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Stains

Topoisomerase II alpha (TOP2A)

 

Reviewer: Semir Vranic, M.D., University of Sarajevo, Bosnia & Herzegovina (see Reviewers page)

Revised: 22 September 2012, last major update June 2010

Copyright: (c) 2002-2012, PathologyOutlines.com, Inc.

 

Definition

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● Topoisomerases are enzymes that wind and unwind DNA to facilitate protein synthesis and DNA replication (Wikipedia, Animation)

● Topoisomerase IIA cuts both strands of the DNA helix to unwind them (Wikipedia)

● Expression is predictive of prognosis in various malignancies

 

Terminology

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● Also called Topo II alpha (TOP2A)

Topo II labeling index: number of TOP2A positive staining nuclei divided by the total number of tumor cells counted multiplied by 100

 

Pathophysiology

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● Gene is located near HER2 locus at 17q12-q21, and is often coamplified with HER2 (Breast Cancer Res Treat 2007;106:181)

● Essential nuclear enzyme for DNA replication, transcription, condensation and segregation (Nat Rev Cancer 2009;9:327, Biochim Biophys Acta 1998;1400:121)

● Expressed in proliferating cells in late S phase and G2-M phase, where it mediates chromosome condensation

● Has circadian rhythm in rectal crypt epithelium (Mod Pathol 2002;15:1191)

● Topoisomerase II is a direct molecular target of anthracycline and etoposide drug action (Curr Opin Oncol 1993;5:1023); note that these drugs may also cause acute leukemia

● Note: amplification of the TOP2A gene does not predict high levels of topoisomerase II alpha protein in human breast tumor samples (Genes Chromosomes Cancer 2004;39:288)

 

Uses

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(1) Breast cancer

● Appears to have prognostic value for survival and predictive value for response to anthracyclines, but results vary by type of Topo IIA expression (gene, RNA, immunohistochemistry), but some authors think evidence is still inconclusive (Cancer Treat Rev 2009;35:662, J Clin Oncol 2008;26:736)

- Deletions associated with poor prognosis (Acta Oncol 2008;47:725)

- TOP2A RNA level is a good prognostic marker (Clin Cancer Res 2010;16:2391)

- Correlates well with Ki-67 (Hum Pathol 1997;28:1180, Am J Clin Pathol 2005:124:342)

- TOP2A gene expression by microarray analysis is highly prognostic in ER+ breast cancer (Breast Cancer Res Treat 2009;113:457)

- Coamplification of HER2 and TOP2A may define a subgroup of high-risk patients who benefit from individually tailored and dose-escalated adjuvant anthracyclines (J Clin Oncol 2006;24:2428)

 

(2) Gynecologic cancers

● May predict response to doxorubicin and etoposide (Anticancer Res 2001;21:2925) and platinum-based agents (Int J Gynecol Pathol 2000;19:248)

 

(3) Prognostic factor in: adrenocortical neoplasms (Applied Immunohistochem Mol Morphol 2001;9:215), CNS astrocytic neoplasms (Mod Pathol 1999;12:1094), hepatocellular carcinoma (Int J Cancer 2009;124:644), Hodgkin’s lymphoma (Clin Cancer Res 2008;14:1759), laryngeal squamous cell carcinoma (Am J Clin Pathol 2008;130:934), malignant peripheral nerve sheath tumor (J Clin Oncol 2003;21:4586), meningioma (Arch Pathol Lab Med 2002;126:1079), oligodendroglioma (Arch Pathol Lab Med 2001;125:892), pancreatic endocrine neoplasms (Arch Pathol Lab Med 2004;128:426) and pheochromocytoma (Applied Immunohistochem Mol Morphol 2000;8:267)

 

(4) Part of ProExC antibody cocktail that differentiates dysplasia from reactive lesions in cervical biopsies (Am J Surg Pathol 2008;32:899, Int J Gynecol Pathol 2010;29:79) and cervical cytology preparations (Am J Clin Pathol 2008;130:765); more sensitive and specific than HPV testing (Arch Pathol Lab Med 2008;132:1648)

 

Interpretation

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 The best tool and cutoff values for TOP2A assessment are unknown

 The most commonly used method is TOP2A gene analysis by FISH (Pathol Res Pract 2010;206:156)

 TOP2A protein expression by immunohistochemistry is also commonly used 

 

Positive stains - normal

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 Tissues with proliferating cells, especially spermatocytes, germinal centers and proliferative endometrium (Mod Pathol 1997;10:168)

 

Positive stains – benign and borderline lesions

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● Sinonasal-inverted papilloma (J Cell Mol Med 2008;12:1551)

 

Positive stains - carcinoma

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● Various cancer types with high mitotic activity, including Hodgkin’s lymphoma (Am J Clin Pathol 1998;109:39), myeloma (Mod Pathol 2001;14:886), penile basaloid squamous cell carcinoma (BJU Int 2008;102:1040), pulmonary small cell carcinoma (Br J Cancer 1998;77:1469), testicular embryonal carcinoma (Br J Cancer 2002;87:624)

 

Negative stains

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● Terminally differentiated tissues (because TOP2A is not expressed in G0 phase): cerebral cortex, skeletal muscle and nerve

Rare positive cells in breast, salivary gland and kidney (Mod Pathol 1997;10:168)

 

Micro images

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Rectal crypts in normal tissue #1; #2

 

FIGURE 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author   MDA-MB453 Topo II 20x IHC by Pathology Outlines.             An external file that holds a picture, illustration, etc.
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Breast carcinoma                                              Breast carcinomas with high and low expression

 

 

Fig. 1.                Figure 1                Figure 2

Hodgkin’s lymphoma         Lung cancer: small cell (+) versus adenocarcinoma (focal +)

                                                                                                                               

 

                FIGURE 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author                Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author               

Meningiomas                       Myeloma                               Ovarian tumors                  

 

 

                FIGURE 2 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author                FIGURE 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author                                               

Pancreatic endocrine       Pituitary adenoma              Pituitary carcinoma

neoplasm

 

 

                                Figure 5

Prostate: various                Prostate: hormone             Seminoma

                                                insensitive

 

 

FIGURE 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author                FIGURE 2 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Thyroid carcinoma:            Thyroid: anaplastic carcinoma

tall cell and papillary         

 

Molecular images

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Breast Carcinoma-FISH of HER2 and TOP2A              TOP2A CEP17 FISH no gene amplification

 

End of Stains > Topoisomerase II alpha

 

 

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