Prognostic Value of p53 and Cyclin D1 in Papillary Thyroid Carcinoma

Jae Yeon Seok; Dong Hae Chung; Yoo Seung Chung; Jung Won Ryu; Young Don Lee

doi:10.16956/kjes.2015.15.2.25

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Seok, Chung, Chung, Ryu, and Lee: Prognostic Value of p53 and Cyclin D1 in Papillary Thyroid Carcinoma

Original Article

Korean J Endocrine Surg 2015;15(2):25-33.

Published online: 10 December 2015

DOI: https://doi.org/10.16956/kjes.2015.15.2.25

Prognostic Value of p53 and Cyclin D1 in Papillary Thyroid Carcinoma

Jae Yeon Seok, Dong Hae Chung, Yoo Seung Chung¹, Jung Won Ryu¹, Young Don Lee¹

Department of Pathology, Gachon University Gil Medical Center, Incheon, Korea

¹Department Surgery, Gachon University Gil Medical Center, Incheon, Korea

Correspondence: Yoo Seung Chung Department of Surgery, Gachon University Gil Medical Center, 1198 Guwol-dong, Namdong-gu, Incheon 405-760, Korea Tel: ＋82-32-460-3244 Fax: ＋82-32-460-3247 E-mail: dryooseung@gilhospital.com, dryooseung@hanmail.net

Received 8 April 2015 Revised 13 May 2015 Accepted 29 May 2015

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Purpose

P53 and cyclin D1 have been evaluated as a prognostic marker in papillary thyroid carcinoma (PTC). However, the relationship between p53/cyclin D1 and PTC prognosis has not yet been confirmed. Therefore, we investigated the relationship between p53/cyclin D1 and PTC prognostic factors.

Methods

919 patients with PTC were enrolled. Immunohistochemistry slides were reviewed for p53 and cyclin D1 immunoreactivity. Patients were classified into two groups according to the p53 and cyclin D1 grade: negative for ≤5% and positive for ＞5%. Medical records were reviewed to evaluate the prognostic factors, lymph node metastatic ratio (LNMR), and MACIS score. We analyzed patients based on p53/cyclin D1(−/−), p53/cyclin D1(−/＋), p53/cyclin D1(＋/−), p53/cyclin D1(＋/＋) separately for evaluation of independent effect of p53 and cyclin D1.

Results

Mean age of the patients was 49.73 years (range 15∼87), and tumor size was 1.19 cm (range 0.1∼5.0). P53 was positive in 809 (88.0%) and cyclin D1 was positive in 748 (81.4%). Positivity of p53 and cyclin D1 were correlated (r=0.448). There was no statistical significance in MACIS score. Positivity of p53 and cyclin D1 were related with larger tumor size, older age, early T stage, more tumor capsulation, and female. LNMR was higher in p53/cyclin D1(＋/−) than p53/cyclin D1(−/−) (P=0.036), p53/cyclin D1(−/＋) than p53/cyclin D1(−/−) (P=0.034), and p53/cyclin D1(＋/＋) than p53/cyclin D1(−/−) (P=0.007).

Conclusion

There was no consistent relationship between p53/cyclin D1 and worse prognostic factors of PTC. However, LNMR was higher in p53(＋) and cyclin D1(＋) cases independently, much more in p53/cyclin D1(＋/＋) than p53/cyclin D1(−/−).

Keywords: Papillary thyroid carcinoma, p53, Cyclin D1, Prognosis, Lymph node metastatic ratio

References

1. Omur O, Baran Y. An update on molecular biology of thyroid cancers. Crit Rev Oncol Hematol. 2014; 90:233–52.

2. Zafon C, Obiols G, Castellví J, Tallada N, Baena JA, Simó R, et al. Clinical significance of RET/PTC and p53 protein expression in sporadic papillary thyroid carcinoma. Histopathology. 2007; 50:225–31.

3. Karlidag T, Cobanoglu B, Keles E, Alpay HC, Ozercan I, Kaygusuz I, et al. Expression of Bax, p53, and p27/kip in patients with papillary thyroid carcinoma with or without cervical nodal metastasis. Am J Otolaryngol. 2007; 28:31–6.

4. Morita N, Ikeda Y, Takami H. Clinical significance of p53 protein expression in papillary thyroid carcinoma. World J Surg. 2008; 32:2617–22.

5. Balta AZ, Filiz AI, Kurt Y, Sucullu I, Yucel E, Akin ML. Prognostic value of oncoprotein expressions in thyroid papillary carcinoma. Med Oncol. 2012; 29:734–41.

6. Kim BS, Kang KH, Lim YA, Kim LS. Clinical significance of p53, ki-67 and galectin-3 expressions in papillary thyroid carcinoma. J Korean Surg Soc. 2009; 77:29–36.

7. Ji WB, Bae JW, Woo SU, Son GS, Lee JB, Koo BW, et al. The significance of bcl-2 and p53 expressions in the papillary thyroid cancer. Korean J Endocr Surg. 2007; 7:231–6.

8. Lee SH, Park SY, Kim NR, Lee YD. The expressions of CK7, CK20, vimentin, p53 and ki-67 in papillary thyroid carcinoma. Korean J Endocr Surg. 2009; 9:7–13.

9. Lee YM, Lee JB. Prognostic value of epidermal growth factor receptor, p53 and galectin-3 expression in papillary thyroid carcinoma. J Int Med Res. 2013; 41:825–34.

10. Shin MK, Kim JW. Clinicopathologic and diagnostic significance of p53 protein expression in papillary thyroid carcinoma. Asian Pac J Cancer Prev. 2014; 15:2341–4.

11. Basolo F, Caligo MA, Pinchera A, Fedeli F, Baldanzi A, Miccoli P, et al. Cyclin D1 overexpression in thyroid carcinomas: relation with clinicopathological parameters, retinoblastoma gene product, and Ki67 labeling index. Thyroid. 2000; 10:741–6.

12. Temmim L, Ebraheem AK, Baker H, Sinowatz F. Cyclin D1 protein expression in human thyroid gland and thyroid cancer. Anat Histol Embryol. 2006; 35:125–9.

13. Lee SH, Lee JK, Jin SM, Lee KC, Sohn JH, Chae SW, et al. Expression of cell-cycle regulators (cyclin D1, cyclin E, p27kip1, p57kip2) in papillary thyroid carcinoma. Otolaryngol Head Neck Surg. 2010; 142:332–7.

14. Kim HJ, Kim YS, Kim SW, Kim KC. Expression of cyclin d1, cytokeratin 7, cytokeratin 20 and vimentin in papillary thyroid cancer and relationship with patient's prognostic factors. Korean J Endocr Surg. 2012; 12:92–7.

15. Melck A, Masoudi H, Griffith OL, Rajput A, Wilkins G, Bugis S, et al. Cell cycle regulators show diagnostic and prognostic utility for differentiated thyroid cancer. Ann Surg Oncol. 2007; 14:3403–11.

16. Rocha S, Martin AM, Meek DW, Perkins ND. p53 represses cyclin D1 transcription through down regulation of Bcl-3 and inducing increased association of the p52 NF-kappaB subunit with histone deacetylase 1. Mol Cell Biol. 2003; 23:4713–27.

17. Ullmannová V, Stöckbauer P, Hradcová M, Soucek J, Haskovec C. Relationship between cyclin D1 and p21 (Waf1/Cip1) during differentiation of human myeloid leukemia cell lines. Leuk Res. 2003; 27:1115–23.

18. Pines J. Four-dimensional control of the cell cycle. Nat Cell Biol. 1999; 1:E73–9.

19. Hay ID, Bergstralh EJ, Goellner JR, Ebersold JR, Grant CS. Predicting outcome in papillary thyroid carcinoma: development of a reliable prognostic scoring system in a cohort of 1779 patients surgically treated at one institution during 1940 through 1989. Surgery. 1993; 114:1050–7.

20. Marcello MA, Morari EC, Ward LS. P53 protein profile by IHC may be helpful to define patient prognosis. Med Oncol. 2012; 29:2309–10.

21. Londero SC, Godballe C, Krogdahl A, Bastholt L, Specht L, Sørensen CH, et al. Papillary microcarcinoma of the thyroid gland: is the immunohistochemical expression of cyclin D1 or galectin-3 in primary tumour an indicator of metastatic disease? Acta Oncol. 2008; 47:451–7.

22. Lantsov D, Meirmanov S, Nakashima M, Kondo H, Saenko V, Naruke Y, et al. Cyclin D1 overexpression in thyroid papillary microcarcinoma: its association with tumour size and aberrant beta-catenin expression. Histopathology. 2005; 47:248–56.

23. Khoo ML, Beasley NJ, Ezzat S, Freeman JL, Asa SL. Overexpression of cyclin D1 and underexpression of p27 predict lymph node metastases in papillary thyroid carcinoma. J Clin Endocrinol Metab. 2002; 87:1814–8.

24. Pesutić-Pisac V, Punda A, Gluncić I, Bedeković V, Pranić-Kragić A, Kunac N. Cyclin D1 and p27 expression as prognostic factor in papillary carcinoma of thyroid: association with clinicopathological parameters. Croat Med J. 2008; 49:643–9.

25. Ioachim E. Expression patterns of cyclins D1, E and cyclindependent kinase inhibitors p21waf1/cip1, p27kip1 in colorectal carcinoma: correlation with other cell cycle regulators (pRb, p53 and Ki-67 and PCNA) and clinicopathological features. Int J Clin Pract. 2008; 62:1736–43.

26. Oh YL, Choi JS, Song SY, Ko YH, Han BK, Nam SJ, et al. Expression of p21Waf1, p27Kip1 and cyclin D1 proteins in breast ductal carcinoma in situ: Relation with clinicopathologic characteristics and with p53 expression and estrogen receptor status. Pathol Int. 2001; 51:94–9.

27. Raju B, Mehrotra R, Oijordsbakken G, Al-Sharabi AK, Vasstrand EN, Ibrahim SO. Expression of p53, cyclin D1 and Ki-67 in premalignant and malignant oral lesions: association with clinicopathological parameters. Anticancer Res. 2005; 25:4699–706.

28. Ryu IS, Song CI, Choi SH, Roh JL, Nam SY, Kim SY. Lymph node ratio of the central compartment is a significant predictor for locoregional recurrence after prophylactic central neck dissection in patients with thyroid papillary carcinoma. Ann Surg Oncol. 2014; 21:277–83.

29. Jeon MJ, Yoon JH, Han JM, Yim JH, Hong SJ, Song DE, et al. The prognostic value of the metastatic lymph node ratio and maximal metastatic tumor size in pathological N1a papillary thyroid carcinoma. Eur J Endocrinol. 2013; 168:219–25.

30. Lang BH, Wong KP, Wan KY, Lo CY. Significance of metastatic lymph node ratio on stimulated thyroglobulin levels in papillary thyroid carcinoma after prophylactic unilateral central neck dissection. Ann Surg Oncol. 2012; 19:1257–63.

Fig. 1.

IHC stain of p53 and cyclin D1 in PTC. Typical histology of inclusion bodies and nuclear groove (A, ×200). IHC of p53 detected in nuclei of multiple tumor cells (B, ×200). Cyclin D1 were detected diffusely in nuclei and cytoplasm of tumor cells (C, ×200).

Table 1.

Clinicopathologic characteristics of 919 thyroid cancer patients

Variables	Results n=919
Age (yr)
Mean (range)	49.73 (15∼87)
Sex
Female	776 (84.4%)
Male	143 (15.6%)
Tumor size (cm)
Mean (range)	1.19 (0.1∼5.0)
PTMC
≤1 cm	479 (52.1%)
＞1 cm	440 (47.9%)
ETE
(−)	326 (35.5%)
(＋)	593 (64.5%)
Capsulation^*
＞50	49 (5.3%)
＞5 and ≤50	181 (19.7%)
≤5	688 (74.9%)
LV invasion
(−)	756 (82.3%)
(＋)	163 (17.7%)
Bilaterality
(−)	632 (68.8%)
(＋)	287 (31.2%)
Multifocality
(−)	486 (52.9%)
(＋)	433 (47.1%)
Histology
PTC	909 (98.9%)
PTC, follicular variant	7 (0.8%)
PTC, oncocytic variant	1 (0.1%)
PTC, tall cell variant	2 (0.2%)
Operation method
Total thyroidectomy with CND	830 (90.3%)
Total thyroidectomy with CND & LND	89 (9.7%)
T stage
T1/2	324 (35.3%)
T3	541 (58.9%)
T4	54 (5.9%)
N stage
N0	412 (44.8%)
N1	507 (55.2%)
Stage
I/II	432 (47.0%)
III	419 (45.6%)
IV	68 (7.4%)

PTMC = papillary thyroid microcarcinoma; ETE = extrathyroidal extension; LV = lymphovascular; PTC = papillary thyroid cancer; CND = central neck cissection; LND = lateral neck dissection. *n=918.

Table 2.

Differences of clinicopathologic characteristics according to p53 and cyclin D1

Variables		p53		P value	Cyclin D1		P value
Variables		(＋) n=809	(−) n=110	P value	(＋) n=748	(−) n=171	P value
Age (yr)	Mean±SD	49.99±11.47	47.81±11.49	0.061	49.86±11.45	49.19±11.69	0.497
Sex	Female	692 (85.5%)	84 (76.4%)	0.013	634 (84.8%)	142 (83.0%)	0.576
	Male	117 (14.5%)	26 (23.6%)		114 (15.2%)	29 (17.0%)
Size (cm)	Mean±SD	1.19±0.73	1.16±0.82	0.709	1.20±0.73	1.13±0.78	0.273
PTMC	＞1 cm	387 (47.8%)	53 (48.2%)	0.946	363 (48.5%)	77 (45.0%)	0.408
	≤1 cm	422 (52.2%)	57 (51.8%)		385 (51.5%)	94 (55.0%)
Recurrence	(＋)	12 (1.5%)	3 (2.7%)	0.409	11 (1.5%)	4 (2.3%)	0.499
	(−)	797 (98.5%)	107 (97.3%)		737 (98.5%)	167 (97.7%)
ETE	(＋)	517 (63.9%)	76 (69.1%)	0.286	477 (63.8%)	116 (67.8%)	0.316
	(−)	292 (36.1%)	34 (30.9%)		271 (36.2%)	55 (32.2%)
Capsulation^*	＞50	41 (5.1%)	8 (7.3%)	0.591	38 (5.1%)	11 (6.4%)	0.007^†
	＞5 and ≤50	161 (19.9%)	20 (18.3%)		162 (21.7%)	19 (11.1%)
	≤5	607 (75.0%)	81 (74.3%)		547 (73.2%)	141 (82.5%)
LV invasion	(＋)	146 (18.0%)	17 (15.5%)	0.504	140 (18.7%)	23 (13.5%)	0.104
	(−)	663 (82.0%)	93 (84.5%)		608 (81.3%)	148 (86.5%)
Multifocality	(＋)	370 (45.7%)	63 (57.3%)	0.023	345 (46.1%)	88 (51.5%)	0.207
	(−)	439 (54.3%)	47 (42.7%)		403 (53.9%)	83 (48.5%)
Bilaterality	(＋)	250 (30.9%)	37 (33.6%)	0.562	231 (30.9%)	56 (32.7%)	0.635
	(−)	559 (69.1%)	73 (66.4%)		517 (69.1%)	115 (67.3%)
T stage	T1/2	291 (36.0%)	33 (30.0%)	0.014^‡	271 (36.2%)	53 (31.0%)	0.030^§
	T3	477 (59.0%)	64 (58.2%)		440 (58.85)	101 (59.1%)
	T4	41 (5.1%)	13 (11.8%)		37 (4.9%)	17 (9.9%)
N stage	N0	359 (44.4%)	53 (48.2%)	0.451	332 (44.4%)	80 (46.8%)	0.569
	N1	450 (55.6%)	57 (51.8%)		416 (55.6%)	91 (53.2%)
Stage	I/II	376 (46.5%)	56 (50.9%)	0.002^∥	350 (46.8%)	82 (48.0%)	0.469
	III	381 (47.1%)	38 (34.5%)		346 (46.3%)	73 (42.7%)
	IV	52 (6.4%)	16 (14.5%)		52 (7.0%)	16 (9.4%)
Meta-ratio^¶		15.36±18.78	13.71±17.64	0.430	15.53±18.99	13.59±16.96	0.262
MACIS		5.08±1.00	4.98±0.89	0.342	5.07±0.99	5.05±0.98	0.800
Follow-up (m)		22.59±7.700	22.64±7.05	0.949	22.52±7.93	22.92±6.11	0.460

PTMC = papillary thyroid microcarcinoma; ETE = extrathyroidal extension; LV = lymphovascular. *n=918,

^† 0.099 by linear by linear analysis,

^‡ 0.073 by linear by linear analysis,

^§ 0.075 by linear by linear analysis,

^∥ 0.947 by linear by linear analysis,

^¶ n=783.

Table 3.

Clinicopathologic characteristics according to p53 and cyclin D1 status

Variables		p53/Cyclin D1 (−/−)	p53/Cyclin D1 (−/＋)	p53/Cyclin D1 (＋/−)	p53/Cyclin D1 (＋/＋)
Variables		n=73	n=37	n=98	n=711
Age (yr)	Mean±SD	48.66±10.76	46.14±12.80	49.59±12.38	50.05±11.35
Sex	Female	58 (79.5%)	26 (70.3%)	84 (85.7%)	608 (85.5%)
	Male	15 (20.5%)	11 (29.7%)	14 (14.3%)	103 (14.5%)
Size (cm)	Mean±SD	1.13±0.86	1.23±0.76	1.13±0.71	1.20±0.73
PTMC	＞1 cm	33 (45.2%)	20 (54.1%)	44 (44.9%)	343 (48.2%)
	≤1 cm	40 (54.8%)	17 (45.9%)	54 (55.1%)	368 (51.8%)
Recurrence	(＋)	1 (1.4%)	2 (5.4%)	2 (2.0%)	7 (1.0%)
	(−)	72 (98.6%)	35 (94.6%)	96 (98.0%)	704 (99.0%)
ETE	(＋)	50 (68.5%)	26 (70.3%)	66 (67.3%)	451 (63.4%)
	(−)	23 (31.5%)	11 (29.7%)	32 (32.7%)	260 (36.6%)
Capsulation^*	＞50	7 (9.6%)	1 (2.8%)	4 (4.1%)	37 (5.2%)
	＞5 and ≤50	9 (12.3%)	11 (30.6%)	10 (10.2%)	151 (21.2%)
	≤5	57 (78.1%)	24 (66.7%)	84 (85.7%)	523 (73.6%)
LV invasion	(＋)	8 (11.0%)	9 (24.3%)	15 (15.3%)	131 (18.4%)
	(−)	65 (89.0%)	28 (75.7%)	83 (84.7%)	580 (81.6%)
Multifocality	(＋)	41 (56.2%)	22 (59.5%)	47 (48.0%)	323 (45.4%)
	(−)	32 (43.8%)	15 (40.5%)	51 (52.0%)	388 (54.6%)
Bilaterality	(＋)	25 (34.2%)	12 (32.4%)	31 (31.6%)	219 (30.8%)
	(−)	48 (65.8%)	25 (67.6%)	67 (68.4%)	492 (69.2%)
T stage	T1/2	22 (30.1%)	11 (29.7%)	31 (31.6%)	260 (36.6%)
	T3	41 (56.2%)	23 (62.2%)	60 (61.2%)	417 (58.6%)
	T4	10 (13.7%)	3 (8.1%)	7 (7.1%)	34 (4.8%)
N stage	N0	36 (49.3%)	17 (45.9%)	44 (44.9%)	315 (44.3%)
	N1	37 (50.7%)	20 (54.1%)	54 (55.1%)	396 (55.7%)
Stage	I/II	36 (49.3%)	20 (54.1%)	46 (46.9%)	330 (46.4%)
	III	27 (37.0%)	11 (29.7%)	46 (46.9%)	335 (47.1%)
	IV	10 (13.7%)	6 (16.2%)	6 (6.1%)	46 (6.50%)
Meta-ratio^†		10.29±12.53	20.23±23.50	15.91±19.22	15.29±18.73
MACIS		5.00±0.89	4.96±0.91	5.09±1.04	5.08±0.99
Follow-up (m)		23.42±6.39	21.08±8.06	22.55±5.90	22.59±7.92

PTMC = papillary thyroid microcarcinoma; ETE = extrathyroidal extension; LV = lymphovascular. *n=918,

^† n=783.

Table 4.

Metastatic LN ratio between groups in 783 patients

		Metastatic LN	Retrieved LN	Meta-ratio
p53(−)	CyclinD1 (−) n=73	2.21±4.32	16.99±16.79	10.29±12.53
	CyclinD1 (＋) n=37	3.81±6.53	18.11±23.83	20.23±23.50
	P value	0.182	0.775	0.034
p53(＋)	CyclinD1 (−) n=98	2.97±6.31	16.10±13.86	15.91±19.22
	CyclinD1 (＋) n=711	2.66±4.38	16.00±12.98	15.29±18.73
	P value	0.501	0.943	0.776
CyclinD1(−)	p53 (−) n=73	2.21±4.32	16.99±16.79	10.29±12.53
	p53 (＋) n=98	2.97±6.31	16.10±13.86	15.91±19.22
	P value	0.375	0.707	0.036
CyclinD1(＋)	p53 (−) n=98	3.81±6.53	18.11±23.83	20.23±23.50
	p53 (＋) n=711	2.66±4.38	16.00±12.98	15.29±18.73
	P value	0.297	0.597	0.258
p53(−)/CyclinD1 (−) n=73		2.21±4.32	16.99±16.79	10.29±12.53
p53(＋)/CyclinD1 (＋) n=37		2.66±4.38	16.00±12.98	15.29±18.73
P value		0.394	0.549	0.007

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