Written By: Karen Selby, RN,
Last modified: September 10, 2021

Cytokeratins are keratin proteins found in the epithelial tissue that lines the outer surfaces of organs and blood vessels. They provide epithelial cells with structural support.

The different types of cytokeratins are numbered based on where they are found in the body.

Cytokeratin 5 is commonly found in the cells on the outermost layer of skin in humans and animals. It is encoded by the KRT5 gene and pairs with the type I keratin K14.

Cytokeratin 5 has become an important biomarker for different types of cancer, including mesothelioma, breast cancer and lung cancer. It helps differentiate squamous carcinomas from adenocarcinomas.

Pathologists use cytokeratin 5 to distinguish mesothelioma from adenocarcinoma, the most common type of lung cancer. They do this by staining tissue samples with cytokeratin 5/6, an antibody that detects cytokeratins 5 and 6.

Cytokeratin 5/6 cannot identify mesothelioma on its own. Pathologists use several immunohistochemical markers when diagnosing the cancer.

Cytokeratin 5 and 5/6 in Diagnosing Mesothelioma

Cytokeratin 5/6 is a positive marker for malignant pleural mesothelioma, found in more than three-fourths of cases. It is also found in certain types of lung cancers and breast cancers. Pathologists use cytokeratin 5/6 to stain cancer tissue samples.

Pleural mesothelioma is often misdiagnosed as lung cancer, especially if tumors have spread beyond the point of origin to other parts of the body.

Using immunohistochemical markers such as cytokeratin 5/6, pathologists can differentiate tumor cells. With rare exceptions, epithelial mesothelioma is the only tumor with glandular morphologic features that shows cytokeratin 5/6.

Cytokeratin 5/6 immunoreactivity is rarely seen in adenocarcinomas of the lung. If a tumor sample shows strong expression of cytokeratin 5/6, it gives pathologists a hint the tumor is malignant mesothelioma rather than a metastatic adenocarcinoma.

However, this marker is not effective for all cell types of mesothelioma. Cytokeratin 5/6 staining is usually weak or negative for sarcomatoid mesothelioma, the least common and hardest-to-treat cell type of the asbestos-related cancer.

The marker is also not effective in telling the difference between pleural mesothelioma and squamous cell carcinomas. About 25 to 30 percent of all lung cancers are squamous cell carcinomas.

Mesothelioma Research Studies Involving Cytokeratin 5/6

Several studies have evaluated cytokeratin 5/6 as a diagnostic marker for mesothelioma.

A 2001 study in the American Journal of Clinical Pathology showed cytokeratin and p63 are highly effective in differentiating cancers of unknown primary sites. This study included 14 malignant mesotheliomas, along with cases of cervical cancer, head and neck cancers and squamous cell lung cancer.

In a 2007 study in the journal Cytopathology, researchers confirmed the value of cytokeratin 5/6 and calretinin as markers for mesothelioma in effusion samples. Effusion, or the buildup of excess fluid, is a common symptom of pleural and peritoneal mesothelioma.

Cytokeratin 5/6 staining was present in 33 of 34 mesothelioma cases in the study, while only six of 67 adenocarcinomas tested positive for the protein. The study noted cytokeratin 5/6 staining may be less useful for peritoneal effusion specimens. Metastatic adenocarcinomas are more likely to express the marker in the abdomen.

A 2002 study in Modern Pathology raised caution over using cytokeratin 5/6 to differentiate mesothelioma from metastatic adenocarcinoma. The study showed many types of nonpulmonary adenocarcinomas may be positive for cytokeratin 5/6. Pathologists must rely on other markers as well.


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