Cancer Clinical Features and Management


Cancer is common and will be the cause of death of about 20% of the population of developed countries. Every clinician should be aware of the many ways in which it presents. Delay in diagnosis may diminish the chances of successful treatment and always creates anxiety for the patient. Expert advice, immediate investigation, and definitive biopsy diagnosis should be obtained speedily.

Clinical features

Symptoms—common symptoms include (1) pain—a presenting feature of 30% of cases of cancer, with sites and distribution that may be characteristic of tumours in certain locations and indicators of a possible underlying malignancy; more likely to occur with rapidly growing tumours; when due to bone involvement is typically worse at night-time; (2) swelling—due to tumour mass; (3) weight loss—an invariable accompaniment of advanced cancer and also a frequent presenting symptom; may be due to direct interference with digestive function, production of factors leading to weight loss and anorexia by the tumour, and possible alteration in protein and energy metabolism.

Other clinical manifestations—these include (1) fever—particularly in lymphomas, renal carcinoma, and any cancer metastatic to the liver; (2) anaemia—usually normochromic; (3) hypercalcaemia—usually due to widespread skeletal metastases, but sometimes paraneoplastic and due to action of parathyroid hormone-related protein (PTH-rP); and (4) paraneoplastic manifestations—these may be endocrine, neurological, dermatological, musculoskeletal, or haematological; frequently present as puzzling medical problems at a time when the primary tumour may not be clinically apparent.

Emergency presentations—many presentations and complications of cancer are medical emergencies that require immediate treatment. These include spinal cord compression, raised intracranial pressure, pathological fractures, pleural and pericardial effusion, ascites, and metabolic disturbances such as hypercalcaemia.

General aspects of investigation and management

The diagnosis and immediate management of suspected cancer requires (1) a high index of clinical suspicion—cancer should be suspected with any unexplained illness, especially in older people; (2) obtaining a tissue diagnosis without undue delay—radiological imaging will often accelerate diagnosis but cannot provide a tissue diagnosis; every attempt should be made to make a histological or cytological diagnosis expeditiously; (3) initiation of treatment without undue delay—patients should start a planned programme of treatment within days, not weeks, of diagnosis.

The multidisciplinary approach—the management of a patient with cancer increasingly involves specialists in different disciplines who, at the outset, decide on the nature and sequence of treatment. These decisions are based on the stage of the tumour (local extent, presence of absence of lymph node spread, presence of absence of distant metastases) and other clinical and pathological determinants of prognosis, and on the likelihood of benefit from surgery, radiotherapy and chemotherapy.

Psychological and pastoral care, and management of pain—these are essential and rewarding aspects of cancer medicine. The attitudes of the medical team and the efficiency, openness, and responsiveness of the organization of care are of great importance in helping the patient cope with the stress of the diagnosis and its treatment.

Long-term consequences of cancer and its treatment—these are now occurring increasingly frequently as cure rates rise. They affect every aspect of general internal medicine and physicians in all specialities need to be aware of the nature of the problems that may occur, which include reduction in fertility, cognitive impairment, musculoskeletal problems, metabolic problems, and second cancers.

Introduction: cancer in general medical practice

Cancer is a common disease—approximately 20% of the population of the United Kingdom will die of cancer. It is a source of concern and perplexity to oncologists when patients are referred to them late in the disease. Symptoms may have been present for a long time, during which their significance has been overlooked, or multiple (and sometimes futile) investigations have been performed with a failure to appreciate the need for speed. To this delay can be added a frequent lack of understanding, on the part of the referring doctor, of the possibilities of treatment, and a failure to inform patients either of the nature of the diagnosis or of its implications and possibilities for therapy.

Yet almost every specialist sees patients with cancer affecting their particular field; unfortunately, these specialists may not be familiar with the principles of cancer medicine. General practitioners, seeing patients with diverse, and often minor, conditions, are in a vulnerable position when the early symptoms of a cancer first appear. Oncologists therefore frequently see patients with disease that has been present for a considerable time before diagnosis, or who have not had a proper explanation of their illness, and who have little idea of what treatment might involve. Every patient with cancer should be referred for expert advice as soon as the diagnosis is made. Delay in diagnosis and starting treatment is likely to worsen the outlook and may even deny the patient a chance of cure.

The complexity of modern cancer therapy, particularly the widening range of cellular targets for drug treatment, has led to the emergence of diverse short- and long-term consequences of treatment that involve every medical speciality.

The principles of cancer management are therefore important for every physician.

Diagnosis and immediate management of suspected cancer would be improved greatly if the following simple rules were adhered to:

  • Cancer should be suspected with any unexplained illness, especially in older people.
  • Imaging with CT, MRI, or isotopic methods, will often accelerate diagnosis. However, a tissue diagnosis cannot be made by these means and every attempt should be made to make a histological or cytological diagnosis expeditiously.
  • Patients should start a planned programme of treatment within days, not weeks, of diagnosis. The need for speed in diagnosis and treatment is tacitly recognized in specialist centres for breast cancer where patients can, in well-regulated clinics, reasonably expect to have a diagnosis made within a few days of first consultation and to begin definitive treatment within 2 weeks. This admirable efficiency should be attainable for most cancers.

Common symptoms and signs of cancer

Many of the symptoms and signs of cancer are due to the local effects of the tumour infiltrating surrounding tissues and causing pressure and distortion of neighbouring structures. Tumours also produce symptoms that are, to some extent, common to all cancers. These are general symptoms due to the metabolic disturbances caused by the tumours and specific symptoms related to hormonal effects and immunological effects of the particular tumour—so-called paraneoplastic syndromes.


Most patients with cancer experience pain at some stage in their illness, as a direct result either of the tumour or of its treatment. Pain is a feature at presentation in about 30% of patients with cancer, but the incidence varies greatly with the site of the tumour. For example, over 90% of patients with primary bone tumours or with metastases to bone have pain, and this has the characteristic feature of being worse at night-time. In contrast, only 5% of patients with leukaemia develop pain. Pain also varies according to the rate of progression of the disease and is more likely to occur with rapidly growing tumours. No symptom of cancer causes greater demoralization than unremitting pain. Any patient with unexplained, persistent pain should be suspected of having malignant disease and appropriate investigations performed. In pain clinics, 80% of patients seen with cancer have pain due to direct tumour infiltration. If the pain is due to neurological infiltration it may be felt at the distribution of the nerve root. Certain pain syndromes are sufficiently common and misleading to warrant separate consideration.

Direct tumour infiltration of bone

The origin of the pain that occurs with tumour infiltration of bone is not fully understood. The periosteum is a pain-sensitive structure and may be the source in many patients. It is probable that osteolytic processes involving prostaglandins are also involved. Pain is a common feature of metastasis at the base of the skull. If the tumour is situated around the jugular foramen, pain is often referred to the vertex of the head and the ipsilateral shoulder and arm. Movement of the head may exacerbate the pain and, later, cranial nerve involvement may cause hoarseness, dysarthria, and dysphasia. Involvement of the 9th to the 12th cranial nerves and the development of ptosis and Horner’s syndrome indicates involvement of the sympathetic nervous system extracranially adjacent to the jugular foramen. When metastases occur in the sphenoid sinus, severe headache, usually felt in both temples or retro-orbitally, is a common feature. There may be a full sensation in the head, nasal stuffiness, and a 6th nerve palsy.

When metastases occur in vertebral bodies the pain frequently precedes neurological signs and symptoms. Persistent thoracic vertebral pain and a positive bone scan is an indication for urgent investigation and treatment. In small-cell lung cancer, for example, a patient with thoracic vertebral pain and a positive bone scan has a 30% chance of developing a paraplegia. Ninety per cent of patients who have epidural spinal cord compression have vertebral body metastasis as the source of the epidural tumour (the management of spinal compression is described later). With metastasis to the odontoid process, patients complain of severe neck pain and stiffness radiating over the skull, up to the vertex. This is then followed by progressive neurological signs, often associated with autonomic dysfunction. In the lower cervical vertebrae pain is felt as an aching sensation, often radiating over both shoulders. If nerve root compression occurs at this site, there will be pain in the root distribution felt in the back of the arm, the elbow, and the ulnar aspect of the hand. The association with Horner’s syndrome suggests involvement of the paravertebral sympathetic system. Lumbar metastases are associated with local pain, worse on lying or sitting and relieved by standing. In lesions in L1 the pain is often felt over the superior iliac crests. In the sacrum, pain may be accompanied by neurological signs with symptoms of bowel and bladder dysfunction and perianal sensory loss and impotence.

Nerve infiltration

When tumours infiltrate peripheral nerves they are often accompanied by an alteration in sensation, with hyperaesthesia, dysaesthesia, and sensory loss. This is a particularly common presentation when tumours invade the paravertebral or retroperitoneal region. Here the pain is often in a root distribution and is unilateral. Another common site is when a metastasis in a rib entraps the intercostal nerves. When tumour infiltrates the brachial plexus the pain is felt in the C7 or T1 distribution. Pain in this site is frequent with the Pancoast syndrome, where an apical lung cancer infiltrates the lower brachial plexus roots. Pain in the C5 distribution occurs with upper root infiltration.

Visceral pain

This is a frequent symptom of cancer; it can cause diagnostic confusion and be difficult to control when a tumour has already been diagnosed. Poorly localized abdominal pain is a frequent feature of ovarian and pancreatic cancer and of peritoneal carcinomatosis. Retroperitoneal pain may be particularly difficult to diagnose. It may vary greatly with position (being relieved on leaning forwards) and be felt variably in the back. Left upper quadrant pain may be a presenting feature of carcinoma of the tail of the pancreas involving the mesentery of the splenic flexure of the colon.

Weight loss

Weight loss is an invariable accompaniment of advanced cancer and also a frequent presenting symptom. Often it results from the physical presence of the tumour interfering with gastrointestinal function, such as in carcinoma of the stomach, pancreas, or colon, or with peritoneal carcinomatosis. Mechanical obstruction of the bowel and loss of appetite commonly accompany these tumours. Loss of appetite is a frequent symptom of any cancer that has metastasized to the liver and usually appears at a point when metastasis is replacing much of the normal liver tissue. The mechanism is not known. Pancreatic cancers, and cancers metastatic to the porta hepatis cause weight loss from a malabsorption syndrome due to obstructive jaundice or blockage of the pancreatic ducts.

Nevertheless, many tumours cause weight loss without direct involvement of digestive organs. It is well recognized that a weight loss of more than 5% is a very adverse prognostic feature in almost all cancers. Usually it indicates that the disease is more widespread than is apparent on clinical investigation, but the mechanisms of this symptom, which is often accompanied by alteration of taste, anorexia, and a general feeling of ill health, are obscure. Sometimes quite profound weight loss can accompany nonmetastatic tumours, which are relatively small. As with advanced cancer, the cachexia syndrome is then also accompanied by anorexia and altered taste. These tumours may produce circulating factors responsible for the weight loss and loss of appetite. Tumour necrosis factor α and interleukin-1β have both been shown to produce cachexic syndromes experimentally. Tumours may themselves contribute to weight loss by alteration in protein and energy metabolism. Negative nitrogen balance has been frequently documented in patients with cancer, particularly when advanced. An increase in whole-body glucose recycling via pyruvate and lactate has also been described in patients with cancer.

The loss of body weight is therefore due to an accumulation of events involving direct interference with digestive function, production of factors leading to weight loss and anorexia by the tumour, and possible alteration in protein and energy metabolism. Later in the course of the illness, antineoplastic treatment with chemotherapy, radiation, and surgery may exacerbate weight loss.

Tumour mass

It is astonishing that patients sometimes report the appearance of a swelling only to have the significance of the finding overlooked by their doctors. The appearance of any mass should lead to prompt investigation. Although imaging techniques can sometimes distinguish benign from malignant swellings, a biopsy will usually be necessary and should be taken without delay. Nowadays it is often unnecessary to undertake surgical excision biopsy. Indeed, doing so may sometimes make subsequent management very difficult. Where there is doubt about the nature of a swelling the correct procedure will usually be needle biopsy. Biopsy is in general preferable to aspiration cytological diagnosis because the precise diagnosis of many cancers depends on architecture as well as on cytology. The great advantage of early biopsy diagnosis is that a planned approach to treatment can then be undertaken by oncologists, radiotherapists, and surgeons together. Injudicious, and often marginal, surgical excision may lead to a greatly increased risk of local recurrence of the tumour. This is a frequent occurrence in sarcomas where an amputation that might have been avoided may then become necessary, or the local recurrence provoked by inadequate excision prove uncontrollable and fatal. Furthermore, for some tumours, chemotherapy may be the appropriate first line of treatment allowing assessment of the tumour response to drug treatment before surgery is undertaken: a good response may modify the need for surgery.


In cancer, fever is usually caused by infection. However, about 30% of patients with cancer develop fever at some stage in their illness and it may be the presenting feature of some tumours, particularly lymphomas, renal carcinoma, and any cancer metastatic to the liver. The fever may be accompanied by sweating, particularly at night. The characteristic feature of the sweats that accompany malignant lymphomas and other cancers is that the patients fall asleep and wake in the middle of the night to find themselves drenched with sweat. Rigors are very uncommon with febrile episodes in cancer, and should always lead to a suspicion that an infective complication is present. Characteristic patterns of fever are seldom observed; usually it is of a low-grade, remittent, type. The Pel–Ebstein fever of Hodgkin’s disease, in which febrile periods are interspersed with several days of normal temperature, is well known but very uncommon.

The cause of the fever of malignant disease is unknown. Endogenous pyrogens may be liberated from mononuclear phagocytes in the liver or bone marrow. Tumour cells have also been shown to produce ‘pyrogens’. The nature of the cytokines responsible is not clear. Exogenously administered tumour necrosis factor and interleukin 2 both produce fever and may be secreted in patients with cancer.

The fever of malignant disease may respond to simple antipyretics such as aspirin or paracetamol. In malignant lymphoma it will disappear with successful treatment of the tumour. In advanced cancer nonsteroidal anti-inflammatory agents may also help, but corticosteroids are more effective, at least for a short period.


The anaemia of malignant disease is multifactorial. Chronic blood loss may occur in cancer of the gastrointestinal tract, as a result of vaginal bleeding, or because of malabsorption of iron. Usually the anaemia is normochromic or slightly hypochromic in nature, and the plasma transferrin and serum iron are low. The iron stores are not reduced as judged by stainable iron in the bone marrow.


Malignant disease is responsible for most of the very severe cases of hypercalcaemia seen in clinical practice. The patient will usually have widespread skeletal metastases, but occasionally the syndrome is paraneoplastic (see below). Parathyroid hormone-related protein (PTH-rP) may contribute to the pathogenesis of both paraneoplastic hypercalcaemia and that produced by bone metastases. For some cancers it appears that metastases in bone release PTH-rP locally and stimulate osteclastic resorption of bone. Resorption releases cytokines such as transforming growth factor-β and insulin-like growth factor 1 which, in turn, provokes more release of PTH-rP from the metastatic tumour. These cytokines may also cause proliferation of the tumour. Bisphosphonates may arrest the process by decreasing the activity of the osteoclasts. In the same way, bisphosphonates interrupt the activity of PTH-rP when this is liberated from a nonmetastatic tumour as a paraneoplastic phenomenon. Bisphosphonates are important both for the treatment of hypercalcaemia and containing growth of bone metastases.

Hypercalcaemic symptoms include anorexia, weight loss, and mental confusion, all of which may simulate metastatic disease.

Paraneoplastic syndromes

Many patients with cancer have complications that are not due to direct invasion of adjacent tissues by the cancer or its metastases. The tumour produces hormones or cytokines, which are responsible for symptoms at a remote site. Alternatively, the tumour provokes an immune response to altered cellular constituents and the paraneoplastic syndrome arises from the resulting immunological reaction. Paraneoplastic syndromes are not rare but each syndrome only occurs in a minority of patients with cancer. Furthermore, although some syndromes, such as the production of parathyroid hormone-related peptide, are found in many cancers, others, such as Cushing’s syndrome, are found in a few neuroendocrine tumours.

It is important to be aware of paraneoplastic syndromes because their appearance may be the first sign of malignant disease. Furthermore, they may lead the physician into believing that the patient has metastases and thus alter management inappropriately. The syndromes themselves may cause considerable disability, which is amenable to treatment. The diversity of paraneoplastic syndromes is such that only a brief description can be given in this chapter. A summary is shown in Table 1.

Cancer can cause almost any clinical syndrome, however bizarre, and should, therefore, enter the list of differential diagnosis in any unusual clinical disorder. There are, however, dangers in making a diagnosis of a paraneoplastic syndrome as a cause of symptoms. For example, most neurological problems in cancer are not due to paraneoplastic manifestations but to the local presence of the tumour. This means that spinal cord signs in a patient with cancer are much more likely to be due to direct compression of the cord than due to transverse myelitis as a paraneoplastic syndrome. Prompt treatment of the space-occupying lesion is essential and a mistaken diagnosis of paraneoplasia is potentially disastrous. Similarly, endocrine syndromes from cancer are often caused by resectable endocrine cancers themselves. Anaemia or thrombosis may be paraneoplastic in origin but more frequently a deep venous thrombosis is due to a direct compressive effect of cancer in the pelvis; and iron-deficiency anaemia should always raise the possibility of occult bleeding. Unless obviously paraneoplastic in nature, symptoms from cancer should, in the first instance, be regarded as likely to be produced by a direct effect of the tumour since this distinction has important therapeutic consequences. 

Investigation and staging

Histopathological diagnosis

The foremost investigation of a cancer is to verify that the diagnosis is correct. Oncologists are completely dependent on the quality of the histopathological examination. Errors are not common but may be very serious, as they may lead to inappropriate investigation or the denial of curative treatment. The latter merits particular consideration of two cancer types.

Misdiagnosis of a lymphoma

Lymphomas may present with histological appearances that resemble anaplastic or undifferentiated carcinoma. The diagnosis should therefore always be considered when this is the pathology report on the biopsy. Nowadays diagnosis of lymphoma has been made much easier as a result of immunohistochemical techniques. The use of antibodies to leucocyte common antigen, or a combination of B-cell and T-cell markers, is invaluable in diagnosis. If tumour cells do not stain, it makes lymphoma unlikely, but does not rule out the possibility. If positive, the diagnosis of lymphoma is virtually certain. Nevertheless, histologists may have difficulty either because the immunohistochemical technique is not sufficiently standardized in the laboratory, or because they mistake infiltrating lymphocytes for the tumour cells. Some undifferentiated pleomorphic lymphomas may be negative for leucocyte common antigen. These present considerable diagnostic difficulties, which may be resolved by examination of the tissue by molecular genetic techniques looking for rearrangement of the T-cell receptor genes or for immunoglobulin gene rearrangement. Other situations in which lymphoma may be overlooked, or a mistaken diagnosis made, are in the pulmonary lesions (or metastases) from small-cell carcinoma, which may be mistaken for lymphoma, or in biopsies from gastric ulcers where malignant lymphoma cells may wrongly be regarded as a chronic inflammatory cellular infiltrate. As non-Hodgkin’s lymphomas can present in many different sites, where the diagnosis is not clear a prudent physician will always ask the pathologist whether the diagnosis of lymphoma has been firmly excluded when a diagnosis of ‘chronic inflammation’ is made in an atypical clinical setting.

Table 1 Paraneoplastic syndromes
Syndrome Clinical features Tumour Comments
Endocrine syndromes *
Cushing’s syndrome Metabolic features (BP ↑ K+↓ glucose ↑) are severe. Obesity, etc. occur in slower growing SCLC tumours SCLC, carcinoid, other neuroendocrine tumours Pro-opiocortin produced by tumour. Occurs in 0.5% of cases. Immunoreactive ACTH ↑ in many more. In SCLC, chemotherapy may help the syndrome. In other tumours resection is curative
Antidiuretic hormone excess Low plasma sodium (less than 1 30 mmol/l with continued urine sodium excretion; below 120 mmol/l altered mental state, confusion, fits, coma, death) SCLC Tumour produces ADH. Slightly low plasma Na is common feature of all advanced cancer (due to pituitary ADH release). Treatment is by water restriction and demeclocycline. Hypertonic saline in emergency
Hypercalcaemia Symptoms of hypercalcaemia often very severe Squamous cancers Immunoreactive PTH-related peptide. Possibly release of cytokines (IL-1 β, osteoclast activating factors) in some cases. Treatment described in Chapter 12.6
T-cell leukaemia  
Some lymphomas  
Gonadotrophin excess Gynaecomastia in men, oligomenorrhoea, thyroid over-activity Gestational trophoblastic tumours β-hCG produced in excess. Clinical syndromes are uncommon. Mechanism of clinical syndrome is incompletely understood
Germ cell tumours  
Adenocarcinoma of the lung  
Other adenocarcinomas  
Hypoglycaemia Clinical features are of hypoglycaemia Sarcoma Major mechanism is non-suppressible insulin- like activity (NSILA, somatomedins) and insulin-like growth factors. Mesothelioma is usually abdominal
Tumours are usually large Mesothelioma  
Adrenal carcinoma  
Osteomalacia Vitamin-D-resistant rickets with bone pain, phosphaturia Benign mesenchyme tumours, fibromas, haemangiomas in soft tissue and bone Low 1,25-OH vitamin D, low PTH. Treatment requires large doses of vitamin D and removal of tumour
Neurological syndromes
Dementia Variable-onset dementia Lung cancer (SCLC) May be due to vascular endothelial disorder induced by the tumour
Cerebellar degeneration Subacute and progressive associated with dementia Hodgkin’s disease, uterine and ovarian cancer CSF1 protein raised and lymphocytosis
Limbic’encephalitis’ Dementia SCLC Pathologically there is hippocampal degeneration
Hodgkin’s disease  
Optic neuritis Visual failure, papilloedema often bilateral SCLC Produced by antibodies (? to altered tumour- related proteins) which bind to retinal ganglion cell
Myelopathy Rapid-onset cord degeneration often mid-thoracic. Usually quickly fatal SCLC CSF1 protein elevated
Amyotrophic lateral sclerosis Lower motor neurone weakness combined with spasticity fasciculation. Mostly in men. Slow course Various Cancer found in 5–10% of cases of ALS
Peripheral neuropathy Either pure sensory neuropathy or a severe sensorimotor neuropathy SCLC. Other intrathoracic tumours (thymoma, oesophageal cancer, lymphoma) CSF1 protein may be elevated. May antedate tumour. Often does not improve if tumour removed. Sensory neuropathy is due to dorsal root ganglion degeneration and specific antibodies have been found
Guillain-Barré syndrome Typical clinical features Lymphomas Association frequently noted but ? genuine
Dermatological syndromes
Acanthosis nigricans Hyperkeratosis and pigmentation in axillas, neck, and flexures Gastric, other intra-abdominal There is a congenital form which must be distinguished
Seborrhoeic keratoses Sudden onset of keratoses (Leser–Tralat syndrome) Gut, non-Hodgkin’s lymphoma Keratoses appear quickly in large numbers
Exfoliative dermatitis Severe erythema and scaling Lymphomas, especially T-cell type Common cause of exfoliative dermatitis
Responds to steroids and treatment of lymphoma
Migratory erythema Blistering, necrotic erythema Glucagonoma
Panniculitis Crops of tender, subcutaneous lesions which look like erythema nodosum Pancreas Probably due to fat inflammation caused by liberation of pancreatic lipases
Porphyria cutanea tarda Nodular or erythematous skin lesions Photosensitive. Hepatocellular carcinoma Very uncommon
Ichthyosis Dry scaly skin with hyperkeratosis of palms and soles Lymphomas Different from congenital form, which may be accompanied by carcinoma of oesophagus
Musculoskeletal syndromes
Finger clubbing and hypertrophic pulmonary osteoarthropathy Clubbing of finger nails.Tenderness over distal ends of radius and ulna, and tibia and fibula. Periosteal reaction on radiography Bronchial carcinoma (not SCLC), benign mesothelioma, diaphragmatic Neurilemmoma One of the great unsolved mysteries of medicine. Cause unknown
Dermatomyositis Erythema of face—cheeks, eyelids—and over backs of hands Wide variety of cancers, especially adenocarcinoma May precede cancer by 6–24 months. In middle age approx. 30% of cases have underlying malignancy
Lambert–Eaton syndrome A myasthenic syndrome with muscle weakness, especially in thighs and pelvis. Ptosis, dysarthria, double vision occur. EMG shows increase in action potential with repeated stimulation SCLC Syndrome often antedates cancer. Muscle strength does not deteriorate with exercise. An IgG autoantibody to voltage- gated calcium channels reduces acetylcholine release. Responds to treatment of tumour and to guanidine
Haematological syndromes
Autoimmune haemolytic anaemia Anaemia may be the presenting symptom. Splenomegaly may occur. Response to steroids is poor. May be associated with ITP Non-Hodgkin’s lymphoma (B-cell type), wide variety of epithelial cancers Antibodies to red cell antigens.
? cross-react with altered tumour surface antigens. Remits with successful treatment
Microangiopathic haemolytic anaemia Mild forms are common, clinically apparent cases rare Mucin-producing adenocarcinomas May respond to anticancer treatment. Procoagulant appears to be produced by the tumour
Thrombocytosis Usually asymptomatic. Mild elevation of platelet count is common. Thrombosis of haemorrhage is rare Carcinoma, Hodgkin’s disease The tumour-associated cytokine has not yet been identified
Granulocytosis Usually asymptomatic. Modest elevations frequently found with liver metastases Adenocarcinomas, melanoma Blood film does not show immature forms. CSFs2 are assumed responsible, but IL-1 and IL-3 have been implicated in some tumours
Erythrocytosis Elevated Hb with normal PaO2 and Hb electrophoresis Renal carcinoma, Wilms’ tumour, adrenal tumours, hepatomas
Erythrocytosis resolves with removal of primary. Erythropoietin is made by the tumour or its release is stimulated

These are some of the most common paraneoplastic syndromes.

* The endocrine syndromes are those where the hormonal syndrome is produced by a non-endocrine cancer.

ACTH, adrenocorticotrophic hormone; ADH, antidiuretic hormone; ALS, amyotrophic lateral sclerosis; BP, blood pressure; CSF1, cerebrospinal fluid; CSF2, colony-stimulating factor; EMG, electromyography; Hb, haemoglobin; hCG, human chorionic gonadotrophin; IL, interleukin; ITP, idiopathic thrombocytopenia.

Mediastinal or metastatic germ cell tumours

These tumours may be mistaken for anaplastic carcinoma, but the recognition of a germ cell tumour is exceedingly important because many of them are curable. Mediastinal germ cell tumours typically present in young adults and with cervical node metastases. Special stains or serum tests for α-fetoprotein or β-human chorionic gonadotrophin may be very helpful, but if negative, do not exclude the diagnosis. Several studies have shown that the use of intensive combination chemotherapy, as for germ cell tumours at other sites, may result in lasting remissions of mediastinal poorly differentiated tumours in young adults, even when there were no other features of the germ cell nature of the neoplasm. In contrast, poorly differentiated adenocarcinoma in the mediastinum of young adults can seldom be ascribed to germ cell tumour, although occasional cases may respond dramatically to chemotherapy.

Investigation of local extent of a tumour

Following diagnosis, clinical staging is the most important first procedure. Clinical examination will often establish the likely extent of the tumour. This may require specialized techniques such as ear, nose, and throat examination and bronchoscopy. The extent of infiltration and fixation to surrounding structures is assessed. CT scanning and MRI have greatly improved the preoperative determination of tumour extent. They have largely replaced more invasive techniques such as angiography and lymphangiography. MRI is particularly valuable in the staging of sarcomas and central nervous system tumours. Both techniques show the extent of the tumour and infiltration of surrounding structures. CT scanning is a valuable aid to needle biopsy diagnosis of deep-seated tumours.

Staging of lymph node spread

Spread to adjacent lymph nodes may be noted clinically or on straightforward investigations, such as chest radiography. Lymphangiography was used formerly to examine pelvic and lower para-aortic nodes but has largely been supplanted by CT. In fact the two techniques give slightly different information, as a CT scan will show enlarged lymph nodes (the assumption being that these are replaced by tumour when the lymph nodes become >2 cm in size), while lymphangiography may show abnormal appearances even when the nodes are not enlarged but contain foci of tumour cells within them.

An important development has been the introduction of so-called ‘sentinel node’ biopsy. In this technique a radioactive tracer, or a blue dye, is injected in the vicinity of the tumour, or into the tumour itself, and the lymph node at the first adjacent site of uptake is sampled, either by biopsy or surgical removal. In the case of breast cancer, the disease in which the technique is most widely used, the sampling may be at the time of operation. The presence or absence of tumour cells in the identified lymph node is taken as an indication of whether lymphatic spread has occurred. Surgery and subsequent treatment, can be modified accordingly. There are unresolved issues about accuracy and specificity of the technique in some tumours, and the confidence with which the results can be used to plan therapy.

Staging for distant metastases

Bone metastases are usually demonstrated by 99Tcm-polyphosphate isotopic scanning. The sensitivity of the examination is high and abnormalities frequently precede detectable changes on plain radiography. However, the specificity is rather lower because any traumatic or inflammatory disorder in bone can give areas of increased uptake. When areas of increased uptake are seen on technetium scanning it is important to follow up with plain skeletal radiography, particularly in the long bones of the limbs. This is because isotope scanning gives no indication of the structural integrity of the bone and the risk of pathological fracture in a limb cannot be assessed on an isotope scan.

Liver metastases are detected by an increase in circulating enzyme levels, particularly alkaline phosphatase and serum glutamic oxaloacetic transaminase. Lactate dehydrogenase is also elevated in a somewhat greater frequency. Nevertheless, liver metastases can be present without alteration in serum enzyme levels and ultrasound scanning is an invaluable non-invasive method of detecting liver metastases. CT and modern ultrasound scanning are approximately equal in sensitivity. Metastases down to 1 cm in size can be detected reliably.

Pulmonary metastases may be detected on the chest radiograph, but if they are less than 1.5 cm in size they may be present even when the radiograph appears normal. Metastases larger than this may also be overlooked if they are situated behind the heart or behind the diaphragm. CT scanning is the best method for demonstrating pulmonary metastases and lesions as small as 0.4 cm in diameter may be seen. CT scanning is therefore an essential investigation in patients who are to undergo extensive or mutilating surgery, such as for sarcomas where metastases to the lungs are particularly frequent, and the presence of metastases may influence the surgical decision.

Brain metastases are detected by CT scanning or, more reliably, by MRI. In a patient who is neurologically normal there is only a low chance of detecting asymptomatic cerebral metastasis by these methods (about 5%). For this reason the technique is not worthwhile as a routine investigation of most cancers.

Surgical staging of cancer

Surgery specifically for staging rather than for treatment is reserved for a few specific tumour sites. In lung cancer, investigation of the mediastinum is extremely important in deciding whether a tumour is operable. CT scanning may demonstrate inoperability either because the tumour is infiltrating the mediastinum or because there is lymph node spread to both ipsilateral and contralateral hilar nodes. However, in other patients, the mediastinum may appear normal and a mediastinoscopy may reveal tumour in mediastinal nodes implying the inoperability of the condition. Staging laparotomy used to be performed in localized Hodgkin’s disease, but is now reserved for specific indications. In ovarian cancer thorough surgical staging is performed at the time of the initial resection, but surgical staging is in this case (as in many other tumour resections) part of the treatment.

The use of a staging notation

This has been valuable in the reporting of results of cancer treatment and is also helpful, in an individual patient, in focusing attention on the extent of the disease and the subsequent planning of treatment. The tumour–nodes–metastasis (TNM) system is widely used. This is particularly valuable for tumours that follow an orderly progression of spread from the primary site to adjacent lymph nodes and then to metastatic sites. Thus, tumours of the head and neck, breast, non-small-cell lung cancer, renal carcinoma, bladder carcinoma, and rectal carcinoma are all well defined by this means. In addition to the TNM system, many classifications contain a stage grouping, by which tumours with varying TNM assignments are grouped together because of equivalence of prognosis or similar approaches to management. An example of the TNM staging system and stage grouping for lung cancer is given in Table 2.

Not all tumours can be summarized by the TNM system. For example, small-cell lung cancer is usually widely metastatic at the time of presentation and a simpler classification into limited (confined to one side of the thorax with ipsilateral supraclavicular nodes) or extensive (disease that is bilateral within the chest or metastatic) is used. This simple classification serves to separate patients in whom radiation treatment may be worthwhile and those in whom it is unlikely to have any benefit. In leukaemia and myeloma, other staging criteria have been developed, which are based on prognostic factors and are not related to anatomical stage. In Hodgkin’s disease and non-Hodgkin’s lymphoma, the presence (B) or absence (A) of constitutional symptoms is added to the anatomical staging system, which is used to define the degree of lymph node spread. These additions were made because the presence of constitutional symptoms confers an adverse prognostic significance in addition to the prognosis related to the anatomical stage.

Table 2  Staging of non-small cell lung cancer


T1 <3 cm diameter    
T2 >3 cm diameter but    
  >2 cm distal to carina, may be visceral pleural invasion    
T3 Involves chest wall or mediastinum    
T4 Invades heart, great vessels, trachea or oesophagus, malignant pleural effusion    
N0 No involved nodes    
N1 Ipsilateral peribronchial or hilar nodes    
N2 Ipsilateral mediastinal or subcarinal    
N3 Contralateral nodes or supraclavicular nodes    
M0 No distant metastases    
M1 Distant metastases    
Stage grouping      
Stage 1 T1, 2 N0 M0
Stage 2 T1, 2 N1 M0
Stage 3a T1, 2 N2 M0
  T3 N0–2 M0
Stage 3b AnyT N3 M0
  T4 Any N M0
Stage 4 AnyT Any N M1

Principles of cancer management

This section summarizes an integrated approach towards cancer management.

Nowadays the management of cancer will nearly always involve more than one specialist and more than one type of treatment. Increasingly, patients with cancer are seen in joint clinics where surgeons, medical oncologists, and radiotherapists plan treatment. Often there will be several possible approaches towards treatment, and these require discussion and assessment by the appropriate experts. It is of great value if a patient is referred for expert opinion before any definitive procedure is undertaken. For example, more information about gynaecological malignancy can often be obtained if a patient with abdominal swelling and ascites and an ultrasound-demonstrable mass in the pelvis is assessed preoperatively by a gynaecological oncologist. The subsequent laparotomy is likely to reveal much more information than if it is carried out as an emergency by an inexperienced surgeon. Similarly, a mass on a limb should be investigated thoroughly, including a biopsy diagnosis, before surgery is undertaken, because the nature of the histological diagnosis may profoundly alter management in the case of a sarcoma. Table 3 lists tumours in which radiotherapy and chemotherapy have an important part to play in management and where these modalities of treatment may sometimes be curative.

Table 3 The management of tumours


Chemotherapy (including endocrine therapy) Radiotherapy
May be curative in: May be curative in:
Hodgkin’s disease Localized Hodgkin’s disease
Non-Hodgkin’s lymphoma Non-Hodgkin’s lymphoma
Germ cell tumours Stage II seminoma
Wilm’s tumour Head and neck cancer
Ewing’s sarcoma  
Adds to cure rate in: Adds to cure rate in:
Stage II breast cancer Ewing’s sarcoma
? Colorectal cancer Localized breast cancer
Ovarian cancer Small-cell lung cancer
Small-cell lung cancer Anal cancer
Cervical cancer
Skin cancer
Rectal cancer
Produces remission and/or prolongs survival in: Produces remission and/or prolongs survival in:
Small-cell lung cancer Non-small cell lung cancer
Advanced breast cancer Glioma
Prostate cancer Prostate cancer
Ovarian cancer Biliary tract cancer
Palliates: Palliates:
Non-Hodgkin’s lymphoma (when incurable) Small-cell lung cancer (extensive)
Bone metastases Non-small-cell lung cancer
Brain metastases Rectal cancer
Oesophageal cancer


Surgeons see more than 80% of patients presenting with cancer for the first time. Following diagnosis and staging to exclude metastases, curative surgery may be undertaken, e.g. in breast or colorectal cancer. The aim of the operation is complete excision of the tumour with a margin of normal, uninvolved tissue around the main tumour mass. The risk of local recurrence is very high with a marginal excision in which a tumour has been ‘shelled out’, because the pseudocapsule around the tumour is likely to be infiltrated with tumour cells. Removal or sampling of the draining lymph nodes will often be undertaken, e.g. in breast cancer, malignant melanoma, and other tumours where involvement of regional lymph nodes is likely (see the discussion of sentinel node biopsy above). In some cancers, such as breast cancer, it has become clear that extensive primary tumours are usually accompanied by distant metastasis. In this situation the role of surgery is mainly to prevent local recurrence and systemic treatment is essential. With other tumours, e.g. cancers of the head and neck, extensive surgery may be the only means of both gaining effective control and in obtaining a cure and in these cases a considerable degree of surgical expertise is necessary. In other situations the tumour may be approached either by surgery or by radical radiotherapy and there may be little to choose between the results. An example is in early prostate cancer where the results of radical radiation and surgery are probably equivalent, and in operable oesophageal cancer, particularly of squamous histology, where long-term results of radiation may be the same as those of surgery. In these situations the benefits of local control, survival, and long-term side-effects have to be judged together in making a decision.

Nowadays local treatment frequently involves surgery and radiation to maximize the chances of local control. Wide local excision is increasingly practised in carcinoma of the breast, and radiation to the breast and to axillary nodes is used as an adjunct. Radiation reduces the risk of local relapse, both in the breast and in the axilla. Local excision and radiotherapy have now replaced mastectomy for many patients with small primary breast cancers. Preoperative radiation of soft tissue sarcoma may sometimes increase the chance of successful compartmental excision of the tumour, and postoperative radiation decreases the risk of local recurrence in patients in whom the excision has been marginal. These are just two examples of the many ways in which the definitive local management of the primary tumour is a matter of discussion between surgical and radiation oncologists.

Optimum local management has become further complicated by the responsiveness of some tumours to modern chemotherapy. An example is the treatment of Ewing’s tumour. In this highly malignant round-cell tumour of childhood, initial chemotherapy usually produces a prompt regression of the main tumour mass, both in the bone and in the surrounding soft tissues. However, the tumour permeates widely through the bone, and local irradiation, given after initial chemotherapy, is a standard means of maintaining local control. However, in large tumours, even with full-dose radiation, the risk of local relapse is still present. For this reason surgery is being used increasingly, provided that the cosmetic and functional results are reasonable. Surgical excision alone may be successful after chemotherapy, but frequently, because of the permeating nature of the tumour, viable tumour is present right up to the resection margins of the bone. In this situation radiation will be needed in addition to the chemotherapy and surgery. This is an example of how, in some tumours, very detailed planning of the approach to treatment by experienced specialists is essential for optimum results.

Specific management problems and medical emergencies

Spinal cord and cauda equina compression

Compression of the spinal cord and cauda equina are common and devastating complications of metastatic cancer. For successful management it is essential to remember one rule—every hour counts. Even if early treatment is not always successful, delay ensures that the patient will become permanently bed- or chair-bound, paralysed, and incontinent.

The metastasis often develops in a vertebra, from which it spreads directly or via the intervertebral foramina to compress the cord (or cauda equina below L1) from the extradural space. Alternatively, the malignant mass may originate in a mass of retroperitoneal nodes, or the primary tumour (for example a bronchial carcinoma) may be in the posterior mediastinum or retroperitoneum. Damage to the cord is by direct compression and by interruption of the arterial supply leading to infarction. It is uncommon for the tumour to be metastatic to the cord itself, although meningeal spread occurs and may cause compression (see carcinomatous meningitis, below). Cord compression may be the first manifestation of cancer but more commonly arises with metastases from a known primary.

Pain often precedes the onset of neurological symptoms. In the case of cord compression it is felt in the thoracic and cervical vertebrae. It is worse on coughing. An exceedingly sinister symptom is vertebral pain with a root distribution. A patient with this symptom needs urgent investigation, as cord compression may be imminent. The next symptom is usually weakness of the legs combined with sensory loss, of which loss of proprioception is especially characteristic. Loss of bladder and bowel sensation is late; once weakness and bladder disturbance begins, progression to irreversible paraplegia occurs in hours or a few days.

The patient often has a sensory level, motor weakness, brisk leg reflexes, and extensor plantar responses. The bladder may be palpable. Radiography of the spine often shows vertebral destruction—loss of a pedicle or compression of the body being typical. MRI (and, less reliably, CT scanning) is indispensible and has now largely replaced myelography. Treatment usually consists of surgical decompression, although for radiation-sensitive tumours such as lymphoma or Ewing’s sarcoma, high-dose corticosteroids and radiation will produce quick relief of compression. If there are multiple sites of block, radiation and steroids may be the only feasible option. The surgical approach to decompression varies according to the nature of the lesion—whether anterior or posterior, cervical or thoracic. Anterior decompression may involve removal of part of the vertebral body, but the risk of destabilization of the spine means that immediate stabilization may be necessary. It is not clear whether radiation is inferior to surgical decompression in patients with tumours that are sensitive to radiation. Radiation is, in any event, usually given after laminectomy.

Outcome is crucially dependent on the functional state of the patient before treatment. Less than 10% of those who are paraplegic before treatment will be able to walk later, 25% will do so if they have some motor function preserved, while almost all patients who can still walk on admission will continue to be able to do so.

Cerebral metastasis

Cerebral metastasis is clearly a serious complication of cancer, occurring in about 30% of all patients. Metastases are more than 10 times as common as primary brain tumours. About 15% of patients with cancer will develop symptomatic brain metastases during life. Thus, there will be approximately 15 000 deaths of patients with symptomatic cerebral metastasis each year in the United Kingdom. Metastasis at this site is life-threatening and disabling, causing severe deterioration in quality of life and great difficulty for patients and their carers.

Most cerebral metastases are intradural, usually in the substance of the brain extending to the meningeal surface. About 80% of these are situated in the cerebrum and the rest in the cerebellum and other regions. Lung cancer and breast cancer are the most common primary sites, and certain tumours are particularly associated with single metastases (cancer of the breast, ovary, and kidney). Although they may be the presenting symptom, cerebral metastases usually occur following diagnosis and treatment of a primary tumour.

In the brain substance, the metastases are vascularized from the cerebral circulation, but there is no evidence that a vascularized metastasis maintains a ‘blood–brain’ barrier—the vascularization is, after all, of nonnervous tissue without the tight endothelial junctions which characterize cerebral capillaries. Indeed, capillary leakiness appears to be a feature of cerebral metastasis and is responsible for the substantial amount of oedema of the brain that typically accompanies it. The blood–brain barrier may, however, be an important impediment to cytotoxic treatment when the metastasis is being established before it is vascularized and at the infiltrating periphery of an established metastasis. It will be a very significant factor in failure of treatment of leptomeningeal cancer.

Symptoms and signs

The typical signs of cerebral metastasis are headache, disturbance of cognitive function and affect, focal fits or grand mal convulsions, and limb paresis. Headache usually reflects a rise in intracranial pressure. It is typically present in the morning and increases in duration and frequency until other signs of raised intracranial pressure become apparent. Focal weakness is present in about half of all patients, and disturbance in higher cerebral function in about 60%.


CT scanning or MRI is the essential diagnostic investigation. On a CT scan most metastases appear hypodense but enhance with contrast material. Typically there will be oedema around the metastases. Occasionally CT scans may be normal even in patients whose symptoms strongly suggest cerebral metastasis and where cerebral metastasis is sometimes proved by further scanning some weeks later or at autopsy. In these patients there may be multiple small metastases without oedema or leptomeningeal spread. MRI has a greater degree of sensitivity and is particularly valuable in detecting leptomeningeal spread of tumour. In the presence of a known primary it is not usually necessary to subject patients to histological confirmation of the tumour. However, after a very long disease-free interval, or where the primary is unknown, histological diagnosis will be essential.


Dexamethasone is started as soon as the diagnosis is made. The usual dose is approximately 16 mg/day, although higher doses can be used if the patient does not respond. The clinical effects are rapid and usually noticeable within 24 h. The maximum effect is achieved in about 4 days. Approximately 80% of patients will respond. Phenytoin or carbamazepine are used to control focal fits.

The most useful nonsurgical treatment is radiation therapy. The therapeutic doses depend on the likely primary site, but usually consist of 30 Gy in 10 fractions in 2 weeks, or 40 Gy in 15 fractions in 3 weeks. The former is the most widely used schedule in the United Kingdom but no schedule has been proved to be superior over another. Solitary cerebral metastases may be removed if they are in an accessible site. The criteria for operation are usually that a solitary metastasis is present, that the diagnosis is uncertain, or that the response to radiation is unpredictable because of doubt about the nature of the primary tumour. The patient must be clinically fit in other respects to undergo surgery, and without life-threatening metastatic disease elsewhere.

There has been recent interest in the use of chemotherapy in the treatment of cerebral metastasis, as it is now clear, e.g. in small-cell lung cancer, that the response to chemotherapy in cerebral metastases is equal to that in metastases at other sites. Responses to chemotherapy in tumours such as small-cell lung cancer may be rapid and dramatic but cranial radiation will usually be necessary as an adjunct to chemotherapy.


The prognosis of cerebral metastasis depends on the clinical setting. If there is a solitary metastasis with no disease elsewhere then a long disease-free interval may result, particularly if the metastasis has occurred after a considerable interval following the primary treatment. In other tumours, where multiple metastases occur either synchronously with the primary tumour or after a short disease-free interval, and where the tumour is a particularly difficult type to treat (such as melanoma and non-small-cell lung cancer), the prognosis is very poor indeed. Overall, only 30% of patients will be alive at 1 year and the median survival is about 7 months. A small randomized trial has suggested that surgical resection of a solitary metastasis adds to survival when compared with radiation and steroids alone.

Carcinomatous ‘meningitis’

Leptomeningeal spread of cancer seems to be increasing in frequency. In autopsy series about 4% of patients dying of advanced cancer have leptomeningeal spread. The frequency is higher in breast cancer (5–10%). This complication is increasing in lymphoma, small-cell lung cancer, ovarian cancer, and some sarcomas. Curiously, adenocarcinomas seem to have a greater propensity for this form of metastasis than other epithelial tumours. There may or may not be intracerebral metastasis at the same time. Malignant cells may enter the cerebrospinal fluid from intracerebral tumour via the arachnoid, or from vertebral deposits growing along nerve roots into the subarachnoid space. However, the most likely source of seeding appears to be directly from the bloodstream. Tumour is present as a thin covering of malignant cells, but the tumour cells may penetrate deeper into the substance of the brain along blood vessels. The tumour may also penetrate cranial and spinal cord nerves as they pass through the subarachnoid space.

Clinical features

The onset is usually over a few weeks and may be subtle at first. Headache is often severe and is due to raised intracranial pressure. Cranial nerve dysfunction is frequent, with diplopia, hearing loss, and facial numbness. There is often back pain and sometimes bladder and bowel dysfunction. A change in mental state may occur. Focal fits are uncommon. On examination there may be an abnormal mental state, signs of raised intracranial pressure, and extensor plantar responses. Focal neurological signs in the limbs are uncommon. Cranial nerve weaknesses are frequent, the most common being ocular muscle palsy, facial weakness, and hearing loss.

Diagnosis and treatment

The diagnosis is made by examining the cerebrospinal fluid. Typically, the opening pressure is high, the white count is raised, the cerebrospinal fluid sugar low, and the protein increased. Cytological confirmation on the first lumbar puncture is obtained in about 60% of patients, but a negative examination does not exclude the diagnosis. Myelography may show typical appearance of multiple small tumour seeds in the subarachnoid space, but MRI is proving invaluable and is now the preferred initial investigation if cerebrospinal fluid cytology is negative and the diagnosis strongly suspected.

Treatment is difficult and often unsuccessful. Temporary improvement can be obtained by the insertion of an intraventricular reservoir to deliver chemotherapy. Chemotherapy administered by lumbar puncture is uncomfortable and may not be effective if there is meningeal invasion supratentorially, since the drugs do not penetrate in high concentration beyond the foramen magnum. In breast cancer and lymphoma, intrathecal methotrexate is effective and may be administered in combination with thiotepa or, in the case of lymphoma, cytosine arabinoside. In addition, whole-brain irradiation is often given if the patient is improving and the clinical situation indicates that this treatment would produce further benefit. In general, however, the prognosis is poor when the meningeal infiltration is from an epithelial tumour, with a median survival of only 4 months.

Pleural effusion

Malignant pleural effusions occur either as a site of metastatic spread from outside the lung or due to direct invasion of the pleural space from an underlying primary bronchial carcinoma, or pulmonary metastasis. The effusions are typically exudates with a protein content of more than 3 g/dl. There is increased capillary permeability through inflammation and as a result of abnormal capillary endothelium in the tumour lining the pleural space. Typical primary sites are: breast and ovarian cancer, as common epithelial tumours metastasizing into the pleural space; lung cancer, as a cause of pleural effusion with underlying lung disease; and sarcomas, as a cause of pleural effusion due to invasion of the pleura by pulmonary metastasis.

Clinical features

The typical features are dyspnoea, which is directly related to the size of the effusion, dry cough, and chest wall discomfort. Even a small effusion may cause dyspnoea in a patient who has underlying lung disease such as chronic bronchitis and emphysema. Many patients have asymptomatic pleural effusions detectable on chest radiograph. The sequence of radiological appearances includes blunting of the costophrenic angle (occurring with volumes of more than 2–3 ml), increasing effusion, and, finally, mediastinal shift, which usually occurs when amounts in excess of 2 litres have accumulated. Ultrasound examination may assist in localizing the effusion and any loculi, which may influence the procedure for aspiration.


The diagnosis, if the primary tumour is not known, is made by demonstrating malignant cells in the pleural fluid. The rate of positivity, in patients known to have an underlying cancer, is about 60% with a low false-positiverate. If pleural cytology is negative on the first aspiration it should be repeated using fresh aspirates. Occasionally, pleural biopsy will be necessary to make a diagnosis, and the combination of the two methods increase the diagnostic yield to about 90%. If both techniques fail, thoracoscopy is more successful, but is, of course, more invasive.

Treatment and prognosis

The primary tumour should be treated if possible. When a pleural effusion persists after treatment of the primary tumour, or if such treatment has been unsuccessful, treatment may need to be directed to the effusion itself. Frequently the effusion will need to be aspirated in order to make the patient comfortable, and pleural sclerotherapy considered. For best results of sclerotherapy it is important to drain the pleural cavity as completely as possible. A small flexible chest drain is ideal and is left in place for some time (12–24 h if possible) to allow the fluid to drain as far as possible. If there has been loculated effusion, the insertion of the drain is best done under ultrasound control. Sclerosis of the two pleural surfaces can be achieved by a variety of means; all give approximately equivalent results. The most favoured techniques are the instillation of talc, tetracycline, bleomycin, or Corynebacterium parvum. They all cause an inflammatory reaction in the pleural space and have an approximately 60% success rate in preventing immediate recurrence of the effusion. When pleural effusion complicates an underlying bronchial carcinoma it is more difficult to control than when it is a metastatic manifestation of a distant neoplasm, such as ovarian cancer. If the effusion is recurrent and is the major cause of morbidity, pleuroperitoneal shunting can be carried out, whereby the pleural fluid drains into the peritoneal cavity.

Pericardial effusion

The most common malignancies to cause pericardial effusion are breast, lung, ovary, and gastrointestinal cancers and non-Hodgkin’s lymphomas. Pathologically, the pericardium may be infiltrated with tumour or diffusely nodular. The accumulation of fluid is due to obstruction of lymphatic and venous drainage of the pericardium.

Symptoms and signs

The symptoms are usually vague in onset, including orthopnoea, dyspnoea, and cough. Fatigue and dizziness also develop. If cardiac tamponade occurs it is associated with severe dyspnoea, vague central chest pain, and anxiety. The physical signs are usually minimal, although when tamponade occurs there will be jugular venous distension, pulses paradoxus, hypotension, and tachycardia.


Investigations include a chest radiograph, which shows enlargement of the cardiac silhouette, and echocardiography, which is a rapid noninvasive technique for demonstrating pericardial effusion.

Diagnosis and management

The diagnosis is made by finding malignant cells in the pericardial fluid. False-negative results occur and the test may need to be repeated. Once the diagnosis has been established, the pericardial fluid may need drainage using a small rubber catheter. Installation of sclerosants can be carried out as for pleural effusions, but troublesome pericardial effusions can be controlled by the formation of a pericardial window through a small left anterior thoracotomy. Some patients, particularly those who have lymphoma, will respond to external-beam radiation with a dose of approximately 30 Gy given in 15 fractions over a 2- to 3-week period. Radiation is also considered for control of chronic pericardial effusion in breast cancer.

Metastatic cancer from an unknown primary site

Approximately 3% of patients present with a metastasis from a cancer where the primary site is not known after full history, physical examination, blood count, and chest radiograph. This clinical situation requires considerable clinical expertise, as the diagnosis creates especial anxiety for the patient. The clinician has to decide on the most effective therapy and to sustain the patient without indulging in futile, invasive, and expensive investigations which will not alter management. The problem with extensive investigations is that they seldom alter management and the overall prognosis in this position is poor (4–6 months median survival). As one investigation after another fails to reveal the primary site, the patient and the doctor may come to consider this a failure and confidence can be badly shaken. Nevertheless, some tumours are potentially curable and, for these, investigation is justified. The common primary sites, when one is discovered, are cancers of the lung, pancreas, liver, gut, and stomach. The tumours for which therapy is possible, and which therefore must not be overlooked, are listed in Table 4.


If the presentation is exclusively in cervical nodes, a full ear, nose, and throat examination is mandatory as local treatment with surgery and/or radiation may produce prolonged survival or even cure for primary cancers as this site. The higher the cervical node, the more likely it is that and ear, nose, and throat tumour is the primary source. Supraclavicular lymph nodes carry a worse prognosis because the likely primary site on the right-hand side is the lung or breast, and on the left-hand side intra-abdominal malignancy may have spread via the thoracic duct. Patients presenting with lymph node enlargement in the axilla are likely to have breast cancer as the primary site and this may not be excluded even with normal mammograms. Malignant melanoma is another possibility at this site and a careful examination for skin lesions should be made. Inguinal lymph nodes usually point to a primary site in the pelvis, vulva or rectum, or prostate. Malignant melanoma may also present with an inguinal mass. Cutaneous metastasis typically occurs from carcinomas of the lung, breast, and melanomas. A pulmonary metastasis may arise from a variety of different sites, of which breast, kidney, gut, melanoma, and sarcoma are the most common. In the liver, the likely source for the primary will be the gastrointestinal tract, although breast and lung primaries are other possibilities. A metastasis presenting in bone is particularly likely to occur from a cancer of the lung, breast, or prostate, the last being particularly likely if there is a mixed lytic and osteoblastic radiological appearance.

Table 4  Metastasis from an unknown primary site. Possibilities for treatment


Potentially curable tumours
Germ cell tumours
Trophoblastic tumours
Effective palliative chemotherapy
Breast cancer
Small-cell lung cancer
Ovarian cancer
Palliative hormonal therapy
Prostate cancer
Breast cancer
Endometrial cancer
Effective (potentially curative) local therapy
Head and neck cancer

The most important single investigation is a review of the histology. The clinician should discuss the diagnosis with the pathologist so that appropriate tests can be carried out. It is absolutely essential to distinguish between an epithelial tumour, a sarcoma, and a lymphoma. Immunohistochemistry may be invaluable in this respect. If there is any question of a germ cell tumour, the section should be stained for α-fetoprotein, β-human chorionic gonadotrophin, and placental alkaline phosphatase. If the histology is that of adenocarcinoma, the diagnosis will be more difficult and special stains may not serve to elucidate the diagnosis further. Where possible, the tissue should be examined for the presence of oestrogen or progesterone receptor, as this would make carcinoma of the breast or ovary more likely. The protein S100 is typically present in melanoma and may be invaluable in distinguishing this diagnosis from anaplastic carcinoma.

Further investigation and management

Investigation must be selective. Since there is specific treatment available for breast and prostate cancer, these diagnoses must always be considered when the histology is adenocarcinoma. Mammography is therefore justifiable, and measurement of serum acid phosphatase and prostatic specific antigen are simple and noninvasive. A pelvic ultrasound examination may show an ovarian mass, which may influence management as platinum-based combination chemotherapy might then be used, whereas it would not be contemplated in many patients with metastasis from an unknown primary site in view of its toxicity. The possibility of a germ cell tumour must always be considered in a young person, and in these circumstances full investigation is necessary if this diagnosis is possible.

Treatment follows pragmatic lines. Locally troublesome or painful metastases are treated with irradiation. If breast cancer seems a possible diagnosis a trial of hormone therapy is fully justified and, similarly, hormone treatment of prostatic cancer should be introduced if this seems a likely diagnosis. As mentioned above, radiation is frequently given to patients with enlarged cervical nodes when the diagnosis is poorly differentiated carcinoma, even if a head and neck primary has not been found.

The use of combination chemotherapy when the primary site is not known is more controversial. In general, responses are infrequent and are not long lasting. This drug treatment should be reserved for patients with more than one lesion and particularly when symptoms occur. It is important not to be dogmatic about this issue because many patients find it quite unacceptable to be told that no treatment of any kind is available to them, and are willing to accept the possible toxicities of chemotherapy in exchange for the chance of response. Most chemotherapy programmes will include an alkylating agent and some include doxorubicin or a taxane.

Supportive care of the patient with cancer

Psychological support

Nearly everyone will have had friends or relatives who have had cancer and who may have died of it, and they will have read articles and seen television programmes about cancer and its management. Many patients will have been worried about the possibility of cancer before they ever consult their general practitioner, or are subjected to a series of diagnostic tests, the effect of which may be to increase their anxiety. At each stage in the diagnostic process physicians should be aware of patients’ feelings and be prepared to talk openly to them about why investigations are being performed. When the diagnosis is established it is essential for the physician to sit quietly with the patient, explaining the nature of the diagnosis and the broad principles that treatment will follow. Sometimes patients will like to have a member of the family with them during this conversation, in case they forget aspects of what is said. The conversation should take place quietly, not on a ward round, with both the patient and the physician seated and the physician calm and unhurried in approach. Avoidance of the word ‘cancer’, body language that indicates discomfiture or embarrassment, and evasion and vagueness are very likely to be interpreted by the patient as signs of a serious or hopeless outlook.

Many patients will be unable to take in all that is said in the first conversation, and physicians need to make it quite plain that they will be very pleased to talk again the next day, to go over points that need further clarification. There is much useful literature for patients to take home, there are professional and expert support groups that patients can contact and, in many hospitals, skilled counsellors who can provide follow-up support after the physician has outlined the basis of treatment. It is essential that all members of the medical team understand what was said and what words were used. The members of the family also need to understand exactly what information has been imparted. It may be necessary to hold back on a precise prognosis; first, because one may not be known until treatment starts, and second, because patients naturally tend to become fixated on the numerical prognosis, which is likely to be extremely inaccurate. If referral to an oncologist is to be made, it is critical to indicate exactly what has been said to the patient. Oncologists are put in an extremely difficult position when patients arrive with a diagnosis of cancer, without any indication at all of whether they know the diagnosis, or what words have been used.

A new difficulty in communication is now displacing the problems that formerly arose from concealment of the diagnosis. Modern cancer management is often complex, with equivalent results sometimes being obtained from approaches that have different early and late effects. A well-intentioned wish to ‘share’ the treatment decisions with the patient, and an increasing resort to litigation when events do not turn out well, has led doctors sometimes to present treatment options as a series of uncertainties in which the outcome will be strongly influenced by chance and fate. It is bad enough to be told you have cancer: worse still if your treatment seems mired in uncertainty. For some patients, treatment options will have been made even less clear by access to unfiltered advice on the internet, from reputable sources, charlatans, and cranks. There is nothing paternalistic in sensible advice from a well-informed, kind, sensitive, and experienced specialist. Questions which arise from complexity of choice and outcome in management increase the need for competent advice; they are not answered by passing the problem to the patient. Much distress, and a feeling of being abandoned, can come from lack of clear guidance.

Following treatment, patients frequently feel anxious and unsettled for many months or more. Even when unpleasant, treatment has the connotation of actively preventing recurrence of the disease. When this stops patients may need support, which they get most often from family and friends. Nevertheless minor symptoms are frequently the cause of anxiety for a year or two. A cancer service should offer all patients easy and informal access to advice that continues after treatment (a contact telephone number and an email address are what is needed). The simple fact of being available provides comfort and reassurance.

When treatment is to be palliative, after relapse or with widespread metastatic disease, it should none the less be made clear to the patient that it is ‘treatment’. Patients dislike feeling that they are being abandoned. Indeed, many wise oncologists see their patients more frequently when they are having palliative treatment than they do during routine treatments or follow-up. They do this because palliative treatment requires great attention to detail, especially with respect to control of pain and other symptoms, and also to provide psychological support for the patient and the family. One of the most common reasons for patients seeking second opinions is that they have been given no feeling that there are possibilities for treatment in their case. Continuity in management is one of the most rewarding aspects of cancer medicine for the physician and for the patient. There is no place for impersonal clinics where patients see different doctors each time they attend, and where the emotional component of their illness cannot be properly explored.

Management of cancer pain

Pain is a common and distressing feature of cancer. A careful history is essential to determine the exact site and nature of the pain and to establish a close and trusting relationship with a patient who feels that the symptom is being taken seriously. Exacerbating factors should be noted and an anatomical diagnosis made as far as possible. If the pain is arising in a bone it may be quickly and effectively helped by radiation treatment. The primary tumour or metastasis may be responsive to treatment with irradiation or chemotherapy. If specific antitumour treatments of this kind are not appropriate, then the only approach is to control the pain with analgesics.

Non-narcotic analgesics are used for mild or moderate pain. Useful agents include aspirin, paracetamol, and nonsteroidal anti-inflammatory drugs such as ketoprofen or naproxen. A combination may be useful. Combination drugs such as co-proxamol or co-dydramol are also helpful. Although prescribing each drug separately allows greater control over the constituents, in practice this may not be helpful, particularly for older patients who often find it difficult to take multiple medication. The aim of treatment should be to prevent pain as far as possible by taking regular analgesics, and to have additional analgesics on hand for an acute exacerbation. Side effects of non-opiate analgesics include gastric irritation (and they should therefore be used cautiously if steroids are being used at the same time), nausea, and constipation, particularly with codeine, oxycodone, or propoxyphene.

If these analgesics do not control the pain, opiate analgesics are essential. Two preparations have made an enormous contribution to pain relief. The first is long-acting morphine sulphate, which can be given twice daily, and the second is short-acting morphine sulphate. The former has a duration of action of 8 to 12 h and the latter of about 4 h. One curious feature of the use of morphine-like drugs is that the dose required to control pain varies greatly from person to person. It must therefore be found by trial and error, and the patient must be prepared to increase the dose under medical supervision. The aim is to produce background pain relief for most of the day and night. Short-acting morphine sulphate is particularly useful for dealing with acute exacerbations of pain.

If oral opiates are unable to control pain fully, continuous subcutaneous infusion is a useful alternative. This approach is particularly valuable in patients who cannot tolerate oral analgesics because of gastrointestinal symptoms, or where the tumour causes nausea or intestinal obstruction. Many pumps are now available, which are designed for continuous infusion through a small-gauge butterfly needle implanted subcutaneously. Patients can manage at home with these infusion pumps, with a nurse calling daily to change the infusion mixture.

Specialized forms of analgesia

A detailed discussion is beyond the scope of this chapter. Among the specialized techniques available are continuous epidural and intrathecal opiate infusion, nerve block procedures (including coeliac plexus block, peripheral nerve block, and epidural blocks), neurosurgical procedures, such as ablation of the peripheral nerve by neurectomy or, more radically, interruption of pain pathways by cordotomy. Each of these procedures has its value and limitations and the advice of specialists in the field of pain relief will be necessary.

Long-term consequences of successful cancer treatment

The welcome improvements in survival for many cancers has brought increasing realization that there are many subsequent medical and social problems that may affect patients, often several years after treatment has ended; their nature and frequency depending on the tumour and on the nature of the treatment. Medical personnel in almost every discipline will encounter these and they will continue to increase in frequency as cure rates improve and treatments are intensified. This is most apparent as a result of the increased cure rate of cancer in childhood and adolescence. This is one of the great triumphs of modern management but surveillance to detect long-term consequences, physical, psychological and metabolic, must extend for many years into adult life. Increasingly, this is true for adults as well. The following are some of the most important consequences.

  • Fertility may be greatly reduced. In fertile boys and men, sperm storage is essential before cytotoxic chemotherapy begins. Cessation of spermatogenesis is almost immediate with many (but not all) chemotherapy agents. In a woman of child-bearing years chemotherapy, especially if it includes alkylating agents, will shorten the reproductive period of her life and may induce the menopause if she is in her mid-30s or later. Advice on this matter is essential if later regrets and unhappiness are to be avoided.
  • Cognitive impairment is a serious consequence of tumours affecting the central nervous system. Children and young adults may suffer lifelong lost opportunity, both socially and occupationally. This may have a great impact on family life and require professional support.
  • Musculoskeletal consequences are common. These are perhaps expected when the primary treatment has involved limb or trunk surgery, but bone rarefaction is a long term consequence of localized radiotherapy at any site when bone has been included within the field. Pathological fracture is more likely to occur in a weight-bearing bone. If the radiation field includes a growing epiphysisis, bone growth ceases with subsequent unilateral shortening. The use of aromatase inhibitors as adjuvant treatment for oestrogen receptor-positive breast cancer is associated with osteoporosis and risk of fracture.
  • Metabolic problems are most frequently encountered when treatment has included drugs such as cisplatin and ifosfamide that frequently cause reduced glomerular filtration and tubular disorders (potassium and calcium loss, impaired acidification). Although these are monitored during treatment, these drugs are useful in the treatment of many tumours, especially in childhood, with long-lasting impairment.
  • Second cancers are increasing in frequency. In adults these include radiation-induced cancers in bone, soft tissue and breast, typically appearing within the radiation field 5–15 years after treatment. Secondary leukaemia is a well-recognized complication of chemotherapy, being particularly likely to occur when this has included etoposide or alkylating agents.
  • Circulatory disorders mainly involve reduced cardiac output and arrythmias associated with anthracycline administration. With more complex regimens of treatment involving drugs that act on tumour vasculature, these complications may increase in frequency.


Further reading

Tobias JS, Hochhauser D (2010). Cancer and its management. Blackwell, Oxford. 

Souhami R, Tobias J (2005). Cancer and its management, 5th edition. Blackwell, Oxford.