Metastasis

Author: Mikael Häggström

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".

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.

Metastasis of unknown primary

Metastases of unknown primary origin

Histopathologic type - see section below for descriptions	Relative incidence among metastases of unknown primary origin
Well and poorly differentiated adenocarcinomas	50%
Undifferentiated carcinoma	30%
Squamous cell carcinoma	15%
Undifferentiated neoplasms	5%

• Memorization-worthy: 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).

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:

Mucicarmine stain showing signet ring cell carcinoma, with the mucin within tumor cells colored pink/red.

• Mucicarmine or Cytokeratin CAM 5.2 (adenocarcinoma)

• CK7 and CK20 can give a broad indication of the primary site. Still use more specific immunohistochemistry stains instead or in addition where applicable. See table below for main patterns.
• NKX3.1 in males (prostate adenocarcinoma), or PAX-8 or estrogen and progesterone receptor in females (female reproductive tract).
• TTF-1 (thyroid or lung tumor)
• GATA3 (urothelial carcinoma, breast tumor)
• CDX2 (gastrointestinal tumor)
• p63 (squamous cell carcinoma)

• S100 (neural, invasive melanoma)
• LCA (CD45) (hematopoietic)
• Synaptophysin (neuroendocrine)

Most common CK7 and CK20 patterns in carcinomas of unknown primary site (CUPs)

		CK20
		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
	Negative	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

• Evaluation of suspected malignancies

Main page

• Main page of Patholines