Abnormal Cell Growth Parts 1 and 2 PDF

Abnormal Cell Growth Part 1 Slide 1. Abnormal Cell Growth In this topic we are going to look at abnormal cell growth. When we consider normal cell growth that gives rise to tissue formation, we know this is a highly regulated process that is brought about by a balan...

Abnormal Cell Growth Part 1 Slide 1. Abnormal Cell Growth In this topic we are going to look at abnormal cell growth. When we consider normal cell growth that gives rise to tissue formation, we know this is a highly regulated process that is brought about by a balance of cell division/proliferation, cell differentiation or cell loss. If any of these processes are altered, it can lead to disease or abnormal cell growth. Slide 2. Overview of Abnormal Cell Growth Part 1 will look at cellular and tissue reactions that lead to changes in tissue structure that arise as a result of too little cell division, increased cell division, increased cell loss, or abnormalities in tissue differentiation. We will look at how non-invasive and invasive cancers can form, in the form of how cervical cancer, can form and undergo metastases. In Part 2: we will look at Neoplasia, another name for ‘new growth’ or cancer, and how cancers can be classified, how tumours are initiated, risk factors associated with cancer, and we will touch on epidemiology as well as looking at ocular tumours. Slide 3. Quantitative Abnormalities in utero Quantitative Abnormalities in cell division which may lead to too much or too little growth in cell division may occur in utero. If too little tissue growth occurs in utero this can lead to congenital or developmental abnormalities that can lead to total or partial failure of organ development. In case of Agenesis or Aplasia, this can lead to total failure of organ development.  Can lead to complete absence of an organ primordium (e.g. kidney) to form. NB. organ primordium is the beginning of development of an organ.  Can have absence of part of an organ e.g. corpus callosum missing from the brain or you can have  Absence of cells within an organ, such as testicular germ cells absent from testes In case of aplasia: get absence of an organ coupled with the persistence of an organ anlage or a rudiment that never developed. NB organ anlage or a rudiment = clusters of embryonic cells that would normally form part of an organ that would then develop into an organ. However, only the clusters of embryonic cells or beginning of development of that organ may be started. So an example of this is when the lung begins to develop but bronchus does not form, so the bronchus ends blindly. Slide 4: Quantitative Abnormalities in utero Other quantitative Abnormalities in utero are hypoplasia or dysgenesis where you get partial failure of development or dysgraphics. The latter is where you get failure of apposed structures to fuse. Hypoplasia (dysgenesis): An example is microphthalmia i.e. smallness of eyes. Here you get reduced size that occurs due to the incomplete development of all or part of an organ. In dysgraphics: defects caused by the failure of apposed structures to fuse, such as spina bifida, where you get incomplete closure of the neural tube such the vertebral column is not completed and the spinal chord remains exposed. Slide 5: Now we will look at Terminology that can be used for Cell/ Tissue Changes Atrophy describes shrinkage in cell size by loss of cell substance that can lead to tissue shrinkage or tissue atrophy. This an occur as decreased workload, loss of innervation, diminished blood supply, inadequate nutrition. An example of decreased workload is eg somebody has leg in plaster, so muscle is not being used, as leg is likely to be non-weight-bearing. When the plaster comes off, that muscle will have undergone some degree of muscle wastage or atrophy due to that lack of workload. If you compare this muscle with that of the weight-bearing leg, you will likely see that it is smaller. In Diabetes, loss of innervation may occur due to decreased sensation, may lead to muscle atrophy. Tissue atrophy may occur as a result of decreased synthesis of product or increased metabolism, as new products are not replaced, or others are used up. Tissue atrophy may occur also as a result decreased cell division or increased cell apoptosis leading to a decrease in size of the tissue due to loss of cells. Slide 6: Atrophy Here you can see an example of atrophy of the brain. LHS shows an atrophied brain and much smaller than RHS image of a non-atrophied brain. Changes in cell division are not always pathological for example in post-menopausal females, because the ovaries are no longer required, the ovaries will undergo atrophy. Slide 7: Terminology that can be used for Cell/ Tissue Changes Hypertrophy is the converse of atrophy, and refers to an increase in the size of cells and therefore an increase in the size of the tissue and/or organ. An example of physiologic hypertrophy is the uterus during pregnancy. Image on LHS shows a very large uterus (pregnant uterus) compared to RHS, a non-pregnant much smaller uterus. If we look at the histology sections through the uterus, we can see cells in physiologic non-pregnant cells and in hypertrophic or enlarged cells of the pregnant uterus. Hypertrophy often goes hand-in-hand or goes together with hyperplasia. Slide 8: Terminology for Cell/ Tissue Changes Hyperplasia is when there is an increase in the number of cells in an organ or tissue which can lead to an increase in size of a tissue/organ, therefore hyperplasia and hypertrophy often go hand in hand. Usually, hyperplasia occurs in response to a definite stimulation e.g. a hormone, and here we have an example of breast epithelium in a lactating and non-lactating person. If we compare the two images we can see that the lactating breast epithelium has increased in thickness and also an increased number of cells i.e. hyperplasia. When the stimulus is removed, a return to normal size and decreased cell number can occur after cessation of the stimulus. Hyperplasia may also occur as a result of increased functional demand, such as in case of chronic inflammation or persistent cell injury, such as in chronic cystitis. Important to note that physiological and pathological hyperplasia can occur. Pathological hyperplasia may arise as a result of abnormal hormonal stimulation, trauma or infection. An example is the papilloma virus which leads to basal cell epithelial hyperplasia and the formation of warts. Slide 9: Terminology that can be used for Cell/ Tissue Changes Metaplasia describes when abnormalities in tissue differentiation occur. Metaplasia is the conversion of one differentiated cell/tissue type to another cell/tissue type. The most common type of metaplasia is squamous metaplasia. Here the replacement of glandular epithelium, a monolayer of cells, with a stratified multi-layered squamous epithelium, and the monolayer of glandular or columnar epithelium is shed. Metaplasia often occurs in a response to injury, particularly persistent injury, for example in uterine cervix. It is thought that metaplasia is a protective response to chronic irritation, as usually you have a monlayer of cells that are replaced by a multilayer of cells that can give more protection than a monolayer of cells. Example of this is in cervix, and we will look at the stages of how a metaplastic cervix can transform into a neoplastic lesion, because metasplasia is a step before transformation into a neoplastic lesion i.e. a cancerous lesion. Diagram below: the changes begin in the basal cell layer, & gradually those stratified epithelial cells displace the cells of the basal cell layer and you get a change in the differentiation pathway as the glandular epithelium has been replaced by the multi-layered stratified epithelium. Hence the term squamous metaplasia. Slide 10: Terminology that can be used for Cell/ Tissue Changes Dysplasia describes when there is an alteration in the size, shape and organization of the cellular components of a tissue; commonly associated with the squamous epithelium, so it is a subsequent stage to metaplasia and it can be a pre-neoplastic lesion i.e. the lesion before a carcinoma develops. Changes that occur include mitosis in the suprabasal cell layers and if you remember when we talked about the skin and corneal epithelium, usually you would only see mitosis in the basal cell layer. In this dysplastic epithelium you may see mitosis in the suprabasal cell layers. You may also see loss of cell polarity, pleomorphism i.e. changes in cell shape, as well as nuclear size and shape may also change. Slide 11: Terminology that can be used for Cell/ Tissue Changes If we look here, we have a normal squamous epithelium on LHS; cell division occurs in basal cell layer. This undergoes squamous metaplasia and then dysplasia subsequently. Here we can see changes in cell mitosis, i.e. cell mitosis in layers other than the basal cell layer. Can get change in cell &/or nuclei size and shape, this is where pleomorphism comes in. If this continues and you get dysplastic changes through the full thickness of the epithelium, a carcinoma in situ will result. Note that in this carcinoma in situ you still have an intact basement membrane underlying the mass of cells. Additionally, in that dysplastic epithelium you may well see proteins being produced that you would not usually see, for instance keratin is usually produced by superficial cell layer, but you may see keratin being produced below the cell surface. Essentially you begin to get total disorder throughout that epithelium which leads to the formation of a carcinoma in situ. Slide 12: Stages in the development of cervical carcinoma If we look at changes in terms of stages in development of cervical cancer we can see why it’s very important that women do have the cells of the cervix checked through cervical smears so that any changes in cell size, shape or differentiation of tissue from columnar epithelium to stratified squamous epithelium can be detected early on, such that carcinoma in situ does not result or to prevent that carcinoma in situ becoming invasive. In all the steps outlined on the slide the cancer is not invasive and has not spread to other parts of the body. The development of cervical carcinoma in situ is usually a response to injury. Usually, the endocervical canal is lined by the mucus secreting monolayer of cells, and the ectocervix is covered by a stratified squamous epithelium, a multilayer of cells. In squamous metaplasia, the columnar cells are gradually displaced by the multilayered squamous epithelium. The squamous metaplasia, or metaplastic epithelium then undergoes dysplasia, with the epithelium becoming dysplastic. Note mitosis abovebasal cell layer, in suprabasal cell layers occurs, loss of cell polarity, changes in nuclei and cell size and shape, and protein synthesis occurs in layers where you would not usually get them. When the full thickness of that dysplastic epithelium occurs, a carcinoma in situ arises. At this stage it is a lesion of clinical importance as you need to treat the lesion before metastases can occur. Slide 13: Stages in the development of invasive cervical carcinoma What do we mean by metastases? Essentially, a carcinoma will become invasive when it has broken through the basement membrane that underlies it. Metaplasia is reversible, so if these cells are detected and the stimulus removed, it is likely that the squamous metaplastic epithelium will revert back to normal columnar epithelium. However, if the metaplastic epithelium then becomes dysplastic, it is more difficult for the epithelium to return to its normal structure, as this is the preneoplastic lesion i.e. the lesion before it becomes the carcinoma. Once the dysplastic epithelium transforms into a carcinoma in situ, where the full thickness of that epithelium is dysplastic, we still have an underlying basement membrane (BM). However, as soon as the cells break through that BM and enter the extracellular matrix (ECM) below, this is when the disease becomes life threatening as those cells will find a blood vessel or lymphatic vessel to enter and then travel around the body to invade another part of body or tissue/organ in order to set up a new growth which is known as a metastases. Here we can see cells breaking through that BM, then the cells invade through the underlying tissues in order to enter the blood vessels to set up the metastases at another site, distal to the site of origin. Slide 14: Stages in the development of invasive carcinoma Development of the invasive stage of cancer is thought to develop several years after the appearance of the carcinoma in situ, and this invasive stage begins with metastasis, which describes the process by which the cancer cells spread to other body parts. A number of steps are required to establish a metases. First of all the cells need to break through or invade through that basement membrane (BM) underlying the carcinoma in situ. In order to do this, the cells bind via integrins to the underlying ECM and develop cell adhesion molecules which bind to the BM. This makes these cells secrete proteolytic enzymes which degrade the underlying BM, so that the cells can wriggle through the BM and the ECM underlying it. In order to continue moving through the ECM, a repeated process of binding to matrix products in order for cells to crawl through the ECM. They do this by developing laminin or fibronectin receptors on the cell pseudopodia so they send out those pseudopodia (extensions of cytoplasm) that bind to the matrix and release more proteolytic enzymes to create a path through the ECM. This continues with binding and degrading of the matrix until cells reach and penetrate a lymphatic or blood vessel. Once inside the vessel, the cancer cells are able to survive and avoid detection by the immune system until they arrest and arrive at the site where they are going to exit the circulation. Slide 15: Stages in the development of invasive carcinoma In order to exit the circulation, the cancer cells perform a similar process to how white blood cells emigrate from the capillaries in an immune response. Essentially, the cells bind and are tripped up  along the edge, roll along the edge and adhere to endothelial cells lining the blood vessels. They will wriggle through the blood vessel wall, between the endothelial cells, in the process of emigration, as described for the immune system cells, in order arrive at the new site & form a new secondary deposit which is the metatases Slide 16: Stages in the development of invasive carcinoma Once at the site, in order to survive and grow as a metastases, the tumour has to grow greater than 0.05 mm. The size and development of tumours is dependent on a blood supply, We know from the wound healing studies that angiogenesis is needed to provide a new blood supply. Tumour cells are very clever as they secrete growth factors VEGF, FGF TGFB and angiogenin, which can stimulate new vessel growth by angiogenesis. It is important that at this stage that the metastases is treated either by surgery, chemo- or radio- therapy, or by inhibitors against angiogenesis, or tissue targeting in order to break down that formation of the cancer. A new blood supply is required for the tumour to grow. Abnormal Cell Growth Part 2: Slide 1: Title Slide Slide 2: In this second part of the topic we look at some of the terminology used to be neoplasia or cancer, how it can be classified, how tumours are initiated. We touch upon epidemiology and risk factors and finally look at ocular tumours. Slide 3: Cancer Terminology Important to understand cancer terminology. Cancer refers to a spectrum of diseases that have abnormal swellings, hence the term ‘tumour’, in common. The correct term is ‘neoplasm’ which means ‘new growth’. There are several ways to describe a tumour; it can be described by its tissue type, its cell type, its site of origin & whether a tumour is benign or malignant. We will look at the differences between these two later. Slide 4: Cancers can be classified by Tissue type  Carcinomas represent ~90% of all cancers, and are derived from epithelial cells.  Sarcoma are solid tumours, derived from connective tissues such as cartilage i.e. chondrosarcoma, muscle: myosarcoma or bone: osteosarcoma.  Leukemias, myelomas and lymphomas represent ~8% of all cancers, and are termed blood cancers. In case of leukemias these are cancers of blood cells that begin in the bone marrow and these cancer cells can then enter blood circulation. Myelomas develop in bone marrow and appear to affect plasma cells. Lymphomas affect cells of lymphatic system such that lymphocytes accumulate in the lymphatic node spleens and other lymphoid tissues.  Blastomas are a type of cancer caused by malignancies in precursoer cells; they resemble embryonic tissue and contain immature and undifferentiated cells. Term ‘blastoma’ is usually used as part of the tumour name e.g. retinoblastoma (see later).  Teratomas are based on their histology as they contain a variety of structures that are derived from all three of the different germ cell layers; can contain hair, bone, teeth, neurones or cartilage  In case of Hodgkins lymphoma and Kaposi’s sarcoma, these are examples of tumours named after the physician that first described them. Slide 5: Cancers can be classified according to cell type from which they are developed  Adenomatous carcinomas are derived from ductal or glandular cells  Squamous carcinomas are derived from squamous epithelial cells  Myeloid cancers are derived from blood cells, originate in bone marrow.  Lymphoid cancers are derived from lymphocytes Slide 6: Cancers/tumours can be classified according to the site of origin such as:  Breast cancer  Prostate cancer  Lung cancer  Bowel cancer Slide 7: Cancers/tumours Here we have tiny skin carcinoma, very small, but can lead to metastases and still be life-threatening, if it does spread to another part of the body. Slide 8: Cancers/tumours Another small epithelial carcinoma Slide 9: Cancers/tumours Large nodule representingbreast cancer Slide 10: Cancers/tumours Cancer of the lungs: large area of abnormal tissue that would reduce function of the lungs Slide 11: Cancers/tumours Colon cancer: large mass is seen within tissue Slide 12: Cancers/tumours Solid tumour, sarcoma that affects the bone; therefore is an osteosarcoma. Slide 13: Cancers/tumours: Benign or Malignant? Cancers can be considered as : Benign or Malignant. Benign cancers may develop into malignant cancers. Benign tumours are generally slow growing, are not considered cancerous, since they do not penetrate or invade through adjacent tissue borders or spread/metastasise to other tissue sites. Generally considered innocuous unless their position becomes life-threatening and interferes with a function that is necessary for survival e.g. meningioma is considered benign, unless it puts pressure on the brain and then it can be extremely dangerous. Malignant tumours, cells proliferate rapidly, and can metastasise to other sites in the body. This is what are called invasive tumours and is when they become life-threatening. Slide 13: Cancers/tumours: Benign or Malignant? Compare and contrast Benign or Malignant cancers. Benign tumours have a slow growth rate; their cells are normal, they resemble those of the parent tissue. They are not infiltrating, as they do not break through the underlying BM, and therefore are not invasive; do not spread to distant sites. Generally considered innocuous, and are only life- threatening if vital function of body is damaged, as is the case of the meningioma (mentioned earlier) putting pressure on the brain. Malignant tumours are fast growing; their cells are abnormal: they do not resemble cells of the parent tissue. They are infiltrating, the cells will break through the underlying BM to form a metastases to spread to different sites. If untreated, these malignantcancers will always be life- threatening. Slide 15: Initiation of tumour How do these tumours arise? Cancers are caused by damage to a cell’s genes. Several genes, usually > 5 genes, need to be altered for a cell to become malignant. The mutated genes are those that would normally regulate cell division; they are called proto-oncogenes (PO) and tumour suppressor genes (TSG). If a PO develops abnormal expression i.e. becomes mutated and develops into an oncogene, this will drive the normal proliferation of cells into a neoplastic state i.e. drives accelerated cell proliferation. If there is a mutation is in the TSG such that it loses its function, it can no longer suppress cell proliferation and again it drives cell proliferation to a neoplastic state. Slide 16: Heredity 5-10% cancers are inherited. Cancer genes identified have included p53 which is missing or mutated in Li-Fraumeni syndrome. This is an inherited autosomal dominant disorder which makes people susceptible to a spectrum of malignancies, including the development of breast cancer, CNS tumours such as brain tumours, osteosarcoma, tumours that affect adrenal glands and leukaemias. Additionally, Rb is another cancer-causing gene, with 40% of all cancers having a mutation in the rB gene. All those that inherit the RB gene will inherit familial retinoblastoma later on (see later). Some people are more susceptible than others to development of cancers, as they are more susceptible to environmental factors or may have defects in their DNA repair mechnaisms. Slide 17: Risk Factors Geographical location, diet, exposure to chemicals and physical agents are all risk factors that may contribute to cancer. Environmental factors include viruses and tobacco. In case of viruses, this can lead to chronic irritation and damages of cells. In case of tobacco, this can affect or is responsible for 30% cancers in UK. Food, chemicals, pollution and radiation are all potential mutagens, causing DNA mutations. The genetic risk factors are based on sex, age and race. Slide 18: Neoplasia/Cancer represents major problem in society, especially as the population ages.  Cancer accounts for 28% UK deaths; 47% women & 53% men  Economic and heathcare costs in UK attributed to cancer are >£15.8 billion/annum Slide 19: Incidence of Cancer Incidence of cancer increases drastically after the age of 40 years, with the drop in incidence in over 80 years likely to be linked the reduced population at this age. Slide 20: Incidence of invasive cancers in males and females The incidence of invasive cancers increases exponentially, culminating in a lifetime risk of 1 in 2 in males, and 1 in 3 in females. The increase in later life is largely due to the increase in epithelial cell carcinomas in people over the age of 60 years. Slide 21: Incidence cancers in adults vs children What do we mean by this? Here we can see that epithelial carcinomas represent 9% of cancers in children. Looking at diseases of cancers in adults, 84% are attributed to epithelial carcinomas, with majority, 29%, atrributed to basal and squamous cell carcinomas as you can see in this pie chart. Slide 22: Survival rate 5 years following treatment Looking at the survival rate 5 years following treatment, the percent of people surviving cancers tends to differ dependent on the type of cancer. We can see that the more aggressive cancers are less amenable to treatment, whereas thyroid and non-melanoma skin cancers are highly treatable and hence people have a high survival rate following 5-years after treatment. Slide 23: Ocular Tumours There are both benign and malignant ocular tumours. Benign tumours include choroidal nevi and iris nevi. In the case of iris nevi, these originate from melanocytes and very rarely do they become malignant. In case of choroidal nevi, also derived from melanocytes, a benign choroidal melanoma is < 2 disc sizes. If the size of melanoma increases to 5 disc sizes, the melanoma is deemed to be malignant. Malignant ocular tumours include melanoma and retinoblastoma. Slide 24: Ocular Tumours: Melanoma Melanoma is the most common primary intraocular malignancy. In 41% cases, it is identified by routine examination, accounting for 7-800 cases per year in UK. Affects people of 55-65 years; mainly (99%) affects a white population. 80% of cases of melanomas are choroidal melanomas, probably due to the dark pigment here. Melanomas arise from melanocytes in any part of the eye. Slide 25: Ocular Tumours: Malignant choroidal melanoma Here we have an example of a malignant choridal melanoma : a dark mass beneath the retinal blood vessels. Often the disease is asymptomatic, unless in proximity of macula where you would get a decrease in visual acuity and field defect. Here we can see a muchroom-shaped melanoma due to it invading through Bruch’s membrane. Slide 26: Ocular Tumours: Retinoblastoma Retinoblastoma is a rare childhood cancer, affecting 1:20 000 live births. 25-30% of cases are inherited and it is the most common intraocular neoplasm within children within the first 2 years of life. Retinoblastoma is caused by mutations in the Rb or retinoblastoma tumour suppressor gene. Inheritance is via an autosomal dominant inheritance. There are two types of retinoblastoma: sporadic or inherited, but whichever type loss of two retinoblastoma genes are required. This is known as a two-hit hypothesis. Slide 27: Ocular Tumours: Retinoblastoma The two-hit hypothesis means that both alleles of the Rb1 gene must be affected for retinoblastoma to develop. In inherited retinoblastoma, the person will inherit one germ-line mutation, with one of these mutated alleles present at birth. One further event/mutation in any retinal cell will lead to the loss of two functional Rb1 genes. In inherited retinoblastoma, there is a high risk of bilateral retinoblastoma. In the case of sporadic retinoblastoma, a person is born with two normal alleles i.e. 2 normal functional RB1 genes, however they will loose 1 of their Rb genes to a mutation, and then if they have another mutation in the same cell or a daughter cell, they will end up will loss of 2 functional Rb1 genes or 2 mutations which will lead to unilateral retinoblastoma. Slide 28: Ocular Tumours: Retinoblastoma Here we have a child with retinoblastoma. The appearance of a white pupil is due to the reflection of light from the tumour’s white surface. We can also see a surgically excised eye, which is filled with a tumour with calcified flecks. Important to note that if tumour extended into the optic nerve and spread intracranially I.e. metastasised, it could be fatal. Therefore it’s really important thatthis is treated before it does become invasive.