Malignant disease

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Chapter 9 Malignant disease

Introduction

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).

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.

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

Oral cancer (type 16)

Schistosoma japonicum

Bladder

Helicobacter pylori

Stomach

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.

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.

An effective screening procedure should:

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.

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

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.

image 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.

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.

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

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.