Carcinoma of Unknown Primary Treatment (PDQ®): Treatment - Health Professional Information [NCI] - Cellular Classification of Carcinoma of Unknown Primary

The pathologist has a central role in the evaluation of carcinoma of unknown primary (CUP). A thorough evaluation of an adequate specimen for histologic, immunohistochemical, and, when appropriate, electron microscopic evaluations is probably the most important clue in the diagnostic puzzle of CUP. Pathologic evaluations provide guidance for an appropriate clinical evaluation. An obvious corollary to the pathologist's role is the critical interaction between the pathologist, oncologist, and primary physician.[1]

The complexity of the pathologic evaluation tends to be inversely related to the degree of differentiation of the tumor. For well- or moderately differentiated tumors, the pathologic diagnosis of an epithelial cancer versus lymphoma, sarcoma, melanoma, or a germ cell tumor, for instance, is often readily apparent. Commonly used histologic stains such as mucicarmine or diastase-sensitive Periodic Acid Schiff can be important in confirming the diagnosis of certain tumors of gastrointestinal or renal origin.

Special studies can help in distinguishing tumors that are poorly differentiated;[2,3] the generic distinction between a poorly differentiated tumor of epithelial, hematopoietic, or neuroectodermal origin (i.e., melanoma) is important. Microsatellite analysis has been used to assess genetic alterations in cervical lymph nodes. These alterations were identical in 18 patients with normal mucosal histology and malignant nodes, suggesting a site of primary tumor origin.[4]

Other diagnostic tests:

  • Immunohistochemical analysis: Several studies can be important in making these broad distinctions; in particular, studies that evaluate staining for keratins, leukocyte common antigen, and S-100, a neuroectodermal antigen expressed in melanomas.[5]
  • Gene expression profiling: Gene expression profiling using an immunohistochemical panel may allow identification of a potential site of origin in patients with adenocarcinoma of unknown origin. One study reported identification of a potential primary site in 14 of 22 patients.[6] This modality has not been validated against the gold standard and has not been studied prospectively.
  • Prostate-specific antigen (PSA) analysis: This histochemical study can accurately differentiate tumors of prostatic origin from other types of cancer. Prostate cancer is most often found by digital rectal examination. Approximately 3% of CUPs are ultimately shown to be prostate cancer. These cancers, as mentioned above, appear to have a different metastatic distribution than the predominant bony distribution that is generally encountered in prostate cancer. When the primary disease may be suspected to have arisen from the prostate, prostate cancer-specific tests should be performed to rule out a diagnosis of primary prostate cancer.[7]
  • Human chorionic gonadotropin (HCG) and alpha-fetoprotein (AFP) analysis: Immunohistochemical stains are available for both of these proteins. Although neither protein is absolutely specific for germ cell tumors, and AFP is not specific for hepatoma, they are important because germ cell tumors are effectively treated with combination chemotherapy; appropriate therapy may lead to cure.[8] The finding of germ cell tumors by genetic analysis has been associated with a high response rate to cisplatin therapy, thus suggesting that molecular or cytogenetic studies may be useful in identifying undifferentiated tumors that are otherwise unclassifiable.[9]
  • Polymerase chain reaction (PCR) analysis: In patients with suspected nasopharyngeal carcinoma, DNA amplification of Epstein-Barr virus (EBV) genomes can be used for diagnosis with tissue provided by fine-needle aspiration biopsy. The presence of EBV in metastases from an occult primary tumor suggests the development of overt nasopharyngeal carcinoma.[10] A single study has shown that the i(12p) marker chromosome may be used as a diagnostic tool in patients with suspected midline germ cell tumors.[11]

    Another study used a molecular assay to evaluate ten tissue type-specific gene markers, using quantitative reverse transcriptase PCR technology to detect tumors originating from the lung, breast, colon, ovary, pancreas, and prostate. About 60% of patients had the putative site of origin identified, thus allowing for administration of treatment-specific therapy.[12,13]

  • Electron microscopic analysis: Electron microscopy (EM) evaluation can sometimes aid in the diagnosis of CUP. In particular, the presence of desmosomes and bundles of tonofilaments are characteristic of squamous cell cancers. The presence of core granules that are diagnostic of neuroendocrine origin is seen in poorly differentiated neuroendocrine tumors of unknown primary site.[14]

    Acinar spaces and microacinic spaces are seen with adenocarcinomas. Electron dense secretory granules are seen in tumors of neuroectodermal origin. Premelanosomes can be found in most amelanotic melanomas.

    The features mentioned above are generally associated with differentiation along a particular line. Often poorly differentiated tumors do not display such characteristics, making the EM evaluation of little value. It is estimated that EM may aid in distinguishing a primary diagnosis that has not been obtained by light microscopy approximately 10% of the time.[15,16,17] Because of the development of immunohistochemical stains, EM is rarely needed.


  1. Haskell CM, Cochran AJ, Barsky SH, et al.: Metastasis of unknown origin. Curr Probl Cancer 12 (1): 5-58, 1988 Jan-Feb.
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  3. Mackay B, Ordonez NG: Pathological evaluation of neoplasms with unknown primary tumor site. Semin Oncol 20 (3): 206-28, 1993.
  4. Califano J, Westra WH, Koch W, et al.: Unknown primary head and neck squamous cell carcinoma: molecular identification of the site of origin. J Natl Cancer Inst 91 (7): 599-604, 1999.
  5. Battifora H: Recent progress in the immunohistochemistry of solid tumors. Semin Diagn Pathol 1 (4): 251-71, 1984.
  6. Horlings HM, van Laar RK, Kerst JM, et al.: Gene expression profiling to identify the histogenetic origin of metastatic adenocarcinomas of unknown primary. J Clin Oncol 26 (27): 4435-41, 2008.
  7. Yam LT, Winkler CF, Janckila AJ, et al.: Prostatic cancer presenting as metastatic adenocarcinoma of undetermined origin. Immunodiagnosis by prostatic acid phosphatase. Cancer 51 (2): 283-7, 1983.
  8. Greco FA, Hainsworth JD: Cancer of unknown primary site. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 2033-51.
  9. Motzer RJ, Rodriguez E, Reuter VE, et al.: Molecular and cytogenetic studies in the diagnosis of patients with poorly differentiated carcinomas of unknown primary site. J Clin Oncol 13 (1): 274-82, 1995.
  10. Feinmesser R, Miyazaki I, Cheung R, et al.: Diagnosis of nasopharyngeal carcinoma by DNA amplification of tissue obtained by fine-needle aspiration. N Engl J Med 326 (1): 17-21, 1992.
  11. Bosl GJ, Ilson DH, Rodriguez E, et al.: Clinical relevance of the i(12p) marker chromosome in germ cell tumors. J Natl Cancer Inst 86 (5): 349-55, 1994.
  12. Varadhachary GR, Talantov D, Raber MN, et al.: Molecular profiling of carcinoma of unknown primary and correlation with clinical evaluation. J Clin Oncol 26 (27): 4442-8, 2008.
  13. Hainsworth JD, Rubin MS, Spigel DR, et al.: Molecular gene expression profiling to predict the tissue of origin and direct site-specific therapy in patients with carcinoma of unknown primary site: a prospective trial of the Sarah Cannon research institute. J Clin Oncol 31 (2): 217-23, 2013.
  14. Hainsworth JD, Johnson DH, Greco FA: Poorly differentiated neuroendocrine carcinoma of unknown primary site. A newly recognized clinicopathologic entity. Ann Intern Med 109 (5): 364-71, 1988.
  15. Hanna W, Kahn HJ: The ultrastructure of metastatic adenocarcinoma in serous fluids. An aid in identification of the primary site of the neoplasm. Acta Cytol 29 (3): 202-10, 1985 May-Jun.
  16. Herrera GA, Reimann BE: Electron microscopy in determining origin of metastatic adenocarcinomas. South Med J 77 (12): 1557-66, 1984.
  17. Mackay B, Ordonez NG: The role of the pathologist in the evaluation of poorly differentiated tumors. Semin Oncol 9 (4): 396-415, 1982.
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