Cancer Management Chapter 25: Carcinoma of an unknown primary site
Carcinoma of an unknown primary site is a common clinical syndrome, accounting for approximately 3% of all oncologic diagnoses. Patients in this group are heterogeneous, having a wide variety of clinical presentations and pathologic findings. A patient should be considered to have carcinoma of an unknown primary site when a tumor is detected at one or more metastatic sites, and routine evaluation (see below) fails to define a primary tumor site.
Carcinoma of an unknown primary site is a common clinical syndrome, accounting for approximately 3% of all oncologic diagnoses. Patients in this group are heterogeneous, having a wide variety of clinical presentations and pathologic findings. A patient should be considered to have carcinoma of an unknown primary site when a tumor is detected at one or more metastatic sites, and routine evaluation (see below) fails to define a primary tumor site.
Although all patients with cancer of an unknown primary site have advanced, metastatic disease, universal pessimism and nihilism regarding treatment are inappropriate. Subsets of patients with specific treatment implications can be defined using clinical and pathologic features. In addition, trials of empiric chemotherapeutic regimens incorporating new antineoplastic agents have suggested improved response rates and survival in unselected groups of patients with carcinoma of an unknown primary site.
Epidemiology
Gender
Unknown primary cancer occurs with approximately equal frequency in men and women and has the same prognosis in the two genders.
Age
As with most epithelial cancers, the incidence of unknown primary cancer increases with advancing age, although a wide age range exists. Some evidence suggests that younger patients are more likely to have poorly differentiated histologies.
Disease sites
Autopsy series performed prior to the availability of CT resulted in the identification of a primary site in 70% to 80% of patients. Above the diaphragm, the lungs were the most common primary site, whereas various gastrointestinal (GI) sites (pancreas, colon, stomach, liver) were most common below the diaphragm. Several frequently occurring cancers, particularly those of the breast and prostate, were rarely identified in autopsy series.
With improved radiologic diagnosis, the spectrum of unknown primary cancer has probably changed. Limited recent autopsy data suggest a lower percentage of primary sites identified, particularly in patients with poorly differentiated histology.
Signs and symptoms
Patients with unknown primary cancer usually present with symptoms related to the areas of metastatic tumor involvement.
Site of metastatic involvement
Site of metastatic involvement include the lungs, liver, and skeletal system; therefore, symptoms referable to these areas are common.
Symptoms and physical findings
Constitutional symptoms, such as anorexia, weight loss, weakness, and fatigue are common.
Pathologic evaluation
Optimal pathologic evaluation is critical in the evaluation of patients with carcinoma of an unknown primary site and can aid with the following:
• distinguishing carcinoma from other cancer types,
• determining histologic type,
• identifying the primary site,
• identifying specific characteristics that may direct specific treatments.
Initial approach
Although cytologic evaluation, including fine-needle aspiration biopsy, can often determine whether a lesion is malignant, a tissue biopsy will probably be needed to further evaluate the neoplasm. Tissue is required for paraffin-section immunohistochemistry, which is currently the usual methodology of choice in the work-up. Immunohistochemical methods can reliably distinguish carcinoma from other neoplasms, and can sometimes suggest a specific primary site when interpreted in conjunction with clinical features. Gene expression profile studies show promise as an additional tool in determining the tissue of origin, although more experience in the clinical setting is needed to determine how valuable this technology will be in practice. Electron microscopy, which optimally requires glutaraldehyde fixation, is usually no longer required.
Carcinoma versus other neoplasms
It is important to rule out the possibility of malignant lymphoma, malignant melanoma, and sarcoma.
A battery of antibodies is utilized in an attempt to distinguish carcinoma from other types of neoplasms, as summarized in
Determination of histologic type
There may be clues on initial histologic examination. For example, the presence of gland formation or mucin production would indicate an adenocarcinoma, whereas the presence of keratinization would indicate a squamous cell carcinoma. Evidence of neuroendocrine differentiation may be suggested by the presence of a characteristic, relatively fine chromatin pattern. Immunohistochemistry can also be of use, as expression of keratin subtypes 7 and 20 would favor adenocarcinoma, and expression of keratin subtypes 5/6 and 14 would favor squamous cell carcinoma. Reliable neuroendocrine markers include chromogranin A and synaptophysin.