Pleural Effusion and an Axillary Mass in a Woman With Hypertension
Discussion
The correct answer: Breast.
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]
Immunohistochemical staining of biopsy material can be helpful in narrowing the possible anatomical sites of origin. The results are particularly relevant in the selection of therapeutic strategies and in ensuring that a rare, potentially highly curable cancer is not missed (eg, lymphoma, germ cell tumor).[2]
A critical initial test is examination of several CK subtypes that are more likely to be expressed in certain carcinomas than in others. For example, the CK 7+/CK 20- staining seen in this patient is characteristic of breast and lung cancers (among others), whereas CK 7+/CK 20+ staining would be expected in pancreatic, gastric, and urothelial cancers. A CK 7-/CK 20+ finding would be more suggestive of colon or mucinous ovarian cancer. Furthermore, approximately 70% of lung adenocarcinomas are TTF-1 positive and 60%-80% are napsin A positive. The negative findings in this patient's case make the diagnosis of metastatic lung cancer less likely.
Examination for the presence (or absence) of well-established biomarkers for breast cancer can potentially be helpful in suggesting the site of origin or in helping to define subsequent therapy. These markers include estrogen and progesterone receptors and HER2 overexpression. An additional biomarker, mammaglobin, has been reported to be expressed in 48% of breast cancers but is absent in cancers of the lung, gastrointestinal tract, ovary, and head and neck region.[2]
Of note, mammaglobin was found to be expressed in this patient. Although only 2% of the cells were reported to stain for the estrogen receptor, this finding is still considered positive and supports breast cancer as the correct diagnosis.
Recognized relevant prognostic factors in CUP include baseline performance status, the number and location of metastatic lesions, and the response to cytotoxic chemotherapy.
Unfortunately, the overall prognosis associated with a diagnosis of CUP is poor, with median survival in various series reported to be less than 6 months. However, important exceptions to this outcome include women who present with an isolated metastatic axillary mass, as described in this case.
Previous reports of axillary adenopathy as the initial presentation of cancer in women revealed that the majority had evidence of cancer in the breast at the time of subsequent mastectomy.[3,4] As a result, in the absence of other indications found during routine workup (eg, a single pulmonary lesion suggestive of a primary lung cancer, pathologic findings inconsistent with breast cancer), an isolated adenocarcinoma in the breast (with no evidence of metastatic cancer elsewhere) should be treated as either stage II or stage III breast cancer. Note that this recommendation specifically relates to female patients. If a male patient has CUP with an isolated axillary mass, it is generally assumed that the lung is the origin of the malignancy.
