Chapter 20: Diagnostic investigations
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Source: Adapted from Chernecky and Berger ([26]), Duffy ([39]), EGTM ([46]).
Related theory
The diagnostic value of the tumour marker is dependent on its specificity and sensitivity and the prevalence of cancer in the population. The specificity is the percentage of persons with benign conditions where a negative result is obtained; the greater the specificity, the fewer the false positives. The sensitivity is the number of test results that are positive in the presence of a tumour; the greater the sensitivity, the fewer the false negatives. The limitations of tumour markers for cancer screening particularly are associated with the lack of sensitivity for early invasive disease or pre‐malignant lesions and the lack of specificity for malignancy (Association for Clinical Biochemistry and Laboratory Medicine (ACB) [5], Duffy [39], EGTM [46]). The low prevalence of cancer in the general population prohibits most biomarkers being used in cancer screening. Some markers or tests have been evaluated or are undergoing evaluation for asymptomatic cancer screening such as prostate‐specific antigen (PSA) and carbohydrate antigen 125 (CA 125) (Duffy [39]) (Table 20.1).
Table 20.1 Common tumour markers and clinical application
| Tumour marker or test | Sample source | Normal ranges | Purpose/findings |
|---|---|---|---|
AFP
(alpha‐fetoprotein) | Serum | <14 µg/L | Indication: screening (high‐risk groups) and monitoring hepatic carcinoma, diagnosis hepatoblastoma, diagnosis and monitoring germ cell tumours
Elevated levels: hepatocellular carcinoma, germ cell, hepatoblastoma, lung and pancreatic with metastasis, gastric with liver metastasis
Potential false positives: autoimmune disease, hepatobiliary disease, pregnancy |
B2M
(beta2‐microglobulin) | Serum | 1.2–2.4 mg/L | Indication: monitoring haematological malignancy, multiple myeloma, lymphoma
Potential false positives: chronic liver disease, infection, autoimmune diseases, renal failure |
CA 15‐3
(carbohydrate antigen 15‐3/cancer antigen 15‐3) | Serum | <32 KU/L | Indication: monitoring treatment for advanced breast cancer, detecting recurrence in breast cancer
Elevated levels: advanced breast cancer (80% of patients), may also be elevated in adenocarcinoma with distant metastasis, lung, liver, pancreas, colon, ovarian, cervix and endometrium, prostate
Potential false positives: treatment with colony‐stimulating factor of granulocytes, lung infection diseases, autoimmune diseases, ovarian cysts, renal failure, pregnancy |
CA 19‐9
(carbohydrate antigen 19‐9/cancer antigen 19‐9) | Serum | <37 KU/L | Indication: diagnosis, pre‐operative marker for resectability, surveillance and monitoring in pancreatic carcinoma. Diagnostic aid in cholangiocarcinoma
Elevated levels: pancreatic, colorectal, gastrointestinal, hepatobiliary, lung, testicular carcinoma and cholangiocarcinoma
Potential false positives: benign lung diseases, gastrointestinal pathology, renal failure, ovarian cysts, liver diseases, pancreatitis, cholestasis, bronchiectasis |
CA 125
(carbohydrate antigen 125/cancer antigen 125) | Serum | 0–35 KU/L | Indication: monitoring ovarian and breast carcinoma, monitoring response to chemotherapy, pre‐operatively, post‐operatively and during first three treatments of chemotherapy, annually in women with hereditary ovarian cancer syndrome
Elevated levels: stage I epithelial ovarian (50% of women), stage II epithelial ovarian (90% of women), stage III and IV epithelial ovarian (90% of women), breast, cervix, colon, endometrial, gastrointestinal, liver, lung, lymphoma, non‐Hodgkin's lymphoma, ovarian, pancreatic
Potential false positives: ovulation, menstruation, COPD, lung infections, nephritic syndrome, endometriosis, liver failure, kidney failure, pregnancy, fluid retention |
| Calcitonin | Serum | Male: < 11.8 ng/L
Female: < 4.8 ng/L | Indication: diagnosis and monitoring medullary thyroid cancer, multiple endocrine carcinoma screening, lung cancer, neuroendocrine tumours |
| CEA (carcinoembryonic antigen) | Serum | <5 µg/L | Indication: determining prognosis pre‐operatively, surveillance post curative resection, monitoring advanced colorectal carcinoma
Elevated levels: colorectal carcinoma (60% of patients and 80–100% with hepatic metastasis), may also be elevated in advanced adenocarcinomas of the lung, breast, pancreas, liver, stomach, ovary, prostate, rectum
Potential false positives: smokers, benign diseases, liver failure, kidney failure, Crohn's disease, ulcerative colitis |
| Chromogranin A | Serum (EDTA) | 0–60 pmol/L | Indication: monitoring and detecting recurrence of neuroendocrine tumours, neuroblastomas
Potential false positives: hypertension, sepsis, cardiac failure, cardiomyopathy |
CYFRA 21‐1
(cytokeratin fragment) | Serum | <3.3 ng/mL | Indication: differential diagnosis lung cancer, prognosis non‐small cell lung cancer (NSCLC), treatment monitoring NSCLC, detection or recurrence in squamous cell lung cancer
Potential false positives: effusions, psoriasis, liver diseases, cirrhosis of the liver, renal failure |
hCG
(human chorionic gonadotrophin) | Serum
Urine
CSF | <5 IU/L
<25 IU/L
<2 IU/L | Indication: diagnosis, prognosis and monitoring of germ cell tumour and gestational trophoblastic disease, metastatic spread to brain (CSF)
Elevated levels: testicular seminoma, gestational trophoblastic disease, non‐seminomatous germ cell of testis and ovary
Potential false positives: autoimmune diseases, marijuana use, renal failure, pregnancy |
HER‐2/neu
(human epidermal growth factor receptor) | Tissue | IHC test: 0–1+
FISH test: negative | Indication: breast cancer
Elevated levels: prostate, lung cancer
Potential false positives: renal failure, liver diseases |
HE4
(human epididymis protein 4) | Serum | <150 pmol/L | Indication: ovarian, endometrial, lung, adenocarcinoma
Potential false positives: liver disease, effusions, renal failure |
NSE
(neuron‐specific enolase) | Serum | <13 ng/mL | Indication: diagnosis in lung cancer, support diagnosis in small cell lung cancer (SCLC), differential diagnosis in lung cancer of unknown origin, pre‐treatment and follow‐up in SCLC, prognosis in SCLC and NSCLC, treatment and follow‐up of neuroblastoma, differential diagnosis between Wilms’ tumour and neuroblastoma in paediatrics
Elevated levels: adrenocortical carcinoma, medullary carcinoma of the thyroid, neuroblastoma, pancreatic islet cell tumour
Potential false positives: liver disease, lung disease, renal failure, cerebral haemorrhage and ischaemia, haemolysis |
PLAP
(placental alkaline phosphatase) | Serum | <100 mlU/L | Indication: aid in germ cell tumour diagnosis, monitoring progression, testicular seminoma, ovarian carcinomas
Potential false positives: smokers |
PSA (total)
(prostate‐specific antigen) | Serum | <4 µg/L | Indication: aid diagnosis, determine prognosis, monitoring and early detection of recurrence in patients with prostate cancer
Elevated levels: prostate cancer |
SCCA
(squamous cell carcinoma antigen) | Serum | 0–150 ng/dL | Indication: squamous cancers, cervical cancer, lung cancer
Potential false positives: liver or lung diseases, renal failure |
| S‐100 | Serum | <0.2 ng/mL | Indication: malignant melanoma
Potential false positives: liver disease, autoimmune disease, renal failure |
| COPD, chronic obstructive pulmonary disease; CSF, cerebrospinal fluid; EDTA, ethylenediaminetetraacetic acid; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry. |
There are no tumour markers that are specific for malignancy. An elevated tumour marker may be due to another malignancy or benign disease. A normal tumour marker result does not exclude the presence of a malignancy or recurrence, and in general serum tumour markers are rarely elevated in patients with early malignancy (EGTM [46]). The tumour marker results should always be interpreted in context of laboratory and clinical information, particularly serial results. The results obtained using different methods are not necessarily comparable (ACB [5]).
A tumour marker should have the following characteristics (Duffy [39]):
- a high positive and negative predictive value
- an inexpensive, standardized and automated assay
- clearly defined reference limits
- acceptable to patients undergoing the test
- a large prospective trial to validate its clinical value.
