Neoplasms:

A neoplasm is a new growth of abnormal tissue. Its growth is uncoordinated, exceeds that of normal tissues and persists in the same excessive manner after the cessation of the stimuli that evoked the change. Neoplasms are caused by genetic changes that allow for excessive and unregulated proliferation that is independent of physiologic growth regulatory stimuli. These transformed cells continue to replicate oblivious of the normal physiological regulatory controls and depend o the host for their nutrition and blood supply. Malignant neoplasms (cancers) unlike their benign counterparts, tend to be genetically heterogeneous with a propensity to attach to any site, invade and destroy adjacent tissue structure and spread to distant sites where they repeat the same process. The first stage in the growth of malignant neoplasm is the genetic damage that affects the genes involved in the regulation of cell growth. This results in the mutant phenotypes that: Are self sufficient in growth signals, Are insensitive to growth inhibitory signals, Evade apoptosis Have unlimited replicative potential Have sustained angiogenesis and or exhibit angiogenic mimicry Have the ability to invade and metastasize Show genomic instability resulting from defects in DNA repair and hence the presence of sub clones within the same neoplasm. Carcinogenesis is a multistep process at both genetic and phenotypic levels resulting from multiple mutations.(community/cycling) As the neoplasm grows selection pressures e.g. nutritional factors (ischemia), cytokine sensitivity and host immune responses, tumour cell variants may arise that can take advantage or survive the selection pressures(cell to cell signaling, upregulation, reduced immune regulation, loss of contact inhibition) and these sub clones expand resulting in tumour heterogeneity (conversion/transformation/phenotype switching/diversity). Some of the sub clones may have an increased metastatic potential, others may be non antigenic, require fewer growth factors or develop nutrient receptors. This is referred to as tumour progression The initial growth of the tumor is localized to a primary site and shows a logarithmic pattern. As it enlarges the rate of growth slows(Lag-Death) partly due to selection pressures, primarily ischemia, which inhibit mitosis and growth of individual cells and groups of cells. Tumour progression occurs when tumour cell variants arise (phenotype switch/heterogeneity) that can surmount these selection pressures and these sub clones then proliferate until other selection pressures come into play an the cycle is repeated. This results in a heterogeneous tumour that invades and later metastasizes to other sites.

Clinically the staging of malignant neoplasms provides an estimate of the degree of the spread of a malignant neoplasm the criteria being modified according to the site as outlined below: Stage 0 I II III IV Extent of spread No invasion Confined to primary site Local spread to neighboring tissues Greater local spread to involve adjacent organs Spread to lymph nodes and distant metastases Biofilm equivalents Lag Log Maturation Detachment and erosion Detachment and erosion

Normal cell

DNA damage failure of DNA repair and or somatic mutations in DNA repair, cell growth and apoptosis genes

Mutant cell

Activation of growth promoting genes, inactivation of tumour suppressor genes, altered apoptosis leading to uncontrolled cell growth and clonal expansion

Clonal expansion

Escape from immunity, angiogenesis and additional mutations to overcome selection pressures resulting in tumor progression and heterogeneity

Non antigenic cell

Nutrient receptors on surface

Invasive cells

Growth factor producing cell

Invasion and Metastasis of Neoplasm

Flow chart showing the molecular basis of carcinogenesis and tumour progression.

(adapted from Robbins Basic Pathology 8th edition) References: Kumar, Abbas Fausto and Mitchel. Robbins Basic Pathology: Chapter 6 Neoplasia. 8th edition.2007. pp173. Anderson J.R ed. Muirs Textbook of Pathology. Chapters 13 and 14. 12th edition. 1985. Thomas JG etal. Changing paradigm of biofilms. 2007