It is often important to determine the site of origin of a metastatic carcinoma of unknown primary site, particularly because this may affect the choice of the treatment. Determination of the primary site may take several steps. Clinical features, such as age, sex, and site of metastases may give a first indication. A detailed pathologic examination of the most accessible biopsied tissue specimen is mandatory in CUP cases. Pathologic evaluation typically consists of hematoxylin-and-eosin stains and immunohistochemical tests. Electron microscopy is rarely used currently, although it may beselectively useful when making treatment decisions. Role of Serum Tumor Markers and Cytogenetics Most tumor markers, including CEA, CA-125, CA 19-9, and CA 15-3, when elevated, are nonspecific and not helpful in determining the primary tumor site. Men who present with adenocarcinoma and osteoblastic metastasis should undergo a PSA test. Patients with an elevated PSA should be treated as having prostate cancer. In patients with undifferentiated or poorly differentiated carcinoma (especially with a midline tumor), elevated Beta-human chorionic gonadotropin (B-hCG) and alpha fetoprotein(AFP) levels suggest the possibility of an extragonadal germ cell (testicular)tumor. Cytogenetic studies had a larger role in the past, although interpretation of these older studies can be challenging. With the availability of immunohistochemical stains, cytogenetic cytogenetic analyses are indicated only occasionally.
Role of Immunohistochemistry CK 7 and CK20 are two of the most commonly used CKs in surgical pathology. A 5% cut-off percentage for positivity may eliminate more “false positive” results.
(1) CK7+/CK20+ in carcinomas of bile duct, lung-mucinous bronchioloalveolar, pancreas; urothelium; also primary mucinous tumors of ovary (74%), upper GI tract (78%), endocervix
(2) CK7+/CK20- in carcinomas of bile duct, breast, endocervical and endometrial adenocarcinoma, esophagus (distal,), lung (not mucinous, bronchioloalveolar), salivary gland, thyroid; also mesothelioma
(3) CK7-/CK20+ in carcinoma of colon (particularly early stage); CK20 is less sensitive for poorly differentiated colonic carcinoma; primary mucinous tumors of lower GI tract (79%,) and primary bladder adenocarcinomas (29%,)
(4) CK7-/CK20- in carcinomas of adrenal cortex and prostate
(5)CK7 and CK20 can be used to distinguish primary lung carcinoma (CK7+/CK20-) from metastatic colonic carcinoma to lung (CK7-/CK20+)
(6)CK7 cab be used to distinguish chromophobe carcinoma (diffuse CK7+ staining) and oncocytoma (usually CK7-)
(7)CK 20 can be used to distinguish Merkel cell carcinoma (CK20+, dot like, TTF1 -) and metastatic small cell carcinoma of lung (CK20-, TTF1+)
Additional immunostains for further work up. BRST-1,ER,PR,Gross cystic disease fibrous protein-15--> Breast cancer Thyroid transcription factor 1---> Lung and thyroid cancer Thyroglobulin ---> Thyroid cancer Chromogranin, synaptophysin, NSE,CD56---> Neuroendocrine cancer CDX-2 ---> Gastrointestinal cancer Calretinin, mesothelin---> Mesothelioma Leukocyte common antigen---> Lymphoma S-100, HMB-45---> Melanoma URO-III, thrombomodulin ---> Bladder cancer AlphaFetoprotein ---> Hepatocellular cancer, germcell cancer Beta-Human chronic gonadotropin --->Germ cell cancer Prostate specific antigen ---> Prostate cancer Please review following powerpoint presentation for work up of CUP.