Metastatic Cancer With Unknown Primary Site

Metastatic Cancer With Unknown Primary Site

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In metastatic cancer with an unknown primary site, finding the primary site is imperative to permit planning of treatment as soon as possible. Examination of an additional tissue sample very often proves helpful in this diagnostic process, and is often done if the initial biopsy result is equivocal.

Communication with the pathologist is essential for identification of the primary pathology. Special stains and genomic and proteomic testing can be done with a clear plan of action. If those do not yield a diagnosis, the pattern of organ system involvement and the cytologic diagnosis may help in identifying the primary. Clinical reassessment of the patient, including close questioning about signs and symptoms, may bring to light previously unreported issues that may help guide diagnosis.

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. [1]

The American Cancer Society estimates that 34,170 persons (17,810 males; 16,360 females) will be diagnosed with cancers of unspecified primary sites in the United States in 2016. [2] 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 are estimated to be 42,700 in 2016 (23,900 males; 18,800 females). [2] 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, since 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.

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.

Cancer of unknown primary origin represents 2-6% of all cancers diagnosed in the United States, and for for 2-9% of cancers diagnosed worldwide.

Median survival ranges from 11 weeks to 11 months. [3] The 5-year overall survival rate is about 11%.

Most series reporting on or reviewing cancer of unknown primary origin patient groups give an approximate equal incidence for men and women. The median age on presentation for both men and women ranges from 59-66 years.

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Hainsworth JD, Rubin MS, Spigel DR, Boccia RV, Raby S, Quinn R, 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. 2012 Oct 1. [Medline].

[Guideline] National Comprehensive Cancer Network. Occult Primary (Cancer of Unknown Primary [CUP]) Version 2. 2016. NCCN. Available at http://www.nccn.org/professionals/physician_gls/pdf/occult.pdf. Accessed: March 31, 2016.

Meleth S, Whitehead N, Swinson T, Lux L. Technology assessment on genetic testing or molecular pathology testing of cancers with unknown primary site to determine origin. Technology Assessment Report. RTI International-University of North Carolina at Chapel Hill Evidence-based Practice Center for the Agency for Healthcare Research and Quality (AHRQ). February 20, 2013. Available at http://www.cms.gov/Medicare/Coverage/DeterminationProcess/downloads/id90TA.pdf.

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Pentheroudakis G, Briasoulis E, Kalofonos HP, Fountzilas G, Economopoulos T, Samelis G, et al. Docetaxel and carboplatin combination chemotherapy as outpatient palliative therapy in carcinoma of unknown primary: a multicentre Hellenic Cooperative Oncology Group phase II study. Acta Oncol. 2008. 47 (6):1148-55. [Medline].

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TTF-1 (lung, thyroid)

ER, PR (breast)

GCDFP-15 (gynecologic)

CK- 19 (pancreas)

Urothelin (genitourinary) 

WT-1 (ovarian, mesothelial)

Winston W Tan, MD, FACP Associate Professor of Medicine, Mayo Medical School; Consultant and Person-in-Charge of Genitourinary Oncology-Medical Oncology, Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic Jacksonville; Vice Chairman of Education, Division of Hematology/Oncology, Mayo Clinic Florida

Winston W Tan, MD, FACP is a member of the following medical societies: American College of Physicians, American Society of Clinical Oncology, American Society of Hematology, Philippine Medical Association, Texas Medical Association

Disclosure: Nothing to disclose.

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 

Nasir Shahab, MD is a member of the following medical societies: American College of Physicians, American Society of Hematology

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Benjamin Movsas, MD 

Benjamin Movsas, MD is a member of the following medical societies: American College of Radiology, American Radium Society, American Society for Radiation Oncology

Disclosure: Nothing to disclose.

Wafik S El-Deiry, MD, PhD Rose Dunlap Professor of Medicine, Chief, Division of Hematology and Oncology, Penn State Hershey Medical Center

Wafik S El-Deiry, MD, PhD is a member of the following medical societies: American Association for Cancer Research, American Society for Clinical Investigation, American Society of Gene and Cell Therapy

Disclosure: Nothing to disclose.

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 Association for Physician Leadership, European Society for Medical Oncology, Association of Clinical Research Professionals, American Federation for Clinical Research, Eastern Cooperative Oncology Group, Society for Immunotherapy of Cancer, American Medical Informatics Association, American College of Physicians, American Federation for Medical Research, American Medical Association, American Society of Hematology, Massachusetts Medical Society

Disclosure: Nothing to disclose.

Michael Perry, MD, MS, MACP† Former Nellie B Smith Chair of Oncology Emeritus, Former Director, Division of Hematology and Medical Oncology, Former Deputy Director, Ellis Fischel Cancer Center, University of Missouri-Columbia School of Medicine

Metastatic Cancer With Unknown Primary Site

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