The PAX8 test is a diagnostic tool used in oncology that detects the presence of the Paired Box 8 (PAX8) protein within tumor cells. PAX8 is a transcription factor that attaches to DNA and manages gene activity, guiding how cells develop and function. The primary purpose of this test is not to diagnose cancer itself, but to help pathologists determine the original tissue where a tumor started, especially when the cancer has spread to distant sites. By acting as a molecular fingerprint, PAX8 helps distinguish between different types of tumors, a process known as lineage tracing. Identifying the tissue of origin dictates the most effective treatment plan.
The Role of PAX8 in Normal Development
The PAX8 protein plays a role during the embryonic period, acting as a regulator that determines the fate of several cell lines. Its presence is required for the formation and sustained function of a select group of organs.
PAX8 is involved in the development of the thyroid gland, regulating genes responsible for producing thyroid-specific hormones. It is also active in the renal epithelium, the lining of the kidney tubules, guiding the specification of renal cells and supporting the kidney’s excretory system. Additionally, PAX8 is active in the Müllerian system, the embryonic structure that develops into the female reproductive tract (fallopian tubes, uterus, cervix, and upper vagina). This involvement in the thyroid, kidney, and Müllerian tract is the reason for its utility as a diagnostic marker. In healthy adults, PAX8 expression is restricted almost exclusively to the epithelial cells of these organs.
PAX8 as a Tool for Cancer Identification
The PAX8 test uses immunohistochemistry (IHC) to visualize the protein within a tissue sample. A specific antibody is applied to a thin slice of the tumor tissue. If PAX8 is present, the antibody binds to it, triggering a chemical reaction that produces a visible color change under a microscope.
The concept behind this application is that many tumors, even after they metastasize, retain the molecular characteristics of their original cell type. Since PAX8 is a lineage-specific transcription factor, its presence acts as a reliable “fingerprint” indicating the tumor originated from a PAX8-expressing organ. This makes it an effective method for determining the primary source of a metastatic tumor when the initial site is unclear.
The test is valuable because PAX8 is typically absent in many other common cancers, such as those originating in the breast, lung, colon, or prostate. The absence of staining can be as informative as a positive result, allowing pathologists to quickly rule out potential primary sites. Combining the PAX8 result with other IHC markers helps doctors narrow down possibilities and establish an accurate diagnosis for targeted treatment.
Cancers Classified Using PAX8
The PAX8 marker is sensitive and specific for malignancies arising from the three organ systems where the protein is normally expressed. This includes most epithelial tumors of the thyroid, kidney, and Müllerian tract. Its utility lies in classifying undifferentiated or metastatic cancers whose origin is not immediately obvious.
Ovarian Cancer
PAX8 is a marker for most types of epithelial ovarian cancer, which originate from the Müllerian system. Approximately 98% of non-mucinous epithelial ovarian carcinomas, including high-grade serous and endometrioid subtypes, show positive PAX8 staining. The high-grade serous type, the most common form, is almost universally positive for PAX8, with positivity rates often reaching 99%. This marker helps distinguish ovarian cancer from other tumors in the pelvic and abdominal regions, such as malignant mesothelioma or metastatic breast and gastrointestinal cancers, which are typically PAX8-negative. When ovarian cancer has spread to the abdominal cavity, PAX8 is used on fluid samples to identify the malignant cells as being of Müllerian origin, confirming the gynecologic origin and guiding the initial treatment plan.
Renal Cell Carcinoma (Kidney)
PAX8 is a sensitive marker for renal cell carcinoma (RCC), the most common form of kidney cancer. Studies show that PAX8 is expressed in about 90% of all RCC cases, including the clear cell, papillary, and chromophobe subtypes. This high positivity rate makes it an excellent marker for identifying a tumor as a primary renal malignancy. The marker is useful for differentiating RCC from other abdominal tumors, such as adrenal carcinomas or urothelial carcinomas of the upper urinary tract. Since urothelial carcinomas are generally PAX8-negative, the expression status helps the pathologist accurately classify the tumor type.
Thyroid Cancer
PAX8 positivity is a characteristic of thyroid malignancies that arise from the follicular cells. These include papillary thyroid carcinoma and follicular thyroid carcinoma, which account for the vast majority of thyroid cancers. PAX8 is positive in roughly 90% of thyroid cancer cases, confirming the tumor’s origin from the thyroid gland. PAX8 helps distinguish a metastatic thyroid tumor from other cancers that may have spread to the same location, such as a primary tumor from a nearby structure. The presence of the PAX8-PPARγ gene fusion is also implicated in some follicular thyroid carcinomas, further linking the protein to the disease.
Interpreting a PAX8 Test Result
A pathologist interprets the PAX8 test by examining the stained tissue sample under a microscope. A positive result is indicated by a strong color change localized to the nucleus of the cancer cells, confirming the tumor cells are producing the PAX8 transcription factor. A positive finding suggests a primary tumor originating from the Müllerian tract, the kidney, or the thyroid.
The pathologist uses this result alongside other clinical information and additional molecular markers to make a definitive diagnosis. For instance, if a metastatic tumor is PAX8 positive, other markers like Thyroid Transcription Factor-1 (TTF-1) or WT-1 may be used to pinpoint the exact primary site. Conversely, a negative PAX8 result means the protein was not detected, effectively ruling out an origin from the PAX8-positive organ systems. The PAX8 status is not a standalone diagnosis but guides the clinical team in selecting the appropriate course of action, including treatment planning.