G.G. Dark

A.R. Abdul Razak

Clinical examination of the cancer patient


Cancer is a significant global health-care problem, with an estimated worldwide incidence of 10 million new cases per year, 46% of which are in developed countries. Mortality is high, with more than 7 million deaths per year. The global costs and socioeconomic impact are considerable. The most common solid organ malignancies arise in the lung, breast and gastrointestinal tract (Fig. 11.1), but the most common form worldwide is skin cancer. Tobacco is a major factor in the aetiology of 30% of cancers, including those of the lung, nasopharynx, bladder and kidney, and these could be prevented by smoking cessation. Diet and alcohol contribute to a further 30% of cancers, including those of the stomach, colon, oesophagus, breast and liver. Lifestyle modification could reduce these if steps were taken to avoid animal fat and red meat, reduce alcohol, increase fibre, fresh fruit and vegetable intake, and avoid obesity. Infections account for a further 15% of cancers, including those of the cervix, stomach, liver, nasopharynx and bladder, and some of these could be prevented by infection control and vaccination.

The ten hallmarks of cancer

The formation and growth of cancer constitute a multistep process, during which sequentially occurring gene mutations result in the formation of a cancerous cell. For cells to initiate carcinogenesis successfully, they require key characteristics, collectively referred to as the hallmarks of cancer.

1 Genome instability and mutation

Random genetic mutations occur continuously throughout all cells of the body and very rarely confer a selective advantage on single cells, allowing overgrowth and dominance in local tissue environments. Multistep carcinogenesis results from successive clonal expansions of pre-malignant cells, each expansion being triggered by acquisition of a random enabling genetic mutation. Under normal circumstances, cellular DNA repair mechanisms are so effective that almost all spontaneous mutations are corrected without producing phenotypic changes, keeping the overall mutation rates very low. In cancer cells, the accumulation of mutations can be accelerated by compromising the surveillance systems that normally monitor genomic integrity and force genetically damaged cells into either senescence or apoptosis. Therefore, they can become more sensitive to mutagenic actions or develop DNA repair mechanism failure.

2 Resisting cell death

There are three principal mechanisms through which cell death occurs in healthy tissues:

• Apoptosis is programmed cell death and is frequently found at markedly reduced rates in cancers, particularly those of high grade or those resistant to treatment. The cellular apoptotic system has regulatory elements which sense intrinsic and extrinsic pro-apoptotic signals and initiate a cascade of proteolysis and cell disassembly with nuclear fragmentation, chromosomal condensation, and shrinking of the cell with loss of intercellular contact, followed by cellular fragmentation and the formation of apoptotic bodies that are phagocytosed by neighbouring cells. The most important regulator of apoptosis is the TP53 tumour suppressor gene, often described as the ‘guardian of the genome’, as it is able to induce apoptosis in response to sufficient levels of genomic damage. The largest initiator of apoptosis via TP53 is cellular injury, particularly due to DNA damage from chemotherapy, oxidative damage and ultraviolet (UV) radiation.

• Autophagy is a catabolic process during which cellular constituents are degraded by lysosomal machinery within the cell. It is an important physiological mechanism, which usually occurs at low levels in cells but can be induced in response to environmental stresses, particularly radiotherapy and cytotoxic chemotherapy, which induce elevated levels of autophagy that are cytoprotective for malignant cells, thus impeding rather than perpetuating the killing actions of these stress situations. Severely stressed cancer cells have been shown to shrink via autophagy to a state of reversible dormancy.

• Necrosis is the premature death of cells and is characterised by the release of cellular contents into the local tissue microenvironment, in marked contrast to apoptosis, where cells are disassembled in a step-by-step fashion and the resulting cellular fragments phagocytosed. Necrotic cell death results in the recruitment of inflammatory immune cells, promotion of angiogenesis, cellular proliferation and tissue invasion. Necrotic cells also release stimulatory factors, which promote proliferation of neighbouring cells and can promote rather than inhibit carcinogenesis.

3 Sustaining proliferative signalling

Cancer cells can sustain proliferation beyond what would be expected for normal cells; this is typically due to growth factors, which are able to bind to cell surface-bound receptors that activate an intracellular tyrosine kinase-mediated signalling cascade, ultimately leading to changes in gene expression and promoting cellular proliferation and growth. Sustained proliferative capacity can result from over-production of growth factor ligands or receptors and production of structurally altered receptors, which can signal in the absence of ligand binding and activation of intracellular signalling pathway components so that signalling is no longer ligand-dependent.

The cell cycle

The cell cycle is comprised of four ordered, strictly regulated phases referred to as G1 (gap 1), S (DNA synthesis), G2 (gap 2) and M (mitosis) (Fig. 11.2). Normal cells grown in culture will stop proliferating and enter a quiescent state called G0 once they become confluent or are deprived of serum or growth factors. The first gap phase (G1) prior to the initiation of DNA synthesis represents the period of commitment that separates M and S phases as cells prepare for DNA duplication. Cells in G0 and G1 are receptive to growth signals, but once they have passed a restriction point, they are committed to enter DNA synthesis (S phase). Cells demonstrate arrest at different points in G1 in response to different inhibitory growth signals. Mitogenic signals promote progression through G1 to S phase, utilising phosphorylation of the retinoblastoma gene product (pRb). Following DNA synthesis, there is a second gap phase (G2) prior to mitosis (M), allowing cells to repair errors that have occurred during DNA replication and thus preventing propagation of these errors to daughter cells. Although the duration of individual phases may vary, depending on cell and tissue type, most adult cells are in a G0 state at any one time.

Stimulation of the cell cycle

Many cancer cells produce growth factors, which drive their own proliferation by a positive feedback known as autocrine stimulation. Examples include transforming growth factor-alpha (TGF-α) and platelet-derived growth factor (PDGF). Other cancer cells express growth factor receptors at increased levels due to gene amplification or express abnormal receptors that are permanently activated. This results in abnormal cell growth in response to physiological growth factor stimulation or even in the absence of growth factor stimulation (ligand-independent signalling). The epidermal growth factor receptor (EGFR) is often over-expressed in lung and gastrointestinal tumours and the HER2/neu receptor is frequently over-expressed in breast cancer. Both receptors activate the Ras–Raf–MAP kinase pathway, causing cell proliferation.

4 Evading growth suppressors

In healthy tissues, cell-to-cell contact in dense cell populations acts as an inhibitory factor on proliferation. This contact inhibition is typically absent in many cancer cell populations. Growth-inhibitory factors can modulate the cell cycle regulators and produce activation of the CDK inhibitors, causing inhibition of the CDKs. Mutations within inhibitory proteins are common in cancer. Loss of restriction by disruption of pRb regulation can be found in human tumours, which produces a loss of restraint on transition from G1 to S phase of the cell cycle. Disruption of p53 function will have downstream effects on p21 that alter the coordination of DNA repair with cycle arrest and that result in the affected cell accumulating genomic defects. Down-regulation of p21 and p27, which can be found in tumours with normal p53 function, correlates notably with high tumour grade and poor prognosis.

5 Enabling replicative immortality

For cancer cells to evolve into macroscopic tumours, they need to acquire the ability for unlimited proliferation. Telomeric DNA sequences, which protect and stabilise chromosomal ends, play a central role in conferring this limitless replicative potential. During replication of normal cells, telomeres shorten progressively as small fragments of telomeric DNA are lost with successive cycles of replication. This shortening process is thought to represent a mitotic clock and eventually prevents the cell from dividing further. Telomerase, a specialised polymerase enzyme, adds nucleotides to telomeres, allowing continued cell division and thus preventing premature arrest of cellular replication. The telomerase enzyme is almost absent in normal cells but is expressed at significant levels in many human cancers.

6 Inducing angiogenesis

All cancers require a functional vascular network to ensure continued growth and will be unable to grow beyond 1 mm3 without stimulating the development of a vascular supply. Tumours require sustenance in the form of nutrients and oxygen, as well as an ability to evacuate metabolic waste products and carbon dioxide. This entails the development of new blood vessels, which is termed angiogenesis (Figs 11.3 and 11.4).

Angiogenesis is dependent on the production of angiogenic growth factors, of which vascular endothelial growth factor (VEGF) and platelet-derived endothelial growth factor (PDGF) are the best characterised. During tumour progression, an angiogenic switch is activated and remains on, causing normally quiescent vasculature to sprout new vessels continually that help sustain expanding tumour growth. Angiogenesis is governed by a balance of pro-angiogenic stimuli and angiogenesis inhibitors, such as thrombospondin (TSP)-1, which binds to transmembrane receptors on endothelial cells and evokes suppressive signals.

A number of cells can contribute to the maintenance of a functional tumour vasculature and therefore sustain angiogenesis. These include pericytes and a variety of bone marrow-derived cells such as macrophages, neutrophils, mast cells and myeloid progenitors.

7 Activating invasion and metastasis

Invasion and metastasis are complex processes involving multiple discrete steps; it begins with local tissue invasion, followed by infiltration of nearby blood and lymphatic vessels by cancer cells. Malignant cells are eventually transported through haematogenous and lymphatic spread to distant sites within the body, where they form micrometastases that will eventually grow into macroscopic metastatic lesions (see Fig. 11.3).

Cadherin-1 (CDH1) is a calcium-dependent cell–cell adhesion glycoprotein that facilitates assembly of organised cell sheets in tissues, and increased expression is recognised as an antagonist of invasion and metastasis. In situ tumours usually retain cadherin-1 production, whereas loss of cadherin-1 production due to down-regulation or occasional mutational inactivation of CDH1 has been observed in human cancers, supporting the theory that CDH1 plays a key role in suppression of invasion and metastasis.

Cross-talk between cancer cells and cells of the surrounding stromal tissue is involved in the acquired capability for invasive growth and metastasis. Mesenchymal stem cells in tumour stroma have been found to secrete CCL5, a protein chemokine that helps recruit leucocytes into inflammatory sites. With the help of particular T-cell-derived cytokines (interleukin (IL)-2 and interferon (IFN)-γ), CCL5 induces proliferation and activation of natural killer cells and then acts reciprocally on cancer cells to stimulate invasive behaviour. Macrophages at the tumour periphery can foster local invasion by supplying matrix-degrading enzymes such as metalloproteinases and cysteine cathepsin proteases.

8 Reprogramming energy metabolism

Under aerobic conditions, oxidative phosphorylation functions as the main metabolic pathway for energy production; cells process glucose, first to pyruvate via glycolysis and thereafter to carbon dioxide in the mitochondria. Whilst under anaerobic conditions, glycolysis is favoured to produce adenosine triphosphate (ATP). Cancer cells can reprogramme their glucose metabolism to limit energy production to glycolysis, even in the presence of oxygen. This has been termed ‘aerobic glycolysis’. Up-regulation of glucose transporters, such as GLUT1, is the main mechanism through which aerobic glycolysis is achieved.

This reprogramming of energy metabolism appears paradoxical, as overall energy production from glycolysis is significantly lower (18-fold) than that from oxidative phosphorylation. One explanation may be that the increased production of glycolytic intermediates can be fed into various biosynthetic pathways, including those that generate the nucleosides and amino acids, necessary for the production of new cells.

9 Tumour-promoting inflammation

Almost all tumours show infiltration with immune cells on pathological investigation and historically this finding was thought to represent an attempt of the immune system to eradicate the cancer. It is now clear that tumour-associated inflammatory responses promote tumour formation and cancer progression.

Cytokines are able to alter blood vessels to permit migration of leucocytes (mainly neutrophils), in order to permeate from the blood vessels into the tissue, a process known as extravasation. Migration across the endothelium occurs via the process of diapedesis, where chemokine gradients stimulate adhered leucocytes to move between endothelial cells and pass through the basement membrane into the surrounding tissues. Once within the tissue interstitium, leucocytes bind to extracellular matrix proteins via integrins and CD44 to prevent their loss from the site.

As well as cell-derived mediators, several acellular biochemical cascade systems consisting of pre-formed plasma proteins act in parallel to initiate and propagate the inflammatory response. These include the complement system activated by bacteria, and the coagulation and fibrinolytic systems activated by necrosis, and also in burns and trauma, as well as cancer. Other bioactive molecules, such as growth factors and pro-angiogenic factors, may be released by inflammatory immune cells into the surrounding tumour microenvironment. In particular, the release of reactive oxygen species, which are actively mutagenic, will accelerate the genetic evolution of surrounding cancer cells, enhancing growth and contributing to cancer progression.

10 Evading immune destruction

The immune system operates as a significant barrier to tumour formation and progression, and the ability to escape from immunity is a hallmark of cancer development. Cancer cells continuously shed surface antigens into the circulatory system, prompting an immune response that includes cytotoxic T cell, natural killer cell and macrophage production. The immune system is thought to provide continuous surveillance, with resultant elimination of cells that undergo malignant transformation.

However, deficiencies in the development or function of CD8+ cytotoxic T lymphocytes, CD4+ Th1 helper T cells, or natural killer cells can each lead to a demonstrable increase in cancer incidence. Also, highly immunogenic cancer cells may evade immune destruction by disabling components of the immune system. This is done through recruitment of inflammatory cells, including regulatory T cells and myeloid-derived suppressor cells, both actively immunosuppressive against the actions of cytotoxic lymphocytes (see Fig. 4.6, p. 80).

Cancers develop and progress when there is loss of recognition by the immune system, lack of susceptibility due to escape from immune cell action and induction of immune dysfunction, often via inflammatory mediators.

Environmental and genetic determinants of cancer

The majority of cancers do not have a single cause but rather are the result of a complex interaction between genetic factors and exposure to environmental carcinogens. These are often tumour type-specific but some general principles do apply.

Environmental factors

Environmental triggers for cancer have mainly been identified through epidemiological studies that examine patterns of distribution of cancers in patients in whom age, sex, presence of other illnesses, social class, geography and so on differ. Sometimes, these give strong pointers to the molecular or cellular causes of the disease, such as the association between aflatoxin production within contaminated food supplies and hepatocellular carcinomas. However, for many solid cancers, such as breast and colorectal, there is evidence of a multifactorial pathogenesis, even when there is a principal environmental cause (Box 11.1).

image 11.1   Environmental factors that predispose to cancer

Environmental aetiology Processes Diseases
Occupational exposure (see also ultraviolet and radiation) Dye and rubber manufacturing (aromatic amines) Bladder cancer
Asbestos mining, construction work, shipbuilding (asbestos) Lung cancer and mesothelioma
Vinyl chloride (PVC) manufacturing Liver angiosarcoma
Petroleum industry (benzene) Acute leukaemia
Chemicals Chemotherapy (e.g. melphalan, cyclophosphamide) Acute myeloid leukaemia
Cigarette smoking Exposure to carcinogens from inhaled smoke Lung and bladder cancer
Viral infection Epstein–Barr virus Burkitt’s lymphoma and nasopharyngeal cancer
  Human papillomavirus Cervical cancer
  Hepatitis B and C viruses Hepatocellular carcinoma
Bacterial infection Helicobacter pylori Gastric mucosa-associated lymphoid tissue (MALT) lymphomas, gastric cancer
Parasitic infection Liver fluke (Opisthorchis sinensis) Cholangiocarcinoma
  Schistosoma haematobium Squamous cell bladder cancer
Dietary factors Low-roughage/high-fat content diet Colonic cancer
  High nitrosamine intake Gastric cancer
  Aflatoxin from contamination of Aspergillus flavus Hepatocellular cancer
Radiation Ultraviolet (UV) exposure Basal cell carcinoma
Non-melanocytic skin cancer
  Nuclear fallout following explosion (e.g. Hiroshima) Leukaemia
Solid tumours, e.g. thyroid
  Diagnostic exposure (e.g. computed tomography (CT)) Cholangiocarcinoma following thorotrast usage
  Occupational exposure (e.g. beryllium and strontium mining) Lung cancer
  Therapeutic radiotherapy Medullary thyroid cancer
Inflammatory diseases Ulcerative colitis Colon cancer
Hormonal Use of diethylstilbestrol Vaginal cancer
  Oestrogens Endometrial cancer
Breast cancer


Smoking is now established beyond all doubt as a major cause of lung cancer, but there are obviously additional predisposing factors since not all smokers develop cancer. Similarly, most carcinomas of the cervix are related to infection with human papillomavirus (HPV subtypes 16 and 18). For carcinomas of the bowel and breast, there is strong evidence of an environmental component. For example, the risk of breast cancer in women of Far Eastern origin remains relatively low when they first migrate to a country with a Western lifestyle, but rises in subsequent generations to approach that of the resident population of the host country. The precise environmental factor that causes this change is unclear, but may include diet (higher intake of saturated fat and/or dairy products), reproductive patterns (later onset of first pregnancy) and lifestyle (increased use of artificial light and shift in diurnal rhythm).

Genetic factors

A number of inherited cancer syndromes are recognised that account for 5–10% of all cancers (Box 11.2). Their molecular basis is discussed in Chapter 3, but in general they result from inherited mutations in genes that regulate cell growth, cell death and apoptosis. Examples include the BRCA1, BRCA2 and AT (ataxia telangiectasia) genes that cause breast and some other cancers, the FAP gene that causes bowel cancer, and the Rb gene that causes retinoblastoma. Although carriers of these gene mutations have a greatly elevated risk of cancer, none has 100% penetrance and additional modulating factors, both genetic and environmental, are likely to be operative. Exploration of a possible genetic contribution is a key part of cancer management, especially with regard to ascertaining the risk for an affected patient’s offspring.

image 11.2   Inherited cancer predisposition syndromes

Syndrome Malignancies Inheritance Gene
Ataxia telangiectasia Leukaemia, lymphoma, ovarian, gastric, brain, colon AR AT
Breast/ovarian Breast, ovarian, colonic, prostatic, pancreatic AD BRCA1, BRCA2
Bloom’s syndrome Leukaemia, tongue, oesophageal, colonic, Wilms’ tumour AR BLM
Cowden’s syndrome Breast, thyroid, gastrointestinal tract, pancreatic AD PTEN
Familial adenomatous polyposis Colonic, upper gastrointestinal tract AD APC, MUTYH
Fanconi anaemia Leukaemia, oesophageal, skin, hepatoma AR FACA, FACC, FACD
Gorlin’s syndrome Basal cell skin, brain AD PTCH
Hereditary non-polyposis colon cancer (HNPCC) Colonic, endometrial, ovarian, pancreatic, gastric AD MSH2, MLH1, MSH6, PMS1, PMS2
Li–Fraumeni syndrome Sarcoma, breast, osteosarcoma, leukaemia, glioma, adrenocortical AD TP53
Melanoma Melanoma AD CDK2 (TP16)
Multiple endocrine neoplasia (MEN)-1 Pancreatic islet cell, pituitary adenoma, parathyroid adenoma and hyperplasia AD MEN1
MEN-2 Medullary thyroid, phaeochromocytoma, parathyroid hyperplasia AD RET
Neurofibromatosis 1 Neurofibrosarcoma, phaeochromocytoma, optic glioma AD NF1
Neurofibromatosis 2 Vestibular schwannoma AD NF2
Papillary renal cell cancer syndrome Renal cell cancer AD MET
Peutz–Jeghers syndrome Colonic, ileal, breast, ovarian AD STK11
Prostate cancer Prostate AD HPC1
Retinoblastoma Retinoblastoma, osteosarcoma AD RB1
von Hippel–Lindau syndrome Haemangioblastoma of retina and CNS, renal cell, phaeochromocytoma AD VHL
Wilms’ tumour Nephroblastoma, neuroblastoma, hepatoblastoma, rhabdomyosarcoma AD WT1
Xeroderma pigmentosum Skin, leukaemia, melanoma AR XPA, XPC, XPD (ERCC2), XPF


(AD = autosomal dominant; AR = autosomal recessive)


When a patient is suspected of having cancer, a full history should be taken; specific questions should be included as to potential risk factors such as smoking and occupational exposures. A thorough clinical examination is also essential to identify sites of metastases, and to discover any other conditions that may have a bearing on the management plan. In order to make a diagnosis and to plan the most appropriate management, information is needed on:

The overall fitness of a patient is often assessed by the Eastern Cooperative Oncology Group (ECOG) performance scale (Box 11.3). The outcome for patients with a performance status of 3 or 4 is worse in almost all malignancies than for those with a status of 0–2, and this has a strong influence on the approach to treatment in the individual patient.

The process of staging determines the extent of the tumour; it entails clinical examination, imaging and in some cases surgery, to establish the extent of disease involvement. The outcome is recorded using a standard staging classification that allows comparisons to be made between different groups of patients. Therapeutic decisions and prognostic predictions can then be made using the evidence base for the disease. One of the most commonly used systems is the T (tumour), N (regional lymph nodes), M (metastatic sites) approach of the International Union against Cancer (UICC, Box 11.4). For some tumours, such as colon cancer, the Dukes system (p. 914) is used rather than the UICC classification.


Histological analysis of a biopsy or resected specimen is pivotal in clinching the diagnosis and in deciding on the best form of management. The results of histological analysis are most informative when combined with knowledge of the clinical picture; therefore biopsy results should be reviewed and discussed within the context of a multidisciplinary team meeting.


Immunohistochemical (IHC) staining for tumour markers can provide useful diagnostic information and can help with treatment decisions. Commonly used examples of IHC in clinical practice include:

Apr 9, 2017 | Posted by in GENERAL SURGERY | Comments Off on Oncology
Premium Wordpress Themes by UFO Themes
%d bloggers like this: