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Author: Mikael Häggström [note 1]

Gross processing

For suspected tumors in bone or other tissue that generally needs decalcification, try to grossly separate some suspicious soft tissue to be processed without decalcification, as decalcification might affect any molecular studies that will later be indicated. See site-specific grossing guidelines for further directions.

Primary tumor versus metastasis

Major metastasis pathways: Main origins and sites of metastases for some common cancer types. Primary cancers are denoted by "...cancer" and their main metastasis sites are denoted by "...metastases".[1]

Indications of a metastasis rather than primary tumor are mainly:

  • Tumors that are unlikely to arise at the location at hand.
  • Tumors conforming to more likely metastasis pathways.

If a suspected malignancy is present, generally check the patient history for any history of cancer, especially for tumors in more common metastasis sites, which mainly include lung, bone, liver and/or brain. In case of such history, preferably look at the microscopy slides of the past cancer to help determining whether the current case is of the same origin, versus a primary at the current body location, versus a metastasis of yet another location. If there is no known history of cancer, still consider a metastasis of unknown primary origin, especially for suspected malignancies in lymph nodes, liver, lungs, bones, or skin.[2]

Metastasis of unknown primary

Metastases of unknown primary origin[3]
Histopathologic type
- see section below for descriptions[3]
Relative incidence among metastases of unknown primary origin[3]
Well and poorly differentiated adenocarcinomas 50%
Undifferentiated carcinoma 30%
Squamous cell carcinoma 15%
Undifferentiated neoplasms 5%
  • Memorization-worthy:[note 2] Do not diagnose a renal cell carcinoma metastasis without radiologic evidence of a renal tumor. To be a plausible primary tumor for a renal cell carcinoma metastasis, a renal tumor should be visible radiologically. In cases of suspected renal cell carcinoma but no renal imaging is available, it is reasonable to ask the ordering doctor to allow you to wait with signing out the pathology report until renal radiology has been performed.

Undifferentiated malignancy

Histopathology of a biopsy of a lymph node with cancer of unknown primary origin, showing undifferentiated high-grade tumor cells.

An initial panel of cytokeratin (CK, such as by CK AE1/AE3 cocktail), S100, vimentin and LCA (CD45) can be used (see source article for subsequent work-up).[4]

Alternatively, a more comprehensive panel can be performed upfront, with the most pertinent panel suggested below (with main associated primary origins in parentheses), but it should be tailored to additional clues from each individual case:[5]

Mucicarmine stain showing signet ring cell carcinoma, with the mucin within tumor cells colored pink/red.
  • S100 (neural, invasive melanoma)
  • LCA (CD45) (hematopoietic)
  • Synaptophysin (neuroendocrine)
Most common CK7 and CK20 patterns in carcinomas of unknown primary site (CUPs)[6]
Positive Negative
CK7 Positive
  • Urothelial carcinoma
  • Pancreatic adenocarcinoma
  • Ovarian mucinous carcinoma
  • Bladder adenocarcinoma
  • Gastric adenocarcinoma
  • Cholangiocarcinoma
  • Breast carcinoma
  • Lung adenocarcinoma
  • Endometrial adenocarcinoma
  • Endocervical adenocarcinoma
  • Ovarian (serous) carcinoma
  • Cholangiocarcinoma
  • Small cell lung carcinoma
  • Mesothelioma
  • Thyroid carcinoma
  • Salivary gland tumours
  • Kidney (papillary)
  • Urothelial carcinoma (subset)
  • Pancreatic adenocarcinoma
  • Gastric adenocarcinoma
  • Esophageal adenocarcinoma[7]
  • Colorectal adenocarcinoma
  • Merkel cell carcinoma
  • Gastric adenocarcinoma
  • Prostate adenocarcinoma
  • Renal (clear cells)
  • Hepatocellular carcinoma
  • Adrenocortical carcinoma
  • Non-seminoma germ cell tumours
  • Mesothelioma
  • Small cell lung carcinoma
  • Gastric adenocarcinoma

Metastatic adenocarcinoma

Typical features of adenocarcinomas. In reality, the appearance varies significantly from case to case. Vacuoles are more prominent in mucinous tumors, but can be seen in serous tumors as well.

If metastatic adenocarcinoma seems to be the case (always consider this in at least lung adenocarcinoma), look at the history and radiology reports for a most likely primary. Generally, perform immunohistochemistry with one or two stains that are most typical for the suspected primary, and optionally add CK7 and CK20 as a broad screening.

Generally, classify by degree of differentiation as follows:

  • Well differentiated: > 95% of tumor has glandular formations
  • Moderately differentiated: 50 - 95% glandular
  • Poorly differentiated: < 50% glandular
Degree of differentiation, with example from a colorectal adenocarcinoma.

Example report:

A. Right lung mass, CT-guided needle biopsy:
  • Metastatic adenocarcinoma, moderately differentiated.

Comment: Immunohistochemistry was performed, and showed tumor cells positive for CDX2 and CK 20, and negative for CK 7, consistent with metastasis from a gastrointestinal primary tumor.

Further workup

Perform additional biomarker testing as per local guidelines for the corresponding primary tumor at metastatic/advanced stage (such as mismatch repair proteins and next generation sequencing in case of metastatic colon adenocarcinoma).

Further reading


  1. For a full list of contributors, see article history. Creators of images are attributed at the image description pages, seen by clicking on the images. See Patholines:Authorship for details.
  2. Further information on what is memorization-worthy or not: Learning pathology

Main page


  1. List of included entries and references is found on main image page in Commons: Wikimedia Commons: Metastasis sites for common cancers.svg
  2. Lymph nodes, liver, lungs, bones, or skin are the main sites of cancer of unknown primary origin (CUP):
    . Cancer of Unknown Primary Origin. Memorial Sloan Kettering Cancer Center. Retrieved on 20222-10-14.
  3. 3.0 3.1 3.2 Collado Martín R, García Palomo A, de la Cruz Merino L, Borrega García P, Barón Duarte FJ, Spanish Society for Medical Oncology (2014). "Clinical guideline SEOM: cancer of unknown primary site. ". Clin Transl Oncol 16 (12): 1091-7. doi:10.1007/s12094-014-1244-0. PMID 25392080. PMC: 4239766. Archived from the original. . 
  4. Lin F, Liu H (2014). "Immunohistochemistry in undifferentiated neoplasm/tumor of uncertain origin. ". Arch Pathol Lab Med 138 (12): 1583-610. doi:10.5858/arpa.2014-0061-RA. PMID 25427040. Archived from the original. . 
  5. Partly inspired by:
    Beauchamp K, Moran B, O'Brien T, Brennan D, Crown J, Sheahan K (2023). "Carcinoma of unknown primary (CUP): an update for histopathologists. ". Cancer Metastasis Rev. doi:10.1007/s10555-023-10101-6. PMID 37394540. Archived from the original. . 
  6. Selves J, Long-Mira E, Mathieu MC, Rochaix P, Ilié M (2018). "Immunohistochemistry for Diagnosis of Metastatic Carcinomas of Unknown Primary Site. ". Cancers (Basel) 10 (4). doi:10.3390/cancers10040108. PMID 29621151. PMC: 5923363. Archived from the original. . 
  7. Elliot Weisenberg, M.D.. Esophagus - Carcinoma - Adenocarcinoma. Pathology Outlines. Last author update: 1 June 2013. Last staff update: 31 October 2022

Image sources