eMedicine Specialties > Oncology > Special Topics in Oncology

Metastatic Cancer, Unknown Primary Site

Author: Winston W Tan, MD, Assistant Professor of Medicine, Mayo Medical School; Consulting Staff, Mayo Group Practices
Coauthor(s): Surabhi Amar, MD, Fellow, Department of Internal Medicine, Division of Hematology/Oncology, Mayo Clinic Jacksonville; Nasir Shahab, MD, Clinical Assistant Professor, Department of Internal Medicine, Division of Medical Oncology and Hematology, University of Missouri at Columbia; Michael Perry, MD, MS, MACP, Nellie B Smith Chair of Oncology Emeritus, Professor, Department of Internal Medicine, Division of Hematology and Oncology, University of Missouri /Ellis Fischel Cancer Center
Contributor Information and Disclosures

Updated: Mar 4, 2009

Introduction

Background

In spite of the increasing sophistication in the diagnostic workup for malignancies, detailed investigations fail to reveal a primary site of origin for a subset of patients with metastatic cancer. This is often referred to as carcinoma of unknown primary origin (CUP) or occult primary malignancy. In 2007, the American Cancer Society estimated that 32,100 persons (15,720 males; 16,380 females) would be diagnosed with cancers of unspecified primary sites for that year.1 This would suggest that cancer of unknown primary origin constitutes about 2% of all cancers diagnosed in the United States. However, deaths due to cancer of unknown primary site were estimated to be 45,230 in 2007 (24,440 males; 20,790 females).1 This discrepancy between incidence and mortality is believed to be due to a lack of specificity in the listing of cause of death on death certificates.

The exact incidence of cancer of unknown primary origin in the United States is not precisely known. It is almost certainly underreported, and its true incidence is most probably between 2% and 6%. In 15-25% of cases, the primary site cannot be identified even on postmortem examination. The inability to identify a primary site of cancer poses many challenges. The primary site of cancer usually dictates the treatment, expected outcome, and overall prognosis. The diagnosis of carcinoma of unknown primary thus generates anxiety among patients and caregivers, who may feel that the evaluation has been incomplete.

Pathophysiology

Cancers are thought to arise from a single cell that escapes the controls of normal cell replication, forms a tumor at the site of origin, and ultimately metastasizes to other organs. In some cases, the original tumor may remain small or undetectable at the time of metastasis, leading to the clinical presentation of cancer of unknown primary origin. Whether a specific genetic or mutational factor plays a role in cancer of unknown primary origin remains uncertain.

Frequency

United States

Cancer of unknown primary origin represents 2-6% of all cancers diagnosed in the United States.

International

Cancer of unknown primary origin accounts for 2-9% of cancers diagnosed worldwide.

Mortality/Morbidity

Median survival ranges from 11 weeks to 11 months. The 5-year overall survival rate is about 11%.

Sex

Most series reporting on or reviewing cancer of unknown primary origin patient groups give an approximate equal incidence for men and women.

Age

The median age on presentation for both men and women ranges from 59-66 years.

Clinical

History

Because most patients with malignant neoplasms of unknown origin have fairly advanced-staged cancers, the constitutional symptoms of malaise, weakness, fatigue, and weight loss are present in nearly all patients.

Physical

The clinical presentation of cancer of unknown primary origin is extremely variable, and depends on the extent and type of organ involvement. Most patients present with multiple areas of involvement in multiple visceral sites, the most common sites of involvement being lung, bone, lymph nodes, and liver. Attempts have been made to subclassify patients based on histologic type, involved organ sites, and sensitivity to treatment.

The definition of cancer of unknown primary origin varies depending on the study, but most studies involve some minimum investigations before the term is used. The patient should have a biopsy-proven malignancy. The evaluation should include a detailed history and physical examination, including head and neck, rectal, testicular, pelvic, and breast examinations. Lab and radiological studies 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 for occult blood, chest radiograph, computed tomography of abdomen and pelvis, mammography in women, and measurement of prostate-specific antigen (PSA) in men.

Patients have early dissemination of their cancer without symptoms at the primary site. The symptoms are often at the site of metastases.

  • Ascites should lead one to evaluate for a GI or an ovarian primary.
  • An axillary mass in a female should make the clinician check for breast cancer.2,3
  • A cervical node should lead to a thorough ENT examination.4
  • A brain metastasis should lead to a search for a lung, breast, or kidney primary.
  • Bone metastasis should lead to evaluation for prostate, breast, lung, renal, or thyroid primary.
  • A testicular mass should lead to measurement of tumor markers such as beta-human chorionic gonadotropin (beta-HCG) and alpha-fetoprotein (AFP).

Further investigations are dictated by any positive findings on initial evaluation. Depending on the clinical situation, these may include computed tomography of the chest, breast magnetic resonance imaging, upper or lower endoscopy. 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.

Intensive testing also adds to the morbidity for the weak and frail patient. A large negative cost-to-benefit ratio exists for an extensive unguided clinical evaluation, with one study quoting a 9.5% increase in 1-year survival at a cost of 2-8 million dollars.5,6,7 When these investigations fail to reveal a potential primary lesion, a cancer of unknown primary origin is assumed. The goal of initial evaluation should be to detect the small subset of patients who warrant potentially curative management.

Causes

See Pathophysiology.

More on Metastatic Cancer, Unknown Primary Site

Overview: Metastatic Cancer, Unknown Primary Site
Differential Diagnoses & Workup: Metastatic Cancer, Unknown Primary Site
Treatment & Medication: Metastatic Cancer, Unknown Primary Site
Follow-up: Metastatic Cancer, Unknown Primary Site
References
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References

  1. American Cancer Society. Statistics for 2007. American Cancer Society Statistics. Available at http://www.cancer.org/docroot/stt/stt_0.asp. Accessed July 11, 2007.

  2. Copeland EM, McBride CM. Axillary metastases from unknown primary sites. Ann Surg. Jul 1973;178(1):25-7. [Medline].

  3. Merson M, Andreola S, Galimberti V, et al. Breast carcinoma presenting as axillary metastases without evidence of a primary tumor. Cancer. Jul 15 1992;70(2):504-8. [Medline].

  4. Davidson BJ, Spiro RH, Patel S, et al. Cervical metastases of occult origin: the impact of combined modality therapy. Am J Surg. Nov 1994;168(5):395-9. [Medline].

  5. Levine MN, Drummond MF, Labelle RJ. Cost-effectiveness in the diagnosis and treatment of carcinoma of unknown primary origin. CMAJ. Nov 15 1985;133(10):977-87. [Medline].

  6. Maisey MN, Ellam SV. Investigating the adenocarcinoma of unknown origin (ACUP): a cost benefit analysis. Rev Epidemiol Sante Publique. 1984;32(1):57-61. [Medline].

  7. Schapira DV, Jarrett AR. The need to consider survival, outcome, and expense when evaluating and treating patients with unknown primary carcinoma. Arch Intern Med. Oct 23 1995;155(19):2050-4. [Medline].

  8. Kole AC, Nieweg OE, Pruim J, et al. Detection of unknown occult primary tumors using positron emission tomography. Cancer. Mar 15 1998;82(6):1160-6. [Medline].

  9. Battifora H. Recent progress in the immunohistochemistry of solid tumors. Semin Diagn Pathol. Nov 1984;1(4):251-71. [Medline].

  10. Motzer RJ, Rodriguez E, Reuter VE, et al. Molecular and cytogenetic studies in the diagnosis of patients with poorly differentiated carcinomas of unknown primary site. J Clin Oncol. Jan 1995;13(1):274-82. [Medline].

  11. Feinmesser R, Miyazaki I, Cheung R, et a;. Diagnosis of nasopharyngeal carcinoma by DNA amplification of tissue obtained by fine-needle aspiration. N Engl J Med. Jan 2 1992;326(1):17-21. [Medline].

  12. Bosl GJ, Ilson DH, Rodriguez E, et al. Clinical relevance of the i(12p) marker chromosome in germ cell tumors. J Natl Cancer Inst. Mar 2 1994;86(5):349-55. [Medline].

  13. Sandberg AA, Meloni AM, Suijkerbuijk RF. Reviews of chromosome studies in urological tumors. III. Cytogenetics and genes in testicular tumors. J Urol. May 1996;155(5):1531-56. [Medline].

  14. Garrow GC, Greco FA, Hainsworth JD. Poorly differentiated neuroendocrine carcinoma of unknown primary tumor site. Semin Oncol. Jun 1993;20(3):287-91. [Medline].

  15. Hainsworth JD, Greco FA. Treatment of patients with cancer of an unknown primary site. N Engl J Med. Jul 22 1993;329(4):257-63. [Medline].

  16. Pavlidis N, Briasoulis E, Hainsworth J, et al. Diagnostic and therapeutic management of cancer of an unknown primary. Eur J Cancer. Sep 2003;39(14):1990-2005. [Medline].

  17. Moertel CG, Reitemeier RJ, Schutt AJ, et al. Treatment of the patient with adenocarcinoma of unknown origin. Cancer. Dec 1972;30(6):1469-72. [Medline].

  18. Righi PD, Sofferman RA. Screening unilateral tonsillectomy in the unknown primary. Laryngoscope. May 1995;105(5 Pt 1):548-50. [Medline].

  19. Guarischi A, Keane TJ, Elhakim T. Metastatic inguinal nodes from an unknown primary neoplasm. A review of 56 cases. Cancer. Feb 1 1987;59(3):572-7. [Medline].

  20. Mistry RC, Qureshi SS, Talole SD, et al. Cervical lymph node metastases of squamous cell carcinoma from an unknown primary: Outcomes and patterns of failure. Indian J Cancer. Apr-Jun 2008;45(2):54-8. [Medline].

  21. Hainsworth JD, Spigel DR, Farley C, et al. Phase II trial of bevacizumab and erlotinib in carcinomas of unknown primary site: the Minnie Pearl Cancer Research Network. J Clin Oncol. May 1 2007;25(13):1747-52. [Medline].

  22. Abbruzzese JL, Abbruzzese MC, Lenzi R, et al. Analysis of a diagnostic strategy for patients with suspected tumors of unknown origin. J Clin Oncol. Aug 1995;13(8):2094-103. [Medline].

  23. Altman E, Cadman E. An analysis of 1539 patients with cancer of unknown primary site. Cancer. Jan 1 1986;57(1):120-4. [Medline].

  24. Greco FA, Hainsworth JD. Cancer of unknown primary site. In: De Vita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice. 2005:2213-34.

  25. Hainsworth JD, Erland JB, Kalman LA, et al. Carcinoma of unknown primary site: treatment with 1-hour paclitaxel, carboplatin, and extended-schedule etoposide. J Clin Oncol. Jun 1997;15(6):2385-93. [Medline].

  26. Hainsworth JD, Johnson DH, Greco FA. Cisplatin-based combination chemotherapy in the treatment of poorly differentiated carcinoma and poorly differentiated adenocarcinoma of unknown primary site: results of a 12-year experience. J Clin Oncol. Jun 1992;10(6):912-22. [Medline].

  27. Hess KR, Abbruzzese MC, Lenzi R, et al. Classification and regression tree analysis of 1000 consecutive patients with unknown primary carcinoma. Clin Cancer Res. Nov 1999;5(11):3403-10. [Medline].

  28. Montero AJ, Varadhachary GR, Abbruzzese JL. Unknown Primary Carcinomas. In: Kantarjian HN, Koller CM, Wolff RA. MD Anderson Manual of Medical Oncology. McGraw Hill; 2006:937-954.

  29. Neumann KH, Nystrom JS. Metastatic cancer of unknown origin: nonsquamous cell type. Semin Oncol. Dec 1982;9(4):427-34. [Medline].

  30. Panagopoulos E, Murray D. Metastatic malignant melanoma of unknown primary origin: a study of 30 cases. J Surg Oncol. May 1983;23(1):8-10. [Medline].

  31. Pavlidis N, Fizazi K. Cancer of unknown primary (CUP). Crit Rev Oncol Hematol. Jun 2005;54(3):243-50. [Medline].

  32. Reintgen DS, McCarty KS, Woodard B, et al. Metastatic malignant melanoma with an unknown primary. Surg Gynecol Obstet. Mar 1983;156(3):335-40. [Medline].

  33. Ringenberg QS. Tumors of unknown origin. Med Pediatr Oncol. 1985;13(5):301-6. [Medline].

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Further Reading

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Keywords

metastatic cancer review article, cancer metastasis, metastases, cancer treatment, cancer diagnosis, cancer of unknown primary, CUP, carcinoma of unknown primary, tumor of unknown primary, cancer of unknown origin, carcinoma of unknown origin, unknown primary cancer, unknown primary carcinoma, metastatic carcinoma, metastatic tumor, occult primary malignancy

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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: Roche Grant/research funds Other; Sanofi Aventis Grant/research funds Other; Genentech Grant/research funds Other; Bristol Myers Squibb Grant/research funds Other

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, Professor, Department of Internal Medicine, Division of Hematology and Oncology, University of Missouri /Ellis Fischel Cancer Center
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: Bionumerik Consulting fee Consulting; Proactya Consulting fee Consulting; GSK Consulting fee Consulting; NovoNordisk Consulting fee Consulting; Amgen Honoraria Speaking and teaching; GSK Consulting fee Speaking and teaching

Medical Editor

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.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

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.

CME Editor

Rajalaxmi McKenna, MD, FACP, Consulting Staff, Department of Medicine, Southwest Medical Consultants, SC, 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, Division of Hematology/Medical Oncology, Department of Internal Medicine, University of Arizona College of Medicine at Tucson; Consulting Staff, 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; Amplimed Consulting fee Consulting

 
 
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