Neoplasia = new growth = neoplasm.
All tumors have two basic components: (1) neoplastic cells that constitute tumor parenchyma and (2) reactive stroma made up of connective tissue, blood vessels and variable numbers cells of the adaptive and innate immune system.
Benign tumors. A tumor is said to be benign when its gross and microscopic appearances are considered relatively innocent, implying that it will remain localized, will not spread to other sites, and it amenable to local surgical removal. However "benign" tumors may cause significant morbidity and are sometimes even fatal.
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| Tumor Nomenclature |
Mixed tumor: neoplastic cells have two different morphologic patterns but derive from the same germ cell layer.
Teratomas: tumor containing mature or immature cells or tissues belonging to more than one germ cell layer.
Hamartoma: tumor-like malformation composed of a haphazard arrangement of tissues indigenous to particular site.
CHARACTERISTICS OF BENIGN AND MALIGNANT NEOPLASMS
Differentiation and Anaplasia
Differentiation refers to the extent to which neoplastic parenchymal cells resemble the corresponding normal parenchymal cells, both morphologically and functionally; lack of differentiation is called anaplasia. In general benign tumors are differentiation. Lack of differentiation (anaplasia) is considered a hallmark of malignancy. Anaplasia is often associated with many other morphologic changes.
- Pleomorphism = variation in size and shape. Thus cells within the same tumor are not uniform, but range from small cells with an undifferentiated appearance, to tumor giant cells many times larger than their neighbors.
- Abnormal nuclear morphology. Characteristically the nuclei are disproportionately large for the cells ratio that may approach 1:1 instead of the normal 1:4 or 1:6.
- Mitoses. Unlike benign tumors and well differentiated malign tumors, many cells in undifferentiated tumors are in mitosis.
- Loss of polarity. Sheets or large masses of tumor cells grow in an anarchic, disorganized fashion.
- Other changes. Rapidly growing malignant tumors develop large central areas of ischemic necrosis.
Metaplasia is defined as the replacement of one type of cell with another type. Metaplasia is nearly always found in association with tissue damage, repair and regeneration
Dysplasia means disordered growth and is characterized by a constellation of changed that include a loss in the uniformity of the individual cells as well as a loss in their architectural orientation. Dysplastic cells may exhibit considerable pleomorphism and often contain large hyperchromatic nuclei with a high nuclear to cytoplasmic ratio.
Local invasion
The growth of cancers is accompanied by progressive infiltration, invasion and destruction of the surrounding tissue, whereas nearly all benign tumors grow as cohesive expansive masses that remain localized. Because benign tumors grow and expand slowly they usually develop a rim of compressed fibrous tissue called a capsule that separates them from the host tissue. In contrast malignant tumors are in general poorly demarcated from the surrounding normal tissue and a well-defined cleavage plane is lacking. Next to the development of metastases, invasiveness is the most reliable feature that differentiates cancers from benign tumors.
Metastasis
Metastasis is defined by the spread of a tumor to sites that are physically discontinuous with primary tumor. Metastasis may occur through one of 3 pathways:
- Direct seeding of body cavities or surfaces
- Lymphatic spread
- Hematogenous spread
Tumors do not contain functional lymphatics, but lymphatic vessels located at the tumor margins are sufficient for the lymphatic spread of tumor cells. The pattern of lymph node follows the natural routes of lymphatic drainage. Local lymph nodes are sometimes bypassed (skipped metastasis) because of venous-lymphatic anastomoses or because inflammation or radiation has obliterated lymphatic channels. Biopsy of sentinel nodes is often used to assess the presence or absence of metastatic lesions in the lymph nodes. A sentinel node is the first node in a regional lymphatic basin that receives lymph flow from the primary tumor.
Understandably the liver and the lungs are most frequently involved in such hematogenous dissemination, because all portal area drainage flows to the liver and all caval blood flows to the lungs.
Environmental factors
Although both genetic and environmental factors contribute to the development of cancer, environmental influence appear to be the dominant risk factors for most cancers.
- Infectious agents. About 15% of all cancers worldwide are believed to be caused directly or indirectly by infectious agents. E.g. human papilloma virus (HPV) is responsible for a large majority of cases of cervical carcinoma.
- Smoking has been implicated in cancer of the mouth, pharynx, larynx, esophagus, pancreas, bladden and ofcourse 90% of lung cancer.
- Alcohol consumption.
- Diet.
- Obesity.
- Reproductive history. There is strong evidence that life long cumulative exposure to estrogen stimulation, particularly if unopposed by progesterone, increases the risk of cancers of the breast and endometrium.
- Environmental carcinogens.
Age has an important influence on the likelihood of being afflicted with cancer. Most carcinomas occur in the later years of life (>55 years). The rising incidence of cancer with age is likely explained by the accumulation of somatic mutations and the decline in immune competence that accompanies aging may also be a factor.
Acquired predisposing conditions
Acquired conditions that predispose to cancer can be divided into chronic inflammations, precursor lesions and immunodeficiency states. Chronic inflammatory disorders and precursor lesions span a diverse set of conditions that are all associated with increased cellular replication, which creates a fertile soil for development of malignant tumors. Immunodeficiency states predispose to virus-induced cancers. Precursor lesions can be defined as localized morphologic changes that are associated with a high risk of cancer.
- Chronic inflammation
Tissue injury is accompanied by a compensatory proliferation of cells that serves to repair the damage. In some cases, chronic inflammation may increase the pool of tissue stem cells, which may susceptible to transformations. - Precursor lesions
Many precursor lesions arise in the setting of chronic inflammation and can be recognized by the presence of metaplasia. E.g. Barrett esophagus, endometrial hyperplasia - Immunodeficiency
Particularly patients who have deficits in T-cell immunity (AIDS) are associated with Kaposi sarcoma, non-Hodgkin lymphoma.
Carcinogensis results from the accumulation of complementary mutations in a stepwise fashion over time.
- Mutations that contribute to the development of the malignant phenotype are referred to as driver mutations. The first driver mutation that starts a cell on the path to malignancy is the initiating mutation. However to develop cancer additional driver mutations are required.
- Loss-of-function mutations in genes that maintain genomic integrity appear to be a common early step on the road to malignancy.
All cancers display eight fundamental changes in cell physiology, which are considered the hallmarks of cancer.
- 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 molecule that inhibit the proliferation of normal cells, usually because of inactivation of tumor suppressor genes that encode components of these growth inhibitory pathways.
- Altered cellular metabolism. Tumor cells undergo a metabolic switch to aerobic glycolysis (Warburg effect), which enabled the synthesis of the macromolecules and organelles that are needed for rapid cell growth.
- Evasion of apoptosis.
- Limitless replicative potential.
- Sustained angiogenesis.
- Ability to invade and metastasize.
- Ability to evade the host immune response.
Oncogenes
Genes that promote autonomous cell growth in cancer cells are called oncogenes, and their unmutated cellular counterparts are called proto-oncogenes. Oncogenes are created by mutations in proto-oncogenes and encode proteins called oncoproteins that have the ability to promote cell growth in the absence of normal growth-promoting signals.
Proto-oncogenes have multiple roles, but all participate at some level in signaling pathways that drive proliferation. Thus proto-oncogenes may encode growth factors, growth factor receptors, signal transducters, transcription factors, or cell cycle components. The corresponding oncogenes generally encode oncoproteins that serve functions similar to their normal counterparts, with the important difference that they are usually constitutively active. Tyrosine kinase pathway appears to be the most frequently mutated oncogenic pathway.
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| Tyrosine kinase pathway in cancer |
Growth factor receptors. The oncogenic versions of growth factor receptors are associated with mutations that lead to constitutive growth factor-independent tyrosine kinase activity. Hence the mutant receptors deliver continuous mitogenic signals to the cell, even in the absence of growth factor in environment. Receptor tyrosine kinases can be constitutively activated by multiple mechanisms incl. point mutations, gene rearrangement and gene amplification.
- ERBB1 encodes the epidermal growth factor receptor (EGFR), which is incolved by point mutations. Seen in lung adenocarcinomas.
- ERBB2 encodes a different member of the receptor tyrosine kinase family, HER2. Amplified in certain breast carcinomas.
PI3K is negatively regulated by PTEN = tumor suppressor gene.
Alternations in Nonreceptor Tyrosine Kinases.
Mutations that confer oncogenic activity occur in several nonreceptor tyrosine kinases that normally localize to the cytoplasm or the nucleus. Despite their nonmembranous localization most of the oncoproteins also activate the same signaling pathways as receptor tyrosine kinases. Example ABL tyrosine. In chronic myelogenous leukemia (CML) and some ALL, the ABL gene is translocated from its normal abode on chromosome 9 to chromosome 22, where is fuses with the BCR gene. The resultant chimeric gene encodes oncogenic BCR-ABL tyrosine kinase.
Invasion of Extracellular Matrix
Tissues are organized into compartments separated from each other by two types of ECM: basement membrane and interstitial connective tissue. Each of there components of ECM is made up of collagens, glycoproteins and proteoglycans. A carcinoma must first breach the underlying basement membrane, then traverse the interstitial connective tissue and ultimately gain access to the circulation by penetrating the vascular basement membrane.
I. Dissociation of cancer cells from one another is often the result of alterations in intercellular adhesion molecules. E-cadherin mediate the homotypic adhesion of epithelial cells, serving to both hold the cells together and to relay signals between the cells. In several epithelial tumors for example the E-cadherin function is lost.
II. Degradation of the basement membrane and interstitial connective tissue is the second step in invasion. Tumor cells accomplish this by either secreting proteolytic enzymes themselves or by inducing stromal cells (e.g. fibroblasts and inflammatory cells) to elaborate proteases. One of the important protease is matrix metalloproteinases (MMP). MMPs regulate tumor invasion not only by remodeling insoluble components of the ECM but also by releasing growth factors such as VEGF.
III. The third step in invasion involves changes in attachment of tumor cells to ECM proteins using receptors such as integrin.
IV. Locomotion is the final step; propelling tumor cells through the degraded basement membranes and zones of matrix proteolysis. Movement is stimulated and directed by tumor cytokines, such as autocrine motility factors.
Vascular dissemination and homing of tumor cells
Once in the circulation, tumor cells are vulnerable to destruction by variety of mechanisms: mechanical shear stress, apoptosis stimulated by loss of adhesion, innat and adaptive immune defenses. within the circulation tumor cells tend to aggregate in clumps.
The site at which circulating tumor cells leave the capillaries to form secondary depositis is related to the anatomic location and vascular drainage of the primary tumor and the tropism of particular tumors for specific tissue. Such organ tropism may be related to the following mechanisms:
- Tumor cells may have adhesion molecules whose ligands are expressed preferentially on the endothelial cells of the target organ
- Chemokines have an important role in determining the target tissues for metastasis
- In some cases the target tissue may be a nonpermissive environment -unfavorable soil.
Antigens found in tumors that elicit an immune response have been demonstrated in many experimentally induced tumors and in some human cancers. Tumor antigens can be classified according to their molecular structure and source. The main classes of tumor antigens are:
- Products of mutated genes. Mutated genes found in tumor encode mutant protein that is recognized as nonself. E.g. BCR-ABL fusion proteins
- Overexpressed or aberrantly expressed cellular proteins. Tumor antigens may also be the normal cellular proteins that are abnormally expressed in tumor cells
- Tumor antigens produced by oncogenic viruses.
- Oncofetal antigens. Oncofetal antigens are proteins that are expressed at high levels on cancer cells and in normal developing (fetal) tissues.
- Altered cell surface glycolipids and glycoproteins
- Cell type -specific differentiation antigens. Tumors express molecules that are normally present on the cells of origin. These antigens are called differentiation antigens because they are specific for particular lineages or differentiation stages of various cell types.
It is evident that tumor cells develop mechanisms to escape or evade the immune system. Several such mechanisms may be operative:
- Selective outgrowth of antigen-negative variants. During tumor progression, strongly immunogenic subclones maybe 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.
- Activation of immunoregulatory pathways. Tumor cells actively inhibit tumor immunity by engaging normal pathways of immune regulation that serve as checkpoints in immune responses.
- Secretion of immunosuppressive factors by cancer cells.
- Induction of regulatory T cells (Tregs)
Genetic aberration that increase mutation rates are very common in cancers and expedite the acquisition of driver mutations that are required for transformation and subsequent tumor progression. For example the mutations in DNA-repair genes themselves are not oncogenic but their abnormalities greatly enhance the occurrence of mutations in other genes during normal cell division.
- Hereditary Nonpolyposis Colon Cancer Syndrome (aka Lynch syndrome). HNPCC is an autosomal dominant disorder resulting from DNA mismatch repair - proofreading. One of the hallmarks of patients with mismatch repair defects is microsatellite instability. Microsatellites are tandem repeats of one to six nucleotides found throughout the genome. In normal people the length of these microsatellites remains constant. In people with HNPCC these satellites are unstable and increase or decrease in length in tumor cells, creating alleles not found in normal cells. Mismatch repair genes that play a role in HNPCC are MSH2, MLH1 (30% of cases)
- Xeroderma Pigmentosum. Patients with Xeroderma Pigmentosum are at increased risk for development of cancers of the skin following exposure to the UV light. UV radiation causes cross-linking of pyrimidine residues, preventing normal DNA replication. Such DNA damage is repaired by the nucleotide excision repair system.
- Diseases with defects in DNA repair by Homologus recombination.Several rare autosomal recessive cancer syndromes have been described that are characterized by hypersensitivity to certain kinds of DNA-damaging agents such as ionizing radiations (Bloom syndrome & ataxia-telangiextasia) or DNA cross linking agents (Fanconi anemia)
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