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Contributed by Pamela Wirth, Ph.D. and Gulisa Turashvili, M.D., Ph.D.

• Found in almost all body tissues

• Adenomatous thyroid nodules: retained PTEN expression is typically seen in adenomatous nodules, while loss of PTEN is associated with Cowden syndrome (Cancers (Basel) 2023;15:1575)
• Most endometrial carcinomas show intact PTEN expression
• Primary colorectal cancers often retain PTEN expression (Cancer Med 2013;2:496)

• Significant percentage of malignancies show reduced or absent PTEN expression (Cold Spring Harb Perspect Med 2019;9:a036293)
  • Glioblastomas (70% reduced or lost expression)
  • More than 50% of prostate carcinomas exhibit loss of PTEN expression, which is often associated with gene deletion, mutations or epigenetic changes (J Urol 2020;203:344;J Cancer Res Clin Oncol 2018;144:2117)
  • Sporadic colorectal cancers (60% reduced or lost expression)
  • Acute myeloid leukemia (75% reduced or lost expression)
  • Pancreatic carcinomas (50% reduced or lost expression)
• Complete loss of PTEN protein is more frequent in metastatic versus primary breast cancer (Hum Pathol 2014;45:522)
• PTEN loss is observed in 30 - 50% of sporadic endometrial carcinoma cases (Int J Gynecol Pathol 2012;31:48)
• Negative PTEN IHC is commonly found in tumors associated with Cowden syndrome (Am J Clin Pathol 2024;161:490)
• Loss of cytoplasmic PTEN may distinguish intraductal prostatic carcinoma (loss of PTEN) from high grade prostatic intraepithelial neoplasia (PIN) (positive for PTEN) (Am J Surg Pathol 2015;39:169)

How is PTEN staining used in the diagnosis of cancers?

1. Loss of PTEN expression may help identify patients likely to respond to targeted therapies
2. Positive PTEN expression predicts poor response to chemotherapy
3. PTEN expression is only clinically relevant if expressed in cell nuclei
4. PTEN loss indicates a better prognosis

A. Loss of PTEN expression may help identify patients likely to respond to targeted therapies. PTEN mutations or loss of PTEN expression leads to uncontrolled activation of the PI3K / AKT / mTOR pathway, which promotes cancer cell growth and survival. While there is no specific therapy targeting PTEN itself, drugs targeting the PI3K pathway can counteract the effects of PTEN loss. Answer B is incorrect because positive PTEN expression typically indicates normal tumor suppressor function, and its loss, not its presence, is associated with more aggressive disease, poor prognosis and treatment resistance. Answer D is incorrect because PTEN loss is associated with a worse prognosis in many carcinomas due to its critical role as a tumor suppressor. Its loss leads to enhanced cancer cell growth, survival and invasion. Answer C is incorrect because while PTEN also has functions in the nucleus, such as maintaining genomic stability and regulating the cell cycle, its tumor suppressive role is not restricted to the nucleus. Normal expression of PTEN can occur in the nucleus and cytoplasm (see image above). PTEN loss in these areas can be associated with aggressive tumor behavior and poor prognosis.

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Reference: PTEN

What is the significance of PTEN loss in prostate cancer when detected by FISH?

1. It indicates a better overall prognosis
2. It is associated with an increased risk of recurrence and poor outcomes
3. It may suggest a high grade prostatic intraepithelial neoplasia (PIN)
4. It predicts sensitivity to hormone therapy

B. It is associated with an increased risk of recurrence and poor outcomes. When PTEN is lost or mutated, the PI3K / AKT / mTOR pathway becomes dysregulated, promoting cancer cell proliferation and survival, which contributes to cancer progression, increased risk for recurrence and poorer outcomes in patients. Answer A is incorrect because PTEN loss is linked to higher grade tumors, more advanced stages and an increased risk of recurrence in prostate cancer. Answer D is incorrect because PTEN loss does not predict sensitivity to hormone therapy in prostate cancer. Hormone therapy (such as androgen deprivation therapy) targets the androgen receptor pathway, which is distinct from the PI3K / AKT pathway regulated by PTEN. Answer C is incorrect because PTEN loss is associated with prostate cancer progression, not benign conditions like high grade PIN, which does not typically exhibit PTEN loss.

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Reference: PTEN