The adenoma–carcinoma progression

Neoplasms may be benign or malignant; the essential difference is the capacity to invade and metastasize. The cells of benign tumours do not invade surrounding tissues but remain as a local conglomerate. Malignant tumours are invasive and their cells can directly invade adjacent tissues or enter blood and lymphatic channels, to be deposited at remote sites. This malignant genotype develops as a result of the progressive acquisition of cancer mutations (by point mutation, chromosomal loss or translocation). This progressive accumulation of mutations may lead to the formation of cancer stem cells. In a similar manner to other stem cells these cancer stem cells are pleuripotent (i.e. have the ability to give rise to more than one cell type). It is proposed they produce cells that form the epithelial, structural, and vascular components needed for cancer formation. However the cells arising from a cancer stem cell lack the normal response to the normal cell cycle controls and are, therefore, tumour forming. Such cancer stem cells could explain why cancers can relapse or metastasize. The acquisition of the malignant phenotype can be recognized histologically as a tumour develops from a benign adenoma through to a dysplastic lesion, and finally into an invasive carcinoma (Fig. 6.2). The concept of tumour progression from a benign to malignant phenotype provides the rationale behind screening and early detection programmes; i.e. if benign or pre-invasive lesions are removed, this will prevent invasive disease.

Fig. 6.2 Colorectal adenoma-carcinoma progression.

By the progressive acquisition of genetic mutations, normal colorectal epithelium forms a benign polyp, which can progress to an invasive or metastatic cancer.

Invasion and metastasis

Benign tumours rarely threaten life but may cause a variety of cosmetic or functional abnormalities. In contrast, malignant tumours invade and relentlessly replace normal tissues, destroying supporting structures and disturbing function; they can spread to distant tissues (metastasize), eventually causing death. Metastases are cancer deposits similar in cell type to the original cancer found at remote (secondary) sites in the body.

The process of invasion and metastasis is complex (Fig. 6.3) and is dependent on the biology of the tumour. For metastases to occur it would appear that further mutations need to occur in the cancer cells. These extra mutations can be called the metastatic signature. Some tumours metastasize earlier in their clinical course than others. This variation may depend on the tissue of origin of the primary tumour, but can also vary widely according to the phenotype of individual tumours. For example, cancer of the breast is thought to metastasize early, and micrometastases are often present but not detectable when the patient first presents. Some patients with apparently localized colorectal cancer are cured by radical surgery, but others receiving the same treatment deteriorate rapidly with metastatic disease.

Fig. 6.3 Invasion and metastasis.

Cancers invade adjacent tissues by direct infiltration. Spread to distant sites (metastasis) is via the bloodstream or lymphatics, or across body cavities (transcoelomic spread). Following initial growth, cancer cells lose local adherence and invade blood vessels. They are then transported via the bloodstream to adhere in distant organs and grow into secondary tumours.

The mechanisms that control invasion and metastasis are obscure (Fig. 6.4). Local pressure effects from the expanding tumour and the increased motility of tumour cells may play a role in local invasion. Malignant cells secrete a number of factors that may determine their biological behaviour and promote growth at both primary and metastatic sites. The matrix metalloproteinases (MMPs) are endoproteinases with enzymatic activity directed against components of the extracellular matrix. Their action facilitates tumour cell invasion and metastasis by degrading extracellular collagens, laminins and proteoglycans. Other proteases, such as urokinase, plasminogen-activating factor and the cathepsins, are also involved in metastasis formation. Clumps of cancer cells can then embolize to distant tissues and form metastases. The location for the development of metastases could be a simple mechanical property with organs that have fine capillary beds, such as liver and lung, trapping circulating malignant cells which then develop into metastases. The survival of metastatic deposits depends on angiogenesis, which is mediated by an imbalance between positive and negative regulatory molecules released by the tumour cells and surrounding normal cells. Negative factors, such as angiostatin or endostatin, will inhibit new vessel formation. Positive factors, such as vascular endothelial growth factors or fibroblast growth factors, will enhance metastasis. Cancer cells also secrete prostaglandins, which can induce osteolysis and may promote the development of skeletal deposits.

Fig. 6.4 Metastasis.

Following initial growth, cancer cells lose local adherence and invade blood vessels. They are then transported via the bloodstream to adhere in distant organs and grow into secondary tumours.

Natural history and estimate of cure

Calculations based on an exponential model of tumour growth suggest that three-quarters of the lifespan of a tumour is spent in a ‘pre-clinical’ or occult stage, and that the clinical manifestations of the disease are limited to the final quarter. For cure, every malignant cell must be eradicated. There should be no recurrent tumour during the patient’s lifetime, or evidence of residual tumour at death. This rigid definition of cure is rarely attainable. Instead, a normal duration of life without further clinical evidence of disease is generally accepted as evidence of cure, even though microscopic deposits of tumour may still be present.

Measuring and comparing the outcome(s) of cancer treatment can be a difficult exercise. Cancer survival data is not normally distributed but skewed with many events happening early in the study period. Survival data is generally expressed as a time from a predefined starting point (e.g. time of surgery) to a similarly defined end point (e.g. disease relapse). Other time points may also be used and so a careful and precise definition of the time period used is essential. In addition, not all patients will have experienced the defined end point by the end of the study period. This phenomenon is known as censoring and mean survival time will be unknown for a subset of the study group. Other confounding factors such as age and the stage of disease also need to be considered. Hence special methods of data interpretation are required. These various statistical methods of cancer data interpretation and comparison are termed survival analysis.

Measures used in survival analysis include, survival and hazard probabilities, Kaplan–Meier equations and graphs (Fig 6.5), Cox’s proportional hazard models, univariate and multivariate analysis. Survival is the probability that a subject survives from the starting point to the end point of the study period. Hazard is the probability that the subject has a specified event at one particular moment in time. ‘Cure’ rates of individual cancers are assessed by survival rates at various times after treatment. Conventionally, 5- and 10-year intervals are used. Cure rates vary according to the aggressiveness of the disease and the success of treatment. In some patients with cancer (e.g. stomach and lung), metastases grow rapidly and cause death within a few years of clinical presentation. In others (e.g. cancer of the breast and melanoma), many years may elapse before metastatic spread becomes evident and, even when metastases have occurred, life may be long. It is for this reason that 5-year survival rates cannot provide a satisfactory estimate of cure for all tumours.

Fig. 6.5 Kaplan–Meier survival curve.

Screening

If cancer can be detected before it causes symptoms, then it is generally smaller, has less chance of having metastasized and is therefore more amenable to cure. Detecting benign lesions with malignant potential, pre-invasive cancer, and invasive malignancy before it becomes symptomatic is called screening (Fig. 6.6). Screening is expensive and its effectiveness in relation to cost must be critically evaluated before routine use (EBM 6.1). Screening is most effective when targeted at specific risk groups and when the screening test has a high level of acceptability to the target population. For successful screening, the test used must be able to detect the cancer at a stage when earlier treatment will lead to fewer deaths from the cancer. In any given population, the likelihood of a cancer being present is generally low (< 1%); hence, the test must be sensitive in order to detect these relatively rare lesions. The test must also be specific (i.e. have a low false-positive rate); otherwise, individuals will undergo unnecessary investigation or even inappropriate treatment. Finally, the proposed treatment of a cancer patient detected by a screening programme must be effective. In the UK, cervical cytology is offered to women on a 3-yearly basis until the age of 60, and mammographic screening (Fig. 6.7) is offered to women between 50 and 64 years on a 3-yearly basis. Other tumour types that might be amenable to screening are listed with their relevant screening tests in Table 6.2.

Fig. 6.6 Cervical cytology.

A group of severely dyskaryotic squamous cells in a ThinPrep liquid-based cytology preparation

(Courtesy of Dr A.R.W. Williams, Senior Lecturer/Honorary Consultant in Pathology, University of Edinburgh).

Fig. 6.7 Single mammogram showing malignancy (arrow) in peripheral breast tissue.

(Courtesy of Mr M. Barber, Consultant Breast Surgeon, Western General Hospital, Edinburgh).

Table 6.2 Examples of cancer types that are or could be the subject of screening programmes

The cancer patient’s journey

The management of cancer frequently involves surgery, be it radical for cure or palliative to relieve distressing symptoms. Because of the complexity of modern cancer management, cancer services in a hospital are currently organized around a multidisciplinary team approach. The team commonly includes surgeons, oncologists (radiotherapy/chemotherapy), radiologists, pathologists and clinical nurse specialists (Table 6.3).

Table 6.3 Multidisciplinary team involved in cancer care

Local effects

A tumour that lies on the surface of the body may become visible, change in shape or pigmentation, bleed, or discharge mucus or pus. A hollow viscus or duct may be obstructed by a tumour, e.g. a bronchus (causing pulmonary collapse), a segment of bowel (causing intestinal obstruction) or the bile duct or pancreatic duct (causing jaundice, or pancreatitis). A tumour within a closed space may cause pressure symptoms. For example, increased intracranial pressure may complicate intracerebral tumours, and paraplegia may arise from a spinal cord tumour. Invasion of an organ by a tumour may compromise its normal functions and cause organ failure. Invasion of tissues such as the pancreas, bone or nerves can cause severe pain. A cancer can also mimic the pain of benign disease: for example, dyspeptic symptoms in stomach cancer.

Systemic effects

Weight loss is often the key symptom that alerts both patients and their doctor to the possibility of malignant disease. A proportion of patients become so emaciated that they appear to die of starvation. This syndrome is known as cancer cachexia, and is clinically characterized by anorexia, severe weight loss, lethargy, anaemia and oedema.

The secretory products of some tumours can produce characteristic clinical syndromes. These products may be appropriate to the organ of origin. Thus, a tumour of the adrenal cortex may secrete excess corticosteroid and cause Cushing’s syndrome; a parathyroid tumour may secrete excess parathormone and cause hypercalcaemia; and an islet cell tumour of the pancreas may secrete excess insulin and cause hypoglycaemia. On the other hand, secretory products may be inappropriate to the site of a tumour. Such ‘ectopic’ secretion occurs predominantly in tumours of neuroendocrine origin, and produces a variety of endocrine syndromes.

Diagnostic investigations

Initial investigations to make the diagnosis should proceed in a logical order, starting with simple blood tests (e.g. tumour markers) and progressing through more complex imaging investigations, with the ultimate aim of obtaining histological or cytological confirmation of the diagnosis (Table 6.4). Plain radiology may demonstrate a soft tissue tumour, e.g. tumours of the lung or bone, but for tumours of the stomach or intestine, contrast studies are necessary. For some deep-seated tumours, e.g. those of the pancreas or brain, other methods of imaging are needed. These include angiography, radioactive scintigraphy and ultrasonography (US), CT (Fig. 6.9), MRI and positron emission tomography (PET). Neoplastic disease can be confirmed cytologically, e.g. by the demonstration of malignant cells in secretions, in washings from hollow viscera, or in needle aspirates. Biopsies obtained at either upper or lower gastrointestinal endoscopy can provide material for histology, as can ultrasound or CT-guided Tru-cut needle biopsies. In some instances, it may be necessary to perform an examination under anaesthetic or diagnostic laparoscopy (Fig. 6.10) to obtain suitable diagnostic material. In general, a treatment plan for the management of a patient cannot be formulated until a histological or cytological diagnosis has been made. However, there are circumstances in which this is not possible (e.g. in certain patients with pancreatic cancer), and then clear radiological evidence may be used instead.

Table 6.4 Investigations for the diagnosis of cancer

Benign tumours

Provided sufficient surrounding tissue is excised to ensure its complete removal, a benign tumour is cured by local excision. Some benign tumours, e.g. pleomorphic adenomas of the parotid, extend beyond their apparent macroscopic limits. Removal of the involved segment of the gland or organ is then the only sure way to cure.

Malignant tumours

A radical cancer operation implies complete removal of the tissue bearing the tumour, together with a margin of unaffected surrounding tissue. In some tumours, there is sequential spread, first locally, then to lymph nodes, and then to distant organs such as the liver and lungs. In this situation, careful local removal, along with the locoregional lymph nodes (known as ‘en bloc resection’), can be curative. Often, however, the spread of a tumour may be more unpredictable and in essence the removal of local lymph nodes is simply to provide information for the stage of the cancer, rather than being of true therapeutic benefit. The management of regional lymph nodes thus depends on the site and type of the tumour. With some tumours, e.g. those of the gastrointestinal tract, regional lymph nodes are routinely resected on the basis that sequential spread may have occurred. In other tumours (e.g. breast cancer), lymph node sampling or sentinel node biopsy may be more appropriate, especially if en bloc lymph node resection may be associated with significant morbidity: for example, limb lymphoedema.

Complete radical excision, which is confirmed by histological examination with no evidence of lymph node metastasis, carries a high chance of surgical cure. A good example is the regional lymphadenectomy performed for colon cancer (Fig. 6.12). During any operation for cancer, care is taken to try to avoid the spillage of malignant cells which may cause cancer recurrence. In some sites (e.g. testis), it is usual to ligate the main vessels draining the area before the tumour is mobilized, so that further malignant cells are not shed into the circulation. Overall, a careful and meticulous approach to all aspects of the operation is vital. Attention to each detail improves the outcome of surgery.

Fig. 6.12 Sigmoid cancer.

A Operative specimen. B The diagram shows the structures that have been removed with this en bloc resection.

There are data to suggest that surgery performed in specialist centres where surgeons are regularly performing radical operations produces better survival rates than surgery in non-specialist centres. Hence, surgeons are increasingly sub-specialized and concentrate on performing selected operations (EBM 6.2). One of the recent advances in surgical techniques is minimally invasive surgery. Using minimally invasive surgery the trauma related to surgery can be significantly reduced which can enhance the postoperative recovery. These techniques are being increasingly employed in the treatment of cancer. Early results suggested there might be an increase in metastases to the surgical wounds using these techniques, however, it is now recognised that minimally invasive surgical techniques can be used in the treatment of patients with cancer with no detriment to their outcome (EBM 6.3).

Adjuvant treatment

As mentioned previously, the most accurate staging of a patient with cancer is generally available after pathological evaluation of the resected specimen. Once this information is available, the patient can be discussed by the multidisciplinary team with a view to the need for further therapy.

Clearly, it is sometimes not possible to remove all the local disease. Moreover, early systemic dissemination may have occurred. Thus, an adjuvant to surgery is needed to provide both local and systemic control. For example, adjuvant chemotherapy may help prevent both local recurrence and distant metastasis, and this is commonly used in patients with colorectal or breast cancer and who have lymph node involvement. However, surgical excision must be adequate, and adjuvant radiotherapy or chemotherapy must not be regarded as a safety net for careless surgical practice. In some cancers, such as ovarian cancer, transcoelomic spread occurs early and a radical operation is impossible. Here surgical reduction of the tumour burden may contribute to the success of systemic treatment, which is aimed at controlling the disease as a whole.

Achieving a balance between the relief of symptoms and the morbidity induced by radical cancer therapy is often difficult, and it is important to remember that the quality of life is as important as the duration of survival. Chemotherapy is potentially toxic; morbidity and quality of life must always be considered before undertaking this form of treatment.

The success of adjuvant chemotherapy varies from one histological type of cancer to another. In general, drugs are given in combination over a period of 6–12 months. Toxicity, such as mouth ulcers, diarrhoea, weakness and alopecia, is common but in general tolerable. Results in colorectal and breast cancer suggest that the likelihood of death from recurrent cancer is reduced by about 20–30% in patients with evidence of lymph node metastasis.

Because of the localized nature of radiotherapy, it is administered to reduce the chances of local recurrence rather than of distant metastasis. Radiotherapy may be given prior to surgery to try to ‘down-stage’ or shrink a bulky and fixed tumour (e.g. rectal cancer) and thus make surgery easier to perform. Sometimes radiotherapy is given to rectal cancers preoperatively, even if the cancer is surgically resectable, to improve subsequent local recurrence rates; this is termed neoadjuvant radiotherapy. Alternatively, it may be given to the postoperative patient in whom the chances of local recurrence are thought to be high (e.g. a patient in whom the margins at the edge of the resection specimen are involved with tumour). When tumours are relatively radiosensitive, radiotherapy can reduce the need for radical surgery and a more cosmetically acceptable conservative operation is then possible (e.g. lumpectomy and radiotherapy, as opposed to mastectomy in breast cancer).

The impact of intensive chemo- and radiotherapy on growth in children with malignant disease can be significant. The potential for cure, which is possible in many childhood malignancies, has to be balanced against the long-term morbidity of growth failure as a side effect of such treatment.

Other modes of adjuvant therapy include less toxic therapies, such as administration of the antioestrogen tamoxifen in women with breast cancer. Experimental models have shown that monoclonal antibodies, synthetic peptides, antisense oligonucleotides and soluble adhesion molecules can inhibit tumour growth. Gene therapy carries the potential to restore the function of altered tumour suppressor molecules. MMP inhibitors and angiogenesis inhibitors offer other potential avenues for novel anticancer therapy.