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 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
At autopsy, a primary site is identified in 70% to 80% of patients. Above the diaphragm, the lungs are the most common primary site, whereas various gastrointestinal (GI) sites (pancreas, colon, stomach, liver) are most common below the diaphragm. Several frequently occurring cancers, particularly those of the breast and prostate, are rarely identified at autopsy.
Signs and symptoms
Patients with unknown primary cancer usually present with symptoms related to the areas of metastatic tumor involvement.
Sites of metastatic involvement
Sites 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(Drug information on paraffin)-section immunohistochemistry, which is currently the usual methodology of choice in the workup. 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 are now available 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 vs 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 Table 1. The staining result obtained with any single marker is unreliable, as exceptions may occur for each antibody. For example, although keratin is a relatively reliable marker of carcinoma, some carcinomas (eg, adrenal cortical carcinoma or undifferentiated carcinoma of the thyroid) may be keratin-negative, whereas some types of sarcoma are characteristically keratin-positive (eg, epithelioid sarcoma).
Immunohistochemical studies useful in the differential diagnosis of carcinoma vs another neoplasm
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 p63 or keratin subtypes 5/6 and 14 would favor squamous cell carcinoma. Reliable neuroendocrine markers include chromogranin A and synaptophysin. In situ hybridization studies may be helpful in some circumstances, such as the identification of Epstein-Barr virus RNA in a cervical lymph node biopsy suggesting a nasopharyngeal primary of the identification of human papillomavirus in an inguinal lymph node biopsy suggesting a cervical primary.
Determination of primary site in metastatic adenocarcinoma
Immunohistochemical staining can suggest the primary site in patients with adenocarcinoma of unknown primary site in about two-thirds of cases. Useful stains are listed in Table 2, however most of these stains must be interpreted in conjunction with tumor histology and clinical features.
Identification of specific treatment target characteristics
Even if the primary site is not determined, characteristics of the carcinoma may suggest specific treatment options or impart prognostic information. Examples of the former may include determination of estrogen or progesterone(Drug information on progesterone) receptors or expression of members of the epidermal growth factor receptor family (eg, HER2/neu). Examples of the latter may include Ki-67, which is a surrogate marker of the proliferation rate of a neoplasm.
Most useful organ-specific markers
Molecular genetic tumor profiling
Specific gene expression profiles based on the tissue of origin have been identified for many tumor types. Several assays using either quantitative reverse transcriptase polymerase chain reaction or gene microarray techniques are now available and at least one is approved for Medicare reimbursement; they can be performed on tumor tissue from formalin-fixed, paraffin-embedded biopsy specimens. In tumors of a known primary, these assays can correctly identify the tissue of origin in over 85% of metastases; in unknown primary cancers, they yield diagnoses that are usually compatible with clinical features and response to empiric treatment. Clinical identification of a primary site is unusual in patients with the initial diagnosis of unknown primary cancer; however, this group provides an ideal subset for evaluating the accuracy of molecular profiling predictions. In a recent study, molecular profiling of the original biopsy yielded the "correct" diagnosis in 15 of 20 such patients.
The value of the molecular profiling diagnosis in directing therapy and improving treatment outcome is unknown, but it is being evaluated in ongoing prospective trials.
Although information is still incomplete, it is likely that gene expression profiling will be a valuable addition to the diagnosis and management of patients with these malignancies.
Clinical evaluation
After a biopsy has established metastatic carcinoma, a relatively limited clinical evaluation is indicated to search for a primary site. Recommended evaluation includes a complete history, physical examination, chemistry profile, complete blood count, chest radiograph, and CT scan of the abdomen.
Symptomatic areas
Specific radiologic and/or endoscopic evaluation of symptomatic areas should be pursued. In addition, mammography, ultrasonography, and breast MRI should be performed in women with clinical features suggestive of metastatic breast cancer (eg, estrogen receptor-positive tumor and/or specific metastatic involvement including axillary nodes, bones, or pleura), and serum prostate-specific antigen (PSA) level should be measured in men with features suggestive of prostate cancer (eg, blastic bone metastasis). In young men with poorly differentiated carcinoma, serum human chorionic gonadotropin (hCG) and alpha-fetoprotein (AFP) levels should always be measured.
Asymptomatic areas
In general, radiologic or endoscopic evaluation of asymptomatic areas is not productive and should be avoided. An exception is positron emission tomography (PET) scanning, which detects a primary site in almost 40% of cases and frequently changes the approach to treatment. The PET scan is now considered a standard part of the initial evaluation of patients with carcinoma of an unknown primary site.
Cervical lymphadenopathy
Metastatic squamous carcinoma in cervical lymph nodes usually involves upper or mid-cervical locations. All patients should undergo a thorough search for a primary site in the head and neck region, including direct endoscopic examination of the oropharynx, hypopharynx, nasopharynx, larynx, and upper esophagus. Any suspicious areas should be biopsied. Fiberoptic bronchoscopy should be considered in patients with involvement of low cervical or supraclavicular nodes. This type of evaluation will identify a primary site, usually in the head and neck, in 85% to 90% of these patients. Further evaluation with PET scanning can identify a primary site in 15% to 30% of the remaining patients and should be considered. Low cervical adenopathy (level IV, supraclavicular) may also represent an upper GI primary.
Inguinal lymphadenopathy
Patients with metastatic squamous cell cancer presenting in inguinal lymph nodes almost always have an identifiable primary site in the perineal area. Women should undergo careful examination of the vulva, vagina, and cervix; men should have careful inspection of the penis. Anoscopy should be performed to exclude lesions in the anorectal area.
