Pleural Effusion and an Axillary Mass in a Woman With Hypertension

Maurie Markman, MD


March 30, 2021


This case is a classic example of cancer of unknown primary site or origin (CUP). CUP represents approximately 5% of cancers diagnosed in the United States (50,000 to 60,000 cases each year), with various series reporting that the site of origin is not diagnosed in between 2% and 6% of all cancer cases.[1] Worldwide, the incidence of CUP is even higher, resulting from the limited availability of sophisticated (and expensive) diagnostic technology in many regions. The median age at diagnosis of CUP is 60 years, and men and women are equally likely to be affected.

A cancer is considered a CUP if, after routine clinical assessment, physical and laboratory examination, standard imaging studies, and routine pathologic evaluation (biopsy or surgical removal of a metastatic mass lesion), a site of origin cannot be defined. With the availability of more sophisticated imaging technologies (eg, MRI), the overall percentage of cancers that are defined as a CUP has been reduced. However, even at autopsy, the site of origin of such cancer is often unable to be determined if the location was unknown before the patient's death.

Several theories have been proposed for why a metastatic lesion becomes clinically evident despite the site of origin of the cancer remaining obscure. These include (1) very slow growth of the primary cancer compared with that of the metastasis; (2) spontaneous regression of the primary cancer; (3) a prominent vascular component of the cancer, which enhances the rate of spread; and (4) unique molecular events associated with the cancer, which result in rapid progression and the growth of metastatic lesions.

Approximately 60% of CUPs are adenocarcinomas (well or moderately well differentiated); 25%-30% are poorly differentiated (including poorly differentiated adenocarcinomas); 5% are completely undifferentiated, with no defining histologic features; 5% are squamous cell cancers; and approximately 1% are carcinomas, with evidence of neuroendocrine differentiation.[1]


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