Approach to the Patient with Cancer of Unknown Origin

Jeffrey W. Clark

A malignancy is designated as a cancer of unknown primary (i.e., CUP) after meeting several criteria: (a) a metastatic lesion is histologically confirmed to be malignant, and a primary tumor of any specific organ cannot be identified; (b) routine screening fails to identify the primary source; and (c) a very late metastasis (as occurs in breast cancer, melanoma, and renal cell carcinoma) is also ruled out. Less than 3% of all carcinomas in patients fall into this category, and this percentage is likely to decline further as more sensitive diagnostic techniques continue to be developed.

A CUP poses several problems, ranging from the clinical utility of pursuing further workup to the efficacy of empiric therapy for disease that is already widely metastatic. Any decision to conduct a more-extensive evaluation or treat empirically must include a consideration of the low probability that a potentially curable cancer (usually a germ-cell neoplasm) is present. The evaluation of a CUP can prove expensive and potentially add delay to treatment of a symptomatic patient. However, within this very heterogeneous patient group, there are a few highly responsive malignancies that can be effectively treated if recognized.

Guided by the principle of looking for the most treatable disease, the primary physician should be able to conduct the major part of an effective workup in the outpatient setting and work closely with the oncologist in presenting thoughtful treatment options to the patient.

CLINICAL PRESENTATION AND NATURAL HISTORY OF DISEASE (1, 2, 3 and 4)

Clinical Presentation

Common sites of metastatic presentation are the lung, mediastinum, liver, bone, and lymph nodes. Others include the bone marrow, brain, spinal cord, peritoneum, and retroperitoneum.

Lung

A CUP may present as a solitary nodule, multiple nodules, or pleural effusion (see also Chapters 43 and 44). When a CUP presents in the mediastinum, it may do so as a catastrophic secondary complication, such as dysphagia, stridor, other respiratory difficulty, or superior vena cava syndrome.

Bone

The presentation may be as a lytic or blastic lesion of the axial skeleton, long bones, or skull. Sometimes, the patient reports bone pain or has a pathologic fracture. Often, a CUP is discovered as an incidental radiographic finding. Bone marrow invasion may be heralded by pancytopenia or a myelophthisic picture.

Lymph Node

An isolated firm lymph node is another important presentation of a CUP. Asymmetric cervical, axillary, or inguinal disease is characteristic. Axillary nodes that histologically manifest adenocarcinoma are most commonly associated with ipsilateral breast cancer, even in the presence of normal findings on a breast examination and mammogram. The presence of malignancy in an inguinal node may represent local spread from carcinoma of the vulva, prostate, perineum, endometrium, or ovary, or it may represent systemic involvement by lymphoma. Metastasis from testicular cancer usually does not present as inguinal adenopathy except in cases of previous pelvic and retroperitoneal node dissection.

Liver

Involvement is usually discovered when results of liver function tests are abnormal (e.g., isolated elevation of alkaline phosphatase), an enlarged liver or palpable lesion on the liver is detected on physical examination, or a focal defect is noted on imaging (e.g., abdominal ultrasonography or CT scan) done for another indication. When a primary is discovered, the most frequent sites of origin prove to be from an intra-abdominal source (e.g., pancreas, liver, large or small intestine, or stomach) although metastases to the liver are also frequently seen with other tumors including lung, breast, and melanoma. Cancer that has spread to the peritoneum can lead to malignant ascites. Involvement of the retroperitoneum is usually a silent consequence of spread. Brain metastasis may be asymptomatic, but the new onset of a
focal neurologic deficit or headache is suggestive. Spinal cord involvement may present urgently with symptoms of cord compression (see Chapter 167).

Treatment-Responsive Cancers

A number have been defined. Most manifest a poorly differentiated or undifferentiated histologic appearance. Importantly, extragonadal germ-cell cancers are a subset of poorly differentiated neoplasms that may be potentially curable. They frequently manifest as disease of the mediastinum, retroperitoneum, or lymph nodes. Other suggestive features include patient age of less than 50 years and elevations in serum human chorionic gonadotropin (β-HCG) or a-fetoprotein (AFP) levels. Poorly differentiated carcinoma of neuroendocrine origin (determined by electron microscopy) may also be responsive to treatment.

Ovarian carcinoma is a responsive cancer that may present as adenocarcinoma of the peritoneum causing malignant ascites in a woman with no known primary without evidence of ovarian disease; median survival is longer than would be expected for most other metastatic adenocarcinomas.

Atypical presentations of prostate cancer may include a poorly differentiated or undifferentiated histology and little clinical evidence of a primary lesion, and a prostate-specific antigen (PSA) should be checked in male patients. Again, it is important to always be vigilant in trying to identify cancers, which may potentially be more readily treatable.

Natural History and Clinical Course

Because a CUP represents metastatic disease, it is not surprising that overall median survival is usually relatively short, averaging less than 6 months. Overall, long-term survival is not improved by treatment when all CUP patients are considered as a group, although outcomes for responsive clinical and histopathologic subgroups can be improved considerably with treatment.

DIFFERENTIAL DIAGNOSIS (1, 2, 3, 4 and 5)

Based on data from autopsy studies, pancreatic carcinoma leads the list of causes of cancer of unknown origin, accounting for approximately 25% of cases, and lung cancer is the second most common primary. In terms of location of presenting lesion, lung metastases are more common from primaries above the diaphragm, and liver metastases are more common from tumors below the diaphragm. However, this is not that useful for any individual patient as most cancers can readily metastasize to different locations. From the perspective of workup and management, a consideration of potentially treatable cancers is most important (Table 85-1); this is aided by a differential diagnosis according to region of presentation (Table 85-2). In older men, the most common treatable malignancy is prostate cancer; in younger men, it is germ-cell carcinoma. In women, breast and ovarian cancers lead the list of treatable cancers. Other important causes are cancers of the nasopharynx, oropharynx, and lung (small cell type). As noted, even patients with a poorly differentiated or undifferentiated histology may have a treatable cancer, such as lymphoma, neuroendocrine carcinoma, extragonadal germ-cell cancer, primary peritoneal carcinoma, or carcinoma of the prostate. Over time, even malignancies once considered unresponsive to most therapies, such as melanomas, which can respond to targeted therapy (if a BRAF mutation is present) or to immunotherapy, are becoming more treatable, so it is important to keep this in mind in the evaluation of these patients.

TABLE 85-1 Treatable Malignancies that May Present as Cancer of Unknown Primary

Potentially Curable, Even When Metastatic
	Gestational trophoblastic tumors
	Germ-cell cancer, gonadal (e.g., testicular carcinoma) or extragonadal (e.g., mediastinum)
	Hodgkin disease
	Non-Hodgkin lymphoma
	Oropharyngeal cancers with spread to cervical lymph nodes
Reasonably Responsive to Treatment, Although Incurable
	When Metastatic
	Prostate cancer
	Breast cancer
	Small cell lung carcinoma
	Ovarian carcinoma
	Endometrial cancer
	Thyroid cancer
	Poorly differentiated carcinoma of neuroendocrine type (presents with poorly differentiated or undifferentiated histology)
	Peritoneal carcinomatosis (presents with poorly differentiated or undifferentiated histology)

WORKUP (1, 2, 3, 4, 5 and 6)

Searching for Treatable Disease

When faced with a CUP, the priority is to search for treatable disease. Conducting the workup on the basis of probability rather than on responsiveness to therapy (Table 85-3) may lead to searches that have little impact on outcome. The expense and discomfort incurred by the many diagnostic studies ordered in search of likely but poorly responsive disease can be avoided if the physician adopts the discipline of searching for malignancies that respond to treatment (Tables 85-1, 85-2, 85-3 to 85-4). Treatment in patients with cancer is determined first and foremost by stage of disease, but once metastases have been identified, the tumor is usually sufficiently staged. An exception to this would be malignancies, such as colorectal cancer, where resection of certain metastatic sites (e.g., liver or lung) can sometimes be associated with long-term survival.

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