Cancer can be a devastating diagnosis, made even more difficult for both patients and clinicians when the origin of the cancer is unknown. Most patients are familiar with the more common cancer diagnoses including lung, breast, colorectal, and prostate cancer. Therefore, cancer of unknown origin (CUO) can be a challenging diagnosis to make and even more challenging to relay to patients and subsequently treat.

CUO represents approximately 3% to 5% of all malignancies.1-3 Most patients will present with symptoms consistent with metastases, and upon further investigation, the primary malignant origin cannot be determined based on physical exam, laboratory studies, imaging, or biopsy. For example, a patient may present with weight loss, fatigue, and swollen axillary lymph nodes with subsequent biopsy showing adenocarcinoma. At this point, a thorough history, physical examination, chart review, and relatively focused work-up should be initiated in an attempt to find the primary site of origin.

RELATED: Cancer of Unknown Primary: Molecular Profiling May Direct Treatment

Continue Reading

In addition to basic blood work, some of the more frequently used tumor markers such as carcinoembryonic antigen (CEA), CA-19-9, alpha-fetoprotein, CA-125, and prostate-specific antigen are not diagnostic, and elevated levels are not necessarily indicative of a specific diagnosis. These markers are typically used only as supporting evidence of a possible primary site and to monitor response to therapy, even in CUOs.

Available imaging and diagnostic options include CT, MRI, and PET scans, mammography, colonoscopy, and endoscopy; however, an “all of the above” approach should not be used in attempts at finding the primary site of origin. Once a tissue diagnosis is made, there are a multitude of highly specialized immunohistochemical stains that a pathologist can use in order to help identify the primary site.

The four main subtypes of CUO include adenocarcinoma (70%), poorly differentiated carcinomas (20% to 25%), squamous cell carcinoma (5%), and neuroendocrine carcinoma (1%).4 When adenocarcinoma of unknown origin is diagnosed, the most likely primary sites include the pancreas, gallbladder, biliary ducts, kidney, and lung; prostate and breast cancer are less likely to be the primary site of origin, which is paradoxical to the standard population incidence data.4

Poorly differentiated carcinomas of unknown origin can be from lymphomas, melanomas, germ cell tumors, or sarcomas. Squamous cell carcinoma typically originates in the head and neck, penile, vaginal, cervical, rectal, or lung regions.

Neuroendocrine carcinomas have numerous potential sites of origin, including carcinoid, thyroid, small cell lung cancer, and pheochromocytoma

RELATED: Carcinoma of Unknown Primary: ‘An Opportunity and a Challenge’ for Molecular Tumor Profiling

Treatment for CUO is based on identifying a regimen that is aimed at the most likely site of the patient’s primary malignancy. For example, a male patient with adenocarcinoma of unknown origin who has a family history of colorectal cancer, elevated CEA, prior history of suspicious lesions on colonoscopy, liver metastases, and a biopsy positive for CK20 and CDX-2 would most likely be considered a metastatic colorectal cancer and treated with regimens such as FOLFOX and bevacizumab.3


  1. Pavlidis N, Briasoulis E, Hainsworth J, et al. Diagnostic and therapeutic management of cancer of an unknown primary. Eur J Cancer. 2003;39(14):1990-2005.
  2. Greco FA, Hainsworth JD. Introduction: unknown primary cancer. Semin Oncol. 2009;36(1):6-7.
  3. Varadhachary GR, Raber MN, Matamoros A, Abbruzzese JL. Carcinoma of unknown primary with a colon-cancer profile-changing paradigm and emerging definitions. Lancet Oncol. 2008;9(6):596-599.
  4. Pentheroudakis G, Golfinopoulos V, Pavlidis N. Switching benchmarks in cancer of unknown primary: from autopsy to microarray. Eur J Cancer. 2007;43(14):2026-2036.