FOXL2: Definition

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FOXL2 is a gene and the protein it makes. The FOXL2 protein helps the ovary develop and keeps ovarian cells working normally. Pathologists test for FOXL2 in two ways. A protein test helps identify sex cord-stromal tumors of the ovary. A gene test looks for one specific change that almost every adult granulosa cell tumor carries.

This article explains the FOXL2 protein stain, the FOXL2 C134W mutation test, and what each FOXL2 result on your report means.

What is FOXL2?

FOXL2 is a transcription factor, a protein that switches other genes on and off. It works inside the nucleus of the cell. FOXL2 is active in the supporting cells of the ovary, called granulosa cells. It is also active in some other cells around the eggs and in the ovarian stroma.

FOXL2 helps the ovary develop before birth and keeps it functioning through adulthood.

How do pathologists use FOXL2 to identify tumors?

Pathologists test for the FOXL2 protein using immunohistochemistry. This test uses an antibody that sticks to FOXL2 in a thin slice of tissue. Cells that contain FOXL2 show brown staining in their nuclei under the microscope.

FOXL2 protein is a marker for sex cord-stromal tumors of the ovary. These tumors start in the ovary’s supporting and hormone-making cells. In one large study, more than 95 percent of these tumor types were positive:

About half of Sertoli-Leydig cell tumors were also positive. Almost all tumors outside this group were negative. This makes a positive result strong evidence for a sex cord-stromal tumor.

Why do pathologists use FOXL2 with other markers?

FOXL2 is a sensitive and specific marker, but no single marker catches every case. About 1 in 5 sex cord-stromal tumors in that study were FOXL2-negative. Most of these were Sertoli-Leydig cell tumors.

For this reason, pathologists usually test FOXL2 together with other markers. The panel often includes inhibin, calretinin, and SF-1. At least one of FOXL2, inhibin, or calretinin was positive in almost every sex cord-stromal tumor.

What is the FOXL2 C134W mutation?

The FOXL2 C134W mutation is a small change in the FOXL2 gene. It changes one building block of the FOXL2 protein. This change occurs only in the tumor cells, not in the rest of the body. It is not inherited and does not pass to children.

The mutation is closely tied to adult granulosa cell tumor:

Adult granulosa cell tumor. About 97 percent of these tumors carry the mutation.
Thecoma. About 1 in 5 thecomas carry it.
Juvenile granulosa cell tumor. The mutation is rare in this tumor.
Other tumors. Other ovarian and breast tumors in the original study did not carry it.

Why would my doctor order a FOXL2 mutation test?

A FOXL2 mutation test helps confirm a diagnosis of adult granulosa cell tumor. This tumor can look like other ovarian tumors under the microscope. Finding the C134W mutation strongly supports the diagnosis.

The test is especially helpful in difficult cases. Examples include a tumor with unusual features or a tumor that returns years after surgery. The test is a type of molecular testing. It checks the tumor’s DNA rather than its proteins.

What might my report say about FOXL2?

Your report may include a FOXL2 protein result, a FOXL2 mutation result, or both:

FOXL2 positive. The tumor cells contain FOXL2 protein. This supports a sex cord-stromal tumor.
FOXL2 negative. The tumor cells do not contain FOXL2 protein. This makes a sex cord-stromal tumor less likely, but does not rule one out.
FOXL2 C134W mutation detected. The tumor carries the mutation. This strongly supports adult granulosa cell tumor.
FOXL2 mutation not detected. The tumor does not carry the mutation. This makes adult granulosa cell tumor less likely.

Questions to ask your doctor

Was FOXL2 tested as a protein, a gene mutation, or both?
Was my tumor positive or negative for FOXL2?
Did my tumor carry the FOXL2 C134W mutation?
What other markers did the pathologist test along with FOXL2?
What type of ovarian tumor do the results support?
Can my family inherit this change?
How will these results affect my treatment and follow-up?