Cancer of Unknown Primary

Assistant Professor Suwanit Therasakvichya, MD

Department of Obstetrics and Gynaecology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand


Cancer of unknown primary origin (CUP) is a heterogeneous group of metastatic tumors which primary tumor site remains unidentifiable despite of extensive diagnostic work-up.   The diagnostic code for CUP patients from ICD-O-3 is C80.  It accounts for 25% of all new cancer diagnoses.1   

The initial histological and immunohistochemical evaluation by the pathologist is to establish the type of malignancy into carcinoma, lymphoma, melanoma, germ cell tumor or sarcoma.  Most cases of CUP are carcinomas which are divided into well or moderately differentiated adenocarcinoma (60%), poorly differentiated adenocarcinoma or undifferentiated carcinoma (29%),    squamous cell carcinoma (5%), undifferentiated neoplasm (5%), and neuroendocrine tumor (1%).  Immunohistochemistry is capable of identifying the site of origin in < 30% of all CUP, with limitation in small biopsy specimens/malignant effusions, and tumor heterogeneity.2 

Autopsy studies provided information on proportional distribution of CUP. In an analysis of 12 post-mortem cohort studies (1944-2000), primary tumor site was identified in 644 (73%) out of 884 patients [lung 27%; pancreas 24%; liver or bile duct 8%; kidney or adrenal 8%; colorectal 7%; genital tract 7%; stomach 6%; unknown 27%].

The diagnostic process in patients with CUP consists of taking a complete medical history including family history of neoplasms. The complete physical examination must be done focusing specially on head and neck region, rectum, and testes for males, and also  breast and pelvic organs for females. 

Laboratory and radiological examinations consist of complete blood count, liver and kidney function test, electrolytes (including calcium), and lactate dehydrogenase (LDH), beta human chorionic gonadotropin (β hCG), alpha-fetoprotein (AFP),  prostate specific antigen (PSA), computer tomography (CT), positron emission tomography (PET), mammography or magnetic resonance imaging (MRI) of the breast.

Application of molecular profiling assays is an option of diagnostic attempt when immunohistochemical stains are unable to predict the tissue of origin., Validation with samples of known tumor type yielded accuracy rate of 82-97%.3  However, it is difficult to confirm the site of origin in most cases. Clinical judgement is required to interpret the result and determine the optimal management.

Treatment should be individually tailored for each clinical pathological profile. Between 15-20% of CUP are defined as favourable prognostic subsets and should be treated similarly to patients with equivalent known primary site with metastatic dissemination. However, mostly CUP had poor prognosis and median overall survival of 6 months.3

CUP without presumable primary site, by histological and immunohistochemical evaluation, is an immense clinical challenge, as the primary site of cancer influences treatment choices, outcome, and prognosis.  Molecular testing may provide information facilitating targeted therapies for CUP.  However, more data is needed to evaluate the effectiveness of treating CUP patients according to molecular study results. 


  1. Siriraj Cancer Registry 2017
  2. Econopoulou P, Mountzios G, Pavlidis N, Pentheroudakis G. Cancer of unknown primary origin in the genomic era: elucidating the dark box of cancer. Cancer Treat Rev.2015;41:598-604.
  3. Losa F, Soler G, Casado A, Estival A, Fernandez S, Gimenez S, et al. SEOM clinical guideline on unknown primary cancer (2017). Clin Transl Oncol 2018;20:89-96.

Event Hours(1)

  • Convention Hall A.

    11:00 am – 11:30 am

    Dr. Malee Warnnissorn (SI)
    Prof. Shanop Shuangshoti (CU)

    Asst. Prof. Suwanit Therasakvichya (SI)