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From the Departments of Surgery,*
Pathology,
Biostatistics,
and the Laboratory of
Epithelial Cancer Biology,
Memorial
Sloan-Kettering Cancer Center, New York, New York
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Abstract |
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 Top Abstract Materials and MethodsResultsDiscussionReferences |
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5% of epithelial thyroid
tumors. The natural history of HC tumors spans a continuum that
includes benign oncocytic adenomas, tumors of unknown malignant
behavior (UMB), minimally invasive nonthreatening malignancy, and
aggressive carcinomas demonstrating widespread invasion. A pivotal
issue in the treatment approach to these tumors is the correlation of
diagnostic histopathological criteria and tumor biology. Although HC
carcinomas were previously considered as follicular carcinomas and were
classified as such by the World Health Organization, they are now
recognized as a distinct clinicopathological entity.1,2
A
recent study demonstrated that the clinical behavior of HC tumors may
be predicted on the basis of well-defined histopathological criteria.
In this study, HC tumors were defined as thyroid neoplasms composed of
follicular cells exhibiting oncocytic features in >75% of the
tumor.1
The diagnosis of HC carcinoma can be challenging
and diligent scrutiny of multiple histopathological sections is
required to define the nature and extent of capsular and vascular
invasion, the hallmarks of malignancy for this disease. This has
prompted investigators to examine the biology of HC neoplasms on a
molecular level. Mutations in the p53 tumor suppressor gene are among the most frequently detected mutations in human cancer.3 A number of studies have reported an increased prevalence of p53 mutations in poorly differentiated and undifferentiated thyroid carcinomas.4-7 However, few studies have addressed the role of p53 gene expression in oncocytic neoplasms with divergent findings.8,9 Studies analyzing p53 alterations in thyroid carcinomas have not considered other molecular components that are part of the p53 pathway. Murine double-minute-2 (mdm-2) overexpression is a common mechanism of p53 inactivation in human cancers, as it inhibits p53-mediated transactivation and shuttles the p53 protein into degradative pathways.10-12 One indirect indicator of p53 activity is the nuclear protein p21 (WAF-1). Wild-type p53 along with other cellular growth factors activate p21 gene expression and the corresponding p21 protein triggers cell-cycle arrest in the G1 phase.13 In addition to cell-cycle control, p53 mediates programmed cell death through the Bcl-2/BAX apoptotic pathway.14 The patterns of p53 expression and those of important related molecules, mdm-2, p21, and Bcl-2 have not been collectively studied in HC neoplasms. Cyclin D1 is a regulator of cell-cycle progression and may have a role in thyroid carcinogenesis.15,16 As a marker of cellular proliferation, Ki-67 stands at the end of various pathways controlling cell division17 and holds potential for prognostic stratification of patients with various cancers. A recent study found Ki-67 and cyclin D1 to be useful in distinguishing HC adenoma from carcinoma.18
To efficiently investigate the various molecules potentially relevant for HC tumor biology and to determine their potential clinical significance, large-scale analysis of multiple molecules in the same tumor tissues is required. The newly evolved and recently validated tissue microarray technique allows such molecular profiling of cancer specimens by immunohistochemistry.19,20 In the present study we use tissue microarrays, following recently established criteria,20 and immunohistochemistry analysis to characterize the significance of alterations in the p53 pathway and other cell cycle-related molecules in a histopathologically well-characterized cohort of patients with HC neoplasms. This molecular data were correlated with clinicopathological parameters and patient outcome to determine their potential prognostic value.
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Materials and Methods |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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The study consisted of patients with HC adenomas (n = 27), HC tumors of UMB (n = 7), and minimally (n = 14) and widely invasive (n = 21) HC carcinomas. Samples of normal thyroid tissue from eighteen patients served as controls. A total of 87 cases were therefore studied. Median age of the study cohort was 53 years (range, 9 to 87 years). There were 63 females (72%) and 24 males (28%). Median follow-up time for the study cohort was 8 years (range, 2 to 22 years).
To confirm the diagnosis of HC tumors, all available histological slides were reviewed (mean of 16 histological slides per patient).1 HCC tumors were defined as such if they were composed of >75% follicular cells with oncocytic characteristics.1,2 Nodular nonencapsulated aggregates of oncocytes in the setting of nonneoplastic or inflammatory thyroid pathology were not considered HC tumors. The identification of a cell as an oncocyte was based on the presence of acidophilic, granular cytoplasm, and nuclei lacking the nuclear features of papillary thyroid carcinomas.
HC adenomas were defined as encapsulated lesions growing in a follicular pattern. HC tumors of UMB were diagnosed based on a solid/trabecular growth pattern with no or incomplete capsular invasion and without vascular invasion. HC carcinoma was diagnosed if the tumor displayed complete capsular invasion and/or vascular invasion. Incomplete capsular penetration and any degree of vascular invasion were considered carcinoma. The presence of incomplete capsular invasion alone was insufficient for the diagnosis of HC carcinoma. Tumors with a single focus of vascular invasion and/or a single focus of complete capsular invasion were classified as minimally invasive HC carcinomas. HC tumors with more than one focus of intra- or extra-capsular vascular invasion, and/or more than one focus of complete capsular invasion were classified as widely invasive HC carcinomas. The majority (88%) of widely invasive HC carcinomas demonstrated both extracapsular angioinvasion and complete capsular penetration. All widely invasive HC carcinomas had more than two foci of invasion. Histopathological review was conducted without the knowledge of clinical characteristics or outcome.1
No patient with UMB or minimally invasive HCC developed recurrence or died of disease. Seventy-three percent of patients with widely invasive HCC recurred and 55% died of disease. Primary tumor size in widely invasive HCC did not significantly correlate with patient outcome.1
Tissues, Array Construction, and Immunohistochemistry
One reference pathologist (RAG) conducted a critical review of all available histological slides. In addition to normal thyroid tissue, only encapsulated lesions demonstrating >75% follicular cells with oncocytic characteristics were included in the study group.2 HC tumors were defined by previously established criteria as described above.1
Normal thyroid tissue, and tissue from all types of HC tumors were
embedded in paraffin. Five-µm sections stained with hematoxylin and
eosin were obtained to confirm the diagnosis and to identify different
viable, representative areas of the specimen. From these defined areas
core biopsies were taken with a precision instrument (Beecher
Instruments, Silver Spring, MD) as previously described.19
Tissue cores with a diameter of 0.6 mm from each specimen were punched
and arrayed in triplicate on a recipient paraffin block.20
Immunohistochemistry analysis performed on triplicate cores taken from
one representative tumor block was demonstrated to be concordant with
full section analysis and can be reliably used to overcome the problem
of tumor heterogeneity in tissue microarray-based analyses if based on
recently established criteria.20
Five-µm sections of
these tissue array blocks were cut and placed on charged
poly-L-lysine-coated slides (Figure 1A)
. These sections were used for
immunohistochemical analysis.21
Tissues known to express
the antigens under study were used as positive controls. Arrayed normal
tissues served as baseline controls.
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Tissue loss is a significant factor for tissue array-based analysis with previously reported rates of tissue damage ranging from 15 to 33%.20,22-24 In our analysis rates of lost cases attributable to tissue damage ranged between 3% and 18% for the different markers.
Immunoreactivity was classified as continuous data (undetectable levels
or 0% to homogeneous staining or 100%) for all markers. Several
investigators (RAG, AH, AS) reviewed and scored slides independently by
estimating the percentage of tumor cells showing characteristic
staining in a semiquantitative manner. For every marker, the entire
tumor tissue of the three core sections was evaluated. A consensus was
obtained between investigators by reading slides under a multiheaded
microscope. Cut-off values used in this study were based on previously
established cut-off values for well-characterized antibodies used in
our laboratory.11,20,25-27
These cut-off values were
modified according to specific clinicopathological correlations in HC
tumors. The cut-off values for tumor cell staining were defined as
follows: 1) high Ki-67 proliferative index if >5% tumor nuclei
stained; 2) p53 nuclear overexpression if >5% tumor nuclei stained;
3) mdm-2 overexpression if >50% tumor nuclei stained; 4) cyclin D1
overexpression if >5% of tumor nuclei stained; 5) Bcl-2
overexpression if >50% of tumor cells demonstrated cytoplasmic
staining; 6) p21 overexpression if >10% of tumor nuclei stained.
Tumors were then grouped into two categories defined as follows: normal
expression (neoplasms below defined cut-off value of immunoreactivity
in normal, benign, and tumor cells) and abnormal expression (normal and
neoplastic tissues above defined cut-off values of immunoreactivity).
Representative immunophenotypes for each investigated marker in tumor
tissue are demonstrated in Figure 1A
.
Statistical Analysis
Summary statistics were obtained using established methods.28 Associations between categorical variables were evaluated using the Fisher’s exact test.29 Hypothesis testing was performed using the chi-square test with Yate’s correction28 when variable size or frequency was large enough to justify its use. Outcome was classified according to sites of first disease recurrence. Time to recurrence and tumor-related mortality were calculated from the date of primary surgery. Deaths resulting from disease were treated as an endpoint for disease-specific survival. Those patients who died of other causes free of disease were considered to have been alive without evidence of disease and were censored. Relapse-free survival was calculated from the time of surgery to any local, regional nodal, or distant disease recurrence. The rate of recurrence or death was estimated using the Kaplan-Meier product limit method.30 Univariate survival comparisons were performed using the log-rank test.31 Patients with adenomas were excluded from survival analysis because none of them developed recurrence or died of disease.
In widely invasive tumors, capsular invasion alone was a rare event and vascular invasion alone did not occur: all widely invasive tumors analyzed had capsular invasion and only two of them had no vascular invasion. For that reason, a statistical evaluation of differences between tumors with capsular invasion alone versus tumors with vascular invasion alone was not feasible.
In all statistical analyses, a two-tailed P value 
0.05 was
considered statistically significant. All analyses were performed using
JMP statistical software (SAS Institute, Inc., Cary, NC).
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Results |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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No patient in the normal, adenoma, UMB, or minimally invasive
carcinoma group demonstrated a Ki-67-positive phenotype (high Ki-67
proliferative index), defined as >5% of tumor cells demonstrating
nuclear immunoreactivity. High Ki-67 proliferative index was present
only in patients with widely invasive HC carcinoma (7 of 14, 50%;
Table 1
). This phenotype was associated
with larger tumor size, capsular and vascular invasion, and
extrathyroidal disease extension. Of the seven widely invasive
carcinomas with this phenotype, two had two to four foci and five had
more than four foci of major capsular invasion. Of these seven
Ki-67-positive carcinomas two had two to four foci and four had more
than four foci of vascular invasion.
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. High Ki-67 proliferative index was
also associated with significant tumor-related mortality (8-year
disease-specific survival 37% versus 85%,
P < 0.001; Figure 2B
).
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Overexpression of the Bcl-2 protein defined by >50% tumor cell
cytoplasmic staining was evident in all normal and the majority of
adenomas and UMB (78% and 71%). One fourth of HC carcinomas
demonstrated down-regulation of Bcl-2 expression (Table 2)
. Along the continuum of normal thyroid
tissue [94%, Bcl-2(+)], HC tumors with benign clinical behavior
(oncocytic adenomas [78%, Bcl-2(+)], tumors of unknown malignant
behavior [71%, Bcl-2(+)], minimally [43%, Bcl-2(+)] invasive
carcinomas), and widely [57%, Bcl-2(+)] invasive HC carcinomas a
progressive decline in Bcl-2 expression was identified. Among the
widely invasive carcinomas, Bcl-2 expression >50% was associated with
favorable relapse-free survival and disease-specific survival.
Actuarial 8-year relapse-free survival among patients with
Bcl-2-positive and -negative widely invasive carcinomas was 51% and
18% (P = 0.04), respectively. Corresponding
8-year disease-specific survival for patients with Bcl-2-positive and
-negative tumors was 86% and 18%, respectively
(P = 0.01).
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Expression of Cell-Cycle Regulatory Proteins
No overexpression of p53 was identified in normal thyroid tissue
or HC UMB (Table 2)
. p53 protein half-life is short and expression
levels are low in normal cells and therefore immunohistochemistry
cannot detect these wild-type p53 levels. In cancer cells, most p53
mutations lead to products that accumulate in the nuclei and can be
demonstrated by immunohistochemistry. Positive immunostaining
represents rarely accumulation of wild-type p53, or, more commonly, the
stable protein product of a mutated p53 gene that has lost its
cell-cycle regulatory function. Nuclear p53 expression was present in a
small number of patients with HC adenomas (1 of 27), minimally (1 of
14), and widely (4 of 41) invasive carcinomas suggesting inactivation
of the p53 protein. In contrast, the majority (57 to 71%) of HC
neoplasms demonstrated nuclear staining for mdm-2 (Table 2)
. All HC
tumors with p53-positive phenotype demonstrated mdm-2 overexpression.
p21 protein expression was present in all types of HC neoplasms (range
of positive tumors, 43 to 63%). The p21-positive phenotype was not
identified in any of the normal thyroid cases (Table 2)
. All tumors
demonstrating p21 overexpression were also overexpressing mdm-2.
Although 48% of mdm-2-positive tumors were p21-negative, no
p21-negative tumor showed mdm-2 overexpression. Cyclin D1 expression
was evident in 2 of 87 cases, one each with adenoma and widely invasive
carcinoma. mdm-2 overexpression was significantly more common in
neoplastic tissues (P < 0.001) compared to
normal thyroid tissues. No other cell cycle regulator showed any
meaningful association with tissue type.
Multimarker Phenotypes
To further describe the differential expression of cell growth
promoters and inhibitors in the same tissues we characterized these
neoplasms according to their multimarker phenotypes including all
investigated molecules. The phenotype of normal thyroid tissue was
Ki-67(-), p53(-), mdm-2(-), p21(-), cyclin D1(-), Bcl-2(+).
Multimarker phenotypes in tumor tissues were heterogeneous and could
not distinguish between tumor types. Widely invasive carcinomas
differed from all other tumors primarily through the Ki-67(+)
phenotype. Independent from Ki-67, the most frequently observed
molecular phenotypes in all HC tumors were p53(-), mdm-2(+), p21(±),
cyclin D1(-), Bcl-2(±). This information is summarized in Table 2
.
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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Despite the fact that p53 mutations are among the most frequently
detected mutations in human cancers3
they are
heterogeneously detected in different types of thyroid
carcinoma4-7
and are particularly rare in HC
tumors.8,9,32,33
Our study found only seven cases
displaying p53 overexpression in a cohort of 69 HC tumors (Table 2)
.
There were more tumors that overexpressed p53 in the life-threatening
widely invasive carcinoma group than in the other groups characterized
by benign clinical behavior. This further elaborates earlier findings
of higher p53 immunoreactivity in oncocytic carcinoma compared to
adenoma from a set of carcinomas that were not stratified according to
degree of tumor invasiveness (minimally versus widely
invasive carcinoma).9
However, in our cohort,
overexpression of mdm-2, a p53-binding protein that inactivates p53
function,10-12
was a frequent event (57 to 71%, Table 2
)
across all groups of HC tumors, but was only seen in one case of normal
thyroid tissue. This finding puts the relevance of different members of
the p53 pathway for thyroid tumorigenesis into perspective. The
frequent overexpression of mdm-2 in a cohort that rarely shows p53
mutations suggests that mdm-2 inhibits wild-type p53, thus contributing
to the proliferative potential of these cells. The fact that this is
common in benign and malignant disease suggests that there are other
relevant molecular factors that contribute to the malignant phenotype.
p21 (WAF-1) expression can be an indirect indicator of p53 activity
because it is activated by wild-type p53 and other cellular growth
factors.13
Expression of p21 was negative in normal
thyroid tissue but positive in 43 to 63% of HC tumors of benign and
malignant behavior (Table 2)
. No correlation with p53 expression was
observed. Interestingly, all p21-positive tumors, but no p21-negative
tumors overexpressed mdm-2. This suggests that expression of p21 has a
role in thyroid tumorigenesis. However, the fact that p21 expression
can also be induced independent of p53 via growth factor-related
mechanisms that were not investigated in this analysis complicates the
mechanistic interpretation of this finding. The synchronous
up-regulation of mdm-2 and p21 expression may be attributable to DNA
damage-induced phosphorylation of p53, which has been shown to induce
mdm-2 and p21 in vivo.34
Neither p53, mdm-2,
nor p21 expression were significantly associated with clinical outcome
in this study.
In addition to cell-cycle control, p53 mediates programmed cell death through the Bcl-2/BAX apoptotic pathway.14,35 Bcl-2 is the anti-apoptotic component in this balanced system regulating programmed cell death and its overexpression has been shown to promote tumorigenesis. Bcl-2 was strongly expressed in all normal thyroid tissues analyzed (up to 100% of cells positive for Bcl-2) contrary to observations made in other normal tissue types.25 In conjunction with this observation, a cut-off value for Bcl-2 down-regulation was defined as <50% tumor cells being positive for Bcl-2. Reduction of Bcl-2 levels, as compared to normal thyroid, ranged between 11% and 29% in benign and malignant HC tumors but was more common in malignant tumors. Importantly, Bcl-2 down-regulation was associated with poorer relapse-free and disease-specific survival for patients with widely invasive carcinoma. This is consistent with reports describing the prognostic significance of the Bcl-2-negative phenotype in patients with colorectal cancer.36,37 Hypothetically, this paradoxical finding could be explained by homogeneously strong expression patterns of pro- and anti-apoptotic components of the apoptotic pathway in normal thyroid tissue. In tumors, the expression levels of these counterbalancing molecules may be shifted in favor of inhibiting apoptosis. This hypothesis is supported by recent in vivo studies in mice using gain and loss of function models of BAX and Bcl-2,35 but needs to be confirmed in the context of thyroid tissue in humans. We chose not to investigate the BAX protein in this analysis because of lack of proper reagents for immunohistochemical analysis.
The Ki-67 antigen is a nuclear protein associated with cellular
proliferation.17
Its immunohistochemical detection
correlates with the growth fraction of tumors.38
High
Ki-67 proliferative index has been reported to correlate with prognosis
in patients with various cancers.25,26,39,40
We chose to
investigate Ki-67 expression as a marker at the endpoint of multiple
pathways controlling cellular proliferation. Our data show that no
patient in the normal, adenoma, UMB, or minimally invasive carcinoma
group expressed a high Ki-67 proliferative index defined as
>5% of tumor cells having nuclear immunoreactivity. High Ki-67
proliferative index was present only in patients with widely invasive
HC carcinoma (Table 1)
and was associated with the morphological
criteria of aggressive behavior. In addition, the Ki-67-positive
phenotype was associated with reduced relapse-free survival (Figure 2A)
and higher tumor-related mortality (Figure 2B)
than the Ki-67-negative
phenotype. The expression of Ki-67 is present in a lower percentage of
tumor cells than reported for other malignancies26,39,40
and the positive cells are scattered throughout the tumor specimen. Our
data demonstrate that high Ki-67 proliferative index reflects a
malignant phenotype. Ki-67 status adds relevant information to the
histopathological criteria of invasiveness and holds potential to
identify patients at risk of disease recurrence and tumor-related
death.
An additive effect of Ki-67 and Bcl-2 for prediction of patient prognosis was observed for adverse outcome. The Ki-67(+)/Bcl-2(-) phenotype was associated with the diagnosis of widely invasive HC carcinoma.
Cyclin D1 is a regulator of the G1 checkpoint of the cell-cycle and may have a role in thyroid carcinogenesis.15,16 Erickson and colleagues18 found cyclin D1 to be useful in distinguishing HC adenoma from carcinoma. In our analysis, cyclin D1 was negative in all normal thyroid tissues and, with the exception of one adenoma and one carcinoma, also negative in tumor tissues. This suggests that cyclin D1 overexpression, although a significant marker of tumor aggressiveness in other malignancies27 has a marginal role in HC tumors. Differences between the two studies may be attributable to the use of different reagents, especially the use of a polyclonal antibody in the first study compared to our monoclonal antibody.
In an effort to further define multimolecular phenotypes that identify
HC neoplasms, we characterized the expression of all investigated
molecules across tissue types. A distinct multimarker phenotype was
identified that was representative for normal thyroid tissue:
Ki-67(-), p53(-), mdm-2(-), p21(-), cyclin D1(-), Bcl-2(+).
Multimarker phenotypes in tumor tissues were heterogeneous and could
not distinguish between tumor types. Widely invasive carcinomas
differed from all other tumors primarily through the Ki-67(+)
phenotype. Independent from Ki-67, the most frequently seen molecular
phenotypes in all HC tumors were p53(-), mdm-2(+), p21(±), cyclin
D1(-), Bcl-2(±) (Table 2)
. This demonstrates the complexity of the
neoplastic process that includes multiple molecular changes that can
vary greatly between tumors. Ki-67 represents the endpoint of multiple
growth regulatory pathways and is the only discriminating marker that
correlates with tumor biology.
In summary, our data demonstrate the feasibility of tissue array-based profiling of protein expression patterns in tumor tissues, allowing identification of molecular phenotypes that are associated with patient prognosis. High Ki-67 proliferative index correlates with recurrence and tumor-related mortality among HC tumors. Down-regulation of Bcl-2 also contributes to the aggressiveness of these tumors and may be useful, together with high Ki-67 proliferative index, for diagnosing aggressive widely invasive HC carcinomas. Molecular alterations in the p53 pathway play a role for HC tumorigenesis, but, alone, seem to be insufficient to trigger the development of the malignant phenotype. Further studies addressing different molecular pathways will likely identify factors that contribute further to HC carcinogenesis.
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Acknowledgements |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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Footnotes |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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A. H. and A. S. share first authorship.
Accepted for publication October 3, 2001.
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References |
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