Purpose of This PDQ Summary
General Information
Cellular Classification
Stage Information

Cervical Lymph Nodes Poorly Differentiated Carcinomas Metastatic Melanoma to a Single Nodal Site Isolated Axillary Metastasis Inguinal Node Metastasis

Newly Diagnosed Carcinoma of Unknown Primary

Cervical Lymph Nodes Poorly Differentiated Carcinomas Poorly Differentiated Neuroendocrine Carcinomas Peritoneal Carcinomatosis Isolated Axillary-Nodal Metastasis Inguinal Node Metastasis Melanoma (Melanotic or amelanotic) Occurring in a Single Nodal Site Multiple Involvement Current Clinical Trials

Recurrent Carcinoma of Unknown Primary

Current Clinical Trials

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Changes to This Summary (07/25/2008)
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Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of carcinoma of unknown primary. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board ¹.

Information about the following is included in this summary:

• Clinical features and therapeutic management approaches.
• Cellular classification.
• Staging.
• Treatment options for various tumor types and their subsets.

This summary is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Some of the reference citations in the summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system ² in developing its level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.

This summary is available in a patient version ³, written in less technical language, and in Spanish ⁴.

General Information

The site of origin of a histologically documented carcinoma is not identified clinically in approximately 3% of patients; this situation is often referred to as carcinoma of unknown primary (CUP) origin or occult primary malignancy.[1-6]

The definition of a CUP varies from study to study; however, at a minimum, this determination should include a biopsy of the tumor and a thorough history and complete physical examination that includes head and neck, rectal, pelvic, and breast examinations; chest x-rays; a complete blood cell count; urinalysis; and an examination of the stool for occult blood. The value of other radiographic tests will be discussed in the stage information section. When these results do not reveal signs of a potential primary lesion and the biopsy is not consistent with a primary tumor at the biopsy site, a CUP must be assumed. The majority of CUP are adenocarcinomas or undifferentiated tumors; less commonly, squamous cell carcinoma, melanoma, sarcoma, and neuroendocrine tumors can also present with a primary site of origin that cannot be determined. In approximately 15% to 25% of patients, the primary site cannot be identified even at postmortem examination.[7]

The prognosis for patients with CUP is poor. As a group, the median survival is approximately 3 to 4 months with less than 25% and 10% of patients alive at 1 and 5 years, respectively. CUP is represented by a heterogeneous group of diseases all of which have presented with metastasis as the primary manifestation. Although the majority of diseases are relatively refractory to systemic treatments, certain clinical presentations of CUP carry a much better prognosis. In each instance, distinct clinical and pathologic details require consideration for appropriate, potentially curative, management.[7-10]

A retrospective review of 657 consecutive patients with CUP (270 additional patients were excluded as a result of identification of a primary malignancy, a noncarcinoma cell type, or no malignancy) reported several variables of significant prognostic importance identified by multivariate analysis.[11] Lymph node involvement and neuroendocrine histology were associated with longer survival; male sex, increasing number of involved organ sites, adenocarcinoma histology, and hepatic involvement were unfavorable prognostic factors. Adrenal involvement has also been noted to be a poor prognostic finding.[12]

Conceptually, CUP represents a tumor that has a greater propensity for early dissemination than the more common presentation in which the primary tumor is apparent with or without metastasis.

The distribution of primary sites that are likely to result in CUP contrasts with the distribution of major primary adenocarcinomas as reported in the Surveillance, Epidemiology, and End Results data. Most large studies have shown that carcinoma of the lung and pancreas are the most common primary carcinomas that initially present as CUP. Other common malignancies such as colorectal, breast, and prostate cancers infrequently present as CUP.[7-10]

The pattern of spread of CUP at diagnosis can provide clues to the likelihood of the primary site being above or below the diaphragm. Lung metastases are twice as common in primary sites ultimately found to be above the diaphragm. Liver metastases are more common from primary disease below the diaphragm. The pattern of metastasis from a carcinoma presenting as CUP may be significantly different from that which would be expected from the usual presentation. For instance, bone metastases are approximately three times more common in pancreatic cancer presenting as CUP, while osseous metastasis from lung cancer is about 10 times less common when it presents as CUP compared with the usual presentation. The biologic bases for these differences in presentation, incidence, and pattern of metastases are unknown.[7]

Although only a minority of patients will have curable disease or a disease for which there is substantial palliative benefit, the appropriate use of special diagnostic pathology and selected radiologic studies will identify patients for whom directed therapy will provide the best possible chance for response.

References

1. Pavlidis N, Briasoulis E, Hainsworth J, et al.: Diagnostic and therapeutic management of cancer of an unknown primary. Eur J Cancer 39 (14): 1990-2005, 2003.  [PUBMED Abstract]
   
   
2. McCredie M, Coates M, Churches T, et al.: Cancer incidence in New South Wales, Australia. Eur J Cancer 27 (7): 928-31, 1991.  [PUBMED Abstract]
   
   
3. Muir C, Weiland L: Upper aerodigestive tract cancers. Cancer 75 (1 Suppl): 147-53, 1995.  [PUBMED Abstract]
   
   
4. Parkin DM, Whelan SL, Ferlay J, et al., eds.: Cancer Incidence in Five Continents. Volume VII. Lyon, France: International Agency for Research on Cancer, 1997. 
   
   
5. Briasoulis E, Pavlidis N: Cancer of Unknown Primary Origin. Oncologist 2 (3): 142-152, 1997.  [PUBMED Abstract]
   
   
6. Hainsworth JD, Greco FA: Treatment of patients with cancer of an unknown primary site. N Engl J Med 329 (4): 257-63, 1993.  [PUBMED Abstract]
   
   
7. Neumann KH, Nystrom JS: Metastatic cancer of unknown origin: nonsquamous cell type. Semin Oncol 9 (4): 427-34, 1982.  [PUBMED Abstract]
   
   
8. Moertel CG, Reitemeier RJ, Schutt AJ, et al.: Treatment of the patient with adenocarcinoma of unknown origin. Cancer 30 (6): 1469-72, 1972.  [PUBMED Abstract]
   
   
9. Altman E, Cadman E: An analysis of 1539 patients with cancer of unknown primary site. Cancer 57 (1): 120-4, 1986.  [PUBMED Abstract]
   
   
10. Ringenberg QS: Tumors of unknown origin. Med Pediatr Oncol 13 (5): 301-6, 1985.  [PUBMED Abstract]
    
    
11. Abbruzzese JL, Abbruzzese MC, Hess KR, et al.: Unknown primary carcinoma: natural history and prognostic factors in 657 consecutive patients. J Clin Oncol 12 (6): 1272-80, 1994.  [PUBMED Abstract]
    
    
12. Hess KR, Abbruzzese MC, Lenzi R, et al.: Classification and regression tree analysis of 1000 consecutive patients with unknown primary carcinoma. Clin Cancer Res 5 (11): 3403-10, 1999.  [PUBMED Abstract]
    
    

Cellular Classification

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]



• 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.[6]



• 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.[7] 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.[8]



• Polymerase chain reaction 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.[9] 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.[10]



• 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.[11]

  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.[12-14] Because of the development of immunohistochemical stains, EM is rarely needed.

References

1. Haskell CM, Cochran AJ, Barsky SH, et al.: Metastasis of unknown origin. Curr Probl Cancer 12 (1): 5-58, 1988 Jan-Feb.  [PUBMED Abstract]
   
   
2. Ruddon RW, Norton SE: Use of biological markers in the diagnosis of cancers of unknown primary tumor. Semin Oncol 20 (3): 251-60, 1993.  [PUBMED Abstract]
   
   
3. Mackay B, Ordonez NG: Pathological evaluation of neoplasms with unknown primary tumor site. Semin Oncol 20 (3): 206-28, 1993.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
5. Battifora H: Recent progress in the immunohistochemistry of solid tumors. Semin Diagn Pathol 1 (4): 251-71, 1984.  [PUBMED Abstract]
   
   
6. 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.  [PUBMED Abstract]
   
   
7. Greco FA, Hainsworth JD: Cancer of unknown primary site. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2005, 2213-34. 
   
   
8. 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.  [PUBMED Abstract]
   
   
9. 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.  [PUBMED Abstract]
   
   
10. 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.  [PUBMED Abstract]
    
    
11. 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.  [PUBMED Abstract]
    
    
12. 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.  [PUBMED Abstract]
    
    
13. Herrera GA, Reimann BE: Electron microscopy in determining origin of metastatic adenocarcinomas. South Med J 77 (12): 1557-66, 1984.  [PUBMED Abstract]
    
    
14. Mackay B, Ordonez NG: The role of the pathologist in the evaluation of poorly differentiated tumors. Semin Oncol 9 (4): 396-415, 1982.  [PUBMED Abstract]
    
    

Stage Information

Opinions are divergent concerning the value and extent of evaluation that should be performed to determine the primary tumor in patients who present with carcinoma of unknown primary (CUP). Clinical and pathological investigations to detect tumors that are potentially responsive to treatment (e.g., lymphoma, germ cell tumor, breast, or ovarian tumor) may be undertaken.

The chest radiograph has become an almost routine procedure in general medical practice. Although chest radiography is routinely performed, in the setting of CUP no distinguishing feature clearly separates primary from metastatic disease within the chest. The abdominal computed tomographic (CT) scan is the only radiographic test that may frequently be of value in defining the primary site, because of the inordinately high representation of pancreatic cancer in the CUP process.[1] With the exception of ovarian cancer, however, CT scans rarely identify treatable primary cancers.[2,3]

The clinical biology of the disease, the types of tumors most often encountered, and the high level of inaccuracy of unguided radiographic studies raise issues of cost effectiveness for intensive diagnostic work-up. Two studies have indicated that a large negative cost/benefit ratio exists for an extensive unguided clinical evaluation, with a single study citing a 9.5% increase in 1-year survival at a cost of 2 to 8 million dollars. The most reasonable approach is to develop a comprehensive knowledge of the manner in which CUP patients present and to remember that this presentation is associated with tremendous heterogeneity regarding outcome.[4-9]

A histologic diagnosis of metastatic carcinoma in cervical nodes requires a meticulous examination of the upper aerorespiratory tract. Histologically, these tumors are usually squamous cell carcinoma, but occasionally may be adenocarcinoma, melanoma, or anaplastic tumors. Metastatic adenocarcinoma is generally associated with a poor prognosis. Approximately 2% to 5% of patients with primary squamous cell carcinoma of the head and neck region will present with cervical adenopathy as the primary disease manifestation; about 10% of this group will present with bilateral adenopathy. The 3-year survival rate ranges from 35% to 59% when patients with squamous or undifferentiated tumors are treated with radical radiation therapy, surgery, or both.[10-12]

Investigators have defined a subpopulation of potentially curable patients with 1 or more of the following characteristics:

• Age younger than 50 years.
• Midline tumor distribution, multiple pulmonary nodules or lymph nodes, elevated serum levels of beta human chorionic gonadotropins (HCG) or alpha-fetoprotein (AFP).
• Cells positive for beta HCG or AFP by immunohistochemical stain.
• The presence of neuroendocrine granules.
• Clinical evidence for rapid tumor growth.
• Tumors that were very responsive to chemotherapy or radiation therapy.

In retrospective review, many of these patients, including some complete responders to chemotherapy, did not have any recognizable histopathologic features of germ cell tumors.[13-15] 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.[16]

Approximately 5% of patients with malignant melanoma will present without a documented primary site. Special stains and electron microscopy may be important in establishing the diagnosis. Patients with this diagnosis should, like those with stage II melanoma, have a radical lymph node dissection. Survival is actually slightly better than that seen in patients with stage II melanoma with a documented primary site.[5,17-19] (Refer to the PDQ summary on Melanoma Treatment ⁵ for more information.)

Most patients who present with nodal metastasis above the diaphragm ultimately are documented to have lung cancer, the most common supradiaphragmatic primary malignancy. The presence of isolated axillary metastasis in females, however, raises another possibility. A few studies involving a small number of patients have shown that approximately 50% of patients who present with isolated axillary metastasis of an adenocarcinoma will ultimately be shown to have breast cancer. Although some of these patients will have a positive mammogram after the initial evaluation, approximately 50% of the patients will not. When these patients are treated with local excision, or as having primary breast cancer, 2- to 10-year survival has been obtained in approximately 50% of patients. The availability of estrogen-receptor (ER) and progesterone-receptor (PR) assays may aid in this diagnosis, and these studies should be performed in this setting. If the clinical setting is consistent with breast cancer, and ER and/or PR levels are elevated, CUP with this distribution should be treated as breast cancer.[1,4,20] (Refer to the PDQ summary on Breast Cancer Treatment ⁶ for more information.)

Squamous carcinoma detected in the inguinal lymph nodes is almost always metastatic from the genital or anal/rectal area. In females, careful examination of the vulva, vagina, and cervix is indicated, with biopsy of any suspicious areas. The penis of uncircumcised males should be carefully inspected. In both sexes, the anorectal area should be carefully examined, including biopsy of suspicious areas. Isolated metastases present in the central nervous system, the liver, and the genitourinary tract. Information about these presentations may be found in PDQ summaries that specifically detail their management.

In addition to the above situations, significant palliation can be achieved in certain instances in patients with CUP. Breast, prostate, ovarian, and thyroid cancers are all treatable malignancies, even when metastatic, and they represent approximately 15% of all CUP tumors. As with other CUP presentations, the pattern of spread of these malignancies is somewhat atypical. For instance, patients with prostate cancer who present with CUP have an inordinately high incidence of metastases to nonosseous sites such as lung (75%), liver (50%), and brain (25%). Bone metastases are also less common than lung metastases in thyroid cancer presenting as CUP.

References

1. Copeland EM, McBride CM: Axillary metastases from unknown primary sites. Ann Surg 178 (1): 25-7, 1973.  [PUBMED Abstract]
   
   
2. Abbruzzese JL, Abbruzzese MC, Lenzi R, et al.: Analysis of a diagnostic strategy for patients with suspected tumors of unknown origin. J Clin Oncol 13 (8): 2094-103, 1995.  [PUBMED Abstract]
   
   
3. Karsell PR, Sheedy PF 2nd, O'Connell MJ: Computed tomography in search of cancer of unknown origin. JAMA 248 (3): 340-3, 1982.  [PUBMED Abstract]
   
   
4. Patel J, Nemoto T, Rosner D, et al.: Axillary lymph node metastasis from an occult breast cancer. Cancer 47 (12): 2923-7, 1981.  [PUBMED Abstract]
   
   
5. Klausner JM, Gutman M, Inbar M, et al.: Unknown primary melanoma. J Surg Oncol 24 (2): 129-31, 1983.  [PUBMED Abstract]
   
   
6. Schapira DV, Jarrett AR: The need to consider survival, outcome, and expense when evaluating and treating patients with unknown primary carcinoma. Arch Intern Med 155 (19): 2050-4, 1995.  [PUBMED Abstract]
   
   
7. Levine MN, Drummond MF, Labelle RJ: Cost-effectiveness in the diagnosis and treatment of carcinoma of unknown primary origin. CMAJ 133 (10): 977-87, 1985.  [PUBMED Abstract]
   
   
8. Maisey MN, Ellam SV: Investigating the adenocarcinoma of unknown origin (ACUP): a cost benefit analysis. Rev Epidemiol Sante Publique 32 (1): 57-61, 1984.  [PUBMED Abstract]
   
   
9. Schwartz SC, Klein J, Peters WP: Carcinoma of unknown primary site. In: Stein JH, ed.: Internal Medicine. St. Louis, Mo: Mosby, 1998, pp 729-733. 
   
   
10. DeSanto LW, Neel HB 3rd: Squamous cell carcinoma. Metastasis to the neck from an unknown or undiscovered primary. Otolaryngol Clin North Am 18 (3): 505-13, 1985.  [PUBMED Abstract]
    
    
11. Muraki AS, Mancuso AA, Harnsberger HR: Metastatic cervical adenopathy from tumors of unknown origin: the role of CT. Radiology 152 (3): 749-53, 1984.  [PUBMED Abstract]
    
    
12. Silverman C, Marks JE: Metastatic cancer of unknown origin: epidermoid and undifferentiated carcinomas. Semin Oncol 9 (4): 435-41, 1982.  [PUBMED Abstract]
    
    
13. Greco FA, Vaughn WK, Hainsworth JD: Advanced poorly differentiated carcinoma of unknown primary site: recognition of a treatable syndrome. Ann Intern Med 104 (4): 547-53, 1986.  [PUBMED Abstract]
    
    
14. Hainsworth JD, Wright EP, Gray GF Jr, et al.: Poorly differentiated carcinoma of unknown primary site: correlation of light microscopic findings with response to cisplatin-based combination chemotherapy. J Clin Oncol 5 (8): 1275-80, 1987.  [PUBMED Abstract]
    
    
15. 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.  [PUBMED Abstract]
    
    
16. 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.  [PUBMED Abstract]
    
    
17. Panagopoulos E, Murray D: Metastatic malignant melanoma of unknown primary origin: a study of 30 cases. J Surg Oncol 23 (1): 8-10, 1983.  [PUBMED Abstract]
    
    
18. Reintgen DS, McCarty KS, Woodard B, et al.: Metastatic malignant melanoma with an unknown primary. Surg Gynecol Obstet 156 (3): 335-40, 1983.  [PUBMED Abstract]
    
    
19. Giuliano AE, Cochran AJ, Morton DL: Melanoma from unknown primary site and amelanotic melanoma. Semin Oncol 9 (4): 442-7, 1982.  [PUBMED Abstract]
    
    
20. Merson M, Andreola S, Galimberti V, et al.: Breast carcinoma presenting as axillary metastases without evidence of a primary tumor. Cancer 70 (2): 504-8, 1992.  [PUBMED Abstract]
    
    

Newly Diagnosed Carcinoma of Unknown Primary

The overwhelming majority of patients presenting with carcinoma of unknown primary (CUP) have disseminated disease that is relatively chemoresistant. Potentially curative treatment can be delivered, however, in a few situations.

All patients should undergo a careful head, neck, and lung evaluation including coronal computed tomography and/or magnetic resonance imaging of the head and neck and directed biopsies of the nasopharynx and tongue base. In those patients with squamous cell or undifferentiated carcinoma, tonsillectomies have been recommended and should be considered if the tonsils have not been previously removed.[1] Fluorodeoxyglucose F 18-positron emission tomography scan may identify an occult primary site in the head and neck area.[2,3] If no primary site can be determined, the following approaches should be considered:

• Radical radiation therapy with curative intent to the cervical lymph nodes and possible sites of origin.[4]
• Preoperative radiation therapy followed by radical neck dissection.
• Radical neck dissection.
• Radical neck dissection followed by postoperative radiation therapy to possible sites of origin.[5]

(Refer to the PDQ summary on Metastatic Squamous Neck Cancer with Occult Primary Cancer Treatment ⁷ for more information.)

Patients who have poorly differentiated carcinomas with or without serologic or histologic evidence of beta human chorionic gonadotropins or alpha-fetoprotein should be treated with intensive chemotherapy as used in the treatment of disseminated germ cell tumors.

In a series, more than 220 patients with excellent performance status were treated with aggressive combination chemotherapy. This chemotherapy generally consisted of vinblastine, bleomycin, and cisplatin; however, some patients received a doxorubicin-containing modification of this regimen and some received etoposide instead of vinblastine. The response rate was 63%, with a complete response rate of 26%, and a long-term disease-free survival of 16%.[6] Carboplatin-containing regimens were found to have equal activity.[7] A paclitaxel-based combination yielded a 48% response rate in 71 patients with various histologic types of carcinoma of unknown origin.[8]

In a series of 29 patients with poorly differentiated neuroendocrine carcinomas, 19 were treated with intensive cisplatin-based combination chemotherapy, and six additional patients received doxorubicin combinations. Six patients achieved complete response and four of these patients were alive 19 to 100 months after diagnosis.[9]

Women with peritoneal carcinomatosis of an adenocarcinoma serous histologic type have a favorable response to chemotherapy and improved prognosis. Response and survival rates in these patients approach those seen in ovarian cancer patients, and therapy appropriate for ovarian cancer should be used.[10,11] (Refer to the PDQ summary on Ovarian Epithelial Cancer Treatment ⁸ for more information.)

The most common primary site for isolated axillary metastasis is the breast. Mammography should be performed in all patients with isolated axillary-nodal metastasis. After an adequate evaluation of the breast and lung to rule out these primary sites, the following treatment options should be considered:

• Lymph node dissection with or without mastectomy or radiation therapy to the breast with curative intent.[12]
• Lymph node dissection with or without mastectomy or radiation therapy to the breast with curative intent plus adjuvant chemotherapy with an accepted therapeutic adjuvant approach for breast cancer. This option should be considered especially if breast cancer is proven or if other lymph nodes show adenocarcinoma.[13]

Metastatic carcinoma in inguinal nodes from an unknown primary source occurs in approximately 1% to 3.5% of patients. A diagnostic excisional-node biopsy should be performed when no primary source of carcinoma can be found. The most common pathologic diagnosis in this instance is Hodgkin lymphoma or non-Hodgkin lymphoma, with CUP being less frequent.

Treatment options:

• Superficial groin dissection alone.
• Local excisional biopsy with or without radiation, inguinal node dissection, or chemotherapy.

In a small proportion of patients, local excision alone is sufficient therapy. Initial therapy with radiation may be used successfully in some patients, depending on extent of disease and individual patient characteristics. Isolated metastases also present in the central nervous system, liver, and genitourinary tract.[14] More information can be found in the PDQ summaries for these malignancies.

Approximately 5% of patients present with no detectable primary site.

Treatment option:

• Radical lymph node dissection. For patients who present with a single site of nodal metastasis, this treatment will yield a survival that is slightly better than that obtained in conventional stage II melanoma.

When patients present with widespread metastatic disease and special studies reveal a probable primary tumor for which standard systemic therapy is available, such therapy should be administered. This may include hormonal therapy for prostate and breast cancer, I¹³¹ for thyroid cancer, or cytotoxic single-agent or combination chemotherapy for hormone-refractory breast and ovarian cancers. Standard approaches for such diseases are available in the specific PDQ summaries for each diagnosis.

The majority of patients will not have a definable primary source. For such patients, a variety of combination chemotherapy approaches have been tried with little success. No treatment can be considered standard at present. Therefore, such patients should be considered for available clinical trials.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with newly diagnosed carcinoma of unknown primary ⁹. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site ¹⁰.

References

1. Righi PD, Sofferman RA: Screening unilateral tonsillectomy in the unknown primary. Laryngoscope 105 (5 Pt 1): 548-50, 1995.  [PUBMED Abstract]
   
   
2. Lassen U, Daugaard G, Eigtved A, et al.: 18F-FDG whole body positron emission tomography (PET) in patients with unknown primary tumours (UPT). Eur J Cancer 35 (7): 1076-82, 1999.  [PUBMED Abstract]
   
   
3. Rades D, Kühnel G, Wildfang I, et al.: Localised disease in cancer of unknown primary (CUP): the value of positron emission tomography (PET) for individual therapeutic management. Ann Oncol 12 (11): 1605-9, 2001.  [PUBMED Abstract]
   
   
4. Beldì D, Jereczek-Fossa BA, D'Onofrio A, et al.: Role of radiotherapy in the treatment of cervical lymph node metastases from an unknown primary site: retrospective analysis of 113 patients. Int J Radiat Oncol Biol Phys 69 (4): 1051-8, 2007.  [PUBMED Abstract]
   
   
5. Davidson BJ, Spiro RH, Patel S, et al.: Cervical metastases of occult origin: the impact of combined modality therapy. Am J Surg 168 (5): 395-9, 1994.  [PUBMED Abstract]
   
   
6. Hainsworth JD, Johnson DH, Greco FA: Cisplatin-based combination chemotherapy in the treatment of poorly differentiated carcinoma and poorly differentiated adenocarcinoma of unknown primary site: results of a 12-year experience. J Clin Oncol 10 (6): 912-22, 1992.  [PUBMED Abstract]
   
   
7. Pavlidis N, Kosmidis P, Skarlos D, et al.: Subsets of tumors responsive to cisplatin or carboplatin combinations in patients with carcinoma of unknown primary site. A Hellenic Cooperative Oncology Group Study. Ann Oncol 3 (8): 631-4, 1992.  [PUBMED Abstract]
   
   
8. Greco FA, Burris HA 3rd, Erland JB, et al.: Carcinoma of unknown primary site. Cancer 89 (12): 2655-60, 2000.  [PUBMED Abstract]
   
   
9. Garrow GC, Greco FA, Hainsworth JD: Poorly differentiated neuroendocrine carcinoma of unknown primary tumor site. Semin Oncol 20 (3): 287-91, 1993.  [PUBMED Abstract]
   
   
10. Strnad CM, Grosh WW, Baxter J, et al.: Peritoneal carcinomatosis of unknown primary site in women. A distinctive subset of adenocarcinoma. Ann Intern Med 111 (3): 213-7, 1989.  [PUBMED Abstract]
    
    
11. Dalrymple JC, Bannatyne P, Russell P, et al.: Extraovarian peritoneal serous papillary carcinoma. A clinicopathologic study of 31 cases. Cancer 64 (1): 110-5, 1989.  [PUBMED Abstract]
    
    
12. Merson M, Andreola S, Galimberti V, et al.: Breast carcinoma presenting as axillary metastases without evidence of a primary tumor. Cancer 70 (2): 504-8, 1992.  [PUBMED Abstract]
    
    
13. Ellerbroek N, Holmes F, Singletary E, et al.: Treatment of patients with isolated axillary nodal metastases from an occult primary carcinoma consistent with breast origin. Cancer 66 (7): 1461-7, 1990.  [PUBMED Abstract]
    
    
14. Guarischi A, Keane TJ, Elhakim T: Metastatic inguinal nodes from an unknown primary neoplasm. A review of 56 cases. Cancer 59 (3): 572-7, 1987.  [PUBMED Abstract]
    
    

Recurrent Carcinoma of Unknown Primary

The prognosis for any treated cancer patient with progressing, recurring, or relapsing disease is poor, regardless of cell type or stage. Deciding on further treatment depends on many factors, including the specific cancer, prior treatment, and site of recurrence, as well as individual patient considerations. Treatments that are under clinical evaluation are appropriate and should be considered when possible.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent carcinoma of unknown primary ¹¹. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site ¹⁰.

Get More Information From NCI

Call 1-800-4-CANCER

For more information, U.S. residents may call the National Cancer Institute's (NCI's) Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237) Monday through Friday from 9:00 a.m. to 4:30 p.m. Deaf and hard-of-hearing callers with TTY equipment may call 1-800-332-8615. The call is free and a trained Cancer Information Specialist is available to answer your questions.

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The NCI Web site ¹³ provides online access to information on cancer, clinical trials, and other Web sites and organizations that offer support and resources for cancer patients and their families. For a quick search, use our “Best Bets” search box in the upper right hand corner of each Web page. The results that are most closely related to your search term will be listed as Best Bets at the top of the list of search results.

There are also many other places to get materials and information about cancer treatment and services. Hospitals in your area may have information about local and regional agencies that have information on finances, getting to and from treatment, receiving care at home, and dealing with problems related to cancer treatment.

Find Publications

The NCI has booklets and other materials for patients, health professionals, and the public. These publications discuss types of cancer, methods of cancer treatment, coping with cancer, and clinical trials. Some publications provide information on tests for cancer, cancer causes and prevention, cancer statistics, and NCI research activities. NCI materials on these and other topics may be ordered online or printed directly from the NCI Publications Locator ¹⁴. These materials can also be ordered by telephone from the Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237), TTY at 1-800-332-8615.

Changes to This Summary (07/25/2008)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Newly Diagnosed Carcinoma of Unknown Primary ¹⁵

Added Beldì et al. as reference 4 ¹⁶.

More Information

About PDQ

• PDQ® - NCI's Comprehensive Cancer Database ¹⁷.

  Full description of the NCI PDQ database.

Additional PDQ Summaries

• PDQ® Cancer Information Summaries: Adult Treatment ¹⁸

  Treatment options for adult cancers.

• PDQ® Cancer Information Summaries: Pediatric Treatment ¹⁹

  Treatment options for childhood cancers.

• PDQ® Cancer Information Summaries: Supportive and Palliative Care ²⁰

  Side effects of cancer treatment, management of cancer-related complications and pain, and psychosocial concerns.

• PDQ® Cancer Information Summaries: Screening/Detection (Testing for Cancer) ²¹

  Tests or procedures that detect specific types of cancer.

• PDQ® Cancer Information Summaries: Prevention ²²

  Risk factors and methods to increase chances of preventing specific types of cancer.

• PDQ® Cancer Information Summaries: Genetics ²³

  Genetics of specific cancers and inherited cancer syndromes, and ethical, legal, and social concerns.

• PDQ® Cancer Information Summaries: Complementary and Alternative Medicine ²⁴

  Information about complementary and alternative forms of treatment for patients with cancer.

Important:

This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).