 |
|
Underexpression of p27/Kip in Thyroid Papillary Microcarcinomas With Gross Metastatic Disease
Mark L. C. Khoo, FRCS;
Jeremy L. Freeman, MD;
Ian J. Witterick, MD;
Jonathan C. Irish, MD;
Lorne E. Rotstein, MD;
Patrick J. Gullane, MD;
Sylvia L. Asa, MD, PhD
Arch Otolaryngol Head Neck Surg. 2002;128:253-257.
ABSTRACT
| |
Objective Papillary microcarcinomas (PMCs) of the thyroid (measuring less than
1 cm in maximum dimension) are extremely common incidental histologic findings,
and most of these tumors are not considered clinically significant. However,
rare PMCs behave aggressively and metastasize early, giving rise to clinically
significant metastatic disease. We hypothesized that p27 and MIB-1/Ki-67 immunoreactivity
would allow us to identify this small subgroup of PMCs that have the potential
to behave aggressively.
Methods We reviewed the histopathology reports of 2000 patients who underwent
thyroid surgery at our institution between 1995 and 1999 and identified 22
patients who presented with gross regional metastases from a primary PMC.
The primary and metastatic tumors were stained for ret, p53, p27, and MIB-1
using the avidin-biotin-peroxidase complex technique. A control group of 33
nonmetastasizing PMCs was also analyzed.
Results Immunoreactivity for ret, p53, and MIB-1 showed no difference between
metastasizing and nonmetastasizing PMCs. In most tumors, ret was present,
while p53 immunoreactivity was absent in all tumors. MIB-1 staining was present
in a small number of cells in both groups of tumors. Immunoreactivity for
p27 was quantitated by the intensity of expression as well as the distribution
of positive cells within each tumor. All tumors showed lower p27 expression
than normal thyroid tissue. However, metastasizing PMCs demonstrated a significantly
lower expression of p27 than nonmetastasizing PMCs (P<.001).
Conclusion Our results suggest that p27 immunohistochemical analysis may be a valuable
diagnostic tool in predicting aggressive potential in PMCs.
INTRODUCTION
PAPILLARY microcarcinomas (PMCs) of the thyroid are defined as small
papillary carcinomas measuring less than 1 cm in maximum dimension. They are
extremely common findings on histopathologic analysis following both thyroid
surgery and autopsy, and their clinical significance is still debated. Several
large studies have shown that the vast majority of PMCs behave in an indolent
manner and remain dormant throughout a patient's lifetime. They almost never
give rise to clinically overt disease, nor do they result in morbidity or
mortality.1-2 Therefore, most
clinicians regard these tumors as incidental findings of little clinical significance.
While papillary thyroid carcinomas have a strong propensity to metastasize
to regional lymph nodes, clinically detectable lymph node metastases from
PMCs are very uncommon. Nonetheless, on rare occasions, a PMC behaves aggressively
and metastasizes early, presenting with clinically evident lymph node metastases.
These tumors then seem to confer a definite morbidity and mortality.3 To date, traditional histopathologic assessment has
not been able to distinguish between the typical PMC, which almost always
remains quiescent, and the unusual PMC that has the potential to behave aggressively.
Several genetic alterations have been associated with the development
of papillary thyroid carcinoma. Rearrangements of the ret gene on chromosome 10 have been well described. These ret/PTC rearrangements seem to be specific for papillary thyroid carcinoma
and are thought to occur early in the carcinogenetic process.4
Inactivation of the p53 tumor suppressor gene does
not seem to play a role in the development of well-differentiated carcinomas
of the thyroid gland. However, when dedifferentiation to anaplastic carcinoma
occurs, a p53 mutation is frequently present.5-6
Several other genes have also recently been implicated in thyroid carcinogenesis,
including the tumor suppressor genes p27 and PTEN and the tumor oncogene cyclin D1. In an effort to
identify PMCs that have the potential to behave aggressively, we studied 22
metastasizing PMCs and 33 nonmetastasizing PMCs using immunohistochemical
analysis of ret, p53, MIB-1, and p27.
METHODS AND MATERIALS
We reviewed our database on thyroid cancer and the histopathology reports
of 2000 patients who had undergone thyroid surgery at our institution between
1995 and 1999 and identified 30 patients who had pathologically proven lymph
node metastases from a primary PMC in the thyroid gland (T1 N1 disease). Among
these, 22 patients had gross ( 2 cm) nodal metastases from an occult PMC
of the thyroid gland. These patients initially presented with clinically evident
lymph node metastases from an unknown primary tumor. Only after fine needle
aspiration cytology, and in some cases lymph node excision biopsy, were these
metastases shown to be of thyroid origin. Subsequent thyroidectomy then revealed
the primary lesion to be a PMC.
The other 8 patients had undergone thyroidectomy for various nonmalignant
indications and had been incidentally found to have a PMC as well as microscopic
metastatic deposits in a perithyroidal lymph node. Because the significance
of these lesions with micrometastatic foci remains unknown,3
we elected to exclude these from further analysis.
We immunohistochemically analyzed archival paraffin-embedded tissue
from the 22 tumors with gross metastatic disease for ret, p53, MIB-1, and
p27 staining. The control group, 33 randomly selected nonmetastasizing PMCs,
underwent similar analysis. These PMCs were selected from thyroid glands that
had been excised for nodular hyperplasia. Papillary microcarcinomas from glands
containing malignancy were not included. To extend our analysis on p27, we studied 2 groups of larger papillary carcinomas as well, 14
with gross nodal metastases and 20 without nodal involvement. We hypothesized
that p27 expression might predict the metastatic
potential of papillary carcinomas in general, and we included these larger
tumors as an additional control. In selecting these papillary carcinomas,
we selected typical papillary cancers between 2 and 4 cm in size without evidence
of extrathyroidal extension. We also excluded tumors with poor histologic
features such as tall-cell or columnar-cell differentiation and tumors with
poorly differentiated or anaplastic foci.
IMMUNOHISTOCHEMICAL ANALYSIS
The metastasizing and nonmetastasizing PMCs were analyzed by immunohistochemical
analysis using antibodies for ret, p53, MIB-1, and p27. The 2 groups of larger
papillary carcinomas were analyzed for MIB-1 and p27.
Formalin-fixed, paraffin-embedded sections 3 µm thick were dewaxed
in toluene and rehydrated through graded alcohols to water. Endogenous peroxidase
activity was blocked in 3% hydrogen peroxide. Antigen retrieval was performed
in 10mM citrate buffer (pH, 6.0) inside a microwave pressure cooker for p53,
MIB-1, and p27, and by formic acid pretreatment for ret. Endogenous biotin
detection was blocked with the Avidin-Biotin Blocking Kit (Vector Lab Inc,
Burlingame, Calif). Primary antibody incubations were carried out at room
temperature as follows: ret, rabbit polyclonal (C-19) (Santa Cruz Biotechnology
Inc, Santa Cruz, Calif), 1:1000 dilution, overnight incubation; p53, mouse
monoclonal (D0-7) (Novocastra Ltd, Newcastle upon Tyne, England), 1:100 dilution,
1-hour incubation; MIB-1, mouse monoclonal (MIB-1) (Immunotech, Marseille,
France), 1:200 dilution, 1-hour incubation; and p27/Kip1, mouse monoclonal
(57) (BD PharMingen, Mississauga, Ontario), 1:1000 dilution, 1-hour incubation.
Following washing in phosphate-buffered saline, secondary incubations were
carried out with biotin antimouse/antirabbit IgG followed by streptavidin-HRP
(horseradish peroxidase) (Signet Pathology System, Dedham, Mass) for 30 minutes.
Immunoreactivity was revealed by incubation in 3-amino-9-ethylcarbazol. Slides
were counterstained in hematoxylin and mounted with Crystal Mount (Biomeda
Corp, Foster City, Calif).
QUANTITATION
Quantitation of immunoreactivity was done jointly by 2 of the authors
(M.L.C.K. and S.L.A.); ret and p53 immunoreactivity was assessed by the presence
or absence of staining in some or all of the tumor cells. MIB-1 expression
was quantified as a labeling index based on the number of positive tumor cells
per high-power field. Only nuclear staining in thyroid follicular cells was
considered positive staining for p53 and MIB-1. Immunoreactivity displayed
by fibrovascular stromal and lymphoid cells within the tumors was not considered.
Small tumors were assessed en toto. For larger tumors, 3 separate high-power
fields per tumor were studied and counted, and the final index was an average
of the 3 counts.
Expression of p27 was assessed based on the intensity of nuclear staining
within the tumor cells. Again, immunoreactivity displayed by fibrovascular
stromal and lymphoid cells was not considered. The intensity of staining was
graded as 0 to 4 as follows: grade 0 for total absence of staining; grade
1 for faint nuclear staining (requiring high-power assessment); grade 2 for
moderate nuclear staining (easily seen); grade 3 for strong nuclear staining
(but noticeably less than normal); and grade 4 for staining as strong as adjacent
normal thyroid tissue.
Quantitation of p27 immunoreactivity was based on the prevalent intensity
of staining within the tumor. Most specimens displayed a uniform intensity
of staining throughout the tumor, and in such cases the quantitation was straightforward.
For the occasional tumor with a more heterogeneous expression, we graded the
p27 immunoreactivity according to the intensity displayed by the majority
of tumor cells.
For each group of metastasizing PMCs and carcinomas, we used a corresponding
group of nonmetastasizing tumors as external controls. Internal control within
each slide was provided by adjacent normal thyroid or lymphoid tissue, which
invariably showed strong nuclear staining for p27 and served as the benchmark
for assessment of intensity.
STATISTICAL ANALYSIS
Statistical analysis was performed using the t
test for MIB-1 expression and the  2 test for p27 expression.
For the latter calculation, as very few tumor samples showed either grade
0 or grade 4 p27 expression, we merged grades 0 and 1, and grades 3 and 4.
This resulted in 3 grades per tumor group: grade 0-1, grade 2, and grade 3-4.
Statistical significance was ascribed at P<.05.
RESULTS
ret AND p53
There was no difference in the immunoreactivity for ret and p53 between
the metastasizing and nonmetastasizing PMCs. In most of the tumors ret was
present in both groups, while p53 immunoreactivity was absent in all tumors
in both groups.
MIB-1 (Ki-67)
MIB-1 immunoreactivity was present in a small number of cells in both
metastasizing and nonmetastasizing PMCs. In the nonmetastasizing microcarcinomas,
the MIB-1 labeling index ranged from 0 to 30, with a mean of 6.89 and a median
of 4.5. In the metastasizing microcarcinomas, the MIB-1 labeling index ranged
from 2 to 37, with a mean of 10.17 and a median of 6.5. As is apparent, there
was considerable overlap in the labeling indices between the 2 groups, and
while the mean and median labeling indices were slightly higher in the group
with metastases, these differences were not statistically significant.
p27/Kip1
Nuclear p27 immunoreactivity was very strong in normal thyroid follicular
cells, fibrovascular stromal cells, and lymphocytes. Almost all the tumors,
including both larger carcinomas and microcarcinomas, showed lower than normal
p27 expression, though the degree of underexpression varied. Of 89 tumors,
only 4 showed normal (grade 4) p27 expression. Two of these were nonmetastasizing
PMCs, while the other 2 were nonmetastasizing papillary carcinomas.
For the PMCs as well as the larger papillary cancers, the tumors with
metastases showed significantly less p27 expression than the tumors without
metastases (P<.001 and P<.005,
respectively). Of the 22 metastasizing PMCs, 15 tumors (68.2%) showed very
faint (grade 0 and 1) p27 expression (Figure
1) compared with only 6 tumors with moderate (grade 2) staining
(Figure 2) and 1 tumor with strong
(grade 3) staining. Conversely, of the 33 nonmetastasizing PMCs, only 6 tumors
(18.2%) showed faint (grade 1) p27 expression compared with 15 tumors with
moderate (grade 2) staining, 10 tumors with strong (grade 3) staining (Figure 3) and 2 tumors with very strong (grade
4) staining.
|
|
|
|
Figure 1. Papillary microcarcinoma with
metastases showing faint (grade 1) p27 expression at x20 magnification
(A) and x40 magnification (B).
|
|
|
|
|
|
|
Figure 2. Papillary microcarcinoma with
metastases showing moderate (grade 2) p27 expression at x20 magnification
(A) and x40 magnification (B).
|
|
|
|
|
|
|
Figure 3. Incidentally discovered papillary
microcarcinoma with no evidence of metastasis showing strong (grade 3) p27
expression at x20 magnification (A) and x40 magnification (B).
|
|
|
For the larger papillary carcinomas, the results were similar. Of the
14 papillary carcinomas with metastases, 7 (50%) showed faint (grade 1) p27
expression while 7 (50%) showed moderate (grade 2) p27 expression. However,
of the 20 papillary carcinomas without metastases, only 2 (10%) showed faint
(grade 0-1) p27 expression compared with 8 with moderate (grade 2) staining,
8 with strong (grade 3) staining, and 2 with very strong (grade 4) staining.
The results of the immunostaining for p27 are summarized in Table 1 and Table 2.
|
|
|
|
Table 1. Grading of p27/Kip-1 Immunoreactivity According to Intensity
of Nuclear Staining*
|
|
|
|
|
|
|
Table 2. Statistical Results of p27/Kip-1 Staining*
|
|
|
COMMENT
Papillary thyroid microcarcinomas with gross metastatic disease are
extremely uncommon. However, a small subgroup of PMCs have the potential to
behave aggressively and metastasize early, resulting in increased morbidity
and mortality.3
Routine histopathologic analysis is unable to distinguish between the
typical PMC, which tends to remain quiescent, and the rare PMC with the potential
for aggressive behavior. We undertook this study to try to identify immunohistochemical
markers that might allow us to recognize the potentially aggressive lesions.
We hypothesized that one or several tumor genes might influence the behavior
and metastatic potential of PMCs.
A small number of PMCs are considered incidental findings yet are found
to be associated with micrometastatic disease in lymph nodes on careful histologic
examination. We identified 8 such cases in our series. The true incidence
of this phenomenon is not known, and the clinical significance of these lesions
remains unclear.3 Indeed, the clinical significance
of micrometastatic spread of larger papillary thyroid carcinomas remains controversial.
We therefore elected to omit these cases from our analysis. However, it will
be interesting to apply the results of our study to larger groups of thyroid
carcinomas with micrometastases.
The ret/PTC gene rearrangement, which may take
one of several forms, has been shown to occur only in papillary carcinomas
of the thyroid gland7 and is not seen in other
tumors of thyroid follicular cell origin. These rearrangements result in fusion
of the intracellular domain of the ret protooncogene
with N-terminal portions of other genes that are expressed in follicular epithelium.
Rearrangements of ret in papillary thyroid carcinoma
have been shown to occur early in the carcinogenetic process.4
Interestingly, the incidence of ret/PTC rearrangement
seems to be higher in PMCs than in larger papillary carcinomas. Members of
our group7 have reported that the incidence
of ret/PTC rearrangement in PMCs was almost 80% vs
40% for larger papillary carcinomas.
The significance of ret rearrangements in papillary
thyroid carcinoma is still unclear. Several reports have suggested that ret rearrangement may predict aggressive behavior, including
local invasion and the potential for metastases.8
However, expression of ret/PTC gene products seems to be reduced in papillary
carcinomas with aggressive histologic features such as columnar and tall-cell
papillary variants and papillary tumors showing dedifferentiation toward poorly
differentiated and anaplastic carcinoma. Other reports have suggested that
ret/PTC positivity predicts an indolent phenotype.9-10
We hypothesized that immunoreactivity for ret might help distinguish
between metastasizing and nonmetastasizing PMCs. However, we found that most
of the microcarcinomas stained for ret under immunohistochemical analysis,
and there was no difference between the 2 groups. These results are similar
to those previously reported.7 This indicates
that while ret rearrangement plays a role in the
development of papillary carcinoma, it does not influence the metastatic potential
of early papillary thyroid carcinomas.
p53 Mutation resulting in protein overexpression is a common feature
of poorly differentiated and anaplastic thyroid carcinomas but is uncommon
in well-differentiated thyroid carcinomas. However, p53 overexpression is
seen with increasing frequency in papillary carcinomas with poor histologic
features such as tall-cell or columnar-cell morphologic characteristics11 and in tumors with evidence of dedifferentiation.6 Overexpression of p53 has also been linked to the
potential for papillary carcinomas to metastasize to regional lymph nodes.5, 12
We studied p53 immunoreactivity in both metastasizing and nonmetastasizing
PMCs. None of the tumors showed nuclear accumulation of p53 protein. Therefore,
while p53 inactivation may play a role in the dedifferentiation of well-differentiated
thyroid carcinoma, it does not seem to play a role in the potential for PMCs
to metastasize.
MIB-1/Ki-67 expression is a marker of proliferative activity and has
been shown to be significantly higher in poorly differentiated and anaplastic
carcinomas than in well-differentiated carcinomas.13-15
The relationship between MIB-1 labeling index and the risk of metastases is,
however, less clear. In a study of follicular thyroid carcinoma, Erickson
et al13 found significantly higher MIB-1 expression
in patients with distant metastases. Similarly, Sugitani et al3
found a significantly higher MIB-1 labeling index in patients with PMCs who
died of distant metastases. However, Tallini et al14
found no association between MIB-1 expression and metastases in their patients
with well-differentiated thyroid carcinomas.
In our study, the mean and median MIB-1 labeling indices were higher
in the metastasizing PMCs than in the nonmetastasizing microcarcinomas. However,
the differences were not statistically significant.
The p27/Kip-1 gene is a tumor suppressor gene
that encodes a 27-kd protein, a cyclin-dependent kinase inhibitor. This protein
acts as a negative regulator of the cell cycle, controlling G1
to S phase transition. Reduced p27 function has been implicated in the pathogenesis
of several malignancies. While rearrangements and mutations of the p27 gene are uncommon, underexpression of nuclear p27 protein has been
shown to occur in cancers of several organs.16-25
Furthermore, p27 underexpression seems to predict a more aggressive tumor
phenotype as well as poorer survival. Underexpression of p27 has also been
associated with an increased risk of lymph node metastases in adenocarcinomas
of the colon,16 stomach,17-18
breast,19 prostate,20
and salivary gland.21 In the thyroid gland,
p27 is strongly expressed in the nuclei of normal follicular thyroid cells
but is underexpressed in hyperplastic and neoplastic thyroid disease.22 Thyroid tumors have been shown to express significantly
less p27 than hyperplastic nodules,23 and malignant
tumors express significantly less p27 than do benign tumors.13, 24
Poorly differentiated thyroid carcinomas also express less p27 than well-differentiated
thyroid carcinomas.25 Expression of p27 has
also been reported to show an inverse correlation with MIB-1 expression.22
In this study, we hypothesized that PMCs that demonstrated aggressive
potential and early metastases might have lower p27 expression than typical
PMCs. We quantified the expression of p27 by assessing the intensity of nuclear
staining in thyroid tumor cells. Previous studies have quantified p27 expression
based on a labeling index of positive cells per 1000 cells counted. This strategy
was effective when comparing groups with different thyroid diseases (eg, hyperplasia
vs neoplasia or benign tumors vs malignant tumors). However, in our study
we were comparing groups with similar pathologic characteristics, and we found
that the percentage of cells expressing p27 was very similar between the 2
groups of microcarcinomas and the 2 groups of papillary carcinomas. It was
the intensity of p27 expression that varied between tumors. We therefore graded
the tumors according to the intensity of p27 expression.
Our results show that p27 is significantly underexpressed in metastasizing
PMCs compared with nonmetastasizing PMCs. Thus, p27 immunohistochemical analysis
seems useful to distinguish the rare PMCs that have the potential to behave
aggressively from the typical PMCs that tend to remain quiescent. Our results
also show that p27 underexpression predicts an increased risk of lymph node
metastases in larger papillary thyroid carcinomas. This further illustrates
the value of p27 immunohistochemical analysis in predicting behavior in papillary
thyroid cancer. Our data indicate that PMCs that underexpress p27 should no
longer be regarded as incidental findings of little significance, but as true
papillary carcinomas with the potential for aggressive behavior.
In conclusion, p27 seems to be significantly underexpressed in PMCs
as well as in larger papillary carcinomas of the thyroid that metastasize
to regional lymph nodes. Immunohistochemical analysis for p27 may be a valuable
diagnostic tool in distinguishing PMCs of the thyroid with aggressive potential
from the more typical indolent lesions and may also prove useful for predicting
the metastatic potential of larger papillary cancers of the thyroid.
AUTHOR INFORMATION
Accepted for publication November 2, 2001.
This study was presented at the annual meeting of the American Head
and Neck Society, Palm Desert, Calif, May 16, 2001.
We would like to thank James Ho and Kelvin So for excellent technical
assistance in the completion of this work.
Corresponding author: Sylvia L. Asa, MD, PhD, Department of Pathology,
University Health Network, 610 University Ave, Suite 4-302, Toronto, Ontario,
Canada M5G 2M9 (e-mail: sylvia.asa{at}uhn.on.ca).
From the Department of Otolaryngology, Mount Sinai Hospital, Toronto,
Ontario (Drs Khoo, Freeman, and Witterick), and the Departments of Otolaryngology
(Drs Irish and Gullane), Surgery (Dr Rotstein), and Pathology (Dr Asa), University
Health Network, University of Toronto, Ontario.
REFERENCES
| |
1. Hubert JP, Kiernan PD, Beahrs OH, McConahey WM, Woolner LB. Occult papillary carcinoma of the thyroid. Arch Surg. 1980;115:394-398.
ABSTRACT
2. Fink A, Tomlinson G, Freeman JL, Rosen IB, Asa SL. Occult micropapillary carcinoma associated with benign follicular thyroid
disease and unrelated thyroid neoplasms. Mod Pathol. 1996;9:816-820.
ISI
| PUBMED
3. Sugitani I, Yanagisawa A, Shimizu A, Kato M, Fujimoto Y. Clinicopathologic and immunohistochemical studies of papillary thyroid
microcarcinoma presenting with cervical lymphadenopathy. World J Surg. 1998;22:731-737.
FULL TEXT
|
ISI
| PUBMED
4. Viglietto G, Chiappetta G, Martinez-Tello FJ, et al. RET/PTC oncogene activation is an early event in thyroid carcinogenesis. Oncogene. 1995;11:1207-1210.
ISI
| PUBMED
5. Hosal SA, Apel RL, Freeman JL, et al. Immunohistochemical localization of p53 in human thyroid neoplasms:
correlation with biological behavior. Endocr Pathol. 1997;8:21-28.
ISI
| PUBMED
6. Dobashi Y, Sugimura H, Sakamoto A, et al. Stepwise participation of p53 gene mutation during dedifferentiation
of human thyroid carcinomas. Diagn Mol Pathol. 1994;3:9-14.
ISI
| PUBMED
7. Sugg SL, Ezzat S, Rosen IB, Freeman JL, Asa SL. Distinct multiple RET/PTC gene rearrangements in multifocal papillary
thyroid neoplasia. J Clin Endocrinol Metab. 1998;83:4116-4122.
FREE FULL TEXT
8. Miki H, Kitaichi M, Masuda E, Komaki K, Yamamoto Y, Monden Y. ret/PTC expression may be associated with local invasion of thyroid
papillary carcinoma. J Surg Oncol. 1999;71:76-81.
FULL TEXT
|
ISI
| PUBMED
9. Soares P, Fonseca E, Wynford-Thomas D, Sobrinho-Simoes M. Sporadic ret-rearranged papillary carcinoma of the thyroid: a subset
of slow growing, less aggressive thyroid neoplasms? J Pathol. 1998;185:71-78.
FULL TEXT
|
ISI
| PUBMED
10. Tallini G, Santoro M, Helie M, et al. RET/PTC oncogene activation defines a subset of papillary thyroid carcinomas
lacking evidence of progression to poorly differentiated or undifferentiated
tumor phenotypes. Clin Cancer Res. 1998;4:287-294.
FREE FULL TEXT
11. Ruter A, Dreifus J, Jones M, Nishiyama R, Lennquist S. Overexpression of p53 in tall-cell variants of papillary thyroid carcinoma. Surgery. 1996;120:1046-1050.
FULL TEXT
|
ISI
| PUBMED
12. Chen BK, Ohtsuki Y, Furihata M, et al. Co-overexpression of p53 protein and epidermal growth factor receptor
in human papillary thyroid carcinomas correlated with lymph node metastases,
tumor size and clinicopathologic stage. Int J Oncol. 1999;15:893-898.
ISI
| PUBMED
13. Erickson LA, Jin L, Wollan PC, Thompson GB, van Heerden J, Lloyd RV. Expression of p27kip1 and Ki-67 in benign and malignant thyroid tumors. Mod Pathol. 1998;11:169-174.
ISI
| PUBMED
14. Tallini G, Garcia-Rostan G, Herrero A, et al. Downregulation of p27Kip1 and Ki67/Mib1 labeling index support the
classification of thyroid carcinoma into prognostically relevant categories. Am J Surg Pathol. 1999;23:678-685.
FULL TEXT
|
ISI
| PUBMED
15. Ozaki O, Ito K, Mimura T, Sugino K, Ito K. Anaplastic transformation of papillary thyroid carcinoma in recurrent
disease in regional lymph nodes: a histologic and immunohistochemical study. J Surg Oncol. 1999;70:45-48.
FULL TEXT
|
ISI
| PUBMED
16. Thomas GV, Szigeti K, Murphy M, Draetta G, Pagano M, Loda M. Down-regulation of p27 is associated with development of colorectal
adenocarcinoma metastases. Am J Pathol. 1998;153:681-687.
FREE FULL TEXT
17. Yasui W, Kudo Y, Semba S, Yokozaki H, Yahara E. Reduced expression of cyclin-dependent kinase inhibitor p27Kip1 is
associated with advanced stage and invasiveness of gastric carcinomas. Jpn J Cancer Res. 1997;88:625-629.
FULL TEXT
|
ISI
| PUBMED
18. Kim DH, Lee HI, Nam ES, et al. Reduced expression of the cell-cycle inhibitor p27Kip1 is associated
with progression and lymph node metastases of gastric carcinoma. Histopathology. 2000;36:245-251.
FULL TEXT
|
ISI
| PUBMED
19. Wu J, Shen ZZ, Lu JS, et al. Prognostic role of p27Kip1 and apoptosis in human breast cancer. Br J Cancer. 1999;79:1572-1578.
FULL TEXT
|
ISI
| PUBMED
20. Cheville JC, Lloyd RV, Sebo TJ, et al. Expression of p27kip1 in prostatic adenocarcinoma. Mod Pathol. 1998;11:324-328.
ISI
| PUBMED
21. Takata T, Kudo Y, Zhao M, et al. Reduced expression of p27(Kip1) protein in relation to salivary adenoid
cystic carcinoma metastasis. Cancer. 1999;86:928-935.
FULL TEXT
|
ISI
| PUBMED
22. Lloyd RV, Jin L, Qian X, Kulig E. Aberrant p27kip1 expression in endocrine and other tumors. Am J Pathol. 1997;150:401-407.
ABSTRACT
23. Erickson LA, Yousef OM, Jin L, Lohse CM, Pankratz VS, Lloyd RV. p27kip1 expression distinguishes papillary hyperplasia in Graves' disease
from papillary thyroid carcinoma. Mod Pathol. 2000;13:1014-1019.
FULL TEXT
|
ISI
| PUBMED
24. Wang S, Wuu J, Savas L, Patwardhan N, Khan A. The role of cell cycle regulatory proteins, cyclin D1, cyclin E, and
p27 in thyroid carcinogenesis. Hum Pathol. 1998;29:1304-1309.
FULL TEXT
|
ISI
| PUBMED
25. Resnick MB, Schacter P, Finkelstein Y, Kellner Y, Cohen O. Immunohistochemical analysis of p27/kip1 expression in thyroid carcinoma. Mod Pathol. 1998;11:735-739.
ISI
| PUBMED
RELATED ARTICLE
Archives of Otolaryngology–Head & Neck Surgery Reader's Choice: Continuing Medical Education
Arch Otolaryngol Head Neck Surg. 2002;128(3):332-334.
FULL TEXT
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
US Features of Thyroid Malignancy: Pearls and Pitfalls
Hoang et al.
RadioGraphics 2007;27:847-860.
ABSTRACT
| FULL TEXT
Vitamin D3 Administration Induces Nuclear p27 Accumulation, Restores Differentiation, and Reduces Tumor Burden in a Mouse Model of Metastatic Follicular Thyroid Cancer
Dackiw et al.
Endocrinology 2004;145:5840-5846.
ABSTRACT
| FULL TEXT
|
