Chapter 26: Malignant disease

The terms malignancy, cancer and neoplasia are usually used interchangeably. The differences between a malignant tumour and a benign tumour are summarised in TABLE 26.1.

Malignant disease accounts for 1 in 8 deaths of people under 35 years in Australia and 3 in every 10 (29%) of deaths in those over 45 years.¹ Cancer is the only major cause of death in Australia that is increasing in both sexes. At current rates about 1 in 3 males and 1 in 4 females will develop a cancer, excluding non-melanoma skin cancers, by the age of 75.¹

The six most common causes of death from cancer in Australia and the US are cancer of the lung, bowel, breast, prostate, lymphoma and pancreas.

Neoplasia, especially malignancy of the silent areas, can present as undifferentiated illness and be a real masquerade. The so-called ‘silent’ malignancies that pose a special problem include cancer of the ovary, pancreas, kidney, caecum and ascending colon, liver (hepatoma), melanoma and haematological tissue.

This chapter focuses on the general features of several of these malignancies in order to promote early diagnosis and urgent referral at the primary care level. Specific common cancers are discussed in other chapters.

Acute emergency problems that can develop with various malignancies include spinal cord compression, malignant effusions, disseminated intravascular coagulation and hypercalcaemia.

Although uncommon in children under 15 years, cancer is the second most common cause of death in this age group. The most common cancers (in order) are leukaemias, especially acute lymphocytic leukaemia (34%); brain tumours, especially astrocytoma (20%); lymphomas, especially non-Hodgkin (13%); neuroblastoma; Wilms tumour; soft tissue tumours, especially rhabdomyosarcoma; and bone tumours.

Survival has improved dramatically in recent decades, indicating the value of early diagnosis and referral for expert treatment.

Studies have highlighted the importance of GPs responding to concerns of parents even if they could find no abnormality after examination. Parents of children eventually diagnosed with cancer and who were in dispute with their GP were alerted by signs and symptoms which were often vague, non-specific and common, or unusual or ‘scary’. They felt that their child ‘wasn’t right’.²

The clinical manifestations of malignancy are usually due to:

• pressure effects of the growth

• infiltration or metastases in various organs (e.g. liver, brain, lungs, bone, blood vessels)

• systemic symptoms, including paraneoplastic effects

These can be divided into general non-specific effects and paraneoplastic syndromes, which are the remote effects caused by the tumour.

Undifferentiated general symptoms

• Tiredness/fatigue/weakness

• Anorexia and nausea

• Weight loss

• Fever

• Thirst (hypercalcaemia)

• Drowsiness (hyponatraemia)

Paraneoplastic effects

The paraneoplastic effects or syndromes are very important clinically because they may provide an early clue to the presence of a specific type of cancer, in addition to the possible lethal effect of the metabolic or toxic effect (e.g. hyponatraemia). These effects include:

• ectopic hormone production

• skin abnormalities

• metabolic effects: fever/sweats, weight loss/cachexia

• haematological disorders: anaemia, erythrocytosis/polycythemia, coagulation disorder, others

• neuropathies and CNS abnormalities

• collagen vascular disorders

• nephrotic syndrome

A summary of various paraneoplastic syndromes is presented in TABLE 26.2.

A history of constitutional symptoms that are often quite undifferentiated (often bizarre) may provide the clue to the possibility of an underlying malignancy. An occupational history may be relevant to the clinical problem (see TABLE 26.3).

Familial cancer

Although the great majority of cancer is not inherited, some individuals carry inherited genetic mutations from conception that predispose them to developing certain cancers, particularly colorectal, breast and ovarian cancers. Refer to CHAPTER 18.

A tumour marker is an abnormal characteristic that is specific for a particular type of malignancy (e.g. the Philadelphia chromosome for chronic myeloid leukaemia). Other examples include human chorionic gonadotrophin (HCG) (elevated in trophoblastic tumours and germ cell neoplasms of the testes and ovaries) and the oncofetal antigens—carcinoembryonic antigen (CEA) and alpha-fetoprotein (AFP).

CEA and AFP are not specific markers but are elevated in certain tumours and are very useful in monitoring tumour activity.

Tumour markers have a limited role in diagnosis of malignant disease because several have low sensitivity and specificity. The most valuable are those associated with testis cancer—AFP and beta-HCG. Markers may be an adjunct to diagnosis of certain malignancies, including the rather inaccurate CEA for bowel cancer and CA-125 for ovarian cancer. These markers are summarised in TABLE 26.4.

Lung cancer

Apart from non-melanoma skin cancer, lung cancer is the most common cancer in Australia in terms of both incidence and death, accounting for at least 20% of cancer deaths.¹ In the US it accounts for 28% of cancer deaths in men and 24% of deaths in women. Only 10–25% are asymptomatic at the time of diagnosis but lung cancer can cause an extraordinary variety of clinical symptoms and signs with a reputation for several paraneoplastic syndromes. Refer to CHAPTERS 42 and 49.

The paraneoplastic syndromes include hypercalcaemia, Cushing syndrome, carcinoid syndrome, dermatomyositis, visual loss progressing to blindness from retinal degeneration, cerebellar degeneration and encephalitis.

The presentation of cough and chest pain renders it less of an ‘occult’ malignancy than several other types.

The most important tumours of the kidney are adenocarcinoma (80% of all kidney tumours)³ and nephroblastoma (Wilms tumour).

Kidney cell cancer

Kidney cell cancer (adenocarcinoma, hypernephroma) has a great diversity of presenting symptoms, including:

• general symptoms of neoplasia, e.g. malaise, FUO

• haematuria (60%)

• loin pain (40%)

• loin mass (palpable kidney)

• signs of anaemia

• left supraclavicular lymphadenopathy (Virchow node)

• varicocele (left side)

• hypertension

• symptoms of metastases (to liver, lungs, brain, bones): respiratory symptoms, neurological symptoms and signs, bone pain, pathological fracture (vertebral collapse)

• urinalysis—67% positive for blood

Diagnosis is confirmed by imaging, e.g. CT MRI.

Refer for radical nephrectomy.

The classic triad of symptoms, although in a small percentage of patients, is as follows.

Wilms tumour (nephroblastoma)

Wilms tumour is responsible for 10% of all childhood malignancies. Clinical features include:³

• peak incidence 2–3 years

• general symptoms of neoplasia

• palpable mass 80%

• abdominal pain 30%

• haematuria 25%

Diagnosis is confirmed by urine cytology, ultrasound or CT/MRI scan.

Early diagnosis with nephrectomy and chemotherapy leads to a very favourable prognosis (90% 5-year survival).

Neuroblastoma⁵

Probably the most common cancer in infancy (usually <2–3 years). 90% present under 5 years. It is a tumour of the adrenal medulla (50%) and sympathetic nervous system, especially retroperitoneal neural tissue in abdomen (30%) but also in chest and neck.

First symptoms often vague:

• fatigue, anorexia, nausea, fever

• abdominal pain, abdominal swelling

• anaemia and weight loss

May present with metastases, e.g. bone pain.

Diagnosis: CT scan, skeletal survey; biopsy required.

Treatment is based on surgical resection then chemotherapy ± localised radiotherapy. Good response to therapy especially if <18 months.

Ovarian cancer⁶

Ovarian cancer has the highest mortality rate of all the gynaecological cancers because the majority of patients present in the late stage of the disease. It is responsible for 5% of deaths in females. It is usually asymptomatic prior to the development of metastases. Epithelial tumours are the most common of malignant ovarian tumours. They are uncommon under 40 years of age and the average age of diagnosis is 50 years.

The most common presentation is abdominal swelling (mass and/or ascites), abdominal bloating or discomfort. Non-specific symptoms, which may be present for a long time before diagnosis, include abnormal uterine bleeding, urinary frequency, weight loss, abdominal discomfort, reduced capacity for food, diarrhoea, anorexia, nausea and vomiting (refer to CHAPTER 103).

Diagnosis is supported by pelvic ultrasound and serum CA-125 tumour marker. A new test is the OvPlex™ serum test, which measures five serum markers.

Carcinoma of caecum and ascending colon⁴

Malignancy in this area is more likely to present with symptoms of anaemia without the patient noting obvious blood in the faeces or alteration of bowel habit. Refer to CHAPTER 41.

Pancreatic cancer

This is another cancer with vague symptoms, metastasising early and late presentation. It is mainly ductal adenocarcinoma, which, if in the head of the pancreas, presents with painless jaundice and if in the body and/or tail presents with epigastric pain radiating to the back, relieved by sitting forward (refer to CHAPTER 58).

The leukaemias are caused by an acquired malignant transformation in the stem cell in the haemopoietic system. Acute leukaemia has a rapidly fatal course if untreated, while chronic leukaemia has a variable chronic course with an inevitable fatal outcome. See FIGURE 26.1. The main features of each type are as follows.

The usual age range for acute lymphatic leukaemia (ALL) is 2–10 years with a second peak at about 40 years. The median age of presentation of acute myeloid leukaemia (AML) is 55–60 years.

Acute leukaemia

Symptoms

• General constitutional (e.g. malaise)

• Symptoms of anaemia

• Susceptibility to infection (e.g. sore throat, mouth ulceration, chest infection)

• Easy bruising and bleeding (e.g. epistaxis, gingival bleeding)

• Bone pain (notably in children with ALL) and joint pain

• Symptoms due to infiltration of tissues with blast cells (e.g. gingival hypertrophy in AML)

Signs

• Pallor of anaemia

• Petechiae, bruising

• Gum hypertrophy/gingivitis/stomatitis

• Signs of infection

• Variable enlargement of liver, spleen and lymph nodes

• Bone tenderness, especially sternum

Diagnosis

• FBE and film: normochromic/normocytic anaemia; pancytopenia with circulatory blast cells; platelets: usually reduced

• Bone marrow examination

• PCR studies

• Cytogenetics

Treatment: chemotherapy, immunotherapy, stem cell therapy.

Note: As a rule, relapse of acute leukaemia means imminent death unless bone marrow transplantation is successful. The mean 5-year survival rate for childhood ALL is about 75–80%, for adult ALL 30%; for AML it varies with age with poorer survival, about 20%, over 55 years of age.

Chronic myeloid leukaemia (CML)

Clinical features

• A disorder of middle age, typically 40–60 years

• Insidious onset

• Constitutional symptoms: malaise, weight loss, fever, night sweats

• Symptoms of anaemia

• Splenomegaly (very large); abdominal discomfort

• Priapism

• Gout

• Markedly elevated white cell count (granulocytes)

• Marked left shift in myeloid series

• Presence of Philadelphia chromosome

Chronic lymphocytic leukaemia (CLL)

Clinical features

• A disorder of late middle age and elderly

• Insidious onset

• Constitutional symptoms: malaise, weight loss, fever, night sweats

• Lymphadenopathy (large rubbery nodes)—neck, axilla, groin (80%)

• Moderately enlarged spleen and liver (about 50%)

• Mild anaemia

• Lymphocytosis >15 × 10⁹/L

• ‘Mature’ appearance of lymphocytes

• Consider cytogenetics

Note: Most cases, especially early indolent CLL, require no specific therapy but observation.

THE LYMPHOMAS⁴

Lymphomas, which are malignant tumours of lymphoid tissue, are classified as Hodgkin lymphoma and non-Hodgkin lymphoma on the basis of histological appearance of the involved lymph tissue.

Hodgkin lymphoma

Clinical features

• Painless (rubbery) lymphadenopathy, especially cervical nodes

• Constitutional symptoms (e.g. malaise, weakness, weight loss)

• Fever and drenching night sweats—undulant (Pel–Ebstein) fever

• Pruritus

• Alcohol-induced pain in any enlarged lymph nodes

• Possible enlarged spleen and liver

Diagnosis is by lymph node biopsy with histological confirmation. Other tests: FBE, CXR, CT/MRI (to stage), bone marrow biopsy, functional isotopic scanning. Staging is by using Ann Arbor nomenclature (IA to IVB). Treatment includes chemotherapy, immunotherapy and radiotherapy.

Non-Hodgkin lymphomas

Non-Hodgkin lymphomas are a heterogeneous group of cancers of lymphocytes derived from the malignant clones of B or T cells.

Clinical features

• Painless lymphadenopathy—localised or widespread

• Constitutional symptoms possible, especially sweating

• Pruritus is uncommon

• Extra nodal sites of disease (e.g. CNS, bone, skin, GIT)

• Possible enlarged liver and spleen

• Possible nodular infiltration of skin (e.g. mycosis fungoides)

Diagnosis is by lymph node biopsy.

CXR and CT abdomen to stage.

Multiple myeloma

Multiple myeloma is a clonal malignancy of the differentiated β lymphocyte—the plasma cell. It is regarded as a disease of the elderly, the mean age of presentation being 65 years.⁸ It is asymptomatic in 20% of patients. The classic presenting triad in an older person is anaemia, back pain and elevated ESR which helps to differentiate it from monoclonal gammopathy of uncertain significance (MGUS).

Other investigations include serum protein electrophoresis and immunofixation, Sestamibi scan.

Clinical features

• Bone pain (e.g. backache)—in more than 80% of patients (possible pathological fracture)

• Bone tenderness, e.g. femur, ribs, spine

• Weakness, tiredness, increased thirst

• Anorexia and weight loss

• Recurrent infections, e.g. chest infection

• Symptoms of anaemia

• Bleeding tendency

• Replacement of bone marrow by malignant plasma cells

• Impaired renal failure → kidney failure

• Associated with amyloidosis and hypercalcaemia

Diagnosis

Diagnostic criteria comprise the presence of:⁶

• paraprotein in serum (on electrophoresis)

• Bence–Jones protein in urine

• bony lytic lesions on skeletal survey

Treatment is with chemotherapy including thalidomide or lenalidomide: 5-year median survival. The younger patient may be given a stem cell transplant.⁹

MGUS

Monoclonal gammopathy of undetermined significance (MGUS) involves the production of paraprotein (M protein) by non-cancerous cells in the absence of other clinical manifestations of multiple myeloma. It is associated with various disorders. MGUS is usually asymptomatic but peripheral neuropathy can occur. No chemotherapy treatment is recommended.

Amyloidosis

This uncommon but difficult-to-diagnose disorder caused by the deposition of amyloid protein is classified as primary, familial or secondary (from chronic infection, e.g. TB, inflammation, RA, some cancers, others). It may be localised or generalised. Clinical features depend on the organ targeted such as the heart (CCF), kidney (nephrotic syndrome), GIT (malabsorption), brain (dementia) and peripheral nerves (e.g. CTS). Diagnosis is by tissue biopsy. Treatment, which varies with the type, is basically symptomatic and specialised. In primary amyloid it resembles the treatment for myeloma.

Carcinoid syndrome

Hormone secretion by carcinoid cells causes the characteristic carcinoid syndrome long before local growth or metastatic spread of the tumour is apparent (80% metastasise). Most carcinoid tumours are asymptomatic.

Clinical features

• Classic triad: skin flushing (especially face), diarrhoea (with abdominal cramps), valvular heart disease

• Other possible features: wheezing, telangiectasia, hypotension, cyanosis

• Sites of tumours: appendix/ileum, stomach, bronchi

Diagnosis

• 24-hour urine 5-hydroxyindoleacetic acid

• plasma chromogranin A/hepatic ultrasound

Polycythaemia vera

This is a malignant proliferation of RBCs and also WBCs and platelets.

Clinical features

• Older person

• Fatigue

• Headache, dizziness, tinnitus

• Pruritus after hot bath, shower

• Epistaxis

• Facial plethora

• Splenomegaly

• Thrombosis

Investigations

• FBE and haematocrit

• Bone marrow biopsy

• Genetic mutations—JAK2 mutation

Several tumours are curable by chemotherapy even in the advanced stage. Such tumours are as follows.

Haematological tumours

• Some lymphomas

• Hodgkin lymphoma

• Acute lymphatic leukaemia

• Acute myeloid leukaemia

Solid tumours

• Choriocarcinoma

• Testicular teratoma

• Neuroblastoma

• Wilms tumour (nephroblastoma)

• Burkitt tumour

• Embryonal rhabdomyosarcoma

Tumours curable by adjuvant chemotherapy

• Breast cancer (especially up to stage 2)

• Osteogenic cancer

• Soft tissue cancer

• Colorectal cancer

Common cancers and their 5-year survival rates over a 15-year period (1982–2007) have been published by the Cancer Council Victoria (see TABLE 9.3, CHAPTER 9, and TABLE 26.5, below). These show improving trends for many cancers. The lowest survival rate was for mesothelioma at 4%. Updated statistics reveal that the overall 5-year survival has increased from 48% in 1984–1988 to 68% in 2009–2013.¹¹

It is very helpful for the practitioner to have a working knowledge of possible primary sources of tumour when metastatic lesions are detected in various organs.

Common sites of metastatic presentation are the lymph nodes, liver, lung, mediastinum and bone. Other sites include the brain, bone marrow, peritoneum, retroperitoneum, skin and the spinal cord.

These important sites (listed below) are followed by likely primary sources with the most likely listed first.

• Bone. Breast, prostate, lung, Hodgkin lymphoma, kidney, thyroid, melanoma

• Brain. Breast, lung, colon, lymphoma, kidney, melanoma, prostate

• Liver. Colon, pancreas, liver, stomach, breast, lung, melanoma

• Lung and mediastinum. Breast, lung, colon, kidney, testes, cervix/uterus, Hodgkin lymphoma, melanoma

• Lymph nodes:

  • – High cervical. Hodgkin lymphoma, lymphoma, squamous cell carcinoma, oropharynx, nasopharynx

  • – Low cervical. Lung, stomach, lymphoma, Hodgkin lymphoma, oropharynx, larynx, skin, tongue

  • – Axillary. Breast, lung, lymphoma

  • – Inguinal. Lymphoma, ovary, uterus, vulva, prostate, skin

• Retroperitoneum. Lymphoma, Hodgkin lymphoma, ovary, uterus, testes, prostate

• Skin. Lung, colon, melanoma, Kaposi sarcoma

It is important to keep in mind those malignancies that are potentially curable and to refer as soon as possible.

Cancer without a clear primary source is present in about 5% of all cases. If the diagnosis cannot be made on the history, physical examination and baseline tests, then the key to excluding treatable primaries is adequate immunohistological staining on a tissue biopsy. It is worth referring for investigation as these could be treatable primaries. Adenocarcinoma is common in 40% resulting from lung, colorectal and pancreatic cancer. Poorly differentiated neoplasms include lymphoma, melanoma and sarcoma. The mean survival time in patients with an unknown primary is 6 months.¹²

Preventive measures for malignant disease are addressed in more detail in CHAPTER 9. The significant decrease in deaths from cancer of the stomach in this country in recent years is probably reflected in our improved diet with more fresh fruit and vegetables. Important preventive measures include an appropriate healthy diet, no smoking, sun protection, HPV vaccination and perhaps safe sex measures. Of concern is the rapid increase in the incidence of prostate cancer, chronic myeloid leukaemia, myeloma and non-Hodgkin lymphoma and adenocarcinoma of the oesophagus.

Hand-out sheets from Murtagh’s Patient Education 7th edition:

• Bladder cancer

• Bowel cancer

• Breast cancer/lumps

• Cancer

• Leukaemia

• Lung cancer

• Lymphoma

• Melanoma

• Prostate (various)

• Testicle (various)

• Skin (various)

Optimal cancer care pathways (prevention, early detection, screening recommendations): <jon.emery@unimelb.edu.au>

Royal Australian College of General Practitioners. Early detection of cancers. In: Guidelines for Preventive Activities in General Practice (9th edn). Melbourne: RACGP, 2016.