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Original Studies |
Division of Endocrinology, Metabolic Research Unit and Department of Medicine (K.-C.L., F.S.G., P.P.B.Y.), the Department of Epidemiology and Biostatistics (L.G.), and the Department of Pathology (T.R.M.), University of California, San Francisco, California 94143
Address all correspondence and requests for reprints to: Dr. Keh-Chuan Loh, Department of General Medicine, Tan Tock Seng Hospital, Moulmein Road, Singapore 308433, Republic of Singapore. E-mail: keh_chuan_loh{at}notes.ttsh.gov.sg
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Abstract |
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Patient distribution by the pTNM system were: stage I, 516 patients; stage II, 57 patients; stage III, 104 patients; and stage IV, 23 patients. Over a mean ± SE follow-up of 11.3 ± 0.3 yr, the overall cancer recurrence and mortality rates were 20.5% and 8.4%, respectively. However, the respective cancer recurrence and mortality rates were distinctly different in the various pTNM stages: 15.4% and 1.7% in stage I, 22% and 15.8% in stage II, 46.4% and 30% in stage III, and 66.7% and 60.9% in stage IV tumors. Using actuarial survival plots, a clear separation in both disease-free survival and cancer-specific survival was noted among all the stages (P < 0.0001). Risk factors analyses showed a significant association between all the prognostic variables used in TNM staging (age, tumor size, extent of primary tumor, and presence of nodal or distant metastases) and the observed end points of recurrence or death from thyroid cancer. After correcting for TNM stages, the risk of cancer recurrence was halved in female compared to male patients, whereas this was 1.7-fold higher in multifocal than unifocal tumors. Conversely, cancer mortality was 3.4-fold higher in follicular than papillary thyroid cancer.
In the analysis of effect of primary treatment among 492 patients with tumor more advanced than the T1N0M0 category, patients who underwent less extensive surgery (lobectomy or subtotal thyroidectomy) had a 2.5-fold risk of cancer recurrence (P < 0.0001) and a 2.2-fold risk of death (P < 0.01) compared to those who underwent total or near-total thyroidectomy. Patients not treated with 131I ablation had a 2.1-fold greater risk of cancer recurrence (P < 0.0001) than those given 131I ablation, although no difference was noted in deaths from thyroid cancer.
Based on our data, the pTNM classification is useful in distinguishing patients with different prognostic outcomes. However, the small patient numbers in pTNM stages other than stage I precludes us from evaluating its usefulness as a guide for therapy. Until prospective data could be accrued from controlled treatment trials, we support the standard practice of total thyroidectomy followed by 131I ablative therapy (if focal iodide uptake was noted) in patients with papillary thyroid cancer more advanced than the T1N0M0 category or of multicentric nature and in the majority of patients with follicular thyroid cancer.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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, the TNM system relies on
assessment of three components: the extent of primary tumor (T), the
absence or presence of regional lymph node metastases (N), and the
absence or presence of distant metastatic lesions (M). This
classification may be either clinical, based on evidence acquired
before definitive treatment, or pathological (pTNM), when
intraoperative and surgical pathological data are available. An
interesting feature of the TNM staging system compared to other
classifications is the age factor. Regardless of the T and N
categories, all patients under 45 yr without distant metastases (M0)
are classified as stage I, whereas those with distant metastases (M1)
belong only to stage II. Despite the current widespread acceptance of
the pTNM classification for thyroid cancer staging, there is limited
published clinical data on its prognostic utility (11, 12, 13).
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Among 736 patients treated for papillary or follicular thyroid cancer (including the Hurthle cell variant) at the University of California-San Francisco (UCSF) Medical Center during the period from 1970–1995, 700 patients with complete data were studied retrospectively. These included 612 patients (87%) who received primary treatment at our institution and 88 patients (13%) who were referred for cancer recurrence. Another 36 patients treated for recurrence were excluded due to insufficient data regarding the initial treatment and/or pTNM staging. The study cohort consisted of 208 male and 492 female patients (male/female ratio = 1:2.4). The mean ± SE age at diagnosis was 41.1 ± 0.3 yr; the values for male and female patients were 44.6 ± 1.1 and 39.7 ± 0.7 yr, respectively.
Histological classification
All specimens obtained at surgery or outside histology slides were reviewed by a senior pathologist (T.R.M.) or an associate. The histological classification was made according to the WHO criteria (14). Six hundred and twenty patients (89%) were classified with papillary thyroid cancer, and 80 patients (11%) had follicular thyroid cancer; the latter group included 8 patients with the Hurthle cell variant of follicular cancer.
Primary treatment
Total or near-total thyroidectomy has been used as a standard treatment in our institution for differentiated thyroid cancer since 1970. Macroscopically suspicious nodes were excised, and modified radical neck dissections were performed in patients with confirmed nodal metastases. This is usually followed by a 30- to 50-mCi out-patient dose radioactive 131I ablation of residual thyroid tissue 6–12 weeks after operation if focal uptake is detected in the thyroid bed on a 2- to 3-mCi 131I diagnostic scan. Patients with unifocal papillary cancers 1 cm or less in size (T1N0M0 category) were not given 131I treatment. In these cases, lobectomy was considered adequate if there were no risk factors, such as radiation exposure or family history of thyroid cancer. Patients with residual tumor or distant metastases were treated with a therapeutic dose ranging from 75–200 mCi 131I. Total body iodide scanning was repeated after 6–12 months, and reablation with 131I was performed if there was persistent uptake. All patients were placed on L-T4 suppressive therapy to maintain subnormal or unmeasurable serum TSH levels, depending upon their disease status. However, the primary treatment regimen among the patients treated elsewhere was heterogeneous, and many had less extensive surgery or no 131I ablation.
Observed end point
Prognostic outcomes were obtained from follow-up examinations and the UCSF Cancer Registry. Follow-up duration was calculated from the time of last evaluation or the time of death. The study end point was either cancer recurrence or death from thyroid cancer. Tumor recurrence was defined as new evidence of loco-regional disease or distant metastases occurring more than 6 months after successful primary therapy. Hence, this was evaluated only in patients who had undergone a potentially curative operation followed by successful 131I ablative therapy in those with residual tumor.
Data analysis
Data were analyzed using SAS system 6.11 statistical software (SAS Institute, Cary, NC). Time-dependent variables were analyzed by the Cox proportional hazard models and the Kaplan-Meier product limit estimates of survival curves (15, 16). The primary operation was used as the entry date in survival models; statistical correction (left truncation up to the time of referral to UCSF) for disease-free survival was performed in patients referred for recurrent disease. A log-rank test was used for comparison of survival curves. The observed differences are assumed statistically significant if the probability of chance occurrence is P < 0.05.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Table 2 shows the distribution of
patients according to pTNM staging: stage I, 516 patients; stage II, 57
patients; stage III, 104 patients; and stage IV, 23 patients. In the
group referred for recurrent disease, there were proportionately fewer
patients with stage I but more patients with stage III and IV tumors
(P < 0.0001). Distributions of age, sex, and tumor
type in the respective pTNM stages are presented in Table 3. The mean age at diagnosis increased
with more advanced tumor stages, although this was partly due to the
age criteria used in the staging system (Table 1
). The distributions by
gender and tumor histology were different in the various stages
(P < 0.0001). There was greater female to male
preponderance in stage I compared to other stages. Conversely, the
predominance of papillary to follicular cancer was markedly reduced in
stage II and was not observed in stage IV tumors, respectively.
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shows the type of primary surgery
and adjuvant treatment administered to patients in the respective pTNM
stages. Primary curative surgery was attempted in 97.7% of the total
patients. Total or near-total thyroidectomy was performed in 551
patients (78.7%), whereas 133 patients (19%) had lobectomy or
subtotal thyroidectomy, and 16 patients (2.3%) had noncurative
surgical debulking. Postoperative adjuvant treatment with
131I ablation was administered in 426 patients (60.9%),
whereas 253 patients (36.1%) received no adjuvant treatment. The
remaining 21 patients (3%) were treated by external radiation,
immunotherapy, or systemic chemotherapy. The majority of patients
receiving adjuvant therapy other than 131I ablation had
locally advanced disease or distant metastases with poor avidity for
iodide uptake.
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Treatment outcome and follow-up data are summarized in Table 5. The median follow-up interval was 10.6
yr, with a mean ± SE of 11.3 ± 0.3 yr. Initial
cure, as defined by serum thyroglobulin concentrations less than 4
ng/dL and/or negative total body iodide scans, was achieved in more
than 90% of patients after primary treatment of thyroid cancer; this
fell from 96.7% in stage I to 87.7% in stage II, 80.8% in stage III,
and 26.1% in stage IV tumors. However, 131 of 639 patients (20.5%)
with initial cure had recurrence during follow-up; this increased
progressively from 15.4% in stage I, to 22% in stage II, 46.4% in
stage III, and 66.7% in stage IV tumors. The overall cancer-specific
mortality rate was 8.4%; this increased from 1.7% in stage I, to
15.8% in stage II, 30% in stage III, and 60.9% in stage IV tumors.
Time to recurrence was evaluated in patients with recurrent disease as
the interval from primary treatment that resulted in cure to the first
episode of cancer recurrence. As shown in Table 5, the time to
recurrence was similar in stage I–III tumors, but was markedly shorter
in stage IV tumors. Among patients who succumbed to thyroid cancer, the
time to death progressively decreased from stage I–IV tumors.
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characterizes deaths from thyroid
cancer by pTNM staging. One fifth of the patients who had died from
thyroid cancer were less than 45 yr of age at the time of primary
evaluation and treatment of their malignancy, whereas 62% of the
overall patients were in this age category. The youngest fatality had
stage I papillary thyroid cancer diagnosed and treated at age 13 yr, he
died 10 yr later from widespread peritoneal metastases. Young patients
who succumbed to thyroid cancer were often found to have extrathyroidal
invasion at presentation, as this constituted 5 of the 7 deaths in
stage I patients who presented before 45 yr of age. However, the vast
majority of young individuals with extrathyroidal invasion at diagnosis
demonstrated an otherwise benign course. An analysis of our data
revealed that of the 64 patients who presented below 45 yr of age with
extrathyroidal invasion but not distant metastasis (hence stage I), 5
patients (7.8%) died from thyroid cancer eventually, whereas 43
patients (67%) were alive and disease free at the last follow-up.
Conversely, of the 57 patients who presented at age 45 yr or greater
with extrathyroidal invasion but not distant metastasis (hence stage
III), 24 patients (42%) had died from thyroid cancer, whereas only 14
patients (24.6%) were alive and disease free at last follow-up.
Besides an overrepresentation of male patients among fatalities from
all tumor stages, the absolute number of males who succumbed also
outnumbered the females in stages I–III. Although patients with
follicular thyroid cancer constituted only 11% of the total cases,
this histological type accounted for 42% of the cancer deaths. With
regard to the major cause of cancer-specific deaths, 30% died from
locally invasive tumor, whereas 70% died of distant metastases. A
small proportion of patients with locally invasive tumor at
presentation eventually succumbed to local effects of tumor invasion
into vital structures, including massive hemoptysis, asphyxia, and
venous obstruction. Conversely, distant metastases, commonly to the
lungs, bones, or brain, accounted for most deaths from the other tumor
stages. Other sites of distant metastases noted were the pituitary,
adrenal, liver, pericardium, peritoneum, and skin. There were no
predisposition of age, sex, or the major cause of death between
patients who died from papillary and follicular thyroid cancers.
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shows the disease-free
survival of patients according to pTNM staging; similar plots for
cancer-specific survival are illustrated in Fig. 2. These survival curves demonstrate
distinctly different prognostic outcomes between the different tumor
stages (P < 0.0001, by log-rank test).
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Table 7 shows the risk ratio (RR)
and 95% confidence interval of different prognostic variables for
tumor recurrence obtained by Cox proportional hazards modelling. After
adjusting for age and gender, analysis of the variables used in TNM
staging (tumor size, extent of primary tumor, and presence of nodal or
distant metastases) uniformly depicted a significant association with
tumor recurrence. Both tumor type and tumor focality (variables not
used in TNM staging) also demonstrated an association with tumor
recurrence; the risks were higher in follicular than papillary thyroid
cancers and in multifocal than unifocal tumors. With reference to pTNM
stage I tumors, the RR of recurrence was 2.5 in stage II, 5.6 in stage
III, and 32 in stage IV tumors. In view of the heterogeneous patient
factors among different tumor stages, the effects of sex, tumor
histology, and tumor focality were reevaluated after adjustment for
pTNM staging: both gender and tumor focality remained as significant
predictors of cancer recurrence, whereas tumor type did not confer an
independent risk.
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. After adjusting for age and gender,
analysis of the variables used in TNM staging similarly depicted a
significant association between each variable and mortality. Patients
with T2 tumors, however, showed a nonsignificant trend toward an
increased mortality over T1 tumors. With regard to tumor type and tumor
focality, a significantly higher mortality risk was noted in patients
with follicular compared to papillary thyroid cancers, whereas no
association was noted between tumor focality and mortality. With
reference to pTNM stage I tumors, the RR of death from thyroid cancer
was 5.5 in stage II, 11 in stage III, and 28 in stage IV tumors. The
increased mortality risk associated with follicular thyroid cancer
remained after correction for pTNM staging.
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Table 9 examines the effect of the
extent of primary surgery and the use of 131I ablative
therapy on prognostic outcome. As the small patient numbers in stages
II–IV preclude statistically meaningful evaluation of treatment
according to tumor stage, patients with tumors more advanced than
T1N0M0 were considered together (n = 492) in the respective Cox
models. Patients with T1N0M0 tumors were excluded, as the majority of
them often do well with relatively minimal therapy. With regard to
surgical treatment, the combined results of operations performed within
6 months of initial assessment are grouped together to indicate the
extent of thyroidectomy, if these procedures constituted the intended
primary surgical intervention. In the cohort evaluated, patients who
had less extensive thyroid surgery (subtotal thyroidectomy or
lobectomy) showed an increased risk of recurrence and death,
respectively, compared to subjects with more extensive thyroid surgery
(total or near-total thyroidectomy). Conversely, those undergoing
noncurative debulking surgery constituted a minority of patients with
intrinsically poor prognosis and, therefore, are inappropriate for
comparison. The disease-free and cancer-specific survival for patients
with extensive surgery (total or near-total thyroidectomy)
vs. limited surgery (lobectomy or subtotal thyroidectomy)
are depicted in Figs. 3 and 4, respectively, showing a clear
separation of treatment outcome between the two surgical treatment
subgroups.
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shows a significantly improved
disease-free survival in the subgroup with compared to that without
131I ablative therapy. Although the cancer-specific
survival rates are not statistically different between the two
treatment subgroups, a trend toward reduced survival is noted beyond 20
yr of follow-up in the subgroup without 131I ablative
therapy (Fig. 6).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Using the Cox model with adjustment for age and gender, the variables used in TNM staging (namely tumor size, presence of extrathyroidal invasion, and initial nodal or distant metastatic lesions) are found to be important prognostic factors for recurrence or death from thyroid cancer. With regard to the primary tumor size, none of the patients with an intrathyroidal tumor of 1 cm or less died of cancer, an observation similarly reported by others (6, 19, 20). Conversely, patients with extrathyroidal invasion (T4) had more than 3-fold risk of recurrence and death, respectively, compared to those with large intrathyroidal (T3) tumors, similar to the findings reported by DeGroot et al. (4). We found a 4-fold risk of recurrence and a 2.5-fold risk of cancer-specific death in patients with regional lymph node metastases. The presence of cervical lymph node metastases has been variously reported to be associated with an unchanged (4, 8, 12, 13, 19), worse (1, 6), or even better (21) survival; the discrepancies in earlier reports may be contributed by their correlation with other prognostic factors. Mazzaferri and co-workers had earlier noted an increased risk of recurrence, but not mortality, in patients with nodal metastases (19); however, their more recent analysis of a larger patient cohort showed significantly higher 30-yr cancer recurrence and mortality rates in subjects with bilateral cervical or mediastinal lymph node metastases regardless of tumor histology (6). Using matched pair analysis for similar prognostic risk factors, Hughes and co-workers found that nodal disease carried an increased risk of recurrence and a tendency toward lower 20-yr survival in patients 45 yr or older (22). Most investigators currently agree that regional nodal metastases indicate more extensive disease, and that affected patients have a tendency toward regional nodal recurrence (4, 12, 22, 23, 24).
After correction for pTNM staging, there was a lower risk of recurrence, but not death, from thyroid cancer in the female patients, similar to the observation reported by DeGroot and co-workers (4). Although some investigators identified gender as a strong independent predictor of survival (1, 8, 12), others failed to show gender as a consistent independent prognostic factor (19, 20, 23). In a large population-based study by Gilliland and co-workers, the investigators found that males had a 50% greater risk of death than females after adjusting for other factors in the multivariate models (25). However, as the absolute differences between relative survival for males and females were small, the investigators concluded that gender is not a strong predictor of survival.
We found a higher risk of recurrence, but not death, in patients with multifocal tumors, even after correction for pTNM stages. The biological potential of multifocal thyroid cancer is uncertain, as most studies do not report an association between tumor multicentricity and prognosis (4, 8, 13, 23). However, Mazzaferri and Jhiang (6) reported increased cancer mortality rates in patients with three or more foci of papillary or follicular thyroid cancers, although this association was lost in multivariate analysis. Until more data are available, it is believed prudent to manage patients with multifocal tumors by total or near-total thyroidectomy and 131I remnant ablative therapy (6, 20, 26).
In our series, the increased risk of cancer-specific death noted with follicular thyroid cancer persisted after correction for pTNM staging. The prognostic differences between papillary and follicular thyroid cancer have not been resolved; some investigators have reported a less favorable outcome in patients with follicular cancer (3, 27), others considered the distinction to be of mere academic interest (20, 23, 28). Gilliland et al. (25) found that patients with follicular cancer have lower survival rates than those with papillary cancer, but they noted that the prognosis is more strongly determined by tumor staging and other factors than by tumor histology. Mazzaferri and Jhiang (6) likewise noted a higher mortality in patients with follicular thyroid cancer, but this significance was lost when subjects who presented with distant metastases at diagnosis were excluded. To help resolve this enigma and to provide a more precise risk group assignment, patients with papillary and follicular thyroid cancer are best analyzed as separate cohorts in the pTNM classification.
Like all other thyroid cancer staging systems, the pTNM classification has limitations, as a minority of patients in the low risk group will die of thyroid cancer. In our evaluation, the majority of case fatalities from stage I and II tumors occurred in patients who were diagnosed and treated for thyroid cancer well before age 45 yr. Four of the cancer deaths in our series (three papillary and one follicular thyroid cancers) occurred in individuals less than 30 yr of age at the time of diagnosis. Although most of the young subjects who died from stage I tumor had locally advanced disease, the vast majority of the young cohort with extrathyroidal invasion at diagnosis demonstrated a benign course. Indeed, the challenge would be to identify the risk factors that can effectively select out young patients with advanced disease who will show poor outcome from the majority with relatively good prognosis. Despite the limitations of pTNM classification, our retrospective analysis of a large number of patients shows that this is helpful in defining groups of patients with significantly different probability of cancer recurrence and mortality. The earlier reports on this classification, however, failed to clearly separate patients with stage I and II tumors with regard to prognostic outcome (11, 12, 13), a limitation commonly noted in other staging systems (1, 4, 5). A comparison study on five different prognostic classification schemes (EROTC, AGES, DeGroot’s, AMES, and TNM) by DeGroot and associates on their institutional series indicated that the TNM system is the most satisfactory for stratifying patients by risks (29).
As the small patient numbers precludes us from analyzing the outcome of treatment by pTNM stages, we could not assess the utility of this classification in guiding therapy to avoid overaggressive treatment in patients with excellent prognosis. Until more data become available, our analysis of patients with differentiated thyroid cancer more advanced than the T1N0M0 category supports the current practice to manage these individuals more aggressively. In many studies, recurrence rates are evidently higher after a partial, compared to a total, thyroidectomy, even after adjustment for extent of disease (6, 13, 17, 19, 29). The impact of recurrence on survival is underscored by follow-up results indicating that up to 40–50% of patients who die of thyroid cancer do so because of recurrent disease in the thyroid bed or central compartment of the neck (18). Furthermore, total thyroidectomy facilitates more effective 131I ablative therapy and the use of serum thyroglobulin levels as tumor marker for cancer recurrence during follow-up.
Results from our analysis also support the use of adjuvant
131I ablative therapy in most patients who have undergone
total or near-total thyroidectomy. Similarly, Mazzaferri’s group found
a significantly lower tumor recurrence rate in patients with larger
(
1.5 cm) tumors treated with 131I ablation and
T4 suppression compared to those treated with
T4 suppression alone, notwithstanding that patients given
131I ablative therapy had more adverse risk factors, such
as invasive tumors and cervical nodal metastases (19, 30). Although
improvement in cancer-specific survival was not observed in our patient
cohort with 131I ablative therapy, Mazzaferri and Jhiang
noted improvement in both cancer recurrence and mortality rates when
the 131I-treated cohort was evaluated at a longer interval
of 30 yr (6). Based on their findings, they concluded that total or
near-total thyroidectomy, followed by radioiodine ablation and
life-long thyroid hormone suppression, are indicated in subjects if
their primary thyroid tumors are larger than 1.5 cm or are associated
with multicentricity, local invasion, or metastases (6). DeGroot
and co-workers also found that 131I ablation was associated
with a significant reduction of recurrences independent of the extent
of surgery, and they supported postoperative 131I ablation
of residual thyroid tissue in low risk papillary thyroid cancer
patients with tumors greater than 1 cm (4, 29). However, controversies
still exist regarding the benefit of thyroid remnant ablation, with
others reporting no improvements (13, 31, 32).
Patients with follicular thyroid cancer in our series are not evaluated separately, as they constituted only 11% of the study cohort. However, based on the 3.4-fold higher cancer mortality risk obtained by multivariate analysis, it is prudent to consider total thyroidectomy as standard surgery in most patients with follicular thyroid cancer, followed by 131I ablation if focal iodide uptake is evident on diagnostic scanning (26, 33).
In conclusion, our data support the use of pTNM staging system for differentiated thyroid cancer. Although it may be cautioned that the prognostic value of pTNM staging system could vary among groups of patients, its potential in providing risk stratification deserves further reporting from other centers. Until better predictors of tumor behavior are available, the pTNM classification is shown to be useful for prognostication, and its widespread use will facilitate the exchange of information between centers.
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Acknowledgments |
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Received June 4, 1997.
Revised July 23, 1997.
Accepted August 1, 1997.
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References |
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Y. Kitamura, K. Shimizu, K. Ito, S. Tanaka, and M. Emi Allelotyping of Follicular Thyroid Carcinoma: Frequent Allelic Losses in Chromosome Arms 7q, 11p, and 22q J. Clin. Endocrinol. Metab., September 1, 2001; 86(9): 4268 - 4272. [Abstract] [Full Text] [PDF]
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K. L. Wirfel, M. L. Richards, and R. A. Otto Papillary Cancer of the Thyroid in Low-Risk Patients: The Perspective of the University of Texas Health Science Center at San Antonio Arch Otolaryngol Head Neck Surg, April 1, 2001; 127(4): 458 - 461. [Full Text] [PDF]
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