The site of origin of a histologically documented carcinoma is not identified clinically in approximately 3% of patients; this situation is often referred to as carcinoma of unknown primary (CUP) origin or occult primary malignancy.[1-5]

The definition of a CUP varies from study to study; however, at a minimum, this determination should include a biopsy of the tumor and a thorough history and complete physical examination that includes head and neck, rectal, pelvic, and breast examinations; chest x-rays; a complete blood cell count; urinalysis; and an examination of the stool for occult blood. The value of other radiographic tests will be discussed in the stage information section. When these results do not reveal signs of a potential primary lesion and the biopsy is not consistent with a primary tumor at the biopsy site, a CUP must be assumed. The majority of CUP are adenocarcinomas or undifferentiated tumors; less commonly, squamous cell carcinoma, melanoma, sarcoma, and neuroendocrine tumors can also present with a primary site of origin that cannot be determined. In approximately 15% to 25% of patients the primary site cannot be identified even at postmortem examination.[6]

The prognosis for patients with CUP is poor. As a group, the median survival is approximately 3 to 4 months with less than 25% and 10% of patients alive at 1 and 5 years, respectively. CUP is represented by a heterogeneous group of diseases all of which have presented with metastasis as the primary manifestation. Although the majority of diseases are relatively refractory to systemic treatments, there are certain clinical presentations of CUP that carry a much better prognosis. In each instance, there are distinct clinical and pathologic details that require consideration for appropriate, potentially curative, management.[6-9]

A retrospective review of 657 consecutive patients with CUP (270 additional patients were excluded as a result of identification of a primary malignancy, a noncarcinoma cell type, or no malignancy) reported several variables of significant prognostic importance identified by multivariate analysis. Lymph node involvement and neuroendocrine histology were associated with longer survival; male sex, increasing number of involved organ sites, adenocarcinoma histology, and hepatic involvement were unfavorable prognostic factors.[10] Adrenal involvement has also been noted to be a poor prognostic finding.[11]

Conceptually, CUP represents a tumor that has a greater propensity for “early” dissemination than the more common presentation in which the primary tumor is apparent with or without metastases.

The distribution of primary sites that are likely to result in CUP contrasts with the distribution of major primary adenocarcinomas as reported in the Surveillance, Epidemiology, and End Results (SEER) data. Most large studies have shown that carcinoma of the lung and pancreas are the most common primary carcinomas that initially present as CUP. Other common malignancies such as colorectal, breast, and prostate cancers infrequently present as CUP.[6-9]

The pattern of spread of CUP at diagnosis can provide clues to the likelihood of the primary site being above or below the diaphragm. Lung metastases are twice as common in primary sites ultimately found to be above the diaphragm. Liver metastases are more common from primary disease below the diaphragm. The pattern of metastasis from a carcinoma presenting as CUP may be significantly different from that which would be expected from the usual presentation. For instance, bone metastases are approximately 3 times more common in pancreatic cancer presenting as CUP, while osseous metastasis from lung cancer is about 10 times less common when it presents as CUP compared with the usual presentation. The biologic bases for these differences in presentation, incidence, and pattern of metastases are unknown.[6]

Although only a minority of patients will have curable disease or a disease for which there is substantial palliative benefit, the appropriate use of special diagnostic pathology and selected radiologic studies will identify patients for whom directed therapy will provide the best possible chance for response.

References

1. McCredie M, Coates M, Churches T, et al.: Cancer incidence in New South Wales, Australia. Eur J Cancer 27 (7): 928-31, 1991.  [PUBMED Abstract]
   
   
2. Muir C, Weiland L: Upper aerodigestive tract cancers. Cancer 75 (1 Suppl): 147-53, 1995.  [PUBMED Abstract]
   
   
3. Parkin DM, Whelan SL, Ferlay J, et al., eds.: Cancer Incidence in Five Continents. Volume VII. Lyon, France: International Agency for Research on Cancer, 1997. 
   
   
4. Briasoulis E, Pavlidis N: Cancer of Unknown Primary Origin. Oncologist 2 (3): 142-152, 1997.  [PUBMED Abstract]
   
   
5. Hainsworth JD, Greco FA: Treatment of patients with cancer of an unknown primary site. N Engl J Med 329 (4): 257-63, 1993.  [PUBMED Abstract]
   
   
6. Neumann KH, Nystrom JS: Metastatic cancer of unknown origin: nonsquamous cell type. Semin Oncol 9 (4): 427-34, 1982.  [PUBMED Abstract]
   
   
7. Moertel CG, Reitemeier RJ, Schutt AJ, et al.: Treatment of the patient with adenocarcinoma of unknown origin. Cancer 30 (6): 1469-72, 1972.  [PUBMED Abstract]
   
   
8. Altman E, Cadman E: An analysis of 1539 patients with cancer of unknown primary site. Cancer 57 (1): 120-4, 1986.  [PUBMED Abstract]
   
   
9. Ringenberg QS: Tumors of unknown origin. Med Pediatr Oncol 13 (5): 301-6, 1985.  [PUBMED Abstract]
   
   
10. Abbruzzese JL, Abbruzzese MC, Hess KR, et al.: Unknown primary carcinoma: natural history and prognostic factors in 657 consecutive patients. J Clin Oncol 12 (6): 1272-80, 1994.  [PUBMED Abstract]
    
    
11. Hess KR, Abbruzzese MC, Lenzi R, et al.: Classification and regression tree analysis of 1000 consecutive patients with unknown primary carcinoma. Clin Cancer Res 5 (11): 3403-10, 1999.  [PUBMED Abstract]
    
    

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