Neoplasia

5 Neoplasia



A neoplasm (‘new growth’) is a lesion that results from abnormal growth of a tissue, which is partly or completely autonomous of normal growth controls and persists after the initiating stimulus has been removed.


Neoplasms usually manifest themselves as tumours (abnormal swellings). However, some neoplasms, most notably those derived from haemopoeitic cells do not form tumours, and clinically tumourous lesions can be caused by non-neoplastic disease (e.g. tuberculosis).


This chapter will describe how neoplasms form, how they are classified and how they behave.



CARCINOGENESIS


Carcinogenesis is the process by which normal cells are converted into cells capable of forming neoplasms. There is no single cause of neoplasia, and it is generally accepted that most neoplasms require several events to occur in a single cell (the multistep hypothesis) before a sustainable neoplasm can form. This accounts for the relative rarity of neoplasms when compared with the number of cells in the body, all of which, theoret-ically, have the potential to form neoplasms.


Another factor that protects most cells from neoplasia is that, in order to form a neoplasm, a cell must divide. Thus cells which are postmitotic, such as nerve cells and skeletal muscle cells, rarely form neoplasms, whereas cells such as the epithelium of the gut and the epidermis of the skin, which continually divide, form neoplasms more frequently.


This section will describe the factors that predispose to the formation of neoplasms. Some examples of carcinogens are given in Table 5.1


Table 5.1 Examples of carcinogens







































Carcinogen Neoplasm caused
Chemical:
3,4-benzpyrene (tobacco derivative) Bronchogenic carcinoma
β-naphthylamine Carcinoma of the bladder
Radiation:
Ultraviolet light Ionising radiation

Viruses:  
Human papilloma virus Carcinoma of the cervix
Hepatitis B virus Carcinoma of the liver
Others:
Asbestos fibres Mesothelioma
Aspergillus flavus aflatoxin Carcinoma of the liver
Schistosoma Carcinoma of the bladder


CARCINOGENS


Carcinogens are agents which cause the formation of neoplasms from cells exposed to them. The nature of carcinogens is diverse, but they all have the ability, directly or indirectly, to cause an inheritable change in the genes that control the growth and survival of the target cell.


Many carcinogens are now well known to the public as well as the medical profession: for example, tobacco smoke and asbestos. These have largely been identified by studies of the epidemiology of the neoplasms that they cause. Individual carcinogens can often cause neoplasms in more than one target tissue (e.g. tobacco derivatives can cause neoplasms of bronchial, laryngeal, oral, renal and bladder epithelium), and individual types of neoplasm can be caused by more than one carcinogen (e.g. bronchogenic carcinoma can be caused by tobacco derivatives, asbestos, nickel, or radon gas). However, for many types of neoplasm, the carcinogenic stimulus is not known.



Chemical


A variety of chemicals have been identified as carcinogens in man, and others are suspected to be on the basis of their carcinogenic effects in experimental animals. There is no common structural link between the different types of chemical carcinogen, but they appear to have in common the ability to modify the structure of DNA: for example, by forming adducts or by adding alkyl groups.


Many chemical carcinogens are procarcinogens which require metabolic conversion to their active form by enzymes. If the enzyme required is present in all cell types, the carcinogenic effect is likely to occur at the site of exposure. However, some carcinogens require metabolism in another tissue, which influences where they exert their carcinogenic effects. This is well illustrated by the aromatic amine β-naphthylamine, which requires metabolism by the liver before being active, and as a result causes neoplasms of the bladder where it is concentrated during excretion.


The major classes of chemical carcinogens currently known are as follows.








Radiation


Electromagnetic radiation of wavelengths shorter than the visible spectrum can cause damage to DNA that can result in neoplasia. Ultraviolet light is a significant carcinogen because of the high levels of exposure that can occur during daily life, whereas ionising radi-ation (such as x-rays and gamma-rays) is significantly carcinogenic because of the high levels of energy it possesses.





Viruses


A growing number of viruses have been implicated in the development of neoplasms. There are manyexamples of virally induced neoplasms in animals, study of which has done much to promote our understanding of the molecular genetics of neoplasia. Virally induced neoplasms in humans are (as far as we are aware) rather less common. The most ubiquitous oncogenic viruses are the human papilloma viruses; other viruses with well-established carcinogenic effects are the Epstein-Barr virus and the hepatitis B virus (see Table 5.2).


Table 5.2 Oncogenic viruses















Virus Neoplasm caused
Human papilloma virus

Epstein-Barr virus







Mechanisms of viral carcinogenesis


DNA viruses can be carcinogenic either through integration into the host genome in such a way that interferes with the function of growth-controlling genes, or through their ability to produce proteins that interfere with growth-regulating factors. For example, human papilloma viruses produce proteins that inhibit the function of the p53 and Rb1 gene products (see section on genetics). The best-known examples of oncogenic DNA viruses are the Epstein-Barr virus, which is strongly associated with Burkitt’s lymphoma and nasopharyngeal carcinoma, the hepatitis B virus, which is associated with hepatocellular (liver) carcinoma, and the human papilloma virus (HPV). HPV is associated with neoplasia of a number of different surface epithelia. It is responsible for the common viral wart of the skin and is also the main cause of carcinoma of the cervix, its precursor condition cer-vical intraepithelial neoplasia (CIN), and other forms of analogous intraepithelial neoplasia such as anal intraepithelial neoplasia (AIN). There are many different types of HPV. Individual types have preferred target tissues and have differing oncogenic potential. For example, many different HPV types infect the cervix, but only a small number of types (particularly types 16 and 18) are associated with the development of cervical carcinoma.


Oncogenic RNA viruses are retroviruses which integrate their genetic material into the host genome using the enzyme reverse transcriptase. Although there are many examples of oncogenic retroviruses causingneoplasms in animals, this is rare in man. The best-known examples are Human T-Lymphotrophic Virus-1 (HTLV-1) which causes a form of lymphoma/leukaemia which is endemic in Japan and the Caribbean, and the human immunodeficiency virus (HIV). However, HIV probably does not have a direct carcinogenic effect; the neoplasms that are associated with HIV infection probably arise as a consequence of immunosuppression and may actually be caused by other types of virus. Thus, HIV infection may act as a cofactor for oncogenesis by other viruses. There are other examples of this phenomenon, such as the Epstein-Barr virus requiring malaria infection as a cofactor in the development of Burkitt’s lymphoma.


Other associations between viruses and neoplasms are being described – for example, herpes virus 8 and Kaposi’s sarcoma and myeloma – and it seems likely that further causative associations will be established in the future, particularly in neoplasms of the lymphoreticular system. The sequence of events by which viruses can cause neoplasia is outlined in Fig. 5.1.





Other biological factors



Helicobacter pylori infestation


Helicobacter pylori infestation is a common cause of gastritis and peptic ulceration. Chronic Helicobacter pylori gastritis sometimes leads to intestinal metaplasia of the gastric mucosa. This results in the normal secretory epithelium of the gastric antrum being replaced by an epithelium with intestinal characteristics. Sometimes this epithelium is well differentiated with a mixture of absorptive and goblet cells identical to those seen in the small intestine. In other cases the epithelium is less well differentiated, being identifiable as intestinal rather than gastric by the type of mucin that it produces. In the latter case, there is a small risk of the development of dysplasia (see below, under ‘premalignant conditions’) and ultimately gastric carcinoma. However, the association between Helicobacter pylori infestation and gastric carcinoma appears to be weak and presumably requires multiple cofactors. Nonetheless, this causative link has recently been confirmed in experimental animals infected with Helicobacter pylori.


There is a more direct link between Helicobacter infestation and a far less common neoplasm of the stomach, the so-called mucosa-associated lymphoid tissue (MALT) lymphoma. It has been shown that, despite having characteristics of a malignant neoplasm, such as clonality and invasiveness, MALT lymph-omas sometimes regress when patients are treated with Helicobacter-eradicating antibiotics. However, it is more likely that Helicobacter infestation represents a growth-sustaining stimulus, rather than a conventional carcinogen. These observations have led to some debate about whether MALT lymphomas are true neoplasms or not.






HOST FACTORS







Genetic factors


Changes in the structure and function of a cell’s genetic material are central to the development of neoplasia, and more than one such change is required in an individual cell before neoplasia can occur. If all of an individual’s cells already have an abnormality in a relevant gene as a result of that individual’s inherited genetic make-up (a germ-line mutation), then fewer subsequent changes are required for neoplasia to occur. This is well illustrated by the rare familial retinoblastoma syndrome (Fig. 5.2). If both alleles of the retinoblastoma (Rb1) gene in an individual retinal cell are non-functional, retinoblastoma can develop from that cell. Sporadic retinoblastoma is a rare tumour because it is unusual for both retinoblastoma alleles in an individual cell to acquire mutations that inhibit their function. However, if one allele is already non-functional because it was inherited in a defective form, then the chances of retinoblastoma developing as a result of a subsequent mutation of the other allele are very high. This also demonstrates that the ‘retinoblastoma’ gene is a tumour suppressor gene. This is a common property of the genes that are abnormal in the various familial cancer syndromes.



Another characteristic that the retinoblastoma syndrome shows, that is common in familial cancer syndromes, is that it affects more than one tissue. If individuals with the retinoblastoma syndrome survive the development of retinoblastomas (which are usually bilateral) early in childhood, they have a very high incidence of osteosarcoma during adolescence. The retinoblastoma syndrome is used here as an illustration because its genetics are simple and well characterised. However, there are a number of other familial cancer syndromes, many of which, such as familial polyposis coli, are more common. Increasingly, these syndromes are being identified with mutations in genes that are involved in DNA repair such as the BRCA1 gene associated with familial breast cancer. The best known examples are given in Table 5.3.


Table 5.3 Examples of familial cancer syndromes






























Syndrome Gene affected Resultant neoplasms
Li Fraumeni p53 Breast, ovarian carcinomas, astrocytomas, sarcomas
Retinoblastoma Rb1 Retinoblastoma, osteosarcoma
Familial polyposis coli von Hippel-Lindau APC GI tract carcinomas, mainly colon
VHL Renal carcinoma, phaeochromocytoma, haemangioblastoma
Multiple endocrine neoplasia syndromes (I–III) RET, others Tumours of pituitary parathyroids, thyroid, pancreas, adrenal (combination depends on which syndrome)
Familial breast cancer BRCA 1, BRCA 2 Breast, ovarian syndrome prostatic carcinomas


Immune response


Some neoplasms attract large numbers of inflammatory cells, usually lymphocytes, into their substance, and there is evidence that in some tumours this may convey a better prognosis. These observations have led to the development of the major research subspecialty of tumour immunology, but, at present, treating neoplasms by stimulating the host immune response islittle more than a theoretical concept.


However, evidence has been put forward that the immune system can detect and mount a response against neoplasms, principally via NK cells. The activity of these cells can be stimulated by lymphokines such as interleukin 2, and there is some evidence that factors like interleukin 2 could have therapeutic efficacy against some neoplasms. A more convincing example of an immunological treatment that can suppress the development of a neoplasm is the effect of BCG treatment on carcinoma-in-situ of the bladder, although whether this is due to a specific immunological reaction or shedding of unstable transformed urothelium in response to a non-specific inflammatory response is not clear.


The host immune response has another important indirect effect on the development of neoplasms. There is a strong positive link between immunodeficiency and the development of neoplasia. This is illustrated by the frequency of development of lymphomas and Kaposi’s sarcoma in the acquired immune deficiency syndrome (AIDS), and cutaneous and anogenital squamous carcinomas in organ transplant recipients taking immunosuppressive therapy. In these settings the increased risk of neoplasia seems to be due to an inadequate immune response to oncogenic viruses such as HHV-8 in the case of Kaposi’s sarcoma and HPV in the case of transplant-associated squamous carcinomas.



PREMALIGNANT DISEASE


Given that malignant neoplasms usually develop as the result of multiple steps over a period of time, it is perhaps not surprising that many premalignant diseases have been described. Premalignant lesions are discrete identifiable lesions that may progress to become malignant neoplasms. These can be:




Premalignant conditions are non-neoplastic conditions that frequently lead to the development of neoplasms.


(The distinction between benign and malignant neoplasms will be defined below. The term dysplasia was defined in Chapter 4.)







GENETICS



Chromosomal abnormalities


Very crude DNA abnormalities may manifest themselves as visible changes in chromosomes isolated from neoplastic cells. These abnormalities can occur in a number of forms:







The DNA of many neoplasms, particularly malignant ones, is inherently unstable, and random chromosomal abnormalities are common. However, there are a number of chromosomal abnormalities that are consistently found in certain tumour types, the best known being the ‘Philadelphia chromosome’ (a reciprocal, balanced translocation between chromosomes 9 and 22). At a purely descriptive level, these can be useful for diagnosis, particularly in groups of tumours in which the cells are morphologically similar, such as leukaemias and the ‘small round cell tumours’ of childhood such as neuroblastoma and alveolar rhabdomyosarcoma. Detailed molecular study of these chromosomal abnormalities has yielded some insight into the pathogenesis of some of the neoplasms with specific chromosomal abnormalities. A good example of this is the translocation between chromosomes 14 and 18 that occurs in follicular (low grade) B cell non-Hodgkin’s lymphomas. This translocation results in the bcl-2 gene coming under the control of the immunoglobulin heavy chain gene promoter. As B lymphocytes constitutively express their immunoglobulin genes, this results in inappropriate over-expression of the bcl-2 gene and thus overproduction of the bcl-2 protein. As bcl-2 is an anti-apoptotic protein, this results in the ‘immortalisation’ of the neoplastic B lymphocytes.

Dec 12, 2016 | Posted by in GENERAL & FAMILY MEDICINE | Comments Off on Neoplasia
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