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Differential expression of P16 and P21 in benign and malignant uterine smooth muscle tumors

  • Gynecologic Oncology
  • Published:
Archives of Gynecology and Obstetrics Aims and scope Submit manuscript

Abstract

Purpose

The diagnosis of benign and malignant uterine smooth muscle tumors depends on morphologic criteria such as nuclear atypia, coagulative tumor cell necrosis and mitotic activity. Most of these tumors are readily classifiable into benign or malignant categories using these criteria. However, the distinction between leiomyomas and leiomyosarcomas may at times be problematic. Hence, it would be useful to have additional markers which could help to distinguish these tumors. The aim of the study was to evaluate p16 and p21 expressions in uterine smooth muscle tumors and determine whether p16 and p21 have a potential value in the differential diagnosis of problematic cases. In addition, we evaluated whether the differential expression of p16 and p21 in uterine leiomyosarcomas correlated with tumor recurrence and patient survival.

Methods

p16 and p21 expressions were investigated by immunohistochemistry from paraffin-embedded tissues in 53 cases of uterine smooth muscle tumors consisting of 15 cases of leiomyoma, 14 cases of atypical leiomyoma (leiomyoma with bizarre nuclei), 3 cases of smooth muscle tumor of uncertain malignant potential (STUMP) and 21 cases of leiomyosarcoma. Cases were evaluated with respect to both staining percentage and intensity.

Results

There was a statistically significant difference in p16 and p21 staining percentage and intensity between leiomyosarcomas and the other groups. There was no difference in p16 and p21 expressions between leiomyomas, atypical leiomyomas (leiomyoma with bizarre nuclei) and STUMPs. Multivariate analysis showed that the tumor stage was the only independent significant prognostic factor for overall survival in leiomyosarcomas. Neither p16 nor p21 was correlated with disease-free or overall survival.

Conclusions

Our findings suggested that p16 and p21 may be of value as an adjunct to conventional morphologic criteria in the assessment of problematic uterine smooth muscle tumors.

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References

  1. Zaloudek C, Hendrickson MR (2002) Mesenchymal tumors of the uterus. In: Kurman RJ (ed) Blaustein’s pathology of the female genital tract, fifth edn. Springer, New York, pp 561–615

    Google Scholar 

  2. Bodner-Adler B, Bodner K, Czerwenka K, Kimberger O, Leodolter S, Mayerhofer K (2005) Expression of p16 protein in patients with uterine smooth muscle tumors: an immunohistochemical analysis. Gynecol Oncol 96:62–66

    Article  PubMed  CAS  Google Scholar 

  3. O’Neill CJ, McBrie HA, Connolly LE, McCluggage WG (2007) Uterine leiomyosarcomas are characterized by high p16, p53 and MIB1 expression in comparison with usual leiomyomas, leiomyoma variants and smooth muscle tumours of uncertain malignant potential. Histopathology 50:851–858

    Article  PubMed  Google Scholar 

  4. Atkins KA, Arronte N, Darus CJ, Rice LW (2008) The use of p16 in enhancing the histologic classification of uterine smooth muscle tumors. Am J Surg Pathol 32:98–102

    Article  PubMed  Google Scholar 

  5. Chen L, Yang B (2008) Immunohistochemical analysis of p16, p53, and Ki-67 expression in uterine smooth muscle tumors. Int J Gynecol Pathol 27:326–332

    Article  PubMed  Google Scholar 

  6. Gannon BR, Manduch M, Childs TJ (2008) Differential immunoreactivity of p16 in leiomyosarcomas and leiomyoma variants. Int J Gynecol Pathol 27:68–73

    Article  PubMed  Google Scholar 

  7. Ip PP, Cheung AN, Clement PB (2009) Uterine smooth muscle tumors of uncertain malignant potential (STUMP): a clinicopathologic analysis of 16 cases. Am J Surg Pathol 33:992–1005

    Article  PubMed  Google Scholar 

  8. Lee CH, Turbin DA, Sung YC, Espinosa I, Montgomery K, van de Rijn M, Gilks CB (2009) A panel of antibodies to determine site of origin and malignancy in smooth muscle tumors. Mod Pathol 22:1519–1531

    Article  PubMed  CAS  Google Scholar 

  9. D’Angelo E, Spagnoli LG, Prat J (2009) Comparative clinicopathologic and immunohistochemical analysis of uterine sarcomas diagnosed using the World Health Organization classification system. Hum Pathol 40:1571–1585

    Article  PubMed  Google Scholar 

  10. Palazzo JP, Mercer WE, Kovatich AJ, McHugh M (1997) Immunohistochemical localization of p21(WAF1/CIP1) in normal, hyperplastic, and neoplastic uterine tissues. Hum Pathol 28:60–66

    Article  PubMed  CAS  Google Scholar 

  11. Leiser AL, Anderson SE, Nonaka D, Chuai S, Olshen AB, Chi DS, Soslow RA (2006) Apoptotic and cell cycle regulatory markers in uterine leiomyosarcoma. Gynecol Oncol 101:86–91

    Article  PubMed  CAS  Google Scholar 

  12. Trojani M, Contesso G, Coindre JM, Rouesse J, Bui NB, de Mascarel A, Goussot JF, David M, Bonichon F, Lagarde C (1984) Soft-tissue sarcomas of adults; study of pathological prognostic variables and definition of a histopathological grading system. Int J Cancer 33:37–42

    Article  PubMed  CAS  Google Scholar 

  13. FIGO staging for uterine sarcomas (2009) Int J Gynaecol Obstet 104:179

    Google Scholar 

  14. Mori T, Miura K, Aoki T, Nishihira T, Mori S, Nakamura Y (1994) Frequent somatic mutation of the MTS/CDK41 gene in esophageal squamous cell carcinoma. Cancer Res 54:3396–3397

    PubMed  CAS  Google Scholar 

  15. Caldas C, Hahn SA, DaCosta LT, Redston MS, Schutte M, Seymour AB, Weinstein CL, Hruban RH, Yeo CJ, Kern SE (1994) Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma. Nat Genet 8:27–32

    Article  PubMed  CAS  Google Scholar 

  16. Cohen JA, Geradts J (1997) Loss of RB and MTS1/CDKN2 (p16) expression in human sarcomas. Hum Pathol 28:893–898

    Article  PubMed  CAS  Google Scholar 

  17. Kawaguchi K, Oda Y, Saito T, Yamamoto H, Tamiya S, Takahira T, Miyajima K, Iwamoto Y, Tsuneyoshi M (2003) Mechanisms of inactivation of the p16INK4a gene in leiomyosarcoma of soft tissue: decreased p16 expression correlates with promoter methylation and poor prognosis. J Pathol 201:487–495

    Article  PubMed  CAS  Google Scholar 

  18. Qiao X, Bhuiya TA, Spitzer M (2005) Differentiating high-grade cervical intraepithelial lesion from atrophy in postmenopausal women using Ki-67, cyclin E and p16 immunohistochemical analysis. J Low Genit Tract Dis 9:100–107

    Article  PubMed  Google Scholar 

  19. Regauer S, Reich O (2007) CK17 and p16 expression patterns distinguish (atypical) immature squamous metaplasia from high-grade cervical intraepitheial neoplasia (CIN III). Histopathology 50:629–635

    Article  PubMed  CAS  Google Scholar 

  20. Cameron RI, Maxwell P, Jenkins D, McCluggage WG (2002) Immunohistochemical staining with MIB1, bcl2 and p16 assists in the distinction of cervical glandular intraepithelial neoplasia from tubo-endometrial metaplasia, endometriosis and microglandular hyperplasia. Histopathology 41:313–321

    Article  PubMed  CAS  Google Scholar 

  21. Ip PP, Tse KY, Tam KF (2010) Uterine smooth muscle tumors other than the ordinary leiomyomas and leiomyosarcomas: a review of selected variants with emphasis on recent advances and unusual morphology that may cause concern for malignancy. Adv Anat Pathol 17:91–112

    Article  PubMed  Google Scholar 

  22. Yang W, Klos KS, Zhou X, Yao J, Yang Y, Smith TL, Shi D, Yu D (2003) ErbB2 overexpression in human breast carcinoma is correlated with p21Cip1 up-regulation and tyrosine-15 hyperphosphorilation of p34Cdc2: poor responsiveness to chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil is associated with Erb2 overexpression and with p21Cip1 overexpression. Cancer 98:1123–1130

    Article  PubMed  CAS  Google Scholar 

  23. Shariat SF, Tokunaga H, Zhou J, Kim J, Ayala GE, Benedict WF, Lerner SP (2004) P53, p21, pRB, and p16 expression predict clinical outcome in cystectomy with bladder cancer. J Clin Oncol 22:1014–1024

    Article  PubMed  CAS  Google Scholar 

  24. Jung JM, Bruner JM, Ruan S, Langford LA, Kyritsis AP, Kobayashi T, Levin VA, Zhang W (1995) Increased levels of p21WAF1/CIP1 in human brain tumors. Oncogene 11:2021–2028

    PubMed  CAS  Google Scholar 

  25. Dobashi Y, Noguchi T, Nasuno S, Katayama K, Kameya T (2001) CDK-inhibitors-associated kinase activity: a possible determinant of malignant potential in smooth muscle tumors of the external soft tissue. Int J Cancer 94:353–362

    Article  PubMed  CAS  Google Scholar 

  26. El-Ghobashy AA, Shaaban AM, Innes J, Prime W, Herrington CS (2007) Differential expression of cyclin-dependent kinase inhibitors and apoptosis-related proteins in endocervical lesions. Eur J Cancer 43:2011–2018

    Article  PubMed  CAS  Google Scholar 

  27. Huang LW, Chou YY, Chao SL, Chen TJ, Lee TT (2001) p53 and p21 expression in precancerous lesions and carcinomas of the uterine cervix: overexpression of p53 predicts poor disease outcome. Gynecol Oncol 83:348–354

    Article  PubMed  CAS  Google Scholar 

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The authors declare that they have no conflict of interest.

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Correspondence to Mustafa Fuat Acikalin.

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Ünver, N.U., Acikalin, M.F., Öner, Ü. et al. Differential expression of P16 and P21 in benign and malignant uterine smooth muscle tumors. Arch Gynecol Obstet 284, 483–490 (2011). https://doi.org/10.1007/s00404-010-1690-z

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  • DOI: https://doi.org/10.1007/s00404-010-1690-z

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