skin cancers (basal cell carcinoma, squamous cell carcinoma, and melanoma) due to impairment in the excision of UV-damaged DNA [21, 22].
Ionizing radiation:
Electromagnetic (x-rays, γ-rays) and particulate (α particles, β particles, protons, neutrons) radiations are all carcinogenic.
Cancers produced:
Medical or occupational exposure, for example., leukemia and skin cancers.
Nuclear plant accidents: Risk of lung cancers.
Atomic bomb explosion: Survivors of atomic bomb explosion (dropped on Hiroshima and Nagasaki) -› increased incidence of leukemia -> mainly acute and chronic myelogenous leukemia after about seven years.
Subsequently, increased mortality due to solid tumors (e.g., breast, colon, thyroid, and lung).
Therapeutic radiation:
Papillary carcinoma of the thyroid follows irradiation of head and neck and
Angiosarcoma of liver due to radioactive thorium dioxide used to visualize the arterial tree.
Mechanism: Hydroxyl free radical injury to DNA.
Tissues that are relatively resistant to radiation-induced neoplasia: Skin, bone, and the gastrointestinal tract.
UV rays cause skin cancer:
Squamous cell carcinoma.
Basal cell carcinoma.
Malignant melanoma.
Lymphoid tissue: most sensitive to radiation.
Bone: least sensitive to radiation.
UV radiation: induces formation of pyridine dimers in DNA leading to mutations.
Acute leukemia: most frequent malignant tumor caused by radiation.
Total body radiation: lymphopenia is the first hematological feature.
Xeroderma pigmentosum is caused due to abnormalities in nucleotide excision repair.
Ionizing radiation: Damages DNA.
Ionizing radiation causes genetic damage which cannot be repaired by nucleotide excision repair.
Various viruses implicated in human tumors and associated lesions.
Bacteria:-
Helicobacter pylori:
Diseases caused by H. pylori are (1) peptic ulcers, (2) gastric adenocarcinomas, and (3) gastric lymphomas, gastric adenocarcinomas.
Chronic inflammation: H. pylori causes chronic inflammation (chronic gastritis) - > followed by gastric atrophy - > intestinal metaplasia -> dysplasia - > cancer,
Genes: H. pylori causing gastric adenocarcinoma contains cytotoxin-associated A (CagA) gene that can penetrate into gastric epithelial cells - > initiation of signals - > unregulated growth factor stimulation.
Gastric lymphoma:
H. pylori produces lymphoma of B-cell origin, which are called as lymphomas of mucosa-associated lymphoid tissue or maltomas. H. pylori is associated with translocation in MALT lymphomas.
Fungi:
Fungi may cause cancer by producing toxic substances (mycotoxins). Aflatoxin B, produced by Aspergillus flavus is a potent carcinogen responsible for hepatocellular carcinoma.
Parasites:
Two parasites that can cause tumors are:
Schistosoma is strongly implicated in carcinoma of urinary bladder (usually of squamous cell type). The ova of the parasite can be found in the affected tissue.
Clonorchis sinensis (Chinese liver fluke) lodges in the bile ducts -> produces an inflammatory reaction, epithelial hyperplasia, and sometimes adenocarcinoma of the bile ducts (Cholangiocarcinoma).
Hormones:
Hormones in the body may act as cofactors in carcinogenesis.
Estrogen.
Endometrial carcinoma: It may develop in females with estrogen-secreting granulosa cell tumor of ovary or those receiving exogenous estrogen.
Adenocarcinoma of vagina: Increased frequency of adenocarcinoma of vagina is observed in daughters of mothers who received estrogen during pregnancy. Abnormal vascularity of tumor: Estrogens can make existing tumors abnormally vascular (e.g., adenomas and focal nodular hyperplasia).
Androgenic and anabolic steroids: They may cause hepatocellular tumors.
Hormone-dependent tumors.
Prostatic carcinoma usually responds to administration of estrogens or castration.
Confirmation of lesion as neoplastic usually requires cytological and/or histopathological examination of the suspected organ or tissue. Different laboratory methods available for the diagnosis of malignant tumors are:
9.1 Morphological methods
9.1.1 Histopathological examination
Histopathological diagnosis is based on the microscopic features of neoplasm and by this method of examination, accurate diagnosis can be made in majority of cases.
Clinical data: It should be provided for accurate pathologic diagnosis, for example:
Radiation causes changes in the skin, which mimic changes seen in cancer.
Sections taken from the site of a healing fracture can mimic an osteosarcoma.
Adequate and representative area of the specimen should be sent.
In this method, tissue is hardened rapidly by freezing (hence termed frozen section) and sections are cut by special instrument called freezing microtome or cryostat (microtome in a refrigerated chamber). Its uses are:
Rapid diagnosis: Frozen section is used for quick histologic diagnosis (within minutes) and is useful for determining the nature of a tumor (benign or malignant) lesion, especially when the patient is still on the operation table. It will help to determine whether a lesion is a neoplasm and, if so, whether it is benign or malignant.
Evaluation of the margins of an excised cancer to know whether excision of the neoplasm is complete. If resection margins are inadequate, additional tissue can be removed immediately, without the need for a subsequent operation.
Demonstration of fat mainly in nonneoplastic lesions.
To know the lymph node (sentinel) status in carcinoma, knowing the extent of regional tumor metastases may be useful in deciding the further surgery.
To determine whether additional workup is necessary for a particular tissue specimen while it is still fresh. For example, if the metastatic tumor found in a lymph node is recognized as a poorly differentiated carcinoma, special fixation and electron microscopy may be needed for proper diagnosis.
Various techniques for tissue sampling a Weddle biopsy: It is called a cutting-needle or core.
Needle oriel biopsy. Using cutting needle, a core of this seems wide and 2 cm long is obtained for histologic examinations or special studies that permit evaluation of architectural structure. Tissue obtained is small and interpretation may be difficult.
Endoscopy biopsy: It is performed through endoscopy. Usually performed for lesions in gastrointestinal, respiratory, urinary, and genital tracts.
Incision biopsy: In this, the representative tissue sample is obtained by incising the lesions. Incisional biopsy (along with fine-needle aspiration) is often the method of choice for inoperable lesions, too large for excision, or when excision causes functional or cosmetic impairment.
Excision biopsy: In this, entire abnormal lesion is surgically removed. It provides generous amounts of tissue for diagnosis and may be surgical therapy for some tumors (e.g., small- to medium-sized breast cancers).
Pitfalls in biopsy interpretation: These include inadequate tissue sampling and artifacts due to procedure itself (e.g. thermal damage caused by an electrocautery or laser) [27, 28, 29].
9.1.3 Cytological examination
It is performed on many tissues and is usually done for identifying neoplastic cells.
Methods of obtaining cells.
Exfoliative cytology: It is the study of spontaneously exfoliated (shed) cells from the lining of an organ into a body cavity.
Fine-needle aspiration cytology.
It involves aspiration of cells and attendant fluid with a small-bore needle. The smears are prepared and stained, followed by microscopic examination of cells. It is a widely-used simple and quick procedure.
Liquid-based cytology (thin prep): This is a special technique for preparation of samples that provides uniform monolayered dispersion of cells on smears.
Cytological characteristics of cancer cells:
Cancer cells have decreased cohesiveness and show cellular features of anaplasia. Cytological, differentiation can be made between normal, dysplastic, carcinoma in situ, and malignant cells.
Disadvantages of cytological examination:
Diagnosis is based on the features of individual cells or a clump of cells, without the supporting evidence of loss of orientation.
The invasion that is diagnostic of malignant tumor under histology cannot be assessed by cytology [27, 28, 29].
9.1.4 Histochemistry and cytochemistry
These are stains, which identify the chemical nature of cell contents or their products. H&E staining cannot demonstrate certain specific substances/constituents of cells. This requires some special stains. Common histochemical and cytochemical stains useful in diagnosis of tumors are listed in
Immunohistochemistry:-
It is an immunological method of identifying the antigenic component in the cell or one of its components by using specific antibodies. It is widely used in the diagnosis or management of malignant neoplasms.
Uses of Immunohistochemistry:-
# To categorize undifferentiated cancers:
Many malignant tumors of diverse origins resemble each other and are difficult to distinguish on routine hematoxylin and eosin (H&E) sections.
Example: Few anaplastic carcinomas, lymphomas, melanomas, and sarcomas may look almost similar. They should be accurately diagnosed because of their different modes of treatment and prognosis.
In poorly differentiated carcinoma, intermediate filaments (e.g., cytokeratins) show positivity.
Malignant melanomas when unpigmented (amelanotic melanoma) appear similar to other poorly differentiated carcinomas. They express HMB-45 and S-100 protein, but negative for cytokeratins.
Desmin is found in neoplasms of muscle cell origin.
To determine the origin of poorly differentiated metastatic tumors: It may be determined by using tissue-specific or organ-specific antigens.
For prognosis or to select the mode of treatment:
Identification of hormone (estrogen/progesterone) receptors in breast cancer cells is of prognostic and therapeutic value. These cancers respond well to antiestrogen therapy and have a better prognosis.
Breast cancers with BRBB2 protein (HER2/neu) positivity have a poor prognosis [27, 28, 29].
9.1.5 Immunohistochemical markers
Apart from the various immunochemical markers mentioned above, other markers useful are as follows:
Neuroendocrine tumors show positivity for cytokeratins like carcinomas, but they can be identified by their contents, namely:
Chromogranins (proteins found in neurosecretory granules).
Neuron-specific enolase (NSE).
Synaptophysin.
Soft tissue sarcomas: They show intermediate filament positivity.
Vimenttin used to identify mesenchyme.
Desmin is positive in smooth or striated muscle fibers.
Muscle-specific actin marker for muscle tissue.
Neurofilament proteins: Marker for tumors of neurons, neuroblastoma, and ganglioneuroma.
Neuron-specific enolase in neuroblastoma.
Glial fibrillary acidic protein (GFAP), also intermediate filament expressed in glial cell neoplasms.
Malignant lymphomas: Generally positive for leukocyte common antigen (LCA, CD45). Markers for lymphomas and leukemias are called cluster designations (CDs) and are useful to differentiate T and B lymphocytes, monocytes, granulocytes and the mature and immature variants of these cells.
Vascular tumors derived from endothelial cells include benign hemangiomas and malignant angiosarcomas, and are positive for factor VIII-related antigens or certain lectins.
Proliferating cells: Cells in cell cycle show positivity for Ki-67 and proliferating cell nuclear antigen (PCNA) [27, 28, 29].
9.1.6 Electron microscopy
It helps in the diagnosis of poorly differentiated/undifferentiated cancers, which cannot identify the origin by light microscopy, for example, carcinomas show desmosomes and specialized junctional complexes, structures that are not seen in sarcomas or lymphomas [27, 28, 29].
9.1.7 Flow cytometry
It quantitatively measures various individual cell characteristics, such as membrane antigens and the DNA content of tumor cells. Flow cytometry is useful for identification and classification of tumors of T and B lymphocytes (leukemias and lymphomas) and mononuclear-phagocytic cells.
Circulating tumor cells.
Detection, quantification, and characterization of rare solid tumor cells (e.g., carcinoma and melanoma) circulating in the blood are emerging as a diagnostic modality, although presently in the research stage. Few latest devices detect three-dimensional flow cells coated with antibodies specific for tumor cells of interest (e.g., carcinoma cells) in the blood.
It will be useful for early diagnosis, assessing the risk of metastasis, and assessing the response of tumor cells to therapy.
Tumor makers:
Tumor markers are products of malignant tumors that can be detected in the cells themselves or in blood and body fluids.
Usefulness
Detection of cancer, for example, PSA is the most common and useful tumor marker used to screen prostatic adenocarcinoma. High levels of PSA are found in the blood of prostatic carcinoma patients but it also may be elevated in benign prostatic hyperplasia.
Determine the effectiveness of therapy.
Detection of recurrence.
9.2 Molecular profiling of tumors
9.2.1 Traditional cancer typing
Traditionally cancer is diagnosed and classified according to the morphological (histopathology/ cytopathology) appearance of the cells and their surrounding tissue. It has limitations such as (i) relies on a subjective review of the tissue, which is dependent on the knowledge and experience of a pathologist, and, therefore, may not be reproducible, (ii) limited ability to determine the individual recurrence risk of cancer, (iii) insufficient to reflect the complicated underlying molecular events that drive the neoplastic process, and (iv) histopathology reports lack or offer very little information regarding the potential drug treatment regime to which cancer will respond. Traditional pathology reports help to determine treatment that leads to better outcomes. However, tumors with identical pathology may have different origins and respond differently to a treatment.
Tumor markers are products of malignant tumors tar fun be detected in the cells themselves or in blood and body fluids.
Usefulness:
Detection of cancer, for example PSA is the most common and useful tumor marker used to screen prostatic adenocarcinoma. High levels of PA are found in the blood of prostatic carcinoma patients but it also may be elevated in benign prostatic hyperplasia.
Determine the effectiveness of therapy.
Detection of recurrence.
Types of markers (Table): These may be tumor-associated hormones, oncofetal antigens, specific proteins, mucin and glycoproteins, enzymes, and molecular markers.
Molecular diagnosis:
Molecular diagnosis can be done by different techniques such as FISH technique and PCR (polymerase chain reaction) analysis.
10.1 Diagnosis of cancer
Monoclonal (malignant) versus polyclonal (benign): To differentiate benign (polyclonal) proliferations of T-or B-cells from malignant (monoclonal) proliferations.
Chromosomal alterations: Many hematopoietic neoplasms (leukemias and lymphomas) and few solid tumors (e.g. Ewings Sarcoma) are characterized by particular translocations that can be detected by FISH technique or by PCR analysis [27, 28, 29].
10.2 Prognosis of cancer
Certain genetic alterations are of prognostic value. They can be detected by routine cytogenetics and also by FISH or PCR assays. Example of poor prognostic feature is amplification of tie N-MIC gene and deletions of IP in neuroblastoma and amplification of HER-2/Neu in breast cancer.
10.3 Detection of minimal residual disease
Prognosis of cancer can detect minimal residual disease or the onset of relapse in patients who are treated for leukemia or lymphoma, for example, detection of BCR-ABL transcripts in treated patients with CML.
10.4 Detection of hereditary predisposition to cancer
Germline mutations in many tumor suppressor genes are associated with increased risk for specific cancers. This will help in prophylactic surgery and counseling of relatives at risk, for example, BRCAI, BRCA2, and the RET protooncogene.
For therapeutic decision, It is useful in target therapy [27, 28, 29] (Table 10).
Clnical sydromes
Major forms of underlying cancer
Causal mechanism
Endocrinopathies
Cushing syndrome
Small-cell carcinoma of lung pancreatic carcinoma neural tumors
ACTH or ACTH-like substance
Syndrome of inappropriate antidiuretic hormone secretion
Small-cell carcinoma of lung intracranial neoplasms
Antidiuretic hormone or atrial natriuretic hormones
Hypercalcemia
Squamous cell carcinoma of lung breast carcinoma renal carcinoma adult T-cell leukemia/lymphoma
Parathyroid hormoine-related protein (PTHRP), TGF-a, TNF, IL-1
Hypoglycemia
Ovarian carcionama fibrosarcoma other mesenchymal sarcomas
Hypertophic osteoarthropathy and clubbing of the fingers
Bronchogenic carcinoma Thymic neoplasms
Unknown
Vascular and hematologic changes
Venous thrombosis (Trousseau phenomenon)
Pancreatic carcinoma bronchogenic carcinoma Other cancers
Tumor products (mucins that acticate clotting)
Disseminated thrombotic endocarditis
Acute promyelocytic leukemia prostatic carcinoma
Tumor products that acticate clotting
Nonbacterial thrombotic endocarditis
Advanced cancers
Hypercoagulability
Red call aplasia
Thymic neoplasms
Unknown
Others
Nephrotic syndrome
Various cancers
Tumor antigens, immune complexes
Table 10.
Paraneoplastic syndiomes.
10.5 Molecular profiling of tumors
10.5.1 Traditional cancer typing
Traditionally cancer is diagnosed and classified according to the morphological (histopathology/cytopathology) appearance of the cells and their surrounding tissue. It has limitations such as (1) it relies on a subjective review of the tissue, which is dependent on the knowledge and experience of a pathologist, and, therefore, may not be reproducible, (2) Limited ability to determine the individual recurrence risk of cancer, (3) Insufficient to reflect the complicated underlying molecular events that drive the neoplastic process and (4) Histopathology reports lack or offer very little information regarding the potential drug treatment regime to which cancer will respond. Traditional pathology reports help to determine treatment that leads to better outcomes. However, tumors with identical pathology may have different origins and respond differently to treatment.
10.5.2 Clinical aspects of neoplasia
Both benign and malignant tumors may produce clinical features through their various effects on host.
Local effects:-.
These are due to encroachment on adjacent structures.
Compression (e.g. adenoma in the ampulla of Vater causing obstruction of biliary tract).
Mechanical obstruction: It may be caused by both benign and malignant tumors. Example: Tumors may cause obstruction or intussusception in the GI tract.
“Endocrine insufficiency: It is caused due to destruction of an endocrine gland either due to primary or metastatic cancer.
Ulceration, bleeding, and secondary infections: It may develop in benign or malignant tumors in the skin or mucosa of the GI tract, for example.
Melena (blood in the stool) in neoplasms of the gut.
Hematuria in neoplasms of the urinary tract.
“Rupture” or infarction of tumor.
Functional effects:-.
These include:
Hormonal effects: It may be observed both in benign and malignant tumors of endocrine glands, for example, B-cell adenoma of the pancreas may produce insulin -› to cause fatal hypoglycemia.
Paraneoplastic syndromes: Non endocrine tumors may secrete hormones or hormone-like substances and produce paraneoplastic syndromes (explained below).
Fever: It is most commonly associated with Hodgkin disease, renal cell carcinoma, and osteogenic sarcoma. Fever may be due to release of pyogenes by tumor cells or IL-1 produced by inflammatory cells in the stroma of the tumor [30, 31, 32].
10.5.3 Tumor lysis syndrome
It is a group of metabolic complications that can occur after treatment for leukemias such as acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemias (CLL), lymphomas such as Burkitt lymphoma, and uncommonly in solid tumors.
It is caused by breakdown products of tumor cells following chemotherapy or glucocorticoids or hormonal agent (tamoxifen).
The killed tumor cells release intracellular ions and large amounts of metabolic byproducts into systemic circulation.
Metabolic abnormalities include:
Hyperuricemia: Due to increased turnover of nucleic acids. It can cause uric acid precipitation in the kidney resulting in renal failure.
Hyperkalemia: Due to release of the most abundant intracellular cation potassium.
Hyperphosphatemia: Due to release of intracellular phosphate.
Hypocalcemia: Due to complexing of calcium with elevated phosphate.
It is defined as progressive weight loss accompanied by severe weakness, anorexia, and anemia developing in patients with cancer.
Mechanism: It is poorly understood and may be due to TNF and other cytokines, like IL-1, interferon-y, and leukemia inhibitory factor. They may be produced by macrophages in the tumor or by the tumor cells themselves [30, 31, 32].
11. Tumor staging and granding
11.1 TNM staging systems
It is the cancer staging system that is widely used and varies for each specific form of cancer. Its general principles are:
T refers to the size of the primary tumor.
It is suffixed by a number that indicates the size of the tumor or local anatomical extent. The number varies according to the organ involved in the tumor. With increasing size, the primary lesion is characterized as TI to T4.
T0 is used to denote an in situ lesion.
Refers to lymph node status.
It is suffixed by a number to indicate the number of regional lymph nodes or groups of lymph nodes showing metastases.
N0 would mean no nodal involvement.
M refers to the presence and anatomical extent of distant metastases.
Grading of tumor depends on the degree of differentiation.
Prognosis of tumor depends on:
Histological type.
Grade.
Stage.
11.2 Prognosis
The prognosis of malignant tumors varies and is determined partly by the characteristics of the tumor cells (e.g. grower pale invasiveness) and partly by the effectiveness of therapy [30, 31, 32].
12. Paraneoplastic syndromes
Malignant tumors invade local tissue, produce metastasis, and can produce a variety of products that can stimulate hormonal, hematologic, dermatologic, and neurologic responses.
Definition: Paraneoplastic syndromes are symptom complexes in cancer patients that are not directly related to mass effects or invasion or metastasis or by the secretion of hormones indigenous to the tissue of origin.
Frequency: Though they occur in 10–15% of patients, it is important because:
Maybe the first manifestation of an occult neoplasm.
Maybe mistaken for metastatic disease leading to inappropriate treatment.
May present clinical problems, which may be fatal.
Certain tumor products causing paraneoplastic syndromes may be useful in monitoring recurrence in patients who had surgical resections or are undergoing chemotherapy or radiation therapy.
Some paraneoplastic syndromes, their mechanism, and the common cancers causing them are listed in Table 11 [30, 31, 32].
Liver cell cancer, nonseminomatous germ cell tumors of testis
Carcinoembryonic antigen
Carcinomas of the colon, pancreas, lung, stomach, and heart
Isoenzymes
Prostatic acid phosphatase
Prostate cancer
Neuron-specific enolase
Small-cell cancer of lung, neuroblastoma
Specific proteins
Immunoglobulins
Multiple myeloma and other gammopathies
Prostate-specific antigen and prostate-specific membrane antigen
Prostate cancer
Mucins and other glycoproteins
CA-125
Ovarian cancer
CA-19-9
Colon cancer, pancreatic cancer
CA-15-3
Breast cancer
Cell-free DNA markers
TP53, APC RAS mutants in stool and sarum
Colon cancer
TP53, RAS mutants in stool and serum
pancreatic cancer
TP53, RAS mutants in sputum and sermu
Lung cancer
TP53 mutants in urine
Bladder cancer
Table 11.
Selected tumor markers.
13. Conclusion
With all the advances in genomic analyzes and targeted therapies, it can be safely predicted that we are on the cusp of a golden age of tumor diagnosis and treatment.
Those of you now in medical school can safely assume that expectations of rapid advances in cancer diagnosis and therapy will be fulfilled while you are still in practice.
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Written By
Flora Thanadar Ajmiree
Submitted: 12 December 2022Reviewed: 14 December 2022Published: 20 February 2023
Open access peer-reviewed chapter
