Stains & CD markers
TERT
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PubMed Search: TERT[TI] stains free full text[sb]
TERT
Editorial Board Member: Christian M. Schürch, M.D., Ph.D.
Last author update: 23 April 2021
Last staff update: 12 August 2021
Copyright: 2021, PathologyOutlines.com, Inc.
PubMed Search: TERT[TI] stains free full text[sb]
Table of Contents
Definition / general | Essential features | Terminology | Pathophysiology | Diagrams / tables | Clinical features | Interpretation | Uses by pathologists | Prognostic factors | Microscopic (histologic) description | Microscopic (histologic) images | Positive staining - normal | Positive staining - disease | Negative staining | Molecular / cytogenetics description | Molecular / cytogenetics images | Board review style question #1 | Board review style answer #1Cite this page: Nguyen PN, Hassell LA. TERT. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/stainstert.html. Accessed January 21st, 2025.
Definition / general
- Telomerase reverse transcriptase (TERT) is a catalytic subunit of the enzyme telomerase
- Encoded by TERT gene located on chromosome 5 (HGNC: TERT Telomerase Reverse Transcriptase [Homo Sapiens (Human)] [Accessed 29 March 2021])
Essential features
- TERT / telomerase activity is detected in human cells before the neonatal period and immortal cells (stem cells and cancers) but not in most adult human somatic cells (Cancer Res 1998;58:622, Science 1994;266:2011, Int J Cancer 2001;91:644, Dev Genet 1996;18:173)
- TERT upregulation, especially through TERT promoter mutations, is an important tumorigenic mechanism
- Telomerase diseases: idiopathic pulmonary fibrosis, aplastic anemia, dyskeratosis congenita, acute myeloid leukemia, liver disease and bone marrow failure
- TERT IHC staining pattern varies among types of tumors and clones of antibodies
Terminology
- TERT
- HEST2 (Uniprot: TERT - Telomerase Reverse Transcriptase - Homo Sapiens (Human) [Accessed 29 March 2021])
- Telomerase catalytic subunit
- Telomerase associated protein 2 (TP2)
Pathophysiology
- Telomerase adds the telomeric repeat 5'-(TTAGGG)n-3' to chromosome ends, maintains telomere length and prevents the loss of genetic material during replication (Telomerase Database: Review Articles [Accessed 29 March 2021], Nat Genet 1995;9:104)
- Telomerase consists of 2 main components:
- RNA subunit (hTR) encoded by TERC gene serves as a template (HGNC: TERC Telomerase RNA Component [Homo Sapiens (Human)] [Accessed 29 March 2021])
- Telomerase reverse transcriptase subunit (TERT / TERT) catalyzes the addition of nucleotides to the ends of chromosome's telomeres (Genes Dev 1997;11:3109)
- 4 major domains of TERT:
- TEN: the essential N terminal domain assists the repeat addition processivity function of telomerase (Nat Struct Mol Biol 2008;15:870)
- TRBD: TERT RNA binding domain
- RT: reverse transcriptase domain
- CTE: C terminal extension stabilizes the telomerase DNA complex (J Biol Chem 2002;277:36174)
- Reactivation of telomerase activity in normal human cells elongates telomeres and extends cellular life span (Curr Biol 1998;8:279)
- TERT upregulation mechanism in cancer:
- Amplifications: most frequent in ovarian, lung, esophageal and adrenocortical carcinomas (Nat Genet 2017;49:349)
- Promoter rearrangement: neuroblastoma (Nature 2015;526:700, Nat Genet 2015;47:1411)
- Promoter mutations: most frequent in bladder and liver cancers, melanomas and gliomas (Nat Genet 2017;49:349)
- Methylation of TERT promoter: lung, breast, prostate and colon cancers (J Clin Invest 2019;129:1801)
- TERT involved pathways: c-MYC, NFκB, Wnt / beta catenin (J Mol Endocrinol 2017;58:R129, Nat Genet 1999;21:220, Cancer Res 2003;63:18, J Biol Chem 2012;287:32494)
Diagrams / tables
Images hosted on other servers:
TERT in cancer progression
TERT and potential therapeutic targets
Clinical features
- Loss of telomere contributes to aging (Physiol Rev 2008;88:557)
- TERT immunostaining is associated with TERT mRNA expression and telomerase activity (Histochem Cell Biol 2004;121:391, Neoplasia 2001;3:17, Science 1997;277:955)
- TERT mutation involved diseases: idiopathic pulmonary fibrosis, aplastic anemia, dyskeratosis congenita, acute myeloid leukemia, liver disease and bone marrow failure (N Engl J Med 2009;361:2353, Telomerase Database: Diseases [Accessed 29 March 2021])
- TERT promoter mutations increase TERT transcriptional activity by 2 to 4 times, contributing to telomerase reactivation in human cancers (Science 2013;339:959, Science 2013;339:957)
- TERT promoter testing can help in classification (CNS tumors), diagnosis (malignant lesions from benign histologic mimic) and prognosis (Mayo Clinic Laboratories: Clinical - TERT Promoter Analysis, Tumor [Accessed 29 March 2021], University of Michigan Department of Pathology: TERT Promoter Mutation (Tissue) [Accessed 29 March 2021])
- Telomere / telomerase: targeted therapies may be a promising cancer treatment (Cancer Cell 2002;2:257, Nat Rev Drug Discov 2002;1:383, Cancer Treat Rev 2013;39:444)
Interpretation
- Staining pattern varies among specific types of antibody clones and tumors (see Microscopic description section)
- Most positive normal tissues express nuclear staining (Neoplasia 2001;3:17, Histochem Cell Biol 2004;121:391, Mod Pathol 2004;17:819)
Uses by pathologists
- Mutation status may help provide prognostic and potential treatment implications in glioblastoma and papillary thyroid carcinoma, as well as some other tumors (J Cancer 2019;10:2397, J Clin Endocrinol Metab 2014;99:E754, Clin Endocrinol (Oxf) 2016;85:283, J Clin Endocrinol Metab 2013;98:E1562, Eur J Endocrinol 2015;172:403)
- May help distinguish:
- High risk intraductal papillary mucinous neoplasm (IPMNs) from benign IPMNs / pancreatic juice (Pancreas 2009;38:527)
- Atypical tubal metaplasia from uterine serous carcinoma (Mod Pathol 2011;24:1254)
- Parathyroid carcinomas from adenomas (Int J Mol Med 2009;24:733)
Prognostic factors
- Protein level
- Overexpression of TERT is associated with adverse outcome in solid tumors (Medicine (Baltimore) 2018;97:e11794)
- Wilms tumor: TERT expression (IHC) correlated with the size of the tumor and survival rate (Tumour Biol 2011;32:761)
- Melanoma: TERT protein expression / TERT promoter mutations are associated with poor prognosis (Br J Cancer 2018;118:98, J Natl Cancer Inst 2014;106:dju246)
- Giant cell tumor of bone: IHC TERT+ inversely correlated with recurrence free survival (Mod Pathol 2008;21:423)
- Glioblastomas: strong expression of both TERT and HIF1a tend to have the poorer outcome (J Cancer 2019;10:2397)
- Nuclear expression of TERT is associated with improved overall survival in urothelial bladder cancer (Anticancer Res 2005;25:3109)
- Phyllode tumors: high stromal TERT expression is associated with infiltrate border and increased pleomorphism (Sci Rep 2018;8:3881)
- Non clear cell hepatocellular carcinomas (HCCs): nuclear TERT expression is associated with multiple numbers of tumors and poor prognosis; in contrast, in clear cell HCCs, the cytoplasmic TERT group had more aggressive features and adverse outcome (Oncotarget 2017;8:26288)
- Ovarian carcinomas: high TERT expression correlated with advanced FIGO stage and worse outcome (J Med Assoc Thai 2009;92:308, Gynecol Oncol 2005;98:396)
- Gene level
- Positive TERT immunostaining correlated with tumor grade in sarcomas: 46% low grade, 58% intermediate grade and 72% high grade (Appl Immunohistochem Mol Morphol 2006;14:198, Pathology 2009;41:527)
- TERT mutations are correlated with a better outcome in SHH medulloblastomas but a poor prognosis in group 4 medulloblastomas (Acta Neuropathol 2013;126:917)
- TERT promoter mutations are an indicator of unfavorable outcome in differentiated thyroid carcinomas, especially in papillary thyroid carcinoma (J Clin Endocrinol Metab 2014;99:E754, Clin Endocrinol (Oxf) 2016;85:283, J Clin Endocrinol Metab 2013;98:E1562, Eur J Endocrinol 2015;172:403)
- TERT promoter mutations are strongly associated with hematogenous dissemination in patients with spitzoid melanocytic neoplasms (Sci Rep 2015;5:11200)
- Solitary fibrous tumors with TERT promoter mutations are at higher risk of metastasis and may be associated with an adverse outcome (Mod Pathol 2016;29:1511, Histopathology 2018;73:843, J Clin Pathol 2018;71:832)
- TERT rearrangements (not TERT promoter mutations) are frequent in neuroblastoma and associated with very poor prognosis (Nat Genet 2015;47:1411, Nature 2015;526:700, Biomed Rep 2015;3:443)
Microscopic (histologic) description
- Mitotic cells show diffuse cytoplasmic staining
- TERT negative cells in telomerase positive tumors are partly apoptotic (Histochem Cell Biol 2004;121:391)
- Among 4 commercial markers, PC563 (Oncogene), ab177 (Abcam), Ab-2 (Calbiochem) and NCL-TERT (Novocastra), only 1 provides reproducible IHC staining results: NCL-TERT (Histochem Cell Biol 2004;121:391)
- Most frequently used TERT antibodies (including NCL-TERT) recognize nucleolin rather than telomerase, leading to the inconsistency in the specificity of TERT IHC results (J Cell Sci 2006;119:2797)
| Tissues / tumors | Staining pattern | References | Clone |
| Skin tumors | N/C | J Invest Dermatol 2014;134:2251 | Novocastra / 44F12 / 1:25 |
| C | J Cutan Pathol 2004;31:544 | Calbiochem / Ab-2 | |
| Skin / melanomas | N/C | Arch Pathol Lab Med 2020 Oct 14 [Epub ahead of print] | Abcam / Y182 / 1:100 |
| C | Br J Cancer 2018;118:98 | Rockland / 1:125 | |
| Gliomas | N | Acta Neuropathol 2006;111:569, J Clin Oncol 2006;24:1522 | Novocastra / 44F12 / 1:100 1:25 |
| Glioblastomas | N | J Cancer 2019;10:2397 | Thermofisher / MA5-16033 |
| N/C | Nat Commun 2013;4:2185 | Novocastra / 44F12 / 1:25 | |
| Mesotheliomas | N | Am J Surg Pathol 2002;26:365 | Novus Lab / 1:750 |
| Lung tumors | N/n | Br J Cancer 2004;90:1222 | Novocastra / 44F12 / 1:20 |
| N/C | Anticancer Res 2013;33:2643 | Gene Tex / TERT 2C4 | |
| Liver tumors | N/C | Oncotarget 2017;8:26288 | Abcam / Y182 / 1:100 |
| N/C | Oncotarget 2016;7:27838 | Abcam / Ab5181 / 1:20 | |
| C | Pathol Res Pract 2015;211:316 | Santa Cruz | |
| Breast tumors | N | J Carcinog 2005;4:17 | Novocastra / 44F12 / 1:50 |
| N | Sci Rep 2018;8:3881 | Alpha Diagnostic / 1:100 | |
| Cervical tumors | N/C | Cancer Genomics Proteomics 2020;17:615 | Abcam / Ab5181 / 1:20 |
| N/C | J Clin Pathol 2005;58:911 | DIESSE / Tel 3-36-10 | |
| N | Diagn Cytopathol 2006;34:739 | EMD Biosciences / PC563 / 1:100 | |
| Ovarian tumors | N | Int J Clin Exp Pathol 2015;8:14971 | Rockland / 1:200 |
| N | J Med Assoc Thai 2009;92:308, Gynecol Oncol 2005;98:396 | Novocastra / 44F12 / 1:50 | |
| C | Indian J Pathol Microbiol 2012;55:187 | Gene Tex / 1:80 | |
| Endometrial lesions | N | Int J Gynecol Pathol 2005;24:184 | Novocastra / 44F12 / 1:50 |
| N/C | Mod Pathol 2011;24:1254 | Santa Cruz / Sc-7215 / 1:40 | |
| Colorectal tumors | N/C | Oncol Rep 2015;33:2728 | Abcam / Y182 / 1:100 |
| N/C | Clin Cancer Res 2008;14:7444 | Santa Cruz / TRT H-231 / 1:50 | |
| N/n | Clin Cancer Res 2008;14:7444 | Novocastra / 44F12 / 1:20 | |
| Ulcerative colitis | N | Int J Mol Med 2014;33:1477 | Abcam / Ab5181 / 1:500 |
| Gastric tumors | N | Biomarkers 2009;14:630 | Novocastra / 44F12 / 1:50 |
| C | Mod Pathol 2003;16:700 | Santa Cruz / 1:50 | |
| Urothelial tumors | n | Cytojournal 2006;3:18 | Novocastra / 44F12 / 1:25 |
| N/C | Anticancer Res 2005;25:3109 | Santa Cruz / Sc-7215 / 1:60 | |
| Prostatic tumors | N | Folia Histochem Cytobiol 2013;51:66, Cancer 2002;95:2487 | Novus Lab / 1:1500-1:300 |
| Sarcomas | N/n | Pathology 2009;41:527, Appl Immunohistochem Mol Morphol 2006;14:198 | Novocastra / 44F12 / 1:20 - 1:75 |
| Bone tumors | N/n | Mod Pathol 2008;21:423 | Alexis / ALX-804-504 / 1:25 |
| Pituitary tumors | N/C | Turk Patoloji Derg 2017;33:103 | Bioss / 1:100 |
| Parathyroid tumors | N | Int J Mol Med 2009;24:733 | Novocastra / 44F12 |
| Thyroid | C | Oncol Lett 2018;15:2763 | Rockland / 1:300 |
| C | J BUON 2018;23:229 | Abcam |
Microscopic (histologic) images
Images hosted on other servers:
Expression of TERT in lung tumors
Positive staining - normal
- Solid cell nest of the thyroid gland (Mod Pathol 2004;17:819)
- Normal pancreatic and prostatic tissues (basal cells) (Cell Oncol 2005;27:347, Cancer 2002;95:2487)
- Biliary epithelium (Oncogene 2000;19:3888)
- Spermatocytes, proliferative cells in colon crypts, some basal cells in the urothelial epithelium (Histochem Cell Biol 2004;121:391)
- Epithelial basal layers of normal cervical tissue (J Clin Pathol 2005;58:911)
- Subset of normal adult neurons, especially in the temporal lobe (Acta Neuropathol 2006;111:569)
- Hiyama et al. (Neoplasia 2001;3:17)
- Strong expression: lymphocytes (tonsil, spleen, thyroid), basal cells of endometrial glands, spermatocytes
- Weak expression: lymphocytes (at basal layers of GI tract epithelium, liver), basal keratinocytes (skin), breast epithelial cells, trophoblasts in chorionic villi
Positive staining - disease
- Childhood tumors:
- Neuroblastoma: 59.2% (41/72) (Cancer Res Treat 2018;50:495)
- Wilms: 73.2% (30/41); cytoplasmic staining, as shown on normal kidney tissue, was considered negative (Tumour Biol 2011;32:761)
- Skin:
- Melanomas: 44 - 98%, basal cell carcinomas: 80 - 93% (Br J Cancer 2018;118:98, J Invest Dermatol 2014;134:2251, J Cutan Pathol 2004;31:544)
- 100% squamous cell carcinoma, 80% Bowen disease, 60% actinic keratosis and 100% porokeratosis (J Cutan Pathol 2004;31:544)
- More frequent in acral lentiginous melanoma than other types of cutaneous melanomas (Arch Pathol Lab Med 2020 Oct 14 [Epub ahead of print])
- Soft tissue:
- Sarcomas: 46 - 59%
- Liposarcoma: 63%; malignant peripheral nerve sheath tumor: 65% (Appl Immunohistochem Mol Morphol 2006;14:198, Pathology 2009;41:527)
- Bone
- Osteosarcoma: 71% (Pathology 2009;41:527)
- Giant cell tumor of bones: 35%; most positive cells are mononuclear cells (Mod Pathol 2008;21:423)
- Central nervous system
- Glioblastomas: 60% with strong expression (J Cancer 2019;10:2397)
- Astrocytic tumors: 79.6% (74% low grade and 85% high grade); vessel endothelial cells express TERT in all astrocytic tumor grade (Acta Neuropathol 2006;111:569)
- Ependymoma: 58% (J Clin Oncol 2006;24:1522)
- Lung
- Small cell lung cancer: 100% and non small cell lung cancer: 64.2 - 94.2% (Neoplasia 2001;3:17, Anticancer Res 2013;33:2643)
- Adenocarcinoma: 54.5 - 86%, squamous cell carcinoma: 70.6 - 100% (Anticancer Res 2013;33:2643)
- Malignant mesothelioma: 98.5% (Am J Surg Pathol 2002;26:365)
- Endocrine glands
- Parathyroid carcinoma (Int J Mol Med 2009;24:733)
- Papillary thyroid carcinoma: 46 - 100% (Oncol Lett 2018;15:2763, J BUON 2018;23:229)
- Urothelial carcinoma: 93% primary bladder cancers (Cytojournal 2006;3:18)
- Prostate
- Adenocarcinoma: 64% of cases with Gleason score < 7, 100% of cases with Gleason score ≥ 7 (Cancer 2002;95:2487)
- Breast
- 100% ductal carcinoma in situ / lobular carcinoma in situ and 71 - 97.7% invasive carcinoma (Neoplasia 2001;3:17, J Carcinog 2005;4:17)
- Phyllode tumor: 68.6% of cases show intermediate high stromal TERT expression and 65.5% of cases show intermediate high epithelial TERT expression (Sci Rep 2018;8:3881)
- Gynecological tumors
- Cervical squamous carcinoma: about 85%; high grade squamous intraepithelial lesion: 75% (Cancer Genomics Proteomics 2020;17:615, Diagn Cytopathol 2006;34:739)
- Endometrium: 75% atypical hyperplasia, 91% endometrioid carcinoma, 100% serous papillary / clear cell carcinoma (Int J Gynecol Pathol 2005;24:184, Mod Pathol 2011;24:1254)
- Ovarian carcinoma: 56.5 - 100%; serous borderline tumor: 71.4%; mucinous borderline tumor: 40% (Int J Clin Exp Pathol 2015;8:14971, J Med Assoc Thai 2009;92:308, Indian J Pathol Microbiol 2012;55:187, Gynecol Oncol 2005;98:396)
- Liver
- Hepatocellular carcinoma (HCC): 88 - 94% (Neoplasia 2001;3:17, Pathol Res Pract 2015;211:316, Oncogene 2000;19:3888)
- Non clear cell HCC: 98%; clear cell HCC: 100% (Oncotarget 2017;8:26288)
- Pancreas
- Pancreatic juice: 84% pancreatic ductal adenocarcinoma, 100% intraductal papillary mucinous neoplasm (IPMN) with invasive carcinoma, 80% high grade IPMN and 56% low grade IPMN (Pancreas 2009;38:527)
- Colon
- 100% carcinoma in situ and 71 - 96% invasive carcinoma (Neoplasia 2001;3:17, Oncol Rep 2015;33:2728)
- Stomach
- 100% carcinoma in situ and 55 - 96% invasive carcinoma (Neoplasia 2001;3:17, Biomarkers 2009;14:630, Braz J Med Biol Res 2011;44:100, Mod Pathol 2003;16:700)
Negative staining
- Reactive fibrosis, lipoma, osteoid osteoma, osteoblastoma (Pathology 2009;41:527)
- Pleuritis, benign mesothelial hyperplasia (Am J Surg Pathol 2002;26:365)
- Chronic pancreatitis / pancreatic juice (Pancreas 2009;38:527)
- Ovarian cystadenoma (Indian J Pathol Microbiol 2012;55:187, Gynecol Oncol 2005;98:396)
- Atypical tubal metaplasia (Mod Pathol 2011;24:1254)
- Parathyroid adenoma (90%) (Int J Mol Med 2009;24:733)
- Chronic hepatitis, cirrhosis (Oncogene 2000;19:3888)
Molecular / cytogenetics description
- Polymerase chain reaction (PCR) / gene sequencing
- TERT promoter mutations found in:
- 81% gliosarcoma, 78% oligodendrogliomas, 58% oligoastrocytomas and 54% primary glioblastomas (Acta Neuropathol 2013;126:907)
- Basal cell carcinoma, squamous cell carcinoma, atypical fibroxanthoma and pleomorphic dermal sarcomas (with UV signature) confirmed the pathogenic role of UV exposure in those lesions (Mod Pathol 2014;27:516, Mod Pathol 2014;27:502)
- 70% skin squamous cell carcinomas and urothelial carcinomas with squamous differentiation but < 20% of squamous cell carcinomas in other sites (Ann Diagn Pathol 2015;19:146)
- 71% melanoma and contributed to malignant transformation in precursor lesions (N Engl J Med 2015;373:1926, J Invest Dermatol 2016;136:339, Science 2013;339:957)
- 25% breast metaplastic carcinomas (Mod Pathol 2018;31:1661)
- Phyllodes tumors but rare in fibroadenoma (65% versus 7%) (J Pathol 2016;238:508, Br J Cancer 2015;113:1244, Sci Rep 2018;8:3881)
- 42 - 61% hepatocellular carcinomas, 6 - 19% dysplastic nodules, 44 - 56% hepatocellular adenomas with malignant transformation in hepatocellular carcinomas; serves as a new biomarker for prediction of malignant transformation (Nat Commun 2013;4:2218, Hepatology 2014;60:1983, Cancer Cell 2014;25:428)
- Ovarian clear cell carcinoma (15.9%) but not in other major types of gynecological malignancy (J Pathol 2014;232:473)
- Conjunctival melanoma but rarely in uveal melanoma (Invest Ophthalmol Vis Sci 2014;55:6024)
- Tall cell papillary thyroid carcinoma (with high prevalence) (Endocr Relat Cancer 2013;20:603)
- 74% myxoid liposarcomas (J Exp Clin Cancer Res 2014;33:33)
- 83% nested urothelial carcinoma cases versus 6% of the benign lesions (Mod Pathol 2020;33:1165)
- In gliomas, TERT promoter mutations are strongly correlated with older age, 1p / 19q loss but inversely associated with loss of ATRX expression and IDH1 / IDH2 mutations (Acta Neuropathol 2013;126:267, Acta Neuropathol 2013;126:907)
- TERT promoter mutations may signal the malignant progression of meningiomas (Brain Pathol 2014;24:184)
- High grade prostatic adenocarcinoma, which morphological mimics urothelial carcinoma, is negative for TERT promoter mutations (Appl Immunohistochem Mol Morphol 2019;27:523)
- TERT C228T promoter mutations may play a critical role in the progression of adult granulosa cell tumors (Mod Pathol 2018;31:1107)
- TERT promoter mutations may help differentiate small cell carcinoma of the urinary bladder from small cell carcinoma from other origins (J Hematol Oncol 2014;7:47)
- Dysregulated transcription of TERT relates to HPV induced demethylating TERT transcription start site in cervical cancer (BMC Cancer 2010;10:271, Gynecol Oncol 2012;124:534, Cancer Genomics Proteomics 2016;13:483)
- TERT promoter mutations found in:
- RT-PCR / ISH / FISH
- TERT mRNA expression is associated with N-Myc mRNA expression in neuroblastoma (Endocr J 2004;51:47)
- TERT mRNA expression differentiates the Ig unmutated from Ig mutated B cell chronic lymphocytic leukemia in 89% of cases (Ann Oncol 2004;15:1476)
- ISH: about 60% of glioblastomas expressed TERT mRNA homogeneously (Int J Cancer 2000;88:895)
- TERT expression level was lower in amyotrophic lateral sclerosis patients (Hum Genet 2014;59:555)
Molecular / cytogenetics images
Images hosted on other servers:
TERT expression is lower in ALS patients
In situ hybridization for hTR expression
TERT promoter sequence chromatograms
Board review style question #1
Which of the following cells is not immunoreactive with TERT?
- Basal keratinocytes
- Lymphocytes
- Myocytes
- Neurons
- Spermatocytes
Board review style answer #1
