eMedicine Specialties > Oncology > Special Topics in Oncology

Metastatic Cancer, Unknown Primary Site

Winston W Tan, MD, Assistant Professor of Medicine, Mayo Medical School; Consulting Staff, Mayo Group Practices
Surabhi Amar, MD, Fellow, Department of Internal Medicine, Division of Hematology/Oncology, Mayo Clinic Jacksonville; Nasir Shahab, MD, Clinical Assistant Professor, Department of Internal Medicine, Division of Medical Oncology and Hematology, University of Missouri at Columbia; Michael Perry, MD, MS, MACP, Nellie B Smith Chair of Oncology Emeritus, Professor, Department of Internal Medicine, Division of Hematology and Oncology, University of Missouri /Ellis Fischel Cancer Center

Updated: Mar 4, 2009

Introduction

Background

In spite of the increasing sophistication in the diagnostic workup for malignancies, detailed investigations fail to reveal a primary site of origin for a subset of patients with metastatic cancer. This is often referred to as carcinoma of unknown primary origin (CUP) or occult primary malignancy. In 2007, the American Cancer Society estimated that 32,100 persons (15,720 males; 16,380 females) would be diagnosed with cancers of unspecified primary sites for that year.¹ This would suggest that cancer of unknown primary origin constitutes about 2% of all cancers diagnosed in the United States. However, deaths due to cancer of unknown primary site were estimated to be 45,230 in 2007 (24,440 males; 20,790 females).¹ This discrepancy between incidence and mortality is believed to be due to a lack of specificity in the listing of cause of death on death certificates.

The exact incidence of cancer of unknown primary origin in the United States is not precisely known. It is almost certainly underreported, and its true incidence is most probably between 2% and 6%. In 15-25% of cases, the primary site cannot be identified even on postmortem examination. The inability to identify a primary site of cancer poses many challenges. The primary site of cancer usually dictates the treatment, expected outcome, and overall prognosis. The diagnosis of carcinoma of unknown primary thus generates anxiety among patients and caregivers, who may feel that the evaluation has been incomplete.

Pathophysiology

Cancers are thought to arise from a single cell that escapes the controls of normal cell replication, forms a tumor at the site of origin, and ultimately metastasizes to other organs. In some cases, the original tumor may remain small or undetectable at the time of metastasis, leading to the clinical presentation of cancer of unknown primary origin. Whether a specific genetic or mutational factor plays a role in cancer of unknown primary origin remains uncertain.

Frequency

United States

Cancer of unknown primary origin represents 2-6% of all cancers diagnosed in the United States.

International

Cancer of unknown primary origin accounts for 2-9% of cancers diagnosed worldwide.

Mortality/Morbidity

Median survival ranges from 11 weeks to 11 months. The 5-year overall survival rate is about 11%.

Sex

Most series reporting on or reviewing cancer of unknown primary origin patient groups give an approximate equal incidence for men and women.

Age

The median age on presentation for both men and women ranges from 59-66 years.

Clinical

History

Because most patients with malignant neoplasms of unknown origin have fairly advanced-staged cancers, the constitutional symptoms of malaise, weakness, fatigue, and weight loss are present in nearly all patients.

Physical

The clinical presentation of cancer of unknown primary origin is extremely variable, and depends on the extent and type of organ involvement. Most patients present with multiple areas of involvement in multiple visceral sites, the most common sites of involvement being lung, bone, lymph nodes, and liver. Attempts have been made to subclassify patients based on histologic type, involved organ sites, and sensitivity to treatment.

The definition of cancer of unknown primary origin varies depending on the study, but most studies involve some minimum investigations before the term is used. The patient should have a biopsy-proven malignancy. The evaluation should include a detailed history and physical examination, including head and neck, rectal, testicular, pelvic, and breast examinations. Lab and radiological studies should include a complete blood cell count (iron deficiency may point toward an occult gastrointestinal malignancy leading to chronic blood loss), urinalysis (microscopic hematuria may be a sign of occult genitourinary malignancy), liver and renal function tests, stool for occult blood, chest radiograph, computed tomography of abdomen and pelvis, mammography in women, and measurement of prostate-specific antigen (PSA) in men.

Patients have early dissemination of their cancer without symptoms at the primary site. The symptoms are often at the site of metastases.

• Ascites should lead one to evaluate for a GI or an ovarian primary.
• An axillary mass in a female should make the clinician check for breast cancer.^2,3
• A cervical node should lead to a thorough ENT examination.⁴
• A brain metastasis should lead to a search for a lung, breast, or kidney primary.
• Bone metastasis should lead to evaluation for prostate, breast, lung, renal, or thyroid primary.
• A testicular mass should lead to measurement of tumor markers such as beta-human chorionic gonadotropin (beta-HCG) and alpha-fetoprotein (AFP).

Further investigations are dictated by any positive findings on initial evaluation. Depending on the clinical situation, these may include computed tomography of the chest, breast magnetic resonance imaging, upper or lower endoscopy. In suspected head and neck malignancies, panendoscopy of the upper aerodigestive pathways should be performed with even as indicated blind biopsies of the lymphoid tissue in these areas. Diagnostic tonsillectomy may be warranted.

Intensive testing also adds to the morbidity for the weak and frail patient. A large negative cost-to-benefit ratio exists for an extensive unguided clinical evaluation, with one study quoting a 9.5% increase in 1-year survival at a cost of 2-8 million dollars.^5,6,7 When these investigations fail to reveal a potential primary lesion, a cancer of unknown primary origin is assumed. The goal of initial evaluation should be to detect the small subset of patients who warrant potentially curative management.

Causes

See Pathophysiology.

Differential Diagnoses

Other Problems to Be Considered

All chronic debilitating diseases are among the initial differential diagnoses for all cases of advanced cancers. However, once a histological diagnosis of a malignancy is made, the list of differential diagnoses is narrowed to neoplastic conditions.

Workup

Laboratory Studies

Lab studies for metastatic cancer with an unknown primary site should include a complete blood cell count (iron deficiency may point toward an occult gastrointestinal malignancy leading to chronic blood loss), urinalysis (microscopic hematuria may be a sign of occult genitourinary malignancy), liver and renal function tests, stool examination for occult blood, and measurement of PSA in men.

Imaging Studies

Imaging studies should include chest radiograph, computed tomography of abdomen and pelvis, and mammography in women.

Positron emission tomography with 18F-fluoro-2-deoxy-D-glucose (18F-FDG-PET) is increasingly being used in the evaluation of metastatic malignancies.⁸ This may be especially the case in suspected head and neck malignancies. However, this testing lacks specificity and may only be useful to identify promising sites for biopsy. Although promising, high cost and false-positive rates of 20% limit its utility in cases of cancer of unknown primary origin. The combination of PET/CT may reduce the false-positive rate.

Depending on the clinical situation, further imaging studies may include computed tomography of the chest or breast magnetic resonance imaging.

The high level of inaccuracy of unguided radiographic studies raises the issue of cost effectiveness for intensive diagnostic workup of this disorder.

Other Tests

The role of tumor markers like AFP, beta-HCG, CA125, CA 27.29, CA 19.9, and carcinoembryonic antigen (CEA) to establish a specific primary site or to identify patients who respond to chemotherapy remains unclear and should probably be limited to cases in which a particular primary site is favored. Most tumor markers are nonspecific and may not be used to establish definitive diagnoses.

Procedures

Often the diagnostic procedure of choice is a biopsy of the metastatic site and a careful evaluation of the pathology, which lead the clinician to a cost-effective diagnostic evaluation of the disease.

Depending on the clinical situation, upper or lower endoscopy may be warranted. In suspected head and neck malignancies, panendoscopy of the upper aerodigestive pathways should be performed with even as indicated blind biopsies of the lymphoid tissue in these areas. Diagnostic tonsillectomy may be warranted.

Histologic Findings

The pathologist has an indispensable role in the evaluation of cancer of unknown primary origin. The help of a pathologist familiar with cancer of unknown primary origin is essential. Tumors provided for pathological review should come from tissue that has whenever possible been excised if such tissue is available and accessible. Needle biopsy specimens may provide insufficient tissue for diagnosis or provide tissue that has been too damaged or distorted by the biopsy procedure for accurate diagnosis.

Various immunoperoxidase stains are available for providing a differential diagnosis for cancer of unknown primary origin. An experienced and knowledgeable pathologist will be familiar with appropriate DNA microarray techniques and proteonomic studies to establish a definitive diagnosis. The pathologist typically puts the tissue specimen through 1-4 steps, depending on the need. These studies include light microscopy, immunohistochemical stains,⁹ electron microscopy, and chromosomal analysis including cytogenetics.¹⁰   

• Light microscopy: After initial light microscopic evaluation, most tumors are classifiable as epithelial cancers, lymphomas, sarcomas, melanomas, or germ cell tumors. When cytologic distinguishing features are limited, the tumor may be classified as undifferentiated or poorly differentiated carcinoma.
• Immunohistochemistry: These tests help define tumor lineage by using peroxidase-labeled antibody against specific tumor antigens. These include stains for keratin, leukocyte common antigen and S-100 (expressed in melanomas), thyroid transcription factor TTF-1 (for lung and thyroid cancer), PSA, HCG (for germ cell tumors), AFP (for germ-cell tumors and hepatomas), ER, PR, and Her-2 (for breast cancer).
• Electron microscopy: This study has limited utility in identification of the primary site of cancer of unknown primary origin but may rarely be used in poorly differentiated tumors.
• Chromosomal studies: In cases of cancer of unknown primary origin with suspected occult nasopharyngeal carcinoma, DNA amplification of Epstein Barr virus (EBV) in tissue may clinch the diagnosis.¹¹ The presence of iso-chromosome 12p, i(12p), a specific chromosomal marker characteristic of germ cell tumors, can help diagnose extragonadal germ cell tumors in patients with cancer of unknown primary origin.^12,13

The majority of cancers of unknown primary origin are adenocarcinomas or undifferentiated tumors (up to 58% in some studies). Less commonly, squamous cell carcinoma, melanoma, sarcoma, and neuroendocrine tumors can also present as metastasis with an unknown primary site of origin.¹⁴ Most studies exclude sarcomas and melanomas from their analysis.

In the approximately 30% of cancers of unknown primary origin in which a full workup establishes a clear pathological diagnosis, the most common epithelial malignancies are lung (15%), pancreas (13%), colon/rectum (6%), kidney (5%), and breast (4%). Sarcomas, melanomas, and lymphomas each contribute 6-8%. The remaining primary tumors are those of stomach (4%), ovary (3%), liver (3%), esophagus (3%), prostate (2%), and a variety of other malignancies (22%).

Staging

Patients with cancer of unknown primary origin are presumed to all have stage IV disease at the time of initial presentation.

Treatment

Medical Care

The treatment of cancer of unknown primary origin continues to evolve.^15,16 The most common scenario is a patient with progressive, metastatic adenocarcinoma with multiple organ involvement.¹⁷ The treatment of this group of patients remains suboptimal.

The overall prognosis of patients with cancer of unknown primary origin with multiple organ involvement and poor performance status is grave; the median survival is only 3-4 months. The 1-year survival rate is less than 15%, with a 5-year survival of 5-10%. Certain clinical factors, like male sex, multiple brain metastases, pleural/lung involvement, liver involvement, adrenal involvement, and adenocarcinoma histology are poor prognostic markers. Others, like lymph node involvement and neuroendocrine histology, are associated with a longer survival.

In contrast, some favorable subsets have been identified that respond well to certain specific treatment strategies. These are discussed below.

Metastasis to cervical lymph nodes

A histologic diagnosis of metastatic carcinoma in the cervical nodes warrants a careful evaluation of the upper aerodigestive tract, including direct visualization of the hypopharynx, nasopharynx, larynx, and upper esophagus. Most of these tumors are squamous cell carcinoma on histology, but adenocarcinoma, melanoma, or anaplastic tumors can also be seen in this location. In patients with squamous or undifferentiated carcinoma, tonsillectomies should be considered.¹⁸ Cervical adenopathy can be the primary disease manifestation in 2-5% of patients with primary squamous cell carcinoma of the head and neck region. In the absence of localization of a primary site, aggressive local therapy is indicated. This may involve any of the following:

• Radical radiation therapy with curative intent to the neck and possible site of origin
• Preoperative radiation therapy followed by radical neck dissection
• Radical neck dissection
• Radical neck dissection followed by radiation to possible sites of origin

Five-year survival rates as high as 30-50% have been achieved with this approach. Role of chemotherapy is debated. One randomized study showed improved response rate and median survival with cisplatin and 5-fluorouracil—based chemotherapy when compared to radiation alone. A single adenocarcinoma-involved lymph node in either the cervical or inguinal areas with no evidence of disease elsewhere may be managed with surgical excision alone and watchful  expectation.¹⁹ Radiation therapy to the involved and local fields may be provided as well. Combination therapy may be superior to monotherapy with 5-year survival rates of 35% reported.

Patients with cervical nodes metastases from squamous cell carcinoma from cancer of unknown primary have an overall survival comparable to that of patients with known primary. In a retrospective study of 89 patients cancer of unknown primary treated with curative intent at a single institution, Mistry et al showed that the overall 5-year and 8-year survival rates were 55% and 51%, respectively. All patients were treated with surgery, and 70 patients received more than 40 Gy postoperative radiotherapy.²⁰

Isolated axillary adenopathy in women

Metastatic adenocarcinoma presenting as isolated axillary lymphadenopathy in women is usually a manifestation of an occult breast primary cancer.² Mastectomy specimens in this subset of patients have shown a previously undiagnosed breast primary tumor in 40-70% cases. Immunohistochemical stains with estrogen and progesterone receptor should be performed in this setting, as they may aid in diagnosis. 

Modified radical mastectomy with axillary node dissection has been advocated. A study with 42 patients, however, showed improved survival with systemic chemotherapy and improved local control with breast and axillary radiation. When these patients are treated with local excision or as having primary breast cancer, 50% of patients achieve 2-10 year survival. Currently, management is based on the guidelines for stage II breast cancer.
See related CME at Poorly Differentiated Carcinoma of Unknown Primary Involving the Axilla and Advances in the Treatment of Metastatic Breast Cancer.

Peritoneal carcinomatosis in women

Women with peritoneal carcinomatosis with adenocarcinoma have similarities with patients with ovarian cancer. They often have papillary histology with elevation of CA 125 and a good response to platinum-based chemotherapy, but a primary tumor is not revealed on exploratory laparotomy.

Metastatic melanoma to a single nodal site

Five percent of patients with malignant melanoma may present with nodal metastasis in the absence of a documented primary site. They should be treated with radical lymph node dissection. Survival, surprisingly, is slightly better than that for stage II melanoma in patients with a known primary site.

Poorly differentiated and undifferentiated carcinoma

One third of patients with cancer of unknown primary origin have poorly or undifferentiated carcinoma. A subpopulation of these can be potentially curable. This subgroup includes patients with lymphomas, germ cell tumors, or neuroendocrine tumors. The features that point toward a treatment-responsive tumor include the following:

• Patient younger than 50 years 
• Midline distribution, with elevated levels of beta-HCG or AFP
• Beta-HCG/AFP positive on immunohistochemistry
• Neuroendocrine granules
• Rapid tumor growth
• Iso-chromosome 12p in midline tumors

Platinum-based combination chemotherapy regimens specific for germ cell tumors have been employed in these patients with a response rate of 63%, a complete response rate of 26%, and a 10-year survival rates of 16%.

Poorly differentiated neuroendocrine carcinomas

These tumors are characterized by positive histochemical stains for chromogranin or neuron-specific enolase. These patients often present with extensive liver or bone metastases. In a series of 29 patients, 19 were treated with intensive cisplatin-based chemotherapy, and 6 others received doxorubicin-based combinations. Complete responses were achieved in 6 patients, and 4 of these patients were alive 19-100 months after diagnosis.
 
Inguinal node metastasis

Metastatic carcinoma in inguinal nodes from an unknown site can be found in 1-3.5% of patients. Squamous cell histology in this area is usually metastatic from the genital/anorectal area. The anorectal area should be carefully inspected in both sexes. Vulvar, vaginal, and cervical examination in women and penile examination in men is warranted. Treatment can involve groin dissection alone or with radiation and chemotherapy. In some patients, local excision with or without radiation may be adequate.

Cancer of unknown primary origin in unselected patients

The results from the favorable patient subsets do not apply to most of the patients with cancer of unknown primary origin. The most effective chemotherapy regimens for this group of patients involve combination therapy with a platinum compound (cisplatin or carboplatin) and a taxane (preferably paclitaxel). This combination gives a response rate of about 12-26% and a median survival of 5-7 months. Triple drug therapy does not appear to offer any additional benefit.

Docetaxel and carboplatin chemotherapy was found to be convenient, safe and effective outpatient palliative treatment for CUP. Pentheroudakis et al, in a phase II study of one hour infusion of docetaxel 75 mg/m² and carboplatin AUC of 5 (30 min each) every 3 weeks, treated 47 patients with CUP. A median of 6 cycles were given, response rate was 32% (46% for favorable risk, 17% for unfavorable risk), and granulocyte colony stimulating factor support was used in a third of the patients. Toxicity was mild including grade 3-4 neutropenia (26%), febrile neutropenia (7%), and severe nonhematologic side effects in fewer than 8% of patients. Median time to progression and overall survival were 5.5 and 16.2 months, respectively. (Survival in the favorable risk was 22.6 months; visceral metastases had poor median survival 5.3 months.)

Patients in whom combination therapy fails may benefit from single-agent treatment with gemcitabine with median time to progression of 5 months. A recent phase II clinical trial with bevacizumab and erlotinib has given a median survival of 7-8 months with 33% of patients alive at 1 year.²¹ A confirmation and extension of this trial is anticipated within the next 1-2 years.

Surgical Care

See Medical Care.

Medication

The goals of pharmacotherapy are to induce remission, prevent complications, and reduce morbidity. See Medical Care.

Antineoplastic Agents

These agents inhibit cell growth and differentiation.

Paclitaxel (Abraxane, Taxol)

Mechanisms of action are tubulin polymerization and microtubule stabilization, which in turn inhibits mitosis and may result in breakage of chromosomes.

Dosing

Adult

175 mg/m² IV over 3 h q3wk or 135 mg/m² IV over 24 h q3wk

Pediatric

Not established

Interactions

Coadministration with cisplatin may further increase myelosuppression

Contraindications

Documented hypersensitivity to paclitaxel or polyoxyethylated castor oil; peripheral neuropathy; bone marrow suppression; liver failure; severe cardiac disease

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Premedicate with steroids, H1, and H2 blockers to decrease risk of hypersensitivity reactions; myelosuppression, alopecia, arthralgia/myalgias, and cardiac arrhythmia may occur

Carboplatin (Paraplatin)

Analog of cisplatin. This is a heavy metal coordination complex that exerts its cytotoxic effect by platination of DNA, a mechanism analogous to alkylation, leading to interstrand and intrastrand DNA crosslinks and inhibition of DNA replication. Binds to protein and other compounds containing SH group. Cytotoxicity can occur at any stage of the cell cycle, but cell is most vulnerable to action of these drugs in G1 and S phase.
Has same efficacy as cisplatin but with better toxicity profile. Main advantages over cisplatin include less nephrotoxicity and ototoxicity not requiring extensive prehydration, less likely to induce nausea and vomiting, but more likely to induce myelotoxicity.
Dose is based on the following formula: total dose (mg) = (target AUC) x (GFR+25) where AUC (area under plasma concentration-time curve) is expressed in mg/mL/min and GFR (glomerular filtration rate) is expressed in mL/min.

Dosing

Adult

Combination therapy: 300 mg/m² q4wk

Pediatric

Not established

Interactions

Nephrotoxicity increases with aminoglycosides and other nephrotoxic drugs

Contraindications

Documented hypersensitivity; bone marrow suppression

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Monitor bone marrow function

Follow-up

Prognosis

Median survival ranges from 11 weeks to 11 months. The 5-year overall survival rate is about 11%.

The overall prognosis of patients with cancer of unknown primary origin with multiple organ involvement and poor performance status is grave; the median survival is only 3-4 months. The 1-year survival rate is less than 15%, with a 5-year survival of 5-10%. Certain clinical factors, like male sex, multiple brain metastases, pleural/lung involvement, liver involvement, adrenal involvement, and adenocarcinoma histology are poor prognostic markers. Others, like lymph node involvement and neuroendocrine histology, are associated with a longer survival.

In contrast, some favorable subsets have been identified that respond well to certain specific treatment strategies. See Medical Care.

Miscellaneous

Medicolegal Pitfalls

It is always important to communicate the goals of the diagnostic plan to the patient and his next of kin clearly. Always make sure that the patient is informed of his or her options once a diagnosis is made. The therapeutic choices should be thoroughly reviewed, and complications must be mentioned.

It is important also to make clear that the primary might not be identified in some patients even with thorough standard testing. It is also important to inform patients that identifying the primary in this situation will not alter prognosis.

References

1. American Cancer Society. Statistics for 2007. American Cancer Society Statistics. Available at http://www.cancer.org/docroot/stt/stt_0.asp. Accessed July 11, 2007.

2. Copeland EM, McBride CM. Axillary metastases from unknown primary sites. Ann Surg. Jul 1973;178(1):25-7. [Medline].

3. Merson M, Andreola S, Galimberti V, et al. Breast carcinoma presenting as axillary metastases without evidence of a primary tumor. Cancer. Jul 15 1992;70(2):504-8. [Medline].

4. Davidson BJ, Spiro RH, Patel S, et al. Cervical metastases of occult origin: the impact of combined modality therapy. Am J Surg. Nov 1994;168(5):395-9. [Medline].

5. Levine MN, Drummond MF, Labelle RJ. Cost-effectiveness in the diagnosis and treatment of carcinoma of unknown primary origin. CMAJ. Nov 15 1985;133(10):977-87. [Medline].

6. Maisey MN, Ellam SV. Investigating the adenocarcinoma of unknown origin (ACUP): a cost benefit analysis. Rev Epidemiol Sante Publique. 1984;32(1):57-61. [Medline].

7. Schapira DV, Jarrett AR. The need to consider survival, outcome, and expense when evaluating and treating patients with unknown primary carcinoma. Arch Intern Med. Oct 23 1995;155(19):2050-4. [Medline].

8. Kole AC, Nieweg OE, Pruim J, et al. Detection of unknown occult primary tumors using positron emission tomography. Cancer. Mar 15 1998;82(6):1160-6. [Medline].

9. Battifora H. Recent progress in the immunohistochemistry of solid tumors. Semin Diagn Pathol. Nov 1984;1(4):251-71. [Medline].

10. 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. Jan 1995;13(1):274-82. [Medline].

11. Feinmesser R, Miyazaki I, Cheung R, et a;. Diagnosis of nasopharyngeal carcinoma by DNA amplification of tissue obtained by fine-needle aspiration. N Engl J Med. Jan 2 1992;326(1):17-21. [Medline].

12. Bosl GJ, Ilson DH, Rodriguez E, et al. Clinical relevance of the i(12p) marker chromosome in germ cell tumors. J Natl Cancer Inst. Mar 2 1994;86(5):349-55. [Medline].

13. Sandberg AA, Meloni AM, Suijkerbuijk RF. Reviews of chromosome studies in urological tumors. III. Cytogenetics and genes in testicular tumors. J Urol. May 1996;155(5):1531-56. [Medline].

14. Garrow GC, Greco FA, Hainsworth JD. Poorly differentiated neuroendocrine carcinoma of unknown primary tumor site. Semin Oncol. Jun 1993;20(3):287-91. [Medline].

15. Hainsworth JD, Greco FA. Treatment of patients with cancer of an unknown primary site. N Engl J Med. Jul 22 1993;329(4):257-63. [Medline].

16. Pavlidis N, Briasoulis E, Hainsworth J, et al. Diagnostic and therapeutic management of cancer of an unknown primary. Eur J Cancer. Sep 2003;39(14):1990-2005. [Medline].

17. Moertel CG, Reitemeier RJ, Schutt AJ, et al. Treatment of the patient with adenocarcinoma of unknown origin. Cancer. Dec 1972;30(6):1469-72. [Medline].

18. Righi PD, Sofferman RA. Screening unilateral tonsillectomy in the unknown primary. Laryngoscope. May 1995;105(5 Pt 1):548-50. [Medline].

19. Guarischi A, Keane TJ, Elhakim T. Metastatic inguinal nodes from an unknown primary neoplasm. A review of 56 cases. Cancer. Feb 1 1987;59(3):572-7. [Medline].

20. Mistry RC, Qureshi SS, Talole SD, et al. Cervical lymph node metastases of squamous cell carcinoma from an unknown primary: Outcomes and patterns of failure. Indian J Cancer. Apr-Jun 2008;45(2):54-8. [Medline].

21. Hainsworth JD, Spigel DR, Farley C, et al. Phase II trial of bevacizumab and erlotinib in carcinomas of unknown primary site: the Minnie Pearl Cancer Research Network. J Clin Oncol. May 1 2007;25(13):1747-52. [Medline].

22. Abbruzzese JL, Abbruzzese MC, Lenzi R, et al. Analysis of a diagnostic strategy for patients with suspected tumors of unknown origin. J Clin Oncol. Aug 1995;13(8):2094-103. [Medline].

23. Altman E, Cadman E. An analysis of 1539 patients with cancer of unknown primary site. Cancer. Jan 1 1986;57(1):120-4. [Medline].

24. Greco FA, Hainsworth JD. Cancer of unknown primary site. In: De Vita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice. 2005:2213-34.

25. Hainsworth JD, Erland JB, Kalman LA, et al. Carcinoma of unknown primary site: treatment with 1-hour paclitaxel, carboplatin, and extended-schedule etoposide. J Clin Oncol. Jun 1997;15(6):2385-93. [Medline].

26. 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. Jun 1992;10(6):912-22. [Medline].

27. Hess KR, Abbruzzese MC, Lenzi R, et al. Classification and regression tree analysis of 1000 consecutive patients with unknown primary carcinoma. Clin Cancer Res. Nov 1999;5(11):3403-10. [Medline].

28. Montero AJ, Varadhachary GR, Abbruzzese JL. Unknown Primary Carcinomas. In: Kantarjian HN, Koller CM, Wolff RA. MD Anderson Manual of Medical Oncology. McGraw Hill; 2006:937-954.

29. Neumann KH, Nystrom JS. Metastatic cancer of unknown origin: nonsquamous cell type. Semin Oncol. Dec 1982;9(4):427-34. [Medline].

30. Panagopoulos E, Murray D. Metastatic malignant melanoma of unknown primary origin: a study of 30 cases. J Surg Oncol. May 1983;23(1):8-10. [Medline].

31. Pavlidis N, Fizazi K. Cancer of unknown primary (CUP). Crit Rev Oncol Hematol. Jun 2005;54(3):243-50. [Medline].

32. Reintgen DS, McCarty KS, Woodard B, et al. Metastatic malignant melanoma with an unknown primary. Surg Gynecol Obstet. Mar 1983;156(3):335-40. [Medline].

33. Ringenberg QS. Tumors of unknown origin. Med Pediatr Oncol. 1985;13(5):301-6. [Medline].

Keywords

metastatic cancer review article, cancer metastasis, metastases, cancer treatment, cancer diagnosis, cancer of unknown primary, CUP, carcinoma of unknown primary, tumor of unknown primary, cancer of unknown origin, carcinoma of unknown origin, unknown primary cancer, unknown primary carcinoma, metastatic carcinoma, metastatic tumor, occult primary malignancy

Contributor Information and Disclosures

Author

Winston W Tan, MD, Assistant Professor of Medicine, Mayo Medical School; Consulting Staff, Mayo Group Practices
Winston W Tan, MD is a member of the following medical societies: American College of Physicians, American Society of Clinical Oncology, American Society of Hematology, Philippine Medical Association, and Texas Medical Association
Disclosure: Roche Grant/research funds Other; Sanofi Aventis Grant/research funds Other; Genentech Grant/research funds Other; Bristol Myers Squibb Grant/research funds Other

Coauthor(s)

Surabhi Amar, MD, Fellow, Department of Internal Medicine, Division of Hematology/Oncology, Mayo Clinic Jacksonville
Surabhi Amar, MD is a member of the following medical societies: American Society of Hematology
Disclosure: Nothing to disclose.

Nasir Shahab, MD, Clinical Assistant Professor, Department of Internal Medicine, Division of Medical Oncology and Hematology, University of Missouri at Columbia
Nasir Shahab, MD is a member of the following medical societies: American College of Physicians and American Society of Hematology
Disclosure: Nothing to disclose.

Michael Perry, MD, MS, MACP, Nellie B Smith Chair of Oncology Emeritus, Professor, Department of Internal Medicine, Division of Hematology and Oncology, University of Missouri /Ellis Fischel Cancer Center
Michael Perry, MD, MS, MACP is a member of the following medical societies: Alpha Omega Alpha, American Association for Cancer Research, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Medical Association, American Society of Clinical Oncology, American Society of Hematology, International Association for the Study of Lung Cancer, and Missouri State Medical Association
Disclosure: Bionumerik Consulting fee Consulting; Proactya Consulting fee Consulting; GSK Consulting fee Consulting; NovoNordisk Consulting fee Consulting; Amgen Honoraria Speaking and teaching; GSK Consulting fee Speaking and teaching

Medical Editor

Robert C Shepard, MD, FACP, Associate Professor of Medicine in Hematology and Oncology at University of North Carolina at Chapel Hill; Vice President of Scientific Affairs, Therapeutic Expertise, Oncology, at PRA International
Robert C Shepard, MD, FACP is a member of the following medical societies: American Association for Cancer Research, American College of Physician Executives, American College of Physicians, American Federation for Clinical Research, American Federation for Medical Research, American Medical Association, American Medical Informatics Association, American Society of Hematology, Association of Clinical Research Professionals, Eastern Cooperative Oncology Group, European Society for Medical Oncology, Massachusetts Medical Society, and Society for Biological Therapy
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Benjamin Movsas, MD, Vice-Chairman, Department of Radiation Oncology, Fox Chase Cancer Center
Benjamin Movsas, MD is a member of the following medical societies: American College of Radiology, American Radium Society, and American Society for Therapeutic Radiology and Oncology
Disclosure: Nothing to disclose.

CME Editor

Rajalaxmi McKenna, MD, FACP, Consulting Staff, Department of Medicine, Southwest Medical Consultants, SC, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Jules E Harris, MD, Clinical Professor of Medicine, Division of Hematology/Medical Oncology, Department of Internal Medicine, University of Arizona College of Medicine at Tucson; Consulting Staff, Arizona Cancer Center
Jules E Harris, MD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Association of Immunologists, American Society of Hematology, and Central Society for Clinical Research
Disclosure: GlobeImmune Salary Consulting; Amplimed Consulting fee Consulting

© 1994- by Medscape.
All Rights Reserved
(http://www.medscape.com/public/copyright)