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Metastatic Cancer With Unknown Primary Site Clinical Presentation

  • Author: Winston W Tan, MD, FACP; Chief Editor: Wafik S El-Deiry, MD, PhD  more...
Updated: Apr 01, 2016


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



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 being lung, bone, lymph nodes, and liver. A detailed physical examination should be conducted, and should include head and neck, rectal, testicular, pelvic, and breast examinations.

Patients have early dissemination of their cancer without symptoms at the primary site. Nevertheless, clinical manifestations may suggest the primary site, as follows:

  • Ascites should lead to evaluation for a gastrointestinal or an ovarian primary.
  • An axillary mass in a female should lead to evaluation for breast cancer[4, 5]
  • Cervical lymphadenopathy should lead to a thorough otolaryngologic examination[6]
  • Signs consistent with brain metastasis should lead to a search for a lung, breast, or kidney primary
  • Apparent 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)
Contributor Information and Disclosures

Winston W Tan, MD, FACP Associate Professor of Medicine, Mayo Medical School; Consultant and Person-in-Charge of Genitourinary Oncology-Medical Oncology, Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic Jacksonville; Vice Chairman of Education, Division of Hematology/Oncology, Mayo Clinic Florida

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

Disclosure: Nothing to disclose.


Nasir Shahab, MD 

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

Disclosure: Nothing to disclose.

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.

Specialty Editor Board

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

Disclosure: Received salary from Medscape for employment. for: Medscape.

Benjamin Movsas, MD 

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

Disclosure: Nothing to disclose.

Chief Editor

Wafik S El-Deiry, MD, PhD Rose Dunlap Professor of Medicine, Chief, Division of Hematology and Oncology, Penn State Hershey Medical Center

Wafik S El-Deiry, MD, PhD is a member of the following medical societies: American Association for Cancer Research, American Society for Clinical Investigation, American Society of Gene and Cell Therapy

Disclosure: Nothing to disclose.

Additional Contributors

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 Association for Physician Leadership, European Society for Medical Oncology, Association of Clinical Research Professionals, American Federation for Clinical Research, Eastern Cooperative Oncology Group, Society for Immunotherapy of Cancer, American Medical Informatics Association, American College of Physicians, American Federation for Medical Research, American Medical Association, American Society of Hematology, Massachusetts Medical Society

Disclosure: Nothing to disclose.


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

  1. Greco FA, Hainsworth JD. Cancer of Unknown Primary Site. De Vita VT Jr, Lawrence TS, Rosenberg SA, eds. De Vita, Hellman, and Rosenberg's Cancer: Principles and Practice. 10th Ed. Philadelphia PA: Wolters Kluwer Health; 2015. 1720-37.

  2. American Cancer Society. Cancer Facts & Figures 2016. American Cancer Society. Available at Accessed: March 31, 2016.

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

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

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

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

  7. [Guideline] Fizazi K, Greco FA, Pavlidis N, Daugaard G, Oien K, Pentheroudakis G, et al. Cancers of unknown primary site: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015 Sep. 26 Suppl 5:v133-8. [Medline]. [Full Text].

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

  9. 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].

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

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

  12. Coassin M, Ebrahimi KB, O'Brien JM, Stewart JM. Optical coherence tomography for retinal metastasis with unknown primary tumor. Ophthalmic Surg Lasers Imaging. 2011 Dec 8. 42:e110-3. [Medline].

  13. Molina R, Bosch X, Auge JM, Filella X, Escudero JM, Molina V, et al. Utility of serum tumor markers as an aid in the differential diagnosis of patients with clinical suspicion of cancer and in patients with cancer of unknown primary site. Tumour Biol. 2011 Dec 9. [Medline].

  14. Hainsworth JD, Rubin MS, Spigel DR, Boccia RV, Raby S, Quinn R, et al. Molecular Gene Expression Profiling to Predict the Tissue of Origin and Direct Site-Specific Therapy in Patients With Carcinoma of Unknown Primary Site: A Prospective Trial of the Sarah Cannon Research Institute. J Clin Oncol. 2012 Oct 1. [Medline].

  15. [Guideline] National Comprehensive Cancer Network. Occult Primary (Cancer of Unknown Primary [CUP]) Version 2. 2016. NCCN. Available at Accessed: March 31, 2016.

  16. Meleth S, Whitehead N, Swinson T, Lux L. Technology assessment on genetic testing or molecular pathology testing of cancers with unknown primary site to determine origin. Technology Assessment Report. RTI International-University of North Carolina at Chapel Hill Evidence-based Practice Center for the Agency for Healthcare Research and Quality (AHRQ). February 20, 2013. Available at

  17. Hainsworth JD, Rubin MS, Spigel DR, Boccia RV, Raby S, Quinn R, et al. Molecular gene expression profiling to predict the tissue of origin and direct site-specific therapy in patients with carcinoma of unknown primary site: a prospective trial of the Sarah Cannon research institute. J Clin Oncol. 2013 Jan 10. 31 (2):217-23. [Medline]. [Full Text].

  18. Ariza A, Balañá C, Concha Á, Hitt R, Homet B, Matilla A, et al. Update on the diagnosis of cancer of unknown primary (CUP) origin. Clin Transl Oncol. 2011 Jul. 13(7):434-41. [Medline].

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

  20. 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. 1995 Jan. 13(1):274-82. [Medline].

  21. 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. 1992 Jan 2. 326(1):17-21. [Medline].

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

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

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

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

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

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

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

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

  30. 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. 2008 Apr-Jun. 45(2):54-8. [Medline].

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

  32. Pentheroudakis G, Briasoulis E, Kalofonos HP, Fountzilas G, Economopoulos T, Samelis G, et al. Docetaxel and carboplatin combination chemotherapy as outpatient palliative therapy in carcinoma of unknown primary: a multicentre Hellenic Cooperative Oncology Group phase II study. Acta Oncol. 2008. 47 (6):1148-55. [Medline].

  33. 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. 2007 May 1. 25(13):1747-52. [Medline].

  34. Hainsworth JD, Spigel DR, Thompson DS, Murphy PB, Lane CM, Waterhouse DM, et al. Paclitaxel/carboplatin plus bevacizumab/erlotinib in the first-line treatment of patients with carcinoma of unknown primary site. Oncologist. 2009 Dec. 14 (12):1189-97. [Medline].

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

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

CT scan of neck with contrast. The arrows indicate metastatic lymphadenopathy. Image courtesy of Head and Neck Cancer-Multidisciplinary Approach, Davidson, BJ.
Table. Immunohistochemical markers for cancers of unknown primary
Primary MarkerPrimary Tumor TypeAdditional Markers
CK7- /CK 20 +Colorectal cancer and merkel cell carcinomaCEA and CDX-2  (for GI malignancy)
CK 7 +/CK 20 -Lung,breast, thyroid, endometrial, cervical, pancreas, and cholangiocarcinomaTTF-1 (lung, thyroid)

ER, PR (breast)

GCDFP-15 (gynecologic)

CK- 19 (pancreas)

Ck+7/ CK 20+Urothelial, ovarian, pancreas, cholangiocarcinomaUrothelin (genitourinary) 

WT-1 (ovarian, mesothelial)

CK = cytokeratin; CEA = carcinoembryonic antigen; TTF1 = thyroid transcription factor 1; ER = estrogen receptor; PR = progesterone receptor; GCDFP-15  = gross cystic disease fluid protein–15; WT-1 = Wilms tumor gene 1; PSA = prostate specific antigen
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