Disorders of Growth PDF - UCT/GSH/NHLS

Disorders of growth Dr Brendon Price Consultant Anatomical Pathologist PhD, MBBCh, FC Path(SA)(Anat), MMed (Anat Path) UCT/GSH/NHLS  Learning objectives: Explain the purposes of the various phases of the cell cycle Define labile cells, stable cells and pe...

Disorders of growth Dr Brendon Price Consultant Anatomical Pathologist PhD, MBBCh, FC Path(SA)(Anat), MMed (Anat Path) UCT/GSH/NHLS  Learning objectives: Explain the purposes of the various phases of the cell cycle Define labile cells, stable cells and permanent cells and list examples Define hyperplasia, hypertrophy, atrophy, cachexia, and metaplasia, and list examples Define dysplasia and explain how it is different from neoplasia. Checkpoints Mitosis Phase of cell cycle Purpose G0: Gap 0 / Resting phase The cell is in a "quiescent" state (neither dividing nor preparing to divide). This phase is outside of the cell cycle. G1 phase (start of the cell cycle) The cell grows in size and prepares for DNA replication (S phase) by producing proteins required for DNA synthesis. This is the 1st subphase of interphase. G1/S checkpoint Before the cell enters S phase, it checks for DNA damage and for sufficient cell growth and nutrients. S (synthesis) phase DNA is replicated (but chromosome number remains 2n). If there is DNA damage, it is also repaired. This is the 2 nd subphase of interphase. G2 phase The third and last subphase of interphase. The cell prepares for mitosis by producing more proteins (e.g. microtubules) and grows further in size. G2/M checkpoint The DNA is checked by p53 and other tumour-suppressor proteins. M phase Chromatin condenses into chromosomes and the cell divides by mitosis. Labile, stable, permanent cells After the cell cycle the cell can continue to divide (labile cells), becomes quiescent (stable cells), or differentiate terminally (permanent cells). Differentiation is a process whereby develops a specialised function or morphology due to selective gene expression. Labile cells are cell that regularly divide to replenish themselves. They are in cell cycle regularly e.g. stratified squamous epithelium, gastrointestinal lining epithelium, urothelium, haematopoietic cells, endometrium, ductal cells (including breast and prostate). [Labile cells are regularly injured so need to be replenished. Because labile cells have to replicate DNA often, they are easily affected by carcinogens and are the type of cell most prone to neoplastic transformation as well as being damaged by chemotherapy, hence the name labile]. Stable cells are cells that do not regularly divide but can divide if stimulated to do so. They are usually in G0 e.g. non-exposed epithelia (e.g. hepatocytes, renal tubules, thyroid follicular cells, glandular cells) and mesenchymal cells (e.g. fibroblasts, smooth muscle cells, osteoblasts, endothelial cells, astrocytes). [Stable cells are not often injured so are not programmed to regularly regenerate.]  Permanent cells are cells that cannot divide (post embryonic development). They are always in G0. Examples include neurons, cardiac myocytes, skeletal muscle, podocytes, retinal photoreceptors, lens cells, hair cells of cochlea, osteocytes. Definitions Atrophy = decrease in cell size (by autophagy) and/or number (by apoptosis) Hypertrophy = increase in cell size Hyperplasia = increase in cell number These concepts have already been covered in the cell injury lecture, and should be revised thoroughly. Hyperplasia Hyperplasia constitutes an increase in the number of cells in an organ or tissue. It is usually accompanied by hypertrophy (Increase in the number of organelles (e.g. myofilaments) and size of cells) Can only occur in cells capable of synthesising DNA (such as epithelial, haematopoietic and connective tissue cells). Nerve, cardiac and skeletal muscle cells undergo almost pure hypertrophy when stimulated by increased functional load or hormones  Physiologic hyperplasia Hormonal hyperplasia (e.g endometrial proliferation after oestrogen stimulation) Compensatory hyperplasia (e.g. hyperplasia of the liver after partial hepatectomy  Pathologic hyperplasia E.g excessive hormonal stimulation (e.g.hyperoestrinism and atypical endometrial hyperplasia) and locally produced growth factors on target cells (e.g. proliferation of connective tissue cells in wound healing or squamous epithelium induced by viruses). In pathologic hyperplasia, if the stimulus abates, the hyperplasia disappears. Thus, cells respond to regular growth control, differentiating the process from neoplasia.  Pathologic hyperplasia, however, constitutes fertile soil in which cancerous proliferation may eventually arise. Examples are endometrial and cervical hyperplasia which are precursors of cancers of the endometrium and cervix Metaplasia Metaplasia is a reversible change in which one adult cell type is replaced by another (epithelial or mesenchymal). The most common example is a change from columnar to squamous epithelium, as occurs in the squamous metaplasia of respiratory epithelium in response to chronic irritation (as with protracted cigarette smoking). Other examples include:  Metaplasia = reversible change of one adult cell type to another adult cell type due to reprogramming of stem cells. Chronic irritation (fragile → hardier epithelium) Physical (squamous metaplasia) e.g. Cigarette smoke: ciliated pseudostratified columnar respiratory epithelium of bronchus → stratified squamous epithelium Calculus (stone) / Schistosoma ova: urothelium → stratified squamous epithelium Uterine prolapse: ectocervical non-keratinising squamous & endocervical columnar epithelium → keratinising stratified squamous epithelium with a granular layer (“epidermidisation”) Chemical (intestinal metaplasia) e.g. Gastric acid (gastro-oesophageal reflux): oesophageal stratified squamous epithelium → gastric epithelium or intestinal epithelium with goblet cells Bile reflux: gastric epithelium → intestinal epithelium Metaplasia (contd) Infectious / inflammation e.g. Viral pneumonia: bronchial epithelium → squamous epithelium Helicobacter pylori associated gastritis: gastric epithelium → intestinal epithelium Vitamin A deficiency: Keratinising squamous metaplasia affecting lacrimal ducts, upper airways, and urinary bladder. Connective tissue metaplasias Chemotherapy, haemorrhage, dystrophic calcification → Osseous metaplasia (in muscle = myositis ossificans) Fracture callus → Chondroid metaplasia Metaplasia Consequences of metaplasia: Loss of function of original epithelium e.g. o loss of mucociliary action of respiratory epithelium → respiratory infections o lacrimal ducts blocked by keratin → dry eyes → blindness More prone to dysplasia & carcinoma e.g. o Squamous metaplasia (bronchus / urothelium) → squamous dysplasia → squamous cell carcinoma o Barrett’s metaplasia (goblet cell metaplasia of oesophagus) → dysplasia → adenocarcinoma of oesophagus o Gastric intestinal metaplasia → dysplasia → gastric carcinoma Metaplasia (contd) Although metaplastic epithelium is benign. If the influences which predispose to such metaplasia is persistent this may induce atypical metaplasia, which may progress to cancer. Metaplasia can also occur in mesenchymal cells by which fibroblasts may become transformed to osteoblasts or chondroblasts to produce bone or cartilage Dysplasia Dysplasia refers to disorderly but non-neoplastic growth It is characterised by pleomorphism, hyperchromatism and loss of normal orientation. Dysplastic changes are usually encountered in epithelia, especially in the uterine cervix.  When dysplastic changes are marked and involve the entire thickness of the epithelium, the lesion is considered a preinvasive neoplasm and is referred to as carcinoma-in-situ. This is a forerunner in many cases, of invasive carcinoma Mild degrees of dysplasia, however common in the uterine cervix, do not always lead to cancer and are often reversible when the inciting cause e.g. chronic irritation is removed. Pap smear = ID of dysplastic cells