Chapter 9 Malignant disease

The term ‘malignant disease’ encompasses a wide range of illnesses, including common ones such as lung, breast and colorectal cancer (Table 9.1) as well as rare ones, like the acute leukaemias. Malignant disease is widely prevalent and, in the West, almost one-third of the population will develop cancer at some time during their life. It is second only to cardiovascular disease as the cause of death. Although the mortality of cancer is high, many advances have been made, both in terms of treatment and in understanding the biology of the disease at the molecular level.

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).

Figure 9.1 The adenoma–carcinoma progression sequence.

The genes most commonly affected can be characterized as those controlling cell cycle checkpoints, DNA repair and DNA damage recognition, apoptosis, differentiation, growth factor receptors and signalling pathways and tumour suppressor genes (Table 9.2). Recognition of critical genetic alterations has enabled extensive development of new targeted drugs such as imatinib that inhibits the growth signals of the abnormal tyrosine kinase BCR/ABL. Proliferation may continue at the expense of differentiation which, together with the failure of apoptosis, leads to tumour formation with the accumulation of morphologically abnormal cells varying in size, shape and cytoplasmic or nuclear maturity.

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.

Figure 9.2 The hallmarks of cancer: the next generation.Six biological capabilities acquired during the multistep development of human tumours have been identified as shown in figure. Two others have been identified, viz reprogramming of energy metabolism and evading immune destruction.

(From Hanagan D and Weinberg PA The Hallmarks of cancer: the Next Generation. Cell 2011;144:646–474 with permission.)

Tumour immunology

Tumour cells are usually not recognized and killed by the immune system. There are two main reasons. The first is failure to express molecules such as HLA and co-stimulatory B7 molecules that are required for activation of cytotoxic, or ‘killer’, T lymphocytes. Second, tumours may also actively secrete immunosuppressive cytokines and cause a generalized immunosuppression. Successful strategies for tumour vaccines that overcome these obstacles are developing in renal cancer and prostate cancer. The monoclonal antibody ipilimumab against the inhibitory cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) molecule that is expressed after T-cell activation, is used in melanoma (p. 479)

FURTHER READING

Hodi FS, O’Day SJ, McDermott DF et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363:711–723.

Angiogenesis

For many tumours, there is a progressive slowing of the rate of growth as the tumours become larger. This occurs for many reasons, but outgrowing the blood supply is paramount. New vessel formation (angiogenesis) is stimulated by a variety of peptides produced both by tumour cells and by host inflammatory cells, such as basic fibroblast growth factor (bFGF), angiopoietin 2 and vascular endothelial growth factors (VEGFs), which are stimulated by hypoxia. The anti-VEGF-receptor monoclonal bevacizumab has had some success in colorectal and ovarian cancer.

Invasion and metastasis

Solid cancers spread by both local invasion and by distant metastasis through the vessels of the blood and lymphatic systems. Infiltration into surrounding tissues is associated with loss of cell–cell cohesion, which is mediated by active homotypic cell adhesion molecules (CAMs). Epithelial cadherin (E-cadherin) is expressed by many carcinomas and mutated in some such as familial gastric carcinoma (see p. 252).

Invasion is also determined by the balance of activators to inhibitors of proteolysis. The matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are involved in tumour growth, invasion, metastasis and angiogenesis and are being targeted in new therapeutic drugs for cancer treatment.

Dissemination of tumour cells occurs through intravasation into the vascular and lymphatic vessels and dissemination to distant sites, partly by chance, but also because of specific interactions between receptors and cytokines found on stromal and tumour cells such as TNF, IL-6 and chemokines.

Bone metastasis with osteoclast and osteoblast activation.

FURTHER READING

Chiang AC, Massague J. Molecular basis of metastasis. New England Journal Medicine 2008; 359:2814–2823.

Pritchard CC, Grady WM. Colorectal cancer molecular biology moves into clinical practice. Gut 2011; 60:116–129.

Aetiology and epidemiology

For most patients, the cause of their cancer is unknown, probably representing a multifactorial interaction between individual genetic predispositions and environmental factors.

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
Human papillomavirus types 16, 18	Oral cancer (type 16)
Schistosoma japonicum	Bladder
Helicobacter pylori	Stomach

Box 9.1

Key messages for a healthy lifestyle for preventing cancer

Stop smoking

Moderate alcohol consumption

Healthy weight

Moderate exercise

Healthy eating (fruit and vegetables, high fibre, low fat/salt/sugar)

Limited sun exposure

Minimize occupational risk

Minimize radiation exposure

Vaccination against hepatitis B and HPV

Tobacco

The incidence of lung cancer in both men and women increased dramatically in the last 25 years worldwide, but is now falling in many developed countries. The association of smoking with lung cancer is indisputable and causative mechanisms have been identified: cigarette tobacco is responsible for one-third of all deaths from cancer in the UK. Smoking not only causes lung cancer, it is also associated with cancer of the mouth, larynx, oesophagus and bladder. Smoking is discussed on page 806.

Alcohol

Alcohol is associated with cancers of the upper respiratory and gastrointestinal tracts, and it also interacts with tobacco in the aetiology of these tumours. It may be associated with an increased risk of breast cancer.

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.

Environmental/occupational

Ultraviolet light is known to increase the risk of skin cancer (basal cell, squamous cell and melanoma). The incidence of melanoma is therefore particularly high in the white Anglo-Celtic population of Australia, New Zealand and South Africa, where exposure to UV light is combined with a genetically predisposed population.

Arsenical contamination of water supplies has been linked to high incidence of lung and colon cancers in Southeast Asia particularly where bore holes are the main water source.

Occupational factors. In 1775, Percival Pott described the association between carcinogenic hydrocarbons in soot and the development of scrotal epitheliomas in chimney sweeps. The principal causes now are asbestos (lung and mesothelial cancer) and polycyclic hydrocarbons from fossil fuel combustion (skin, lung, bladder cancers). Organic chemicals, such as benzene, may cause the development of bone marrow conditions such as myelodysplastic syndrome or acute myeloid leukaemia.

Infectious agents

The geographical distribution of a rare malignancy suggests that it might be caused by, or associated with, an infective agent. Chronic persistent infection provides growth stimulation while many viruses contain transforming viral oncogenes.

T-cell leukaemia, seen almost exclusively in residents of the southern island of Japan and in the West Indies, is caused by infection with the locally endemic retrovirus HTLV-1 (human T-cell leukaemia virus) and integration of the oncogene, TAX, into the cellular genome.

Hepatocellular carcinoma occurs in patients with hepatitis B and C virus infections and Burkitt’s lymphoma and nasopharyngeal carcinoma are associated with the Epstein–Barr virus. EBV is also linked with Hodgkin’s lymphoma (see p. 459).

Patients with HIV infection or immunosuppression from organ transplantation have an increased incidence of EBV-related lymphoma and herpesvirus-8-associated Kaposi’s sarcoma.

The incidence of cervical cancer had increased among younger women in association with sexually transmitted HPV (human papillomavirus) infection types 16 and 18, for which an effective vaccine is now available.

Bacterial infection with Helicobacter pylori predisposes to the development of gastric cancer and gastric lymphoma, while Schistosoma japonicum infection predisposes to the development of squamous cell carcinomas in the bladder.

Medications

Oestrogens have been implicated in the development of vaginal, endometrial and breast carcinoma. Certain cytotoxic drugs given, e.g. for Hodgkin’s lymphoma (see later) are themselves associated with an increased incidence of secondary acute myelogenous leukaemia (AML), bladder and lung cancer. Androgens have been associated with both benign and malignant liver tumours.

Radiation

Accidental. The nuclear disasters of Hiroshima, Nagasaki and Chernobyl led to an increased incidence of leukaemia after 5–10 years in the exposed population as well as increased incidences of thyroid and breast cancer. Radiation workers are at an increased risk of malignancy due to occupational exposure unless precautions are taken to minimize this using personal and environmental shielding and to record and limit the amount of personal exposure.

Therapeutic. Long-term survivors following radiotherapy, e.g. for Hodgkin’s lymphoma, have an increased incidence of cancer, particularly at the radiation field margins.

Diagnostic. Imaging procedures involving radiation exposure are associated with an increased risk of cancer. This risk is cumulative, dose dependent and time dependent, i.e. children are at higher risk than adults. The cancer risk of various common investigations is shown in Table 9.5. All doctors should strive to minimize diagnostic exposure to radiation where possible using alternative modalities such as ultrasound or MRI. Good documentation of radiation doses is required. This is particularly so in children and pregnant women.

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.

Epidemiology

The incidence and mortality from cancer varies by tumour type and geographical region across the world.

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 9.3 The most common causes of death from cancer worldwide, excluding non-melanoma skin cancers (NMSC) 2002 estimates.

(From: http://info.canceresearchuk.org/cancerstats/world/the-global-picture/)

Figure 9.4 Percentage of all deaths due to cancer in the different regions of the world.

(From: http://info.canceresearchuk.org/cancerstats/world/the-global-picture/)

Other factors

Incidence and mortality are closely linked for cancers for which treatment has yet to make significant improvements such as lung, stomach and liver, while in countries with effective screening programmes, there is an increasing incidence and decreasing mortality for breast, cervix, bowel and prostate cancers.

The clinical presentation of malignant disease

Asymptomatic detection through screening

Most common cancers start as focal microscopic clones of transformed cells and diagnosis only becomes likely once sufficient tumour bulk has accumulated to cause symptoms or signs. In order to try to make an earlier diagnosis and increase the curative possibilities, an increasing number of screening programmes are being developed which target the asymptomatic or preinvasive stages of the cancer as in cervix, breast and colon or use serum tumour markers as in prostate and ovarian cancers. Genetic screening can be used to target screening to groups at most risk of developing cancer, e.g. BRCA1 positive and breast cancer (see Table 9.3). The aim of screening programmes is to improve individual and/or population survival by detecting cancer at its very early stages when the patient is asymptomatic. This strategy is dependent upon finding tests that are sufficiently sensitive and specific, using detection methods that identify cancer before it has spread and having curative treatments that are practical and consistent with maintenance of a normal lifestyle and quality of life.

Screening is provided to populations, e.g. for breast, cervical and colon cancer in the UK, and also to individuals via annual check-ups, or opportunistic when patients see their doctor for other reasons.

Unfortunately, earlier diagnosis does not necessarily mean longer survival and randomized trials are necessary to prove benefit. With lead time bias, the patient is merely treated at an earlier date and hence the survival appears longer; death still occurs at the same time from the point of genesis of the cancer (Fig. 9.5). With length time bias, a greater number of slowly growing tumours are detected when screening asymptomatic individuals leading to a false impression of an improvement in survival.

Figure 9.5 Lead time bias. Earlier diagnosis, at X, made by screening tests before the clinical diagnosis, at Y, suggests an increased survival time of A + B. The actual survival time (C) remains unchanged.

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

show a reduction in mortality from the cancer.

Cervical cancer. The smear test is cheap and safe but requires a well-trained cytologist to identify the early changes (dyskaryosis and cervical intraepithelial neoplasia, CIN). However, developments in liquid cytology and DNA testing for human papillomavirus (HPV) may overcome this. Effective treatment for high-risk preinvasive malignant changes reduces the incidence and mortality from cervical cancer, although there are no randomized trials. Screening will continue to be required despite the introduction of vaccination against HPV infection for women before they become sexually active because the lag time between infection and the appearance of disease can be in the order of 40–50 years.

Breast cancer. The UK NHS Breast Screening Programme (i.e. biplanar mammography every 3 years) for women aged 50–70 years has been shown to reduce mortality from breast cancer in randomized controlled studies. The test is acceptable to most women with 50–75% of women attending for screening when sufficiently educated about the benefits. In North America, there is continuing debate about whether annual mammography from a younger age is more effective.

The cost is estimated to be between £250 000 and £1.3 million per life saved, money which, according to critics of screening, could be used more appropriately in better treatment.

Women from families with BRCA1, BRCA2 and p53 mutations require intensive screening starting at an earlier age when mammography is inaccurate due to greater breast density and MRI scanning is preferred.

Colorectal cancer (CRC). Faecal occult blood is a cheap test for the detection of CRC. Large randomized studies have shown a reduction in cancer-related mortality of 15–33%. However, the false-positive rates are high, meaning many unnecessary colonoscopies (see p. 291). The UK has recently introduced a national screening programme using faecal occult blood in patients aged 60–64 years, in which positive tests have identified that 10% have cancer and 40% adenomas. A randomized trial in Norway has found an increased number of early stage cancers in the screened population but a high incidence of interval cancers between biennial screens.

Colonoscopy is the ‘gold-standard’ technique for the examination of the colon and rectum and is the investigation of choice for high-risk patients. Universal screening strategies have been recommended in the USA, but the shortage of skilled endoscopists, the expense, the need for full bowel preparation and the small risk of perforation make colonoscopy impractical as a population screening tool at present and CT colonography (‘virtual colonoscopy’) (see Fig. 6.5) may become an alternative along with genetic testing and stool DNA tests.

Other population-based screening programmes that are being used or are in trials are:

Prostate cancer. Serum prostate-specific antigen (PSA) can be used for the detection of this cancer, which is on the increase. Many men over 70 have evidence of prostate cancer at post mortem with no symptoms of the disease and it has been suggested that over 75-year-olds should not have screening PSAs. The test must be interpreted with caution due to the natural increase in PSA with age, benign prostatic hypertrophy and with prostatitis. The early results of screening for prostate cancer have varied greatly from no benefit in a low-risk population to a halving of deaths from prostate cancer in a general population study but with no overall reduction in mortality. Currently national screening programmes are not recommended.

Epithelial ovarian cancer. Serum CA125 can be used for the early detection of this cancer and is the subject of ongoing trials. An improvement in survival of a screened population can be shown but at the cost of many unnecessary laparotomies so that further enhancements are being investigated by serial testing and in combination with transvaginal ultrasound scans.

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.

FURTHER READING

Hugosson J, Carlsson S, Aus G et al. Mortality results from the Göteborg randomised population-based prostate-cancer screening trial. Lancet. Oncology 2010; 11:725–732.

The symptomatic patient with cancer

Patients may offer information of predisposing conditions and family history that alerts the clinician to the likelihood of a cancer diagnosis. Many present with a history of tumour site-specific symptoms, e.g. pain, and physical signs, e.g. a mass, which readily identify the primary site of the cancer. However, some only seek medical attention when more systemic and nonspecific symptoms occur such as weight loss, night sweats, fever, fatigue, recurrent infections and anorexia. These usually indicate a more advanced stage of the disease, except in some paraneoplastic and ectopic endocrine syndromes (see below). Other patients are only diagnosed upon the discovery of established metastases such as the abdominal distension of ovarian cancer, the back pain of metastatic prostatic cancer or the liver enlargement of metastatic gastrointestinal cancer (Table 9.6).

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 Horner’s, cord compression, pancoast tumour, focal CNS deficit, hypopituitarism
	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 Obstructive uropathy, acute kidney injury, urinary retention, stridor, lobar collapse, pneumonia, cholestatic jaundice
Nodal	Peripheral	Supraclavicular fossa, Virchow’s node, lymphoedema
Nodal	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.

Figure 9.6 Paraneoplastic peripheral neuropathy with wasting of small muscles of the hands.

The coagulopathy of cancer may present with thrombophlebitis, deep venous thrombosis and pulmonary emboli, particularly in association with cancers of pancreas, stomach and breast. Some 18% of patients with recurrent pulmonary embolus will be found to have an underlying cancer and many cancer patients are at increased risk of venous thromboembolism (VTE) following diagnosis. Trousseau’s syndrome – superficial thrombophlebitis migrans – refers to this process in the superficial venous system. All patients with active cancer admitted to hospital are at high risk of VTE and should be given prophylaxis with subcutaneous LMW heparin in the absence of any contraindications (see p. 429). Dabigatran, an oral direct thrombin inhibitor, is an alternative therapy.

Other symptoms are related to peptide or hormone release, e.g. carcinoid or Cushing’s syndrome.

Cachexia of advanced cancer is thought to be due to release of chemokines such as tumour necrosis factor (TNF), as well as the fact that patients have a loss of appetite. The unexplained loss of >10% of body weight in a patient should always stimulate a search for an explanation.

Cancer-associated immunosuppression can lead to reactivation of latent infections such as herpes zoster and tuberculosis.

Reactivated herpes zoster (Shingles).

FURTHER READING

Fearon KCH. Cancer cachexia and fat–muscle physiology. N Engl J Med 2011; 365:565–567.

Serum tumour markers

Tumour markers are intracellular proteins or cell surface glycoproteins released into the circulation and detected by immunoassays. Examples are given in Table 9.7. Values in the normal range do not necessarily equate with the absence of disease and a positive result must be corroborated by histology as these markers can be seen in many benign conditions. They are most useful in the serial monitoring of response to treatment. As discussed in subsequent sections, a proportion of low-grade B-cell lymphomas and a majority of cases of myeloma will produce a monoclonal paraprotein of intact immunoglobulin molecule or light chains. This acts as a valuable tumour marker in the diagnosis and assessment of response.

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

Cancer imaging

Radiological investigation by experts is required at various stages: at initial diagnosis and staging of the disease, during the monitoring of treatment efficacy, at the detection of recurrence and for the diagnosis and treatment of complications.

The choice of investigations needs to be guided by the patient’s symptoms and signs, site and histology of the cancer, the curative or palliative potential of treatment and the utility of the information in guiding treatment. The investigations are described under each tumour type.

Contrast agents are used for increased structural discrimination and can be further enhanced with functional specificity for metabolically active tissue with 19fluorodeoxy-glucose uptake and CT-positron emission tomography (CT-PET scan) as used extensively in head and neck cancer, lung cancer and lymphoma. Radionuclide imaging of sentinel lymph nodes is used to guide lymphatic surgery in breast cancer and melanoma. Tumour targeted contrast agents can improve detection rates such as the radiolabelled MAb rituximab for lymphoma or radiolabelled small molecules such as octreotide for neuroendocrine tumours. Research into the use of reporter agents which become visible only upon activation within the tumour environment holds the promise of greater sensitivity and specificity in the future.

Biopsy and histological examination

The diagnosis of cancer may be suspected by both patient and doctor but advice about treatment can usually only be given on the basis of a tissue diagnosis. This may be obtained by endoscopic, radiologically-guided or surgical biopsy or on the basis of cytology (e.g. lung cancer diagnosed by sputum cytology). Malignant lesions can be distinguished morphologically from benign ones by the pleiomorphic nature of the cells, increased numbers of mitoses, nuclear abnormalities of size, chromatin pattern and nucleolar organization and evidence of invasion into surrounding tissues, lymphatics or vessels. The degree of differentiation (or conversely of anaplasia) of the tumour has prognostic significance: generally speaking, more differentiated tumours have a better prognosis than poorly-differentiated ones. In some tumours where the surgical procedure will vary depending on the presence of malignancy, an intraoperative histological opinion can be rapidly obtained using a tissue sample processed using ‘frozen section’ techniques, which requires the availability of a histopathologist. This obviates the need for the sample to be paraffin embedded, which takes hours to days.

Tissue tumour markers. Immunocytochemistry, using monoclonal antibodies against tumour antigens, is very helpful in differentiating between lymphoid and epithelial tumours and between some subsets of these, for example T- and B-cell lymphomas, germ cell tumours, prostatic tumours, neuroendocrine tumours, melanomas and sarcomas. However, there is much overlap in the expression of many of the markers and some adenocarcinomas and squamous carcinomas do not bear any distinctive immunohistochemical markers that are diagnostic of their primary site of origin.

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.

Genomics and proteomics are being investigated in order to target new (and expensive) therapies, e.g. imatinib in CML and GIST, trastuzumab and lapatinib in breast cancer and erlotinib in lung cancer.