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%-80% of patients. Above the diaphragm, the lungs were the most common primary site, whereas various GI sites (pancreas, colon, stomach, liver) were most common below the diaphragm. Several frequently occurring cancers, particularly breast and prostate cancers, 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.

 

TABLE 1: Immunohistochemical studies useful in the
differential diagnosis of carcinoma vs another neoplasm
Immunoperoxidase stains
Tumor Type
Pankeratin
CD45 and other markers
S-100 protein
Vimentin
Carcinoma
+
-
-
-/+
Malignant lymphoma
-
+
-
-/+
Malignant melanoma
-
-
-/+
+
Sarcoma
-
-
-
+

 

Signs and symptoms

Patients with unknown primary cancer usually present with symptoms related to the areas of metastatic tumor involvement.

Sites of metastatic involvement include the lungs, liver, and skeletal system; therefore, symptoms referable to these areas are common.

Constitutional symptoms such as anorexia, weight loss, weakness, and fatigue are common.

Physical findings include peripheral adenopathy, pleural effusions, ascites, and hepatomegaly.

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. Electron microscopy, which optimally requires glutaraldehyde fixation, is usually no longer required. Nucleic acid microarray analysis represents a technology of the future, as it lacks an FDA-approved platform.

TABLE 2: Most useful organ-specific markers
Organ or type of cancer Antibody
Breasts GCDFP-15, estrogen receptor
Lung TTF-1
Gastrointestinal carcinoma CDX-2
Stomach CDX-2 + Hep-Par
Colon CDX-2 + CK20
Liver Hep-Par
Pancreas CK17
Kidneys CD10
Prostate Prostate-specific antigen
Serous/endometrioid gynecologic ER
Urinary bladder CK7, CK20, CK5/6
Seminoma/embryonal carcinoma OCT-4
Mesothelioma Calretinin
Thyroid TTF-1 + thyroglobulin

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 individual 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).

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