Appropriate PTEN Biomarker Uses

To learn more about PTEN, visit PTEN Central

PTEN immunohistochemistry should not be used at this time to make decisions about management of individual patients, as it is an insensitive (half of EIN lesions have normal PTEN expression) and nonspecific (over a third of normal proliferative and anovulatory endometria contain PTEN-null glands) marker of that group of premalignant lesions (EIN) proven to confer an increased cancer risk.  

Anti-PTEN antibodies are the first commercially available “special stain” for neoplastic endometrial disease.  Paraffin tissue immunohistochemistry with anti-PTEN antibody 6H2.1 (Cascade Biosciences, Winchester, MA) (1;2)  shows that over half of endometrioid endometrial adenocarcinomas and their precursor EIN lesions have lost PTEN protein (3) . 

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Inappropriate use
1)Managing the individual patient: The fact that a large fraction of EIN lesions continue to express PTEN protein mean that it is often non-informative for a particular patient.  Additionally, the clinical interpretation of PTEN-null glands in endometria not diagnostic of EIN is uncertain.  This situation is frequently encountered, as over a third of women with normal proliferative or anovulatory ("persistent proliferative") endometria bear scattered PTEN null glands. 
2)Confounding effects: Physiologic changes in PTEN expression during the normal menstrual and life cycle, especially reduced or lost PTEN protein in normal secretory and atrophic glands (4) , justify caution in equating absence of PTEN protein with a neoplastic process.  Correspondingly, an estrogenic environment increases endometrial stromal and normal gland PTEN expression, improving contrast with a localizing PTEN-mutant clone.  The utility of biomarkers such as PTEN will to some extent be depend on the endocrine and clinical context in which it is applied.  

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Appropriate use
1)Pathologist education: PTEN immunohistochemistry can be a useful educational tool for pathologists to delineate extent and configuration of mutant clones, and relate these features to companion routinely stained slides.  This website contains examples of hematoxylin and eosin stained tissues matched with PTEN immunohistochemistry images to show the routine H&E appearance of clonal precancers delimited with single cell resolution.
2)Diagnostic criteria development(12) PTEN is one of many biomarkers that can be applied to series of tissue samples to define the histopathologic appearance of mutant clones.  Other informative markers include clonal analysis by nonrandom X chromosome inactivation(5,6), clonal analysis by outgrowth of altered microsatellites(7,11),  lineage reconstruction(8), and loss of function of other genes such as kras(10), and MLH1(9).  
2)Target relevant tissues for genetic analysis: Immuno-directed microdissection of PTEN-null glands allows isolation of mutant cells at high purity with minimal contamination by genetically normal tissues.  
3)Studies of groups of women to discern trends: PTEN immunohistochemistry may be a valuable investigational tool to study trends in mutant clone progression amongst defined subpopulations of women.  Progression efficiency from premalignant to malignant disease  is driven by accumulation of additional genetic damage and hormonal environment, during which the histopathology of PTEN-null clones changes dynamically.  The changing prevalence and size (disease burden) of PTEN-null clones may provide information about the effects of hormonal environment on mutant clone involution or expansion rates. 

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 Reference List

(1) Perren A, Weng L, Boag A, Ziebold U, Thakore K, Dahia P et al. Immunocytochemical evidence of loss of PTEN expression in primary ductal adenocarcinomas of the breast. Am J Pathol 1999; 155:1253-1260.

(2) Gimm O, Perren A, Weng LP, Marsh DJ, Yeh JJ, Ziebold U et al. Differential Nuclear and Cytoplasmic Expression of PTEN in Normal Thyroid Tissue, and Benign and Malignant Epithelial Thyroid Tumors. Am J Pathol 2000; 156(5):1693-1700.

(3) Mutter GL, Lin MC, Fitzgerald JT, Kum JB, Baak JPA, Lees J et al. Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers. J Natl Cancer Inst 2000; 92:924-930.

(4) Mutter GL, Lin MC, Fitzgerald JT, Kum JB, Ziebold U, Eng C. Changes in endometrial PTEN expression throughout the human menstrual cycle. J Clin Endocrinol Metab 2000; 85:2334-2338.

(5) Mutter GL, Chaponot M, Fletcher J. A PCR assay for non-random X chromosome inactivation identifies monoclonal endometrial cancers and precancers. Am J Pathol 1995; 146:501-508.

(6) Mutter GL, Boynton KA. X chromosome inactivation in the normal female genital tract: Implications for identification of neoplasia. Cancer Res 1995; 55:5080-5084.

(7) Jovanovic AS, Boynton KA, Mutter GL. Uteri of women with endometrial carcinoma contain a histopathologic spectrum of monoclonal putative precancers, some with microsatellite instability. Cancer Res 1996; 56:1917-1921.

(8) Mutter GL, Boynton KA, Faquin WC, Ruiz RE, Jovanovic AS. Allelotype mapping of unstable microsatellites establishes direct lineage continuity between endometrial precancers and cancer. Cancer Res 1996; 56:4483-4486.

(9) Esteller M, Catasus L, Matias-Guiu X, Mutter GL, Prat J, Baylin SB et al. hMLH1 Promoter Hypermethylation Is an Early Event in Human Endometrial Tumorigenesis. Am J Pathol 1999; 155(5):1767-1772.

(10) Mutter GL, Wada H, Faquin W, Enomoto T. K-ras mutations appear in the premalignant phase of both microsatellite stable and unstable endometrial carcinogenesis. Mol Pathol 1999; 52:257-262.

(11) Faquin WC, Fitzgerald JT, Lin MC, Boynton KA, Muto MG, Mutter GL. Sporadic microsatellite instability is specific to neoplastic and preneoplastic endometrial tissues. Am J Clin Pathol 2000; 113(4):576-582.

(12) Mutter GL. Histopathology of genetically defined endometrial precancers. Int J Gynecological Pathology 2000; 19:301-309.

 

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Copyright 1998-2015 by George L. Mutter, MD.  All Rights Reserved