Carcinoma of an Unknown Primary Site

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; they have 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.



Unknown primary cancer occurs with approximately equal frequency in men and women and has the same prognosis in both genders.


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

Sites of Metastatic Involvement

Common sites of metastatic involvement include the lungs, liver, and skeletal system; however, a wide variety of other sites are sometimes involved.

Symptoms and Physical Findings

Patients with unknown primary cancer usually present with signs and symptoms related to the areas of metastatic tumor involvement. In addition, 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, if even a needle core 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 workup. Immunohistochemical methods can reliably distinguish carcinoma from other neoplasms and can often suggest a specific primary site when interpreted in conjunction with clinical features. Gene expression profiling and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) studies are now available as an additional tool for predicting the tissue of origin; emerging clinical data strongly suggest the value of such studies in diagnosis and patient management. It is likely that these molecular studies may be useful in at least a subset of cases, particularly in sorting out the origin of poorly differentiated carcinomas. Electron microscopy, which optimally requires glutaraldehyde fixation, is usually no longer recommended.

Carcinoma vs Other Neoplasms

It is important to rule out the possibility of lymphoma, melanoma, and sarcoma. A battery of antibodies is used 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, because 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).

TABLE 1Immunohistochemical 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, because expression of keratin subtypes 7 and 20 would favor adenocarcinoma, and expression of p40 or 63 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 for the identification of Epstein-Barr virus RNA in a cervical lymph node biopsy, which suggests a nasopharyngeal primary site or the identification of human papillomavirus in an inguinal lymph node biopsy, which suggests a uterine cervical primary site.

Determination of Primary Site in Metastatic Adenocarcinoma

Immunohistochemical staining can suggest the primary site in about three-quarters of patients with adenocarcinoma of unknown primary site. 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 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.

TABLE 2Most 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 qRT-PCR or gene microarray techniques are now available and 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 a group of 20 patients with unknown primary cancer who had an anatomic primary site clinically identified 2 to 78 months after their initial diagnosis, molecular profiling performed retrospectively on the initial biopsy correctly identified the primary site in 15 (75%). In a prospective study, 194 patients with unknown primary cancer received site-specific treatment based on molecular profiling predictions and had a median survival of 12.5 months. Patients predicted to have treatment-responsive tumor types had longer survival than those predicted to have less responsive tumors (13.4 months vs 7.6 months), and median survival of patients with individual tumor types mirrored survival of patients with similar tumors of known primary site (eg, pancreas 8 months, ovary 30 months, breast > 24 months).

Although information is still incomplete, it is likely that gene expression profiling improves diagnosis and treatment in patients with unknown primary cancer and will soon be included in the standard management of these patients.

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 cell 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. However, a couple of exceptions should be mentioned. A positron emission tomography (PET) scan, which detects a primary site in almost 40% of cases, frequently changes the approach to treatment and should be considered in most patients. Colonoscopy should be performed in patients with features suggestive of metastatic colorectal cancer (ie, liver/peritoneal metastases, typical histology and immunohistochemical staining), even in the absence of colon-related symptoms.

Cervical Lymphadenopathy

Metastatic squamous cell 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 thus should be considered. Low cervical adenopathy (level IV, supraclavicular) may also represent an upper GI primary site.

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.


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