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Cancer Diagnosis

By Bruce A. Chabner, MD, Director of Clinical Research; Professor of Medicine, Massachusetts General Hospital Cancer Center; Harvard Medical School
Elizabeth Chabner Thompson, MD, MPH, Founder, BFFL Co

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Patient Education

A diagnosis of cancer may be suspected based on history and physical examination but requires confirmation by tumor biopsy and histopathologic examination. Sometimes the first indication is an abnormal laboratory test result (eg, anemia resulting from colon cancer).

A complete history and physical examination may reveal unexpected clues to early cancer.


Physicians must be aware of predisposing factors and must specifically ask about familial cancer, environmental exposure (including smoking history), and prior or present illnesses (eg, autoimmune disorders, previous immunosuppressive therapy, hepatitis B or hepatitis C, HIV infection, abnormal Papanicolaou test, human papillomavirus infection). Symptoms suggesting occult cancer can include

  • Fatigue

  • Weight loss

  • Fevers

  • Night sweats

  • Cough

  • Hemoptysis

  • Hematemesis

  • Hematochezia

  • Change in bowel habits

  • Persistent pain

Physical examination

Particular attention should be paid to skin, lymph nodes, lungs, breasts, abdomen, and testes. Prostate, rectal, and vaginal examinations are also important. Findings help direct further testing, including x-rays and biopsies.


Tests include imaging tests, serum tumor markers, and biopsy; one or more may be indicated in patients with a suggestive history or physical or laboratory findings.

Imaging tests often include plain x-rays, ultrasonography, CT, PET, and MRI. These tests assist in identifying abnormalities, determining qualities of a mass (solid or cystic), providing dimensions, and establishing relationship to surrounding structures, which may be important if surgery or biopsy is being considered.

Serum tumor markers may offer corroborating evidence in patients with findings suggestive of a specific cancer (see Tumor Immunodiagnosis). Most are not used as routine screening tests, except in high-risk patients. Useful examples include

  • α-Fetoprotein (hepatocellular carcinoma, testicular carcinoma)

  • Carcinoembryonic antigen (colon cancer)

  • β-human chorionic gonadotropin (choriocarcinoma, testicular carcinoma)

  • Serum immunoglobulins (multiple myeloma)

  • DNA probes (eg, BCR probe to identify a chromosomal 9-22 translocation in chronic myelogenous leukemia)

  • CA 125 (ovarian cancer)

  • CA 27-29 (breast cancer)

  • Prostate specific antigen (prostate cancer)

Some of these serum tumor markers may be most useful in monitoring the response to treatment rather than in tumor detection.

Biopsy to confirm the diagnosis and tissue of origin is almost always required when cancer is suspected or detected. The choice of biopsy site is usually determined by ease of access and degree of invasiveness. If lymphadenopathy is present, fine-needle or core biopsy may yield the tumor type; if nondiagnostic, open biopsy is indicated. Other biopsy routes include bronchoscopy for easily accessible mediastinal or central pulmonary tumors, percutaneous liver biopsy if liver lesions are present, and CT- or ultrasound-guided biopsy of lung or soft tissue masses. If these procedures are not suitable, open biopsy may be necessary.

Grading is a histologic measure of tumor aggressiveness and provides important prognostic information. It is determined by examining the biopsy specimen. Grade is based on the morphologic appearance of tumor cells, including the appearance of the nuclei, cytoplasm, and nucleoli; frequency of mitoses; and amount of necrosis. For many cancers, grading scales have been developed.

Molecular tests such as chromosomal analysis, fluorescent in situ hybridization (FISH), PCR, and cell surface antigens (eg, in lymphomas, leukemias, lung, and GI cancers) help delineate the origin of metastatic cancers, particularly for cancers of unknown primary origin, and may be helpful in selecting therapy.


Once a histologic diagnosis is made, staging (ie, determination of the extent of disease) helps in treatment decision-making and influences prognosis. Clinical staging uses data from the history, physical examination, imaging tests, laboratory tests, and biopsy of bone marrow, lymph nodes, or other sites of suspected disease. For staging of specific neoplasms, see details in the organ-relevant chapter.

Imaging tests

Imaging tests, especially CT, PET, and MRI, can detect metastases to brain, lungs, or abdominal viscera, including the adrenal glands, retroperitoneal lymph nodes, liver, and spleen. MRI (with gadolinium contrast) is the procedure of choice for recognition and evaluation of brain tumors, both primary and metastatic. PET scanning is increasingly being used to determine the metabolic activity of a suspect lymph node or mass. Integrated PET–CT can be valuable, especially in lung, head and neck, and breast cancer and in lymphoma.

Ultrasonography can be used to study breast, orbital, thyroid, cardiac, pericardial, hepatic, pancreatic, renal, testicular, and retroperitoneal masses. It may guide percutaneous biopsies and differentiate fluid-filled cysts from solid masses.

Nuclear scans can identify several types of metastases. Bone scans identify abnormal bone growth (ie, osteoblastic activity) before it is visible on plain x-ray. Thus, this technique is useless in neoplasms that are purely lytic (eg, multiple myeloma); routine bone x-rays are the study of choice in such diseases.

Laboratory tests

Serum chemistries and enzymes may help staging. Elevated liver enzyme (alkaline phosphatase, LDH, ALT) levels and elevated bilirubin levels suggest the presence of liver metastases. Elevated alkaline phosphatase and serum Ca may be the first evidence of bone metastases. Elevated BUN or creatinine levels may indicate an obstructive uropathy secondary to a pelvic mass, intrarenal obstruction from tubular precipitation of myeloma protein, or uric acid nephropathy from lymphoma or other cancers. Elevated uric acid levels often occur in patients with rapidly proliferating tumors and in those with myeloproliferative and lymphoproliferative disorders.

Invasive tests

Mediastinoscopy (see Mediastinoscopy and Mediastinotomy) is especially valuable in the staging of non–small cell lung cancer. When mediastinal lymph node involvement is found, patients may benefit from initial chemoradiation and subsequent tumor resection.

Bone marrow aspiration and biopsy are especially useful in detecting metastases from malignant lymphomas and small cell lung cancer. Bone marrow biopsy is positive at diagnosis in 50 to 70% of patients with malignant lymphoma (low and intermediate grade) and in 15 to 18% of patients with small cell lung cancer. Bone marrow biopsy should be done in patients with unexplained hematologic abnormalities (ie, anemia, thrombocytopenia, pancytopenia).

Biopsy of regional lymph nodes is part of the evaluation of many tumors, such as breast, lung, or colon cancers. Removal of a sentinel lymph node (as defined by uptake of dye or radioactivity injected into the tumor site) may allow limited but definitive lymph node sampling.