Chapter 9 Malignant disease
Introduction
Table 9.1 Relative 5-year survival estimates based on survival probabilities observed during 2000–2001, by sex and site, England and Wales
5-year survival (%) | ||
---|---|---|
Men | Women | |
Pancreas | 3 | 2 |
Lung | 6 | 6 |
Oesophagus | 7 | 8 |
Stomach | 12 | 13 |
Brain | 13 | 15 |
Multiple myeloma | 24 | 22 |
Ovary |
| 34 |
Leukaemia | 38 | 36 |
Kidney | 45 | 43 |
Colon | 46 | 45 |
Rectum | 45 | 48 |
Non-Hodgkin’s lymphoma | 51 | 52 |
Prostate | 61 |
|
Larynx | 67 |
|
Bladder | 71 | 61 |
Cervix |
| 68 |
Melanoma | 78 | 90 |
Breast |
| 79 |
Hodgkin’s lymphoma | 84 | 83 |
Testis | 95 |
|
The biology of cancer
Most human neoplasms are clonal in origin, i.e. they arise from a single population of precursor or cancer stem cells. This process is typically initiated by genetic aberrations within this precursor cell. Cancer is increasingly common the older we get and can be related to a time dependent accumulation of DNA damage that is not repaired by the normal mechanisms of genome maintenance, damage tolerance and checkpoint pathways. Malignant transformation may result from a gain in function as cellular proto-oncogenes become mutated (e.g. ras), amplified (e.g. HER2) or translocated (e.g. BCR-ABL). However, these mutations are insufficient to cause malignant transformation by themselves. Alternatively, there may be a loss of function of tumour suppressor genes such as P53 that normally suppress growth. Loss or gain of function may also involve alterations in the genes controlling the transcription of the oncogenes or tumour suppressor genes (p. 46). Over subsequent cell divisions, heterogeneity develops with the accumulation of further genetic abnormalities (Fig. 9.1).
Table 9.2 Common genetic abnormalities in cancer
Gene | Example |
---|---|
Control cell cycle checkpoints | Cyclin D1, p15, p16 |
DNA repair | FANCA, ATM |
Apoptosis | Bcl2 |
Differentiation | PML/RARA |
Growth factor receptors | EGF, VEGF, FGF, BCR/ABL, TGF-B, KIT, L-FLT3 |
Signalling pathways | RAS, BRAF, JAK2, NF1, PTCH |
Hedgehog signalling pathway | See p. 26 |
Tumour suppressor genes | P53, Rb, WT1, VHL |
The hallmarks in developing cancer are shown in Figure 9.2.
Aetiology and epidemiology
Genetic factors
Rather than occurring by somatic mutation in response to mutagens, germline mutations in the genes that predispose to the development of cancer may be inherited and therefore present in all tissues. Examples of such cancer syndromes are given in Table 9.3. Expression of the mutation and hence carcinogenesis, will depend upon the penetrance (due to the level of expression and the presence of other genetic events) of the gene and whether the mutated allele has a dominant or recessive effect. There is a small group of autosomal dominant inherited mutations such as RB (in retinoblastoma), and a small group of recessive mutations (Table 9.3). Carriers of the recessive mutations are at risk of developing cancer if the second allele becomes mutated, leading to ‘loss of heterozygosity’ within the tumour, although this is seldom sufficient as carcinogenesis is a multistep process.
Table 9.3 Familial cancer syndromes
Gene | Neoplasms | |
---|---|---|
Autosomal dominant |
|
|
Retinoblastoma | RB1 | Eye |
Wilms’ tumour | WT1 | Kidney |
Li–Fraumeni | p53 | Sarcoma/brain/leukaemia |
Neurofibromatosis type 1 | NF1 | Neurofibromas/ leukaemia |
Familial adenomatous polyposis (FAP) | APC | Colon |
Hereditary non-polyposis colon cancer (HNPCC) | MLH1 and MSH2 | Colon, endometrium |
Hereditary diffuse gastric cancer syndrome | E-cadherin | Stomach |
Breast ovary families | BRCA1 | Breast/ovary |
BRCA2 | ||
p53 | ||
Melanoma | p16 | Skin |
Von Hippel–Lindau | VHL | Renal cell carcinoma and haemangioblastoma |
Multiple endocrine neoplasia type 1 | MEN1 | Pituitary, pancreas, parathyroid |
Multiple endocrine neoplasia type 2 | RET | Thyroid, adrenal medulla |
Autosomal recessive |
|
|
Xeroderma pigmentosa | XP | Skin |
Ataxia telangiectasia | AT | Leukaemia, lymphoma |
Fanconi’s anaemia | FA | Leukaemia, lymphoma |
Bloom’s syndrome | BS | Leukaemia, lymphoma |
Environmental factors
A wide range of environmental factors have been identified as being associated with the development of malignancy (Table 9.4) and may be amenable to preventative action such as smoking cessation, dietary modification and antiviral immunization (Box 9.1). Environmental factors interact with genetic predisposition. For example, subsequent generations of people moving from countries with a low incidence to those with a high incidence of breast or colon cancer acquire the cancer incidence of the country to which they have moved while northern European people exposed to strong UV radiation have the highest risk of developing melanoma.
Table 9.4 Some causative factors associated with the development of cancer
Smoking | Mouth, pharynx, oesophagus, larynx, lung, bladder, lip |
Alcohol | Mouth, pharynx, larynx, oesophagus, colorectal |
Iatrogenic |
|
Alkylating agents | Bladder, bone marrow |
Oestrogens | Endometrium, vagina, breast, cervix |
Androgens | Prostate |
Radiotherapy (e.g. mantle radiotherapy) | Carcinoma of breast and bronchus |
Diet |
|
High-fat diet | Colorectal cancer |
Environmental/occupation |
|
Vinyl chloride | Liver (angiosarcoma) |
Polycyclic hydrocarbons | Skin, lung, bladder, myeloid leukaemia |
Aromatic amines | Bladder |
Asbestos | Lung, mesothelium |
Ultraviolet light | Skin, lip |
Radiation | e.g. leukaemia, thyroid cancer |
Aflatoxin | Liver |
Biological agents |
|
Hepatitis B virus | Liver (hepatocellular carcinoma) |
Hepatitis C virus | Liver (hepatocellular carcinoma) |
Human T-cell leukaemia virus | Leukaemia/lymphoma |
Epstein–Barr virus | Burkitt’s lymphoma |
Hodgkin’s lymphoma | |
Nasopharyngeal carcinoma | |
Human papillomavirus types 16, 18 | Cervix |
Oral cancer (type 16) | |
Schistosoma japonicum | Bladder |
Helicobacter pylori | Stomach |
Diet
Dietary factors have been attributed to account for one-third of cancer deaths, although it is often difficult to differentiate these from other epidemiological factors. For example, the incidence of stomach cancer is particularly high in the Far East, while breast and colon cancers are more common in the Western, economically more developed countries. Many associations have been observed without a causative mechanism being identified between the incidence of cancer and the consumption of dietary fibre, red meat, saturated fats, salted fish, vitamin E, vitamin A and many others. Food and its role in the causation of gastrointestinal cancer is discussed in Chapter 5 (see p. 218). Increasing levels of obesity in the developed world have been associated with increases in women of cancers associated with oestrogenic stimulation of the breast and endometrium.
Radiation
Table 9.5 Radiation exposure from common diagnostic radiological procedures
Procedure | mSv |
---|---|
CXR | 0.02 |
IVU | 3 |
CT chest | 7 |
CT abdomen | 8–10 |
Whole body CT | 20 |
Percutaneous coronary intervention | 15 |
Myocardial perfusion imaging | 15.6 |
UK background radiation is 2.6 mSv per year. 1 mSv carries a lifetime cancer risk of 1 in 17 500 and 5 mSv a risk of 1 in 3500.
Modified from: Smith-Bindman R, Lipson J, Marcus R et al. Archives of Internal Medicine 2009; 169:2078–2086 and Fazel R, Krumholz HM, Wang Y et al. New England Journal of Medicine 2009; 361:849–857.
Geographical distribution
The incidence of cancer across the world is dependent on the local environmental factors, the diet and the genetics of the population (see above) (Figs 9.3, 9.4). Age is also a factor as most cancers occur in those over the age of 65 who comprise 3.3% of the population in Africa compared with 15.2% in Europe. Reproductive patterns also influence breast cancer. Migrating individuals often take on the risks of the local environmental factors.

Figure 9.4 Percentage of all deaths due to cancer in the different regions of the world.
(From: info.canceresearchuk.org/cancerstats/world/the-global-picture/)
The clinical presentation of malignant disease
Asymptomatic detection through screening
An effective screening procedure should:
be affordable to the healthcare system
be acceptable to all social groups so that they attend for screening
have a good discriminatory index between benign and malignant lesions
Other population-based screening programmes that are being used or are in trials are:
FURTHER READING
Menon U, Gentry-Maharaj A, Hallett R et al. Sensitivity and specificity of multimodal and ultrasound screening for ovarian cancer and stage distribution of detected cancers: results of the prevalence screen of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Lancet. Oncology 2009; 10:327–340.
Paimela H, Malila N, Palva T et al. Early detection of colorectal cancer with faecal occult blood test screening. British Journal of Surgery 2010; 97:1567–1571.
Schroder FH et al. Prostate cancer mortality at 11 years of follow-up. N Engl J Med 2012; 366:981–990.
The symptomatic patient with cancer
Table 9.6 Symptoms and signs of malignant disease
Degree of spread | Anatomical location | Examples of clinical problems |
---|---|---|
Local | Mass | Thyroid nodule, pigmented naevus, breast lump, abdominal mass, testicular mass |
Local infiltration of skin | Dermal nodules, peau d’orange, ulceration | |
Local infiltration of nerve | Neuropathic pain and loss of function | |
Local infiltration of vessel | Venous thrombosis, tumour emboli, haemorrhage, e.g. GI | |
Obstruction of viscera or duct | Small or large bowel obstruction, dysphagia, SVC obstruction | |
Nodal | Peripheral | Supraclavicular fossa, Virchow’s node, lymphoedema |
Central | Mediastinum – SVC obstruction, porta hepatis – obstructive jaundice, para-aortic nodes and back pain | |
Metastatic | Lung | Pleuritic pain, cough, shortness of breath, lymphangitis and respiratory failure, recurrent pneumonia |
Liver | RUQ pain, anorexia, fever, raised serum liver enzymes, jaundice | |
Brain | Headache and vomiting of raised intracranial pressure, focal deficit, coma, seizure | |
Bone | Bone pain, cord compression, fracture, hypercalcaemia | |
Pleura | Effusion, pain, shortness of breath | |
Peritoneum | Ascites, Krukenberg tumours | |
Adrenal | Addison’s disease (hypoadrenalism) | |
Umbilicus | Sister Mary Joseph’s nodule |
Paraneoplastic syndromes are indirect effects of cancer (Box 9.2, Fig. 9.6) that are often associated with specific types of cancer and may be reversible with treatment of the cancer. The effects and mechanisms can be very variable. For example in the Lambert–Eaton syndrome (see p. 1152), there is cross-reactivity between tumour antigens and the normal tissues, e.g. the acetylcholine receptors at neuromuscular junctions.
Box 9.2
Paraneoplastic syndromes
Syndrome | Tumour | Serum antibodies |
---|---|---|
Neurological |
|
|
Lambert–Eaton syndrome | Lung (small-cell) lymphoma | Anti-VGLC |
Peripheral sensory neuropathy | Lung (small-cell), breast and ovary lymphoma | Anti-Hu |
Cerebellar degeneration | Lung (particularly small-cell) lymphoma | Anti-Yo |
Opsoclonus/myoclonus | Breast, lung (small-cell) | Anti-Ri |
Stiff person syndrome | Breast, lung (small-cell) | Anti-amphiphysin |
Limbic, hypothalamic, brain stem encephalitis | Lung | Anti-Ma protein |
| Testicular | Anti-NMDAR |
Endocrine/metabolic |
|
|
SIADH | Lung (small-cell) |
|
Ectopic ACTH secretion | Lung (small-cell) |
|
Hypercalcaemia | Renal, breast, myeloma, lymphoma |
|
Fever | Lymphoma, renal |
|
Musculoskeletal |
|
|
Hypertrophic pulmonary osteoarthropathy | Lung (non-small-cell) |
|
Clubbing | Lung |
|
Skin |
|
|
Dermatomyositis/polymyositis | Lung and upper GI |
|
Acanthosis nigricans | Mainly gastric |
|
Velvet palms | Gastric, lung (non-small cell) |
|
Hyperpigmentation | Lung (small-cell) |
|
Pemphigus | Non-Hodgkin’s lymphoma, CLL |
|
Haematological |
|
|
Erythrocytosis | Renal cell carcinoma, hepatocellular carcinoma, cerebellar haemangioblastoma |
|
Thrombocytosis | Ovarian cancer |
|
Migratory thrombophlebitis | Pancreatic adenocarcinoma |
|
DVT | Adenocarcinoma |
|
DIC | Adenocarcinoma |
|
Renal |
|
|
Nephrotic syndrome | Myeloma, amyloidosis |
|
Membranous glomerulonephritis | Lymphoma |
|
SIADH, syndrome of inappropriate antidiuretic hormone secretion; ACTH, adrenocorticotrophic hormone; CLL, chronic lymphocytic leukaemia; DIC, disseminated intravascular coagulation; NMDAR, N-methyl-D-aspartate receptors.
Other symptoms are related to peptide or hormone release, e.g. carcinoid or Cushing’s syndrome.
Serum tumour markers
Table 9.7 Serum tumour markers
α-Fetoprotein | Hepatocellular carcinoma and non-seminomatous germ cell tumours of the gonads |
β-Human chorionic gonadotrophin (β-hCG) | Choriocarcinomas, germ cell tumours (testicular) and lung cancers |
Prostate-specific antigen (PSA) | Carcinoma of prostate |
Carcinoma embryonic antigen (CEA) | Gastrointestinal cancers |
CA125 | Ovarian cancer |
CA19–9 | Gastrointestinal cancers, particularly pancreatic cancer |
CA15–3 | Breast cancer |
Osteopontin | Many cancers including mesothelioma |
M-band (Ig or light chain) | Myeloma, chronic lymphocytic leukaemia, small lymphocytic lymphoma, lymphoplasmacytic lymphoma, amyloid |
Biopsy and histological examination
Molecular markers of genetic abnormalities have long been available in the haematological cancers and are increasingly available in solid cancers. For example, fluorescent in situ hybridization (FISH, see p. 40) can be used to look for characteristic chromosomal translocations, e.g. in lymphoma and leukaemia, as well as deletions or amplifications, e.g. in breast cancer (see genetic basis of cancer, p. 45). Tissue microarrays can identify patterns of multiple genomic alterations and single nucleotide polymorphisms (SNPs), e.g. in breast cancer and lymphoma (see p. 35), and RNA assays with RT-PCR can be used to identify tissue of origin with prognostic and predictive relevance.