Metastatic Cancer With Unknown Primary Site Workup

  • Author: Winston W Tan, MD; Chief Editor: Jules E Harris, MD   more...
 
Updated: Jan 17, 2012
 

Laboratory Studies

Lab studies for metastatic cancer with an unknown primary site should include a complete blood cell count (iron deficiency may point toward an occult gastrointestinal malignancy leading to chronic blood loss), urinalysis (microscopic hematuria may be a sign of occult genitourinary malignancy), liver and renal function tests, stool examination for occult blood, and measurement of PSA in men.

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Imaging Studies

Imaging studies should include chest radiograph, computed tomography of abdomen and pelvis, and mammography in women.

Positron emission tomography with 18F-fluoro-2-deoxy-D-glucose (18F-FDG-PET) is increasingly being used in the evaluation of metastatic malignancies.[8] This may be especially the case in suspected head and neck malignancies. However, this testing lacks specificity and may only be useful to identify promising sites for biopsy. Although promising, high cost and false-positive rates of 20% limit its utility in cases of cancer of unknown primary origin. The combination of PET/CT may reduce the false-positive rate.[9]

Depending on the clinical situation, further imaging studies may include computed tomography of the chest or breast magnetic resonance imaging.

The high level of inaccuracy of unguided radiographic studies raises the issue of cost effectiveness for intensive diagnostic workup of this disorder.

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Other Tests

The role of tumor markers like AFP, beta-HCG, CA125, CA 27.29, CA 19.9, and carcinoembryonic antigen (CEA) to establish a specific primary site or to identify patients who respond to chemotherapy remains unclear and should probably be limited to cases in which a particular primary site is favored. Most tumor markers are nonspecific and may not be used to establish definitive diagnoses.[10]

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Procedures

Often the diagnostic procedure of choice is a biopsy of the metastatic site and a careful evaluation of the pathology, which lead the clinician to a cost-effective diagnostic evaluation of the disease.

Depending on the clinical situation, upper or lower endoscopy may be warranted. In suspected head and neck malignancies, panendoscopy of the upper aerodigestive pathways should be performed with even as indicated blind biopsies of the lymphoid tissue in these areas. Diagnostic tonsillectomy may be warranted.

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Histologic Findings

The pathologist has an indispensable role in the evaluation of cancer of unknown primary origin. The help of a pathologist familiar with cancer of unknown primary origin is essential. Tumors provided for pathological review should come from tissue that has whenever possible been excised if such tissue is available and accessible. Needle biopsy specimens may provide insufficient tissue for diagnosis or provide tissue that has been too damaged or distorted by the biopsy procedure for accurate diagnosis.[11]

Various immunoperoxidase stains are available for providing a differential diagnosis for cancer of unknown primary origin. An experienced and knowledgeable pathologist will be familiar with appropriate DNA microarray techniques and proteonomic studies to establish a definitive diagnosis. The pathologist typically puts the tissue specimen through 1-4 steps, depending on the need. These studies include light microscopy, immunohistochemical stains,[12] electron microscopy, and chromosomal analysis including cytogenetics.[13]

  • Light microscopy: After initial light microscopic evaluation, most tumors are classifiable as epithelial cancers, lymphomas, sarcomas, melanomas, or germ cell tumors. When cytologic distinguishing features are limited, the tumor may be classified as undifferentiated or poorly differentiated carcinoma.
  • Immunohistochemistry: These tests help define tumor lineage by using peroxidase-labeled antibody against specific tumor antigens. These include stains for keratin, leukocyte common antigen and S-100 (expressed in melanomas), thyroid transcription factor TTF-1 (for lung and thyroid cancer), PSA, HCG (for germ cell tumors), AFP (for germ-cell tumors and hepatomas), ER, PR, and Her-2 (for breast cancer).
  • Electron microscopy: This study has limited utility in identification of the primary site of cancer of unknown primary origin but may rarely be used in poorly differentiated tumors.
  • Chromosomal studies: In cases of cancer of unknown primary origin with suspected occult nasopharyngeal carcinoma, DNA amplification of Epstein Barr virus (EBV) in tissue may clinch the diagnosis.[14] The presence of iso-chromosome 12p, i(12p), a specific chromosomal marker characteristic of germ cell tumors, can help diagnose extragonadal germ cell tumors in patients with cancer of unknown primary origin.[15, 16]

The majority of cancers of unknown primary origin are adenocarcinomas or undifferentiated tumors (up to 58% in some studies). Less commonly, squamous cell carcinoma, melanoma, sarcoma, and neuroendocrine tumors can also present as metastasis with an unknown primary site of origin.[17] Most studies exclude sarcomas and melanomas from their analysis.

In the approximately 30% of cancers of unknown primary origin in which a full workup establishes a clear pathological diagnosis, the most common epithelial malignancies are lung (15%), pancreas (13%), colon/rectum (6%), kidney (5%), and breast (4%). Sarcomas, melanomas, and lymphomas each contribute 6-8%. The remaining primary tumors are those of stomach (4%), ovary (3%), liver (3%), esophagus (3%), prostate (2%), and a variety of other malignancies (22%).

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Staging

Patients with cancer of unknown primary origin are presumed to all have stage IV disease at the time of initial presentation.

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Contributor Information and Disclosures
Author

Winston W Tan, MD  Assistant Professor of Medicine, Mayo Medical School; Consulting Staff, Mayo Group Practices

Winston W Tan, MD is a member of the following medical societies: American College of Physicians, American Society of Clinical Oncology, American Society of Hematology, Philippine Medical Association, and Texas Medical Association

Disclosure: Nothing to disclose.

Coauthor(s)

Surabhi Amar, MD  Fellow, Department of Internal Medicine, Division of Hematology/Oncology, Mayo Clinic Jacksonville

Surabhi Amar, MD is a member of the following medical societies: American Society of Hematology

Disclosure: Nothing to disclose.

Nasir Shahab, MD  Clinical Assistant Professor, Department of Internal Medicine, Division of Medical Oncology and Hematology, University of Missouri at Columbia

Nasir Shahab, MD is a member of the following medical societies: American College of Physicians and American Society of Hematology

Disclosure: Nothing to disclose.

Michael Perry, MD, MS, MACP  Nellie B Smith Chair of Oncology Emeritus, Director, Division of Hematology and Medical Oncology, Deputy Director, Ellis Fischel Cancer Center, University of Missouri-Columbia School of Medicine

Michael Perry, MD, MS, MACP is a member of the following medical societies: Alpha Omega Alpha, American Association for Cancer Research, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Medical Association, American Society of Clinical Oncology, American Society of Hematology, International Association for the Study of Lung Cancer, and Missouri State Medical Association

Disclosure: Nothing to disclose.

Specialty Editor Board

Robert C Shepard, MD, FACP  Associate Professor of Medicine in Hematology and Oncology at University of North Carolina at Chapel Hill; Vice President of Scientific Affairs, Therapeutic Expertise, Oncology, at PRA International

Robert C Shepard, MD, FACP is a member of the following medical societies: American Association for Cancer Research, American College of Physician Executives, American College of Physicians, American Federation for Clinical Research, American Federation for Medical Research, American Medical Association, American Medical Informatics Association, American Society of Hematology, Association of Clinical Research Professionals, Eastern Cooperative Oncology Group, European Society for Medical Oncology, Massachusetts Medical Society, and Society for Biological Therapy

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Benjamin Movsas, MD  Vice-Chairman, Department of Radiation Oncology, Fox Chase Cancer Center

Benjamin Movsas, MD is a member of the following medical societies: American College of Radiology, American Radium Society, and American Society for Therapeutic Radiology and Oncology

Disclosure: Nothing to disclose.

Rajalaxmi McKenna, MD, FACP  Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems

Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis

Disclosure: Nothing to disclose.

Chief Editor

Jules E Harris, MD  Clinical Professor of Medicine, Section of Hematology/Oncology, University of Arizona College of Medicine, Arizona Cancer Center

Jules E Harris, MD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Association of Immunologists, American Society of Hematology, and Central Society for Clinical Research

Disclosure: GlobeImmune Salary Consulting

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