Ideally, cancer is detected in its early stages. Early detection of cancer can help save lives and reduce the suffering associated with some types of cancer. Moreover, the chances of a treatment eradicating all cancerous cells are highest before a tumor has metastasized. The detection and diagnosis of cancer rely on screening and diagnostic tests, including self-examination, patient history, physical examination, radiologic and laboratory tests, and histologic examination of tissue samples. This section describes the diagnostic process.
Early Detection
Early detection enables the initiation of prompt, appropriate treatment at an early stage of cancer growth and significantly improves a patient’s prognosis. Despite the benefits of early detection, relatively few cancers—those of the breast, colon, rectum, cervix, and prostate—currently have available and effective screening tests that are recommended by the American Cancer Society (ACS).[i]
Screening is the process of assessing asymptomatic individuals for the presence of early disease. The principle objectives of cancer screening are to reduce complications and mortality, allow the use of less radical therapy, and lessen the costs associated with treating late-stage disease. When examinations, tests, or procedures used in screening yield positive findings, these results alone are usually not diagnostic but lead to further tests to confirm or eliminate the diagnosis of cancer.[ii]
Screening strategies
A number of methods are widely used for cancer screening, including:
- Self-examinations
- Physical examinations
- Imaging tests
- Laboratory tests
- Genetic tests
Self-Examinations for Cancer Screening
People may screen themselves for the development of some types of cancer. People who perform self-examinations become familiar with their own tissue and thus may be more apt to recognize early signs of some possible malignancies. A person may screen their body visually or by palpation. Visual screening involves looking for the presence of suspicious lesions in the skin, lip, mouth, and external genitalia. Through palpation, a person may detect irregular lumps or nodules in various areas of their body. In particular, the ACS recommends self-examinations for the early diagnosis of cancers of the breast and skin.[iii],[iv]
Physical Examinations for Cancer Screening
Screening for most cancers requires the assistance of a healthcare provider. Healthcare providers use various methods, both noninvasive and invasive, to screen for cancer.
A healthcare provider visually inspects the body to identify suspicious lesions in the skin, retina, lip, mouth, larynx, external genitalia, and cervix. Alternatively, palpation detects lumps or nodules in the breast, mouth, thyroid, subcutaneous tissues, prostate, testes, ovaries and uterus, and enlarged lymph nodes in the neck, axilla, or groin. Unusual lesions, lumps, or nodules indicate further testing.25
Imaging Tests for Cancer Screening
Cancers that are not amenable to early detection through physical examination require imaging tests that provide a view of the internal organs of the body. Two widely used screening tests are colonoscopy, sigmoidoscopy, and mammography.25
Colonoscopy and sigmoidoscopy allows the physician to visualize the inside of the rectum and colon. This screening test is used to identify and remove polyps inside the intestine that may become cancerous. The American Cancer Society recommends a colonoscopy every 10 years or a sigmoidoscopy every five years, starting at age 50 for those at average risk for colorectal cancer.26
Mammography is an x-ray of the breasts which screens the female breast for abnormal growths. The American Cancer Society recommends that women age 40 and over have a yearly mammogram.26
Laboratory Tests Used for Screening Cancer
The development of laboratory tests to screen for some types of malignancies has allowed very early detection for specific cancers. Clinically useful examples of laboratory tests include the PAP smear (for cervical cancer), fecal occult blood testing (for colon cancer), and prostate-specific antigen [PSA] (for prostate cancer).26 Routine blood tests can also be an early screen for hematologic malignancies.
Genetic Tests Used for Screening Cancer
Hundreds of genetic traits are associated with an increased risk of cancer. The growing awareness that cancer is a genetic disorder has encouraged genetic screening for certain malignancies. Understanding of susceptibility to certain cancers has been markedly advanced in recent years through the study of genetic markers.26
Genetic markers, such as the BRCA1 and BRCA2 mutations associated with breast cancer, are alterations in DNA that may indicate an increased risk of developing certain types of cancer. Currently testing for the BRCA1 and BRCA2 genes is provided only for those persons with a documented case of breast cancer in the family background.[v]
Genetic screening for BRCA1 and BRCA2 mutations is not a definitive test for breast cancer. Carrying mutations in these genes does not automatically mean that a person will develop breast cancer. Instead, it indicates that these people should be particularly vigilant about performing other screening tests since their risk of developing breast cancer is high. Likewise, even if no mutations are found in the BRCA1 and BRCA2 genes, a person may still develop breast cancer. Thus, the utility of genetic tests in the screening of breast and other cancers in the greater population remains questionable.28
Screening techniques are more effective when they are used in combination. For example, combining self-breast examination, mammography, and genetic screening usually detects breast cancer earlier than any screening technique alone.
Diagnostic Procedures
This section describes the procedures and tests used to diagnose cancer. Many of the screening tests described in the prior section are also used diagnostically; therefore, this section provides more detailed descriptions of these tests.
In order to diagnose cancer, the following techniques may be used:
- Patient history
- Physical examination
- Imaging studies
- Endoscopy
- Laboratory tests
- Biopsy
Patient History and Physical Examination
Usually the first clues about the presence of cancer in a patient result from a visit to a physician, who takes a patient history and performs a physical examination.
Patient History
A thorough patient history is important for evaluating a patient’s risk factors for cancer, including family history of cancer, exposure to a known carcinogen, or prior illness that might predispose the patient to cancer (e.g., autoimmune diseases, AIDS, and other viral infections).[vi]
Careful questioning can also reveal the presence of any symptoms or signs that might be cancer related and the duration of those symptoms, which can be an important prognostic factor. Additionally, the patient history reveals concurrent conditions, such as diabetes or congestive heart failure, which may affect treatment plans.29
Physical Examination
The physical examination corroborates and clarifies the symptoms described by the patient. The physical examination involves visual examination and palpation to evaluate early warning signs in people with possible symptoms of cancer. A full physical exam includes a rectal exam, and a pelvic exam in females.
Symptoms and Signs
General symptoms and signs of cancer are nonspecific and may be indicative of cancer or another illness. These include unexplained weight loss, fever, fatigue, and pain.[vii]
Some cancers produce specialized signs that are related to the area of the body in which the malignancy resides. A change in bowel habits or bladder function may suggest a malignancy in the gastrointestinal or urinary tracts. For example, pain with urination, blood in the urine, or a change in bladder function might occur with bladder cancer.30
A preliminary diagnosis of cancer often can be made on the basis of the patient history and physical examination. A definitive diagnosis requires more direct analysis of the affected tissues.
Imaging studies
Imaging studies provide visual evidence of the presence of tumors within the body. Imaging can sometimes help to predict whether a tumor is likely to be cancerous and whether biopsy is warranted. Following identification of the presence and location of the cancer, imaging studies also help to stage disease. Several different types of imaging tests evaluate patients with symptoms or signs that suggest the presence of cancer. These include:
- X-ray and computed tomography (CT) scan
- Magnetic resonance imaging (MRI)
- Positron emission tomography (PET)
- Ultrasonography
- Mammography
X-Ray and Computed Tomography (CT) Scan
X-ray
X-rays provide radiographic images of the body. An X-ray gives a two-dimensional view of a body area. X-rays of the chest and gastrointestinal (GI) tracts often provide enough information to diagnose structural changes in these body locations. Chest X-rays directly detect and evaluate suspected lung abnormalities (see Figure 6).[viii]
Figure 6: Chest X-Ray
X-rays in other parts of the body may incorporate the use of contrast agents. Barium, a commonly used contrast agent, highlights the location of abnormalities in the GI tract. Barium may be administered orally, via ingestion, or rectally, via an enema, prior to the X-ray series. An upper GI series consists of a series of X-rays of the esophagus and stomach following ingestion of barium.31
CT scan
CT scans are X-ray images taken from multiple angles or planes and assembled into a cross-sectional image using a computer. Like X-rays, CT scans identify the locations of collections of malignant cells or tumors. A CT shows the organs more clearly than an X-ray (see Figure 7.).31
Figure 7: Example of a CT Scan
Magnetic Resonance Imaging (MRI)
MRI is an imaging technique that uses magnetic fields and radio frequency waves instead of X-rays to generate an image. An MRI produces images by exposing the hydrogen nuclei in body tissue to strong, external magnetic fields. It also allows imaging of an organ on three planes, producing a three-dimensional image of the organ. MRI gives clear images of the brain and spinal cord in cancers that spread to the CNS.31 Figure 8 illustrates an MRI of the brain.
Figure 8: MRI
Positron Emission Tomography (PET)
PET scans evaluate and produce images of the metabolic activity of cells in different parts of the body using a radioactive tracer. Malignant cells tend to have higher metabolic activity; therefore, the tracer collects in areas that contain malignant cells. A positron camera identifies the location of the radioactive tracer and feeds this information to a computer, which generates cross-sectional images of the body.31
The sensitive nature of PET is useful for detection of malignancy, differential diagnosis of tumors found with other imaging studies, tumor grading, and disease staging. An advantage of PET scans over other types of images is that they detect biochemical processes altered during the course of disease before they are seen with other imaging tests.31 Figure 9 shows a PET scan of the body.
Figure 9: PET Scan
Ultrasonography
Ultrasonography uses high-frequency sound waves (called ultrasound) to create images of organs and other tissues. Tissues vary according to their acoustic properties. An image, called a sonogram, is created from the different echoes of ultrasound waves on tissue structures. Ultrasound is particularly useful in assessing masses within the soft tissues.31 Figure 10 shows an ultrasound image of the liver. The dark areas adjacent to the arrows show possible tumors.
Figure 10: Ultrasound
Mammography
Mammography involves radiographic examination of the female breast with equipment and techniques designed to screen for cancer. Mammography can detect tumors within the breast before they become palpable and in many cases before lymph node metastasis occurs.31 Figure 11 shows a mammogram.
Figure 11: Example of a Mammogram
Endoscopy
Endoscopy employs an instrument called an endoscope for visual examination of any cavity of the body. The endoscope transmits light and carries images back to the observer through a flexible bundle of small transparent fibers. In addition to visualizing tissues a small biopsy forceps may be inserted through the endoscope to sample any suspicious areas.[ix]
Endoscopy is used to examine the lungs (bronchoscopy), colon (colonoscopy), upper digestive system (upper endoscopy), uterus (hysteroscopy), abdominal cavity (laparoscopy), bladder (cystoscopy), and other body cavities.32
Sometimes, the changes resulting from cancer are subtle and might be overlooked by imaging techniques or endoscopy. For this reason, laboratory testing often occurs in conjunction with other techniques used to diagnose cancer.
Laboratory tests
Laboratory tests evaluate organ function and determine if a suspected cancer has had an impact on normal physiology.
Body Fluid Tests
Blood and urine provide vital clues to a patient’s health. These tests are routinely performed as part of a comprehensive medical work-up. The choice of tests varies according to a patient’s presenting symptoms.
Hematologic tests
Hematologic tests analyze the composition of blood. These tests assess the complete blood count (CBC). The CBC determines the number of red blood cells, white blood cells (WBCs), and platelets in the blood. The components of the CBC include: [x],[xi]
- WBC count, which yields the absolute number of WBCs in the blood sample
- WBC differential, which gives a picture of the relative ratios of different types of WBCs in the blood
- Hematocrit, which describes the relative volume of blood occupied by red blood cells
- Hemoglobin, which assesses the amount of iron-carrying substance in red blood cells
- Platelet count, which yields the absolute number of platelets in the blood sample.
- Red blood cell (RBC) count, which tells the absolute number of RBCs in the blood sample
- RBC indices, which include:
- Mean corpuscular volume (MCV), which tells the average RBC size
- Mean corpuscular hemoglobin (MCH), which tells the average amount of hemoglobin per RBC
- Mean corpuscular hemoglobin concentration (MCHC), which tells the amount of hemoglobin relative to the size of the cell per RBC
Hematologic tests can detect anemia, a common finding in many cancers, especially those that may be associated with blood loss. Abnormal hematologic tests may directly indicate leukemia and may raise the suspicion of other cancers.33
Table 2 lists the normal values for hematologic tests.
|
Hematologic Test |
Normal Values |
|
Complete blood count – Red blood cell count – White blood cell count – Platelet count |
· 4.2–6.1 million/mm3 · 5,000–10,000/mm3 · 150,000–400,000 million/mm3 |
|
White blood cell differential – Neutrophils – Lymphocytes – Eosinophils – Monocytes – Basophils |
· 55–70% · 20–40% · 1–4% · 2–8% · 0.5–1% |
|
Hematocrit |
Female: 37–47% Male: 42–54% |
|
Hemoglobin |
Female: 12–16 g/dL (7.4–9.9 mmol/L) Male: 14–18 g/dL (8.7–11.2 mmol/L) |
Table 2: Normal Ranges for Hematologic Tests33
Serum Chemistries and Liver Function Tests
Serum chemistries show the composition of the noncellular components of blood. Table 3 lists the normal ranges for these blood chemistries.
|
Serum Test |
Normal Values |
|
Blood urea nitrogen (BUN) |
7–26 mg/dL (2.5–9.3 mmol/L) |
|
Serum creatinine |
0.5–1.2 mg/dL (44–97 µmol/L) |
|
Serum calcium |
8.5–10.5 mg/dL (2.1–2.6 mmol/L) |
|
Serum albumin |
3.2–5.0 g/dL (32–250 g/L) |
Table 3: Normal Range for Blood Chemistries33,[xii]
Liver Function Tests
A series of special blood tests can often determine whether or not the liver is functioning properly. Cancers sometimes alter the function of the liver.
There are many types of liver function tests. For diagnosing cancer, two important tests include the serum alkaline phosphatase test and the lactate dehydrogenase (LDH) test. Table 4 lists normal values for these liver function tests.
|
Liver Function Test |
Normal Values |
|
Alkaline phosphatase |
20–140 IU/L |
|
Lactate dehydrogenase (LDH) |
115–225 IU/L |
Table 4: Normal Ranges for Liver Function Tests33
Tumor Marker Testing
Tumor marker tests measure tumor-associated antigens that circulate in the blood. Many tumor markers are present in very low levels in people without cancer, so they are not specific enough to be used alone for diagnosis. Furthermore, in some patients with cancer, the associated tumor marker may not be found.
For example, the alfa-fetoprotein (AFP) test identifies elevated levels of AFP in the blood. Normally produced by the fetal liver and testes, elevated AFP levels sometimes occur with cancers of these organs. In these cases, the AFP test can also be used to help monitor the treatment of certain cancers.[xiii]
Thus, tumor marker testing plays the largest role after there is a strong suspicion of a particular cancer and is particularly useful to monitor treatment. Some tumor markers (such as BRAF and CD20) determine whether a patient will respond to particular cancer therapies.36 [NCI_tumor markers/p3-7] Table 5 lists the tumor markers associated with some types of cancer.
|
Cancer |
Tumor Marker(s) |
|
Bladder cancer |
· Chromosomes 3, 7, 17, and 9p21 · Fibrin/fibrinogen · Nuclear matrix protein 22 |
|
Breast |
· CA (cancer antigen) 15-3 · CA27.29 · CEA (carcinoembryonic antigen) · ER (estrogen receptor)/PR (progesterone receptor) · HER2/neu · 21-gene signature · 70-gene signature · uPA and PAI-1 |
|
Chronic myeloid leukemia |
· BCR-ABL |
|
Colon |
· BRAF · KRAS · CEA |
|
Gastrointestinal stromal |
· KIT |
|
Germ cell |
· LDH (lactate dehydrogenase) |
|
Liver |
· AFP (alfa-fetoprotein) |
|
Lung |
· ALK (anaplastic lymphoma receptor tyrosine kinase) · Cytokeratin fragments 21-1 · EGFR mutation analysis · KRAS |
|
Lymphoma |
· LDH · B2M (beta-2-microglobulin) |
|
Medullary thyroid cancer |
· Calcitonin |
|
Multiple myeloma |
· B2M (beta-2-microglobulin) · Immunoglobulins |
|
Neuroendocrine tumors |
· CgA (chromogranin) |
|
Non-Hodgkin lymphoma |
· CD20 |
|
Ovary |
· CA 125 · 5-protein signature · HE4 |
|
Pancreas |
· CA 19-9 |
|
Prostate |
· PSA (prostate specific antigen) |
|
Testis |
· HCG (human chorionic gonadotropin) · AFP (alpha fetoprotein) |
|
Thyroid |
· Thyroglobulin |
Table 5: Tumor Markers and Associated Cancers36
Cytological Testing
Tissue Biopsy
In order to obtain cells for cytological testing, a biopsy is taken from the area of the body where cancer is suspected. Biopsy of affected tissue is nearly always the only definitive way to diagnose cancer.[xiv]
Several types of biopsy exist, and each type provides different information. The technique selected must obtain an adequate tissue specimen for the needs of the pathologist. A sample of tissue for biopsy may be obtained by:
- Needle biopsy
- Incisional biopsy
- Excisional biopsy
Needle Biopsy
A needle biopsy entails inserting a needle through the skin and into the tissue or organ of interest and removing a small sample of the tissue (Figure 12).
Figure 12: Needle Biopsy of the Breast
Types of needle biopsy include fine needle aspiration (FNA) and cutting needle biopsy.37
Fine needle aspiration is the least invasive type of needle biopsy and is useful in cancers involving body cavities or fluid. FNA employs a thin needle to obtain a fluid or tissue sample. This procedure is fast, inexpensive, and less invasive than other types of biopsy. It can generally be performed without any anesthesia and causes minimal to no discomfort to the patient.37
Slightly more invasive, a cutting needle biopsy obtains samples from masses deep within the body, such as the liver or lung. A cutting needle is used to obtain a core of tissue from the mass.37
Incisional and Excisional Biopsies
More invasive, incisional and excisional biopsies obtain larger tissue samples than needle biopsies. An incisional biopsy removes a wedge of tissue from a tumor mass. An excisional biopsy excises the entire tumor.37
Cells obtained from biopsies are subjected to pathologic analyses, which not only confirm the preliminary diagnosis of cancer but may also identify the subtype, prognosis, and treatment plan for a particular cancer.
Pathologic Tests
Pathologic tests provide specific information about malignant cells including their origin, maturity, and gene expression. A number of special pathology and cytology studies are used in diagnosing cancer:
- Immunophenotyping
- Hormone receptor assays
- Molecular diagnostics
- Electron microscopy
Immunophenotyping
Analysis of the immunophenotype of a cell precisely determines the origin of malignant cells. Every cell lineage has a distinctive pattern of cell-surface proteins that identify its members. These defining cell-surface markers include cluster of differentiation (CD) antigens and other protein markers. The set of protein markers displayed on a cell distinguishes the identity of a cell and also indicates its state of maturity.37
Immunophenotyping relies on the use of antibodies to identify the CD antigens and protein markers expressed on cells. Following treatment with antibodies, the cells may be immunophenotyped using immunohistochemistry or flow cytometry.37
Immunohistochemistry
In immunohistochemistry, antibodies to cell antigens are applied to a slide containing tissue and then stained with a reagent that reacts specifically with the antibody. Only the cells expressing the target antigen are stained; therefore, they can readily be distinguished from surrounding cells.37 Figure 13 shows an example of an immunohistochemical analysis.
Figure 13: Immunohistochemistry
Flow Cytometry
Alternatively, flow cytometry involves an indirect method of analysis that rapidly screens large numbers of cells and defines relative proportions of cells within the biopsy sample. Flow cytometry analyzes cells in suspension. The test tube containing the fluid sample of cells is attached to the flow cytometer and the cells are drawn through the machine and passed by a laser one at a time. The laser detects the presence or absence of a particular marker on each cell. This analysis yields the percentage of cells that contain that marker within the sample (Figure 14).37
Figure 14: Flow Cytometry
Flow cytometry can also be used to determine the amount of DNA in cells and the percentage of cells in S phase. Cancer specimen with abnormal amounts of DNA or more cells in S phase tend to be more aggressive and harder to treat.37
Electron Microscopy
Electron microscopy provides extremely intense magnification and is useful in differentiating cancers such as melanoma that mimic other cancers.37
Molecular Diagnostics
Molecular diagnostic methods analyze chromosome structure and gene expression. Common molecular diagnostic techniques include:
- Polymerase chain reaction (PCR)
- Fluorescent in situ hybridization (FISH)
- Gene expression microarrays
PCR is a method used to identify genes associated with a particular cancer. It is particularly useful for examining the presence of active genes. This procedure also has the advantages of being highly sensitive and extremely fast.37
The technique of FISH detects chromosomal translocations, which are associated with some types of cancer. FISH utilizes either fluorescently tagged DNA or RNA, which is designed to bind to a specific gene within the cell. The tag is visualized within the cell using a fluorescent microscope (Figure 15).
Figure 15: FISH Result
Gene expression microarrays are tiny devices that evaluate the relative levels of hundreds or thousands of different active genes from one sample at the same time (Figure 16). The results tell which genes are active in a tumor. Gene expression microarrays sometimes help predict prognosis or response to certain treatments. They can also be used to identify the type of cancer when the primary cancer is unknown.37
Figure 16: Example of a Microarray Result
[i] American Cancer Society. American Cancer Society guidelines for the early detection of cancer. 2013; 1-3.
[ii] National Cancer Institute. Cancer Screening Overview (PDQ®). http://www.cancer.gov/cancertopics/pdq/screening/overview/patient/page1/AllPages/Print. Accessed August 15, 2013.
[iii] American Cancer Society. Chronological history of ACS recommendations for the early detection of cancer in asymptomatic people. http://www.cancer.org/healthy/findcancerearly/cancerscreeningguidelines/chronological-history-of-acs-recommendations. Accessed August 15, 2013.
[iv] American Cancer Society. Skin cancer prevention and early detection. 2013; 1-3.
[v] U.S. Preventative Task Force. Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer. Task Force DRAFT Recommendation. 2013; 1-4.
[vi] Bickley LS. Interviewing and the health history. Chapter 2. Bates’ Guide to Physical Examination and History Taking, 10th ed. Philadelphia, PA: Lippincott Williams & Wilkins. 2008: Chapter 2.
[vii] American Cancer Support. The initial symptoms of cancer. 2013:1-2.
[viii] American Cancer Society. Imaging (radiology) tests. 2013; 1-25.
[ix] American Cancer Society. Endoscopy. 2012; 1-8.
[x] Marieb EN. Human Anatomy & Physiology. 5th ed. 2001. Benjamin Cummings, San Francisco. Appendix E.
[xi] Sarma PR. Red cell indices. In: Walker HK, Hall WD, Hurst JW, eds. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd ed. Boston, MA: Butterworths; 1990: Chapter 152.
[xii] Carroll R, Matfin G. Endocrine and metabolic emergencies: hypocalcaemia. Ther Adv Endocrinol Metab. 2010; 1:29-33.
[xiii] National Cancer Institute. Tumor markers. http://www.cancer.gov/cancertopics/factsheet/detection/tumor-markers/print. August 15, 2013.
[xiv] American Cancer Society. Testing biopsy and cytology specimens for cancer. 2013; 1-18.