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Carcinoma of an Unknown Primary Site

Carcinoma of an Unknown Primary Site


Carcinoma of an unknown primary site is an uncommon 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 metastatic cancer is detected at one or more sites and clinical evaluation fails to define a primary tumor site or pattern.

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. Improved diagnostic methods, including more specific immunohistochemistry (IHC) stains and gene expression profiling, allow accurate prediction of the tissue of origin in most patients with carcinoma of an unknown primary site, so that site-specific treatment can be delivered.



Unknown primary cancer occurs with approximately equal frequency in men and women, and the prognosis is the same for both.


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 disease site, whereas various gastrointestinal (GI) sites of disease (pancreas, colon, stomach, liver) are most common below the diaphragm. Recently, gene expression profiling has also predicted most primary sites to be in the GI tract or lungs, but breast and ovarian cancers have been more commonly seen with this assessment method than in historical autopsy series.

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 tissue of origin

• Identifying specific characteristics that may direct specific treatments

Initial Approach

Optimal pathologic evaluation includes specialized studies in all patients with carcinoma of unknown primary site; therefore, a surgical or core needle biopsy is necessary to ensure that sufficient diagnostic material is obtained. Tissue is required for paraffin-section IHC, which 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 assays are also valuable in predicting the tissue of origin and should be obtained when IHC stains cannot predict a specific primary site. 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 1: 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. IHC 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

IHC staining frequently suggests the primary site in patients with adenocarcinoma of unknown primary site. Panels of IHC stains usually provide more information than single stains. 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, human epidermal growth factor receptor type 2 [HER2/neu]). Examples of the latter may include Ki-67, which is a surrogate marker of the proliferation rate of a neoplasm.

TABLE 2: Most useful organ-specific markers

Gene Expression 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 transcription polymerase chain reaction (qRT-PCR) or gene microarray techniques are now available and can be performed on tumor tissue from formalin-fixed, paraffin-embedded biopsy specimens using very few tissue sections. In tumors of a known primary, these assays can correctly identify the tissue of origin in over 85% of metastases. In a group of 24 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 specimen correctly identified the primary site in 18 (75%) patients. A direct comparison between IHC and gene expression profiling studies in a series of blinded poorly differentiated neoplasms demonstrated the superiority of gene expression profiling (79% vs 69% correct predictions of the tissue of origin). Gene expression profiling can therefore accurately identify the tissue of origin in the majority of patients with carcinoma of unknown primary site, and it should be a part of the diagnostic evaluation if the site of origin is not identified by other studies.

Clinical Evaluation

After a biopsy has established the diagnosis of 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; computed tomography scans of the chest, abdomen, and pelvis; and specific radiologic and/or endoscopic evaluation of symptomatic areas. If these studies do not identify a primary site, then the patient should be considered to have carcinoma of unknown primary site. However, further evaluation should be performed in patients with specific clinical presentations.

Additional Evaluation Directed by Clinical Features

Women with clinical features suggestive of metastatic breast cancer (eg, metastatic adenocarcinoma involving axillary nodes, bones, or pleura; hormone receptor or HER2/neu-positive tumor) should have mammography, ultrasonography, and breast magnetic resonance imaging. Men with adenocarcinoma of unknown primary site should have serum prostate-specific antigen (PSA) levels measured and/or tumor staining for PSA. 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. Colonoscopy should be performed in patients with features suggestive of metastatic colorectal cancer (ie, liver/peritoneal metastases, typical histology and IHC staining), even in the absence of colon-related symptoms. Bronchoscopy should be considered in patients with clinical presentations suggestive of lung cancer (eg, metastatic small cell neuroendocrine carcinoma; metastases involving mediastinal and/or supraclavicular lymph nodes).

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 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 identifies a primary site in 15% to 30% of the remaining patients. Low-cervical lymph node involvement with adenocarcinoma (level IV, supraclavicular) may 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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