Cancer of Unknown Primary Staging

Updated: Feb 03, 2021
  • Author: Winston W Tan, MD, FACP; Chief Editor: Wafik S El-Deiry, MD, PhD  more...
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Staging System for Cancer of Unknown Primary

No staging system exists for cancers of unknown primary origin—more precisely, histologically proven metastatic malignant tumors for which the primary site cannot be identified during pretreatment evaluation. [1]  Instead, the staging depends on the histology of the cancer. 

Management of these cases requires a multidisciplinary team, in which the pathologist plays an essential role. Rarely, special immunostains and genomic next-generation sequencing will identify the primary site, and some of these cases may be curable if diagnosed promptly. In most cases, histopathologic analysis will permit classification of these tumors into those with a favorable prognosis, which are mostly approached with locoregional treatment or systemic platinum-based chemotherapy, or an unfavorable prognosis, which are treated with empirical combination regimens involiving platinum or taxane. [5]

Tumors provided for pathologic review should come from tissue that has, whenever possible, been excised, if such tissue is available and accessible. Needle biopsy specimens may provide insufficient tissue for diagnosis or provide tissue that has been too damaged or distorted by the biopsy procedure for accurate diagnosis.

Studies used to evaluate cancer of unknown primary include the following [1, 3] :

  • Light microscopy
  • Immunohistochemical stains [2]
  • Electron microscopy
  • Gene expression profiling

Major subtypes after microscopic evaluation include the following [1] :

  • Well or moderately differentiated adenocarcinoma (60%)
  • Poorly differentiated or undifferentiated adenocarcinoma (29%)
  • Squamous cell carcinoma (5%)
  • Poorly differentiated malignant neoplasm (5%)
  • Neuroendocrine tumors (1%)

See the table below.

Table. Classification of cancer of unknown primary by molecular findings [5] (Open Table in a new window)

Molecular finding

Tumor type

CK7 or CK20; PSA



Germ-cell tumor

Hepatocyte paraffin 1; canalicular pCEA, CD10, or CD13

Hepatocellular carcinoma


Renal cell carcinoma

TTF1; thyroglobulin

Thyroid carcinoma

Chromogranin; synaptophysin; PGP9.5; CD56

Neuroendocrine carcinoma

CK5 or CK6; p63

Squamous cell carcinoma


Specific primary





GCDFP-15; mammaglobulin; ER


CDX2; CK20


CDX2 (intestinal epithelium); CK20; CK7

Pancreas or biliary

ER; CA-125; mesothelin; WT1


AFP=alpha-fetoprotein; ER=estrogen receptor; HCG= human chorionic gonadotropin; PAP=prostatic acid phosphatase; PLAP=placental alkaline phosphatase; PSA=prostate-specific antigen


Management considerations

The histologic subtype, metastasis site, and certain patient characteristics can offer clues to the cancer primary.

Metastasis to cervical lymph nodes:

  • A histologic diagnosis of metastatic carcinoma in the cervical nodes warrants a careful evaluation of the upper aerodigestive tract, including direct visualization of the hypopharynx, nasopharynx, larynx, and upper esophagus

  • Most of these tumors are squamous cell carcinoma on histology, but adenocarcinoma, melanoma, or anaplastic tumors can also be seen in this location; in patients with squamous or undifferentiated carcinoma, tonsillectomies should be considered

  • Cervical adenopathy can be the primary disease manifestation in 2-5% of patients with primary squamous cell carcinoma of the head and neck region

Isolated axillary adenopathy in women:

  • Metastatic adenocarcinoma presenting as isolated axillary lymphadenopathy in women is usually a manifestation of an occult breast primary cancer. [4]

  • Mastectomy specimens in this subset of patients have shown a previously undiagnosed breast primary tumor in 40-70% cases; immunohistochemical stains with estrogen and progesterone receptor should be performed in this setting, as they may aid in diagnosis

Peritoneal carcinomatosis in women:

  • Women with peritoneal carcinomatosis with adenocarcinoma have similarities with patients with ovarian cancer

  • These women often have papillary histology with elevation of carbohydrate antigen (CA)-125 and a good response to platinum-based chemotherapy, but a primary tumor is not revealed on exploratory laparotomy

Poorly differentiated and undifferentiated carcinoma:

One third of patients with cancer of unknown primary origin have poorly or undifferentiated carcinoma. A subpopulation of these can be potentially curable, including patients with lymphomas, germ cell tumors, or neuroendocrine tumors.

The features that point toward a treatment-responsive tumor include the following:

  • Patient younger than 50 years

  • Midline distribution, with elevated levels of beta–human chorionic gonadotropin (HCG) or alpha-fetoprotein (AFP)

  • Beta-HCG/AFP positive on immunohistochemistry

  • Neuroendocrine granules

  • Rapid tumor growth

  • Isochromosome 12p in midline tumors

Inguinal node metastasis:

  • Metastatic carcinoma in inguinal nodes from an unknown site can be found in 1-3.5% of patients

  • Squamous cell histology in this area is usually metastatic from the genital/anorectal area

  • The anorectal area should be carefully inspected in both sexes; vulvar, vaginal, and cervical examination in women and penile examination in men is warranted