Metastatic Cancer With Unknown Primary Site Guidelines

Updated: Apr 04, 2022
  • Author: Winston W Tan, MD, FACP; Chief Editor: Wafik S El-Deiry, MD, PhD  more...
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Guidelines Summary

Clinical guidelines on the diagnosis and management of cancers of unknown primary (CUP) have been 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 [19] :

  • 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. [11]  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). [31]  

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. [31]


NCCN guidelines list the following regimens as preferred for CUP adenocarcinomas [19] :

  • Paclitaxel and carboplatin
  • Gemcitabine and cisplatin
  • CapeOX (capecitabine and oxaliplatin)
  • mFOLFOX6 (fluorouracil [5-FU], oxaliplatin, leucovorin)
  • FOLFIRI6 (leucovorin, 5-FU, irinotecan)

NCCN guidelines list the following regimens as preferred for squamous cell CUP [19] :

  • Paclitaxel and carboplatin
  • mFOLFOX6

NCCN guidelines list the following principles of radiation therapy for CUP [19] :

  • Consider definitive radiotherapy (eg, stereotactic ablative radiotherapy) for patients with localized disease.
  • Consider adjuvant radiation therapy after lymph node dissection if the disease is limited to a single nodal site with extranodal extension or inadequate nodal dissection with multiple positive nodes.
  • Consider palliative radiotherapy for symptomatic patients.

For patients with favorable-risk CUP, ESMO guidelines propose treatment according to CUP subtype, as follows [11] :

  • Poorly differentiated neuroendocrine carcinoma – Platinum + etoposide combination chemotherapy
  • Well-differentiated neuroendocrine tumor – Somatostatin analogues, streptozocin + 5-FU, sunitinib, everolimus
  • Peritoneal adenocarcinomatosis of a serous papillary histological type in females – Optimal surgical debulking followed by platinum-taxane–based chemotherapy
  • Isolated axillary nodal metastases in females – Axillary nodal dissection, mastectomy or breast irradiation, and adjuvant chemotherapy and hormonal therapy
  • Squamous cell carcinoma involving non-supraclavicular cervical lymph nodes – Neck dissection and/or irradiation of bilateral neck and head–neck axis; for advanced stages, induction chemotherapy with platinum-based combination or chemoradiation
  • CUP with a colorectal IHC (CK20+ CDX2+CK7−) or molecular profile – Systemic treatment used for colorectal cancer
  • Single metastatic deposit from unknown primary – Resection and/or radiation therapy ± systemic therapy
  • Men with blastic bone metastases or IHC/serum PSA expression – Androgen deprivation therapy ± radiation therapy

ESMO guidelines list the following commonly used low-toxicity palliative chemotherapy regimens for poor-risk patients with CUP [11] :

  • Cisplatin 60–75 mg/m 2 (Day 1) plus gemcitabine 1000 mg/m 2  (Day 1 an d8) q3wk -  For fit patients
  • Cisplatin 75 mg/m 2 (Day 1) plus etoposide 100 mg/m 2 (Day 1–3) q3wk – For fit patients with neuroendocrine-feature CUP
  • Paclitaxel 175 mg/m 2 plus carboplatin AUC 5 q3wk - Convenient outpatient regimen, monitor neurotoxicity
  • Docetaxel 75 mg/m 2 plus carboplatin AUC 5 q3wk - Convenient outpatient regimen, monitor neurotoxicity
  • Irinotecan 160 mg/m 2 plus oxaliplatin 80 q3wk - Outpatient regimen, monitor for neurotoxicity and diarrhea
  • Oral capecitabine 2000 mg/m 2 (Days 1–14) ± oxaliplatin 85–130 mg/m 2 (Day 1) q3wk - Outpatient regimen, risk for diarrhea and neurotoxicity
  • Gemcitabine 1000 mg/m 2 /irinotecan 100 mg/m 2 (Day 1 + 8) q3wk - Convenient outpatient regimen