Metastatic Cancer With Unknown Primary Site Guidelines

Updated: May 07, 2019
  • Author: Winston W Tan, MD, FACP; Chief Editor: Wafik S El-Deiry, MD, PhD  more...
  • Print

Guidelines Summary

Clinical guidelines on the diagnosis and management of cancers of unknown primary (CUP±en published by the following organizations:

  • National Comprehensive Cancer Network (NCCN)
  • European Society for Medical Oncology (ESMO)
  • Sociedad Espanola de Oncologia Medica (SEOM)

Immunohistochemistry (IHC) tests

The National Comprehensive Cancer Network (NCCN) guidelines recommends immunohistochemistry (IHC) tests to assist in localizing a primary tumor but cautions that they lack uniform specificity and sensitivity and some markers are found on multiple tumors. Large series of markers should be avoided. An undifferentiated panel for determining the most likely cell lineage includes the following [16] :

  • Pan-keratin (AE1/AE3 and CAM5.2):  Carcinoma
  • CK5/6, p63/p40:  Squamous cell carcinoma (SCC)
  • S100, SOX10: Melanoma
  • LCA± CD20± CD3± : Lymphoma
  • OCT3/4± SALL4±: Germ cell tumor
  • WT1, calretinin, mesothelin, D2-40: Mesothelial tumor

Guidelines from the European Society for Medical Oncology (ESMO) note that IHC staining patterns are capable of identifying the site of origin in <  30% of all CUPs. In patients with poorly differentiated cancers or small biopsy specimens/malignant effusions, IHC staining may not be useful or feasible. ESMO recommend selected marker assays as part of the basic immunohistochemical workup of cancers of unknown primary. [8]  See the table below.

Table. Immunohistochemical markers for cancers of unknown primary (Open Table in a new window)

Primary Marker Primary Tumor Type Additional Markers
CK7- /CK 20 + Colorectal cancer and merkel cell carcinoma CEA and CDX-2  (for GI malignancy)
CK 7 +/CK 20 - Lung,breast, thyroid, endometrial, cervical, pancreas, and cholangiocarcinoma

TTF-1 (lung, thyroid)

ER, PR (breast)

GCDFP-15 (gynecologic)

CK- 19 (pancreas)

Ck+7/ CK 20+ Urothelial, ovarian, pancreas, cholangiocarcinoma

Urothelin (genitourinary) 

WT-1 (ovarian, mesothelial)

CK = cytokeratin; CEA = carcinoembryonic antigen; TTF1 = thyroid transcription factor 1; ER = estrogen receptor; PR = progesterone receptor; GCDFP-15  = gross cystic disease fluid protein–15; WT-1 = Wilms tumor gene 1; PSA = prostate specific antigen

The Sociedad Espanola de Oncologia Medica (SEOM) guidelines find IHC testing is cost-effective and recommend it be carried out in all CUPs using a stepwise algorithm. Initial testing may include CKAE1-AE3 (Carcinoma), CLA (Lymphoma), S100, HMB-45, Melan-A (Melanoma), S100, Vimentin (Sarcoma). [28]  

The 20 cytokeratin (CK) subtypes are typically expressed in carcinomas. A CK7 plus CK20 staining pattern can point toward additional IHC staining and specific, clinical tests. For example, a CUP having a IHC profile such as CK7+ CK20− TTF1+ suggests lung cancer and bronchoscopy should be performed, whereas CK 7−, CK20+ and CDX2+ suggest colorectal cancer and colonoscopy should be considered. [28]