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1139
Medullary Thyroid Carcinoma
Clinical Characteristics, Treatment, Prognostic Factors, and a Comparison of
Staging Systems
Electron Kebebew, M.D.1
Philip H. G. Ituarte, M.P.H.,
Allan E. Siperstein, M.D.1
Quan-Yang Duh, M.D.1,2
Orlo H. Clark, M.D.1
1
Ph.D.
1
University of California, San Francisco School of
Medicine, and Department of Surgery, University of
California, San Francisco/Mount Zion Medical Center, San Francisco, California.
2
Veterans Affairs Medical Center, Surgical Services, San Francisco, California.
Presented in part at the 80th Annual Meeting of
The Endocrine Society, June 1998, New Orleans,
Louisiana.
Supported in part by the Mt. Zion Health Systems
and Friends of Endocrine Surgery Fund.
Dr Kebebew is a fellow in Surgical Oncology Basic
Science, with an NIH T32 training grant, and a
resident in surgery at the University of California,
San Francisco.
Address for reprints: Orlo H. Clark, M.D., Department of Surgery, C342, University of California,
San Francisco /Mt. Zion Medical Center, 1600
Divisadero Street, San Francisco, CA 94143-1674.
Received June 17, 1999; revision received October
15, 1999; accepted November 19, 1999.
© 2000 American Cancer Society
BACKGROUND. The clinical courses of patients with medullary thyroid carcinoma
(MTC) vary, and a number of prognostic factors have been studied, but the
significance of some of these factors remains controversial.
METHODS. The study group consisted of 104 patients with MTC or C-cell hyperplasia
managed at the hospitals of the University of California, San Francisco, between
January 1960 and December 1998. Patients were classified as having sporadic MTC,
familial non-multiple endocrine neoplasia (MEN) MTC, MEN 2A, or MEN 2B. The
TNM, European Organization for Research and Treatment of Cancer (EORTC), National Thyroid Cancer Treatment Cooperative Study (NTCTCS), and Surveillance,
Epidemiology, and End Results (SEER) extent-of-disease stages were determined for
each patient. The predictive values of these staging or prognostic scoring systems were
compared by calculating the proportion of variance explained (PVE) for each system.
RESULTS. Fifty-six percent of the patients had sporadic MTC, 22% had familial MTC,
15% had MEN 2A, and 7% had MEN 2B. The overall average age at diagnosis was 38
years, and patients with sporadic MTC presented at an older age (P ⬍ 0.05). Thirty-two
percent of the patients with hereditary MTC were diagnosed by screening (genetic
and/or biochemical). These patients had a lower incidence of cervical lymph node
metastasis (P ⬍ 0.05) and 94.7% were cured at last follow-up (P ⬍ 0.0001) compared
with patients not screened. Patients with sporadic MTC who had systemic symptoms
(diarrhea, bone pain, or flushing) had widely metastatic MTC and 33.3% of those
patients died within 5 years. Overall, 49.4% of the patients were cured, 12.3% had
recurrent MTC, and 38.3% had persistent MTC. The mean follow-up time was 8.6
years (median, 5.0 years) with 10.7% (n⫽11) and 13.5% (n⫽14) cause specific mortality
at 5 and 10 years, respectively. Patients with persistent or recurrent MTC who died of
MTC lived for an average of 3.6 years (ranging from 1 month to 23.7 years). Patients
who had total or subtotal thyroidectomy were less likely to have persistent or recurrent
MTC (P ⬍ 0.05), and patients who had total thyroidectomy with cervical lymph node
clearance required fewer reoperations for persistent or recurrent MTC (P ⬍ 0.05) than
patients who underwent lesser procedures. In univariate analysis, age, gender, clinical
presentation, TNM stage, sporadic/hereditary MTC, distant metastasis, and extent of
thyroidectomy were significant prognostic factors. Only age and stage, however, remained independent prognostic factors in multivariate analysis. The TNM, EORTC,
NTCTCS, and SEER staging systems were all accurate predictors of survival, but the
EORTC prognostic scoring system had the highest PVE in this cohort.
CONCLUSIONS. Screening for MTC and early treatment (total thyroidectomy with
central neck lymph node clearance) had nearly a 100% cure rate. Patients with
postoperative hypercalcitoninemia without clinical or radiologic evidence of residual tumor after apparently curative surgery may enjoy long term survival but
have occult MTC. Only patient age at presentation and TNM stage were independent predictors of survival. The EORTC criteria, which included the greatest number of significant prognostic factors in our cohort, had the highest predictive value.
Cancer 2000;88:1139 – 48. © 2000 American Cancer Society.
KEYWORDS: medullary thyroid carcinoma, stage, prognosis, hereditary, multiple
endocrine neoplasia 2, RET, treatment and prognostic factors.
1140
M
CANCER March 1, 2000 / Volume 88 / Number 5
edullary thyroid carcinoma (MTC) is a rare malignancy. It accounts for 3–10% of all thyroid
carcinomas, but it is responsible for up to 13.4% of all
deaths related to this disease.1–3 MTCs arise from the
parafollicular cells or C cells of the thyroid gland.
Familial MTC (non–multiple endocrine neoplasia
[MEN]) and MEN 2 (A and B) comprise the hereditary
forms of MTC.4,5 Hereditary MTC is inherited in an
autosomal dominant pattern with virtually a 100%
penetrance.6 A germline mutation in the RET protooncogene, which encodes for a transmembrane tyrosine kinase receptor, predisposes individuals to develop MTC. Screening for RET germline mutations has
allowed for early and accurate diagnosis of patients at
risk of developing MTC.7,8 Although significant advances have been made in screening patients at risk
for hereditary MTC and diagnosing MTC by fineneedle aspiration cytology, some patients (especially
those with sporadic MTC) still present late.3 Generally,
the overall survival of patients with MTC is intermediate to that of patients with differentiated thyroid
carcinoma (papillary and follicular) and anaplastic
thyroid carcinoma.9 However, the clinical courses of
patients with MTC vary, with long term survival reported for patients with persistent hypercalcitoninemia.10 A number of clinical (age, stage, gender, hereditary type of MTC, and symptoms), biochemical
(serum calcitonin pre- and postoperative, serum carcinoembryonic antigen [CEA]), and molecular (calcitonin gene expression, calcitonin-related gene peptide, amyloid staining, and specific RET mutations)
prognostic factors in patients with MTC have been
evaluated.9 –20 The significance of some of these factors, however, remains controversial. Furthermore,
relatively few contemporary studies have evaluated
the clinical characteristics, treatment, and prognostic
factors simultaneously in patients with MTC.
The appropriate staging, risk stratification, and
management of patients with MTC still remain of
great interest to physicians (internists, endocrinologists, pediatricians, oncologists, and surgeons alike)
who care for these patients. The prognostic factors
that predict the courses of patients with papillary and
follicular thyroid carcinoma have been addressed in
the literature, with multiple prognostic scoring systems proposed over the last 4 decades.9 In patients
with differentiated thyroid carcinoma, prognostic
scoring systems have been helpful in categorizing patients into “high” or “low” risk groups.9 Some investigators have also compared the various prognostic
staging systems to assess the “best” system for predicting the outcomes of patients with differentiated
thyroid carcinoma.21–25 The utility of the different
prognostic scoring systems in evaluating patients with
MTC who have a higher overall mortality rate than
those with differentiated thyroid carcinoma has not
been addressed. In this study, we evaluated the
courses of patients with MTC or C-cell hyperplasia
who were managed at our institution over 4 decades.
The goal of this investigation was to determine the
important clinical factors that predict patient outcome
in univariate and multivariate analysis. We also applied and compared the different prognostic staging
systems (previously used to stage patients with MTC)
in our cohort to determine the most accurate predictors of survival.
PATIENTS AND METHODS
Patient Selection and Classification
The study group consisted of patients evaluated
and/or treated at the hospitals of the University of
California, San Francisco (UCSF), for MTC or C-cell
hyperplasia between January 1960 and December
1998. The diagnoses of MTC or C-cell hyperplasia were
all confirmed either on histology of resected specimens or by the presence of a germline RET mutation
in those patients with only C-cell hyperplasia.
A total of 108 patients were identified. Two patients were diagnosed at autopsy and two patients
were lost to follow-up: These patients were excluded
from the study group analysis. Data on the remaining
104 patients were used for survival analysis. We classified patients with MTC or C-cell hyperplasia into 4
groups: 1) sporadic, 2) familial non-MEN, 3) MEN 2A,
and 4) MEN 2B.5 Patients without any first-degree
relative with MEN 2, MTC, or a germline RET protooncogene mutation were considered to have sporadic
MTC. Patients in the familial MTC group had a firstdegree relative with MTC but no evidence of MEN 2 (A
and B) in themselves or family members. In the MEN
2A group, the patients had a first-degree relative with
MEN 2A or had MTC or C-cell hyperplasia with hyperparathyroidism and/or pheochromocytoma. The patients in the MEN 2B group had MTC or C-cell hyperplasia with typical phenotypic features (e.g., marfanoid body habitus, mucosal neuroma and intestinal
ganglioneuromatosis) with or without pheochromocytoma. Early in our experience, basal and pentagastrin
or calcium stimulated calcitonin tests were used to
screen patients for hereditary MTC. Since 1994, we
have used DNA analysis for the germline RET protooncogene mutation in exons 10, 11, 13, and 14. The
genetic testing was done commercially. In general,
calcitonin stimulation testing for screening and follow-up consisted of pentagastrin injected intravenously with plasma calcitonin levels measured at 0, 1,
2, 5, and 10 minutes after injection.
Follow-up data were obtained through the UCSF
Outcomes of Patients with MTC/Kebebew et al.
cancer registry and from review of patients’ clinical
records. Prognostic variables were evaluated from the
time of diagnosis to the last follow-up date. The study
endpoints were death from thyroid carcinoma (cause
specific mortality) and tumor status (free of MTC,
recurrent MTC, or persistent MTC). Patients with
short follow-up time or patients who died from unrelated causes were censored in the survival analysis.
Tumor recurrence was defined as new evidence of
MTC (locoregional or distant metastasis) after successful tumor resection in which basal or stimulated
serum calcitonin levels were normal for at least 6
months. Patients with elevated (basal or stimulated)
postoperative serum calcitonin levels were classified
as having persistent MTC.
Data Analysis
Time-independent continuous variables were evaluated using the Student t test or by analysis of variance
for multiple group comparison, and the chi-square
test was used for categorical data. Survival analysis
was done with the SAS 6.12 and StatView 4.51 statistical software packages (SAS Inc., Cary, NC). For univariate analysis of time-dependent variables, the
Kaplan–Meier method and the log rank test were used
to determine significant prognostic factors. In multivariate analysis, a Cox proportional hazards stepwise
regression model was used for all factors found to be
significant in univariate analysis. The observed differences were assumed to be statistically significant if the
probability of chance occurrence was less than 0.05.
The TNM,26 European Organization for Research
and Treatment of Cancer (EORTC),27 National Thyroid
Cancer Treatment Cooperative Study (NTCTCS),22
and Surveillance, Epidemiology, and End Results program (SEER extent of disease)1 stages were determined for each patient in the study cohort (Table 1).
These prognostic classification systems have been
used previously to stage patients with MTC. To compare the predictive values of the different staging systems, the proportion of variance explained (PVE) was
determined for each system.22,23,28,29 The Cox proportional hazards model was used to calculate the PVE as
follows:
PVE ⫽ 关1 ⫺ 共Lr/Lu兲 2/N 兴,
where Lr and Lu were the restricted and unrestricted,
respectively, maximum likelihood ratios from the Cox
proportional hazards model and N was the total number of patients.
1141
TABLE 1
The TNM, EORTC, NTCTCS, and SEER Stage Classifications for
Patients with MTC
Stage classification
TNMa
Stage I
Stage II
Stage III
Stage IV
EORTC
Group 1: ⬍50
Group 2: 50–65
Group 3: 66–83
Group 4: 84–108
Group 5: ⱖ109
Definition
T1, N0, M0
T2–4, N0, M0
Any T, N1, M0
Any T, any N, M1
Scoring system
⫹12 if male
⫹10 if medullary or follicular less differentiated
⫹45 if anaplastic thyroid carcinoma
⫹10 if extrathyroidal tumor invasion
⫹15 if there is 1 distant metastasis
⫹15 (in addition to above ⫹15) for multiple distant metastasis
⫽ Total score
NTCTCS
Stage I
C-cell hyperplasia
Stage II
Tumor size ⬍1 cm
Stage III
Tumor size ⱖ1 cm or positive cervical lymph nodes
Stage IV
Extrathyroidal invasion or extracervical metastates
SEER extent of disease
Local
Tumor confined to the thyroid gland
Regional
Extrathyroid extension or regional lymph node metastasis
Metastasis
Metastasis to extracervical lymph nodes or organ
MTC: medullary thyroid carcinoma; EORTC: European Organization for Research and Treatment of
Cancer; NTCTCS: National Thyroid Cancer Treatment Cooperative Study; SEER: Surveillance, Epidemiology, and End Results.
a
Tumor size: T1 ⱕ1 cm; T2 ⫽ tumor ⬎1 cm but ⬍4 cm; T3 ⬎4 cm; T4 ⫽ tumor of any size extending
beyond thyroid capsule. Lymph node: N0 ⫽ no regional lymph node metastasis; N1 ⫽ positive regional
lymph node metastasis. Distant metastasis: M0 ⫽ no distant metastasis; M1 ⫽ positive distant metastasis.
RESULTS
Clinical Characteristics
Fifty-eight patients (55.8%) had sporadic MTC, 23 patients (22.1%) had familial MTC, 16 patients (15.4%)
had MEN 2A, and 7 patients (6.7%) had MEN 2B (Table
2). The overall mean age at diagnosis for the study
group was 38 years. Patients with sporadic MTC presented at an older age (mean ⫽ 47.3 years) than patients with hereditary MTC (P ⬍ 0.05 even when patients diagnosed by screening were excluded). The
overall male-to-female ratio was 1.0:1.1, with no difference between the sporadic and hereditary MTC
groups. In the sporadic group, 74.2% of patients presented with a thyroid mass, 15.5% had local symptoms
(dysphagia, dyspnea, or hoarseness), and 10.3% had
systemic symptoms (bone pain, flushing, and/or diarrhea) attributable to their tumor. All the patients with
sporadic MTC who presented with systemic symptoms had distant metastases at the time of presentation. It is noteworthy that 4 patients with sporadic
MTC had coexisting occult papillary thyroid carci-
1142
CANCER March 1, 2000 / Volume 88 / Number 5
TABLE 2
Clinical Characteristics of Patients with Sporadic and Hereditary MTC
Features
Sporadic
MEN 2A
MEN 2B
Familial MTC
Total
No. of patients
Age (mean ⫾ SD, yrs)
Gender (male/female)
Presenting symptom or signs
Thyroid nodule
Locala
Systemicb
Family historyc
Stage (TNM)
I
II
III
IV
Unknown
58
47.3 ⫾ 16.9
27/31
16
25.2 ⫾ 15.2
7/9
7
19.9 ⫾ 17.0
5/2
23
29.1 ⫾ 14.6
10/13
104
38.0 ⫾ 16.1
49/55
43
9
6
0
4
0
2
10
6
1
0
0
9
1
1
12
62
11
9
22
9
12
22
13
2
10
3
1
2
—
1
0
5
1
—
10
5
7
1
—
30
20
35
17
2
a
“Local” refers to those patients who presented with dysphagia, hoarseness, dyspnea, or vocal cord paralysis.
Systemic symptoms and signs that prompted workup and the eventual diagnosis of MTC were bone pain, flushing, and diarrhea in the patients with sporadic MTC. Those patients in the hereditary group had
manifestation of pheochromocytoma (2 patients) or bone pain from MTC metastasis that prompted a workup for MTC.
c
“Family history” refers to those patients who were at risk for MTC and were screened for MTC with biochemical and/or genetic testing.
b
noma discovered on permanent histology. In patients
with hereditary MTC, 41.3% presented initially with a
thyroid mass, 4.4% with local symptoms, and 6.5%
with systemic symptoms; 47.8% were diagnosed by
biochemical and/or genetic screening and were
asymptomatic. Of the three patients who presented
with systemic symptoms in the hereditary MTC
groups, one patient had metastasis to the bone and
reported bone pain at presentation. One patient
presented in hypertensive crisis secondary to a pheochromocytoma and one patient presented with a retroperitoneal hemorrhage from a ruptured pheochromocytoma. The latter two patients were then
subsequently found to have a germline RET mutation
by genetic testing and had a prophylactic total thyroidectomy with central neck lymph node clearance.
The patients with MEN 2A presented with significantly
fewer cervical lymph node metastases than patients
with sporadic MTC, MEN 2B, or familial MTC (P ⬍
0.05). Eighty-five percent of the patients with hereditary MTC had bilateral tumors, whereas 66.7% of the
patients with sporadic MTC had bilateral tumors.
There was no difference in the overall stage of MTC at
presentation between patients with hereditary and
sporadic MTC.
Almost half (47.8%) of the patients with hereditary
MTC were diagnosed by screening (biochemical
and/or genetic testing). Of note, 3 of these patients
who underwent prophylactic total thyroidectomy with
central neck lymph node clearance for positive germline RET mutations (2 patients with familial MTC and
1 patient with MEN 2A) had no evidence of MTC or
C-cell hyperplasia on histologic examination, even after calcitonin immunostaining.30 In the remaining 19
patients, 2 had only C-cell hyperplasia and 17 had
MTC. Patients with hereditary MTC diagnosed by
screening had a lower frequency of cervical lymph
node metastases than patients with hereditary MTC
who were not screened (P ⬍ 0.05). Furthermore, 94.7%
of patients diagnosed by screening were free of MTC,
compared with 32.5% of patients with hereditary MTC
who were not screened (P ⬍ 0.0001 with a mean
follow-up time of 6.3 years and 8.8 years, respectively).
Treatment and Outcome
Two patients with MEN 2A await surgery at this time.
In the remaining 102 patients, 76.6% had total or neartotal thyroidectomy, 9.8% had subtotal thyroidectomy,
9.8% had thyroid lobectomy, and 3.8% had incomplete
resection of their tumor. Those patients who had lessthan-total or near-total thyroidectomy had their initial
surgery at other medical centers or were treated before
1974. Fifty-five percent of patients had cervical lymph
node dissection: 85.3% had central neck lymph node
dissection and 14.7% had both central neck and modified radical neck dissection. One patient had a
planned resection of the recurrent laryngeal nerve
because of tumor invasion. There was one recurrent
laryngeal nerve, phrenic nerve, sympathetic nerve,
and spinal accessory nerve injury, each in different
patients, during operative resection of locally invasive
MTC, at our institution. On reoperation, one patient
Outcomes of Patients with MTC/Kebebew et al.
TABLE 3
Evaluation of Clinicopathologic Variables as Risk Factors for
Recurrent or Persistent MTC
1143
TABLE 4
Clinical Prognostic Variables for Patients with MTC in Univariate and
Multivariate Analysis
Clinicopathologic variables
Variable significancea
P value
Clinicopathologic variables
Univariate
P value
Multivariate
P value
Age (yrs)
Gender
Type of MTC
FMTC vs. others
Sporadic vs. others
MEN 2A vs. others
MEN 2B vs. others
TNM stage
I vs. II/III/IV
I/II vs. III/IV
I/II/III vs. IV
Cervical lymph node metastasis
Multicentricity
Extent of thyroidectomy
Total/near total vs. lesser procedures
Total and subtotal vs. lesser procedures
Incomplete resection
Cervical lymph node dissection
S
NS
S
S
S
NS
NS
S
S
S
S
S
NS
S
NS
S
S
NS
0.048
0.187
0.022
0.005
0.017
1.00
0.671
0.002
0.002
0.002
0.006
0.047
0.166
Agea
Gender
Ethnicity
Presenting symptoms and
signsb
M vs. A
M vs. L
M vs. S
Type of MTC
TNM stage
I vs. II
I vs. III
I vs. IV
Tumor size
Cervical lymph node
metastasis
Tumor multicentricity
Treatment
Extent of thyroidectomy
Lymph node dissection
External beam radiation
Chemotherapy
S
S
NS
0.0149
0.0535
0.3638
S
NS
—
0.0272
—
—
S
NS
S
S
NS
S
NS
NS
S
NS
0.0033
0.3178
0.0006
⬍0.0001
0.2323
0.0001
0.1170
0.0758
0.0006
0.084
NS
—
—
S
—
0.0013
—
—
NS
NS
0.5238
0.2015
—
—
—
—
S
NS
NS
NS
⬍0.0001
0.5778
0.7365
0.8855
NS
—
—
—
—
—
—
0.058
0.029
0.006
0.257
MTC: medullary thyroid carcinoma; FMTC: familial MTC; MEN: multiple endocrine neoplasia; S:
significant; NS: not significant.
a
Significance was determined by the chi-square analysis, except for age (t test).
had an injury to the thoracic duct with postoperative
chyle leak, which resolved after evacuation and ligation of the duct.
At last follow-up, 49.4% of the patients with MTC
were free of disease, 38.3% had persistent MTC, and
12.3% had recurrent MTC. In the patients who were
cured, 77.5% had total thyroidectomy with central
neck lymph node clearance and 57.5% had Stage I or
II MTC. Overall, patients who were younger, had familial MTC or MEN 2A, had lower stage MTC, had no
diarrhea or bone pain, and had total or subtotal thyroidectomy were less likely to have recurrent or persistent MTC (Table 3). All of the patients diagnosed by
screening were cured except for a woman age 62 years
who had an asymptomatic MTC metastasis to her
spine at the time of screening. Furthermore, patients
who had total thyroidectomy with central neck lymph
node clearance on average (0.8 vs. 2.8) required fewer
reoperations than patients who had lesser procedures
(P ⬍ 0.031). Eight patients received therapeutic external beam radiation (one patient hyperfractionated) to
the cervical region and four patients received chemotherapy regimens (two patients received systemic chemotherapy, one patient had chemoembolization for
liver metastases, and one patient was treated with
anti-CEA radiolabeled antibody). No appreciable tumor regression was observed in any of these patients.
Two patients, however, were treated by radiofre-
MTC: medullary thyroid carcinoma; S: significant; NS: not significant.
a
Age at presentation was a significant prognostic factor for patients aged ⱕ45 years.
b
M: thyroid mass; A: asymptomatic; L: local; S: systemic (see Table 2 for a description of these
categories).
quency ablation for liver metastases with tumor regression.
Prognostic Factors and Staging Systems
The mean follow-up time was 8.6 years (median, 5.0
years). The overall cause specific mortality was 10.7%
at 5 years and 13.5% at 10 years. Age, gender, clinical
presentation, TNM stage of MTC, distant metastasis,
and extent of thyroidectomy were significant predictors of survival by univariate analysis (Table 4). Only
age and stage of disease remained independent predictors of survival in multivariate analysis (Table 4 and
Fig. 1). The 5-year survival rates by stage were 100%
(I), 90% (II), 86.5% (III), and 55.5% (IV). Patients who
were age ⬍45 years, female, and with MTC confined to
the thyroid had the best overall prognosis (100% survival at 10 years). All the prognostic staging systems
used to evaluate patients with MTC were accurate
predictors of survival (Table 5). The EORTC risk assessment model had the highest PVE value.
DISCUSSION
The differences in prognostic factors reported for MTC
may be due in part to the low frequency of occurrence
1144
CANCER March 1, 2000 / Volume 88 / Number 5
TABLE 5
Comparison of Staging Systems for Patients with MTC
Staging system
EORTC group
1
2
3
4
5
TNM stage
I
II
III
IV
NTCTCS stage
I
II
III
IV
SEER criteria
Local
Regional
Distant
FIGURE 1. Cancer specific cumulative survival by Kaplan–Meier analysis is
shown for all patients with medullary thyroid carcinoma. (A) Survival for
patients ages ⬍ 45 and ⱖ 45 years is compared with (B) survival by TNM
stage of disease at presentation.
of MTC and its heterogeneous clinical behavior. Although there have been large cohort multicenter or
cancer registry– based studies, many of them lack
complete clinical data and suffer from nonuniform
diagnostic criteria. A single-institution study, although
of a smaller cohort, may circumvent such problems. A
long period of follow-up is usually required for such
studies at a single institution, especially to study multiple prognostic factors. We believe our study period
and follow-up interval represent an adequate length of
time to evaluate the important clinical factors that determine the outcomes of patients with MTC.11–13,15,17,18
Furthermore, we have evaluated the influence of a
comprehensive group of clinical factors on the outcomes of patients with MTC.
The mean age at diagnosis in our cohort is similar
to that in other studies.12,15,17–19,23 Although in most
series sporadic MTC accounts for 75–95% of all MTCs,
we found that 54.3% of the patients had sporadic MTC
during the study period.3,12,16,18 –20 The number of hereditary MTC cases in our study is comparable to that
of Modigliani et al.17 The higher proportion of hereditary MTC in our cohort most likely reflects a referral
bias. In addition, a higher frequency of hereditary
MTC may be observed in contemporary series because
Cause specific
mortality (%) by
stage or group
P value
PVE (%)
Rank order based
on PVE
0.0001
15.147
1
0.0017
13.118
2
0.0012
12.715
3
0.0007
12.131
4
0
8.7
33.3
40.0
100.0
0
10.0
14.5
44.5
0
5.3
10.5
38.9
10.8
10.8
29.6
MTC: medullary thyroid carcinoma; PVE: proportion of variance explained; EORTC: European Organization for Research and Treatment of Cancer; NTCTCS: National Thyroid Cancer Treatment Cooperative Study; SEER: Surveillance, Epidemiology, and End Results.
of the increased awareness in screening patients for
MTC that is now possible with commercially available
with genetic testing. Unlike other series,15,17,18,20
which have reported a higher frequency of MEN 2A in
the hereditary types of MTC, we found that 50% of our
patients had familial MTC. Patients with MEN 2A and
MEN 2B accounted for 33.3% and 16.7%, respectively,
of the hereditary MTC cases. Because of the incomplete penetrance of hyperparathyroidism and pheochromocytoma in patients with MEN 2A, the distinction between familial MTC and MEN 2A can be
reliably made only after long term follow-up. This
would ensure that those patients with familial MTC do
not eventually develop hyperparathyroidism and/or
pheochromocytomas.31 The majority of MEN 2B patients presented in the second decade of life, and
familial non-MEN and MEN 2A patients presented
in the third decade of life. The ratio of women to
men (1:1.1) is consistent with the observations of others11–13,15–20 and is unlike the ratios for other thyroid
tumors, which have a female preponderance.1,2
The majority of patients with sporadic MTC (70%)
initially presented with a thyroid nodule or mass,
which led to the diagnosis. Patients who presented
with local symptoms were more likely to have either
persistent or recurrent disease compared with pa-
Outcomes of Patients with MTC/Kebebew et al.
tients who presented with a thyroid nodule (P ⬍ 0.05).
All patients with sporadic MTC who presented with
systemic symptoms had Stage IV MTC, and all were
dead at follow-up. One of 11 patients with seemingly
sporadic MTC was diagnosed as having familial MTC
because of a positive germline RET mutation. None of
the patients diagnosed by screening had cervical
lymph node or distant metastases, with the exception
of the asymptomatic woman age 62 years who was
mentioned earlier. Furthermore, 3 patients who underwent prophylactic total thyroidectomy with central
neck lymph node clearance had no MTC or C-cell
hyperplasia. These observations emphasize that early
detection in patients at risk for MTC allowed for nearly
a 100% rate of cure, compared with the overall 49.4%
cure rate in our cohort. We believe that patients diagnosed by screening warrant a prophylactic total thyroidectomy at about age 6 years. The positive RET
germline mutation should be confirmed at least once
prior to thyroidectomy. Patients with MEN 2B need to
have a total thyroidectomy when they are initially
diagnosed. In children, we recommend central cervical lymph node clearance at the time of total thyroidectomy if 1) the basal or stimulated calcitonin is
elevated, 2) there is a thyroid lesion identified on
ultrasound or at the time of surgery, or 3) there are any
abnormal lymph nodes.
Although C-cell hyperplasia and bilateral MTC are
less common in sporadic MTC, our patients with sporadic MTC had a high rate of bilateral MTC. In all such
cases familial disease must be considered. However,
these patients with sporadic MTC had no family history and 17% had no germline RET mutations in exon
10, 11, 13, and 14. Nonetheless, we recommend that all
patients with MTC be screened for the RET germline
proto-oncogene mutations, as up to 10% of patients
with sporadic MTC may represent an index case of
hereditary MTC.3,31
Fine-needle cytology is normally accurate for diagnosing MTC. In some patients the type of thyroid
carcinoma is difficult to determine and Hürthle cell
neoplasms can occasionally be confused with MTC
cytologically and on frozen section. Staining for amyloid, calcitonin, CEA, and thyroglobulin can help confirm the diagnosis. All patients with MTC must also be
screened for pheochromocytoma prior to any operation.
It is intriguing that the extent of thyroidectomy
was not an independent predictor of mortality, given
the higher likelihood of persistent or recurrent MTC in
those patients who had lesser procedures than total or
subtotal thyroidectomy. We speculate that the long
survival time of some patients with persistent postoperative hypercalcitoninemia may account for this. Fur-
1145
thermore, the majority of the patients with MTC had
total thyroidectomy with central neck lymph node
clearance. Patients who had lesser procedures, however, did require more reoperations than patients who
had total thyroidectomy with central neck lymph node
clearance, as we have previously reported.5 Most of
the patients treated at our institution had a central
neck dissection, removing all fibrofatty tissue from
just above the innominate vein between the carotid
sheath and trachea to the level of the thyroid cartilage
(central neck dissection), and a functional neck dissection, preserving the motor and sensory nerves but
removing all fibrofatty and lymphatic tissue from the
carotid sheath to the trapezius and from the clavicle to
just above the hyoid bone.
In retrospective studies, chemotherapy and radiotherapy have been reported to be either helpful or
detrimental.3,19,32,33 The differing results probably depend on patient selection. In our experience, those
patients with MTC who had chemotherapy and/or
external radiotherapy had shorter survival times (not
statistically significant), but these patients also had
metastatic MTC. We recommend external radiation
treatment when macroscopic tumor is left or is unresectable.
When evaluating patients with persistent hypercalcitoninemia, we first determine whether the patient
has had appropriate initial surgical treatment. We
believe this includes 1) at least a total or near-total
thyroidectomy, 2) central neck dissection, and 3)
modified functional neck and superior mediastinal
dissection.34 Prior to this treatment, we generally obtain a neck ultrasound or magnetic resonance imaging
scan of the neck and mediastinum. A computed tomography scan of the liver and lung is also helpful for
identifying liver and lung metastasis, which, however,
are usually miliary. In our experience, virtually all
patients who have markedly elevated calcitonin levels
after appropriate initial treatment have distant metastasis. Bone scans are useful to screen for bony metastasis. Our study revealed that 38.3% of the patients had
persistent MTC, but these patients lived for 1 month to
23.7 years and 65.9% were alive at last follow-up. This
emphasizes that the subset of patients with postoperative persistent hypercalcitoninemia and no clinical or
radiographic evidence of residual tumor could be followed with apparent long-term survival. As reported
by Tissel et al.,35 Dralle et al.,36 and Moley et al.,37 we
recommend that patients with persistent hypercalcitoninemia have a meticulous total thyroidectomy and
central neck dissection, if not already done; this is a
functional lateral neck dissection in patients who have
what appears to be curable disease. We also recom-
1146
CANCER March 1, 2000 / Volume 88 / Number 5
mend palliative resection of locoregional disease even
in patients with known distant metastasis.38
The overall cause specific mortality observed in
our cohort is slightly better than that reported in other
studies (13.3–32.6% and 21.6 –38.6% at 5 years and 10
years, respectively).15–20 Patient age and stage of
MTC have been consistently observed to be the most
important prognostic factors in patients with
MTC.1,12,13,15,17,18 Indeed, in our study, these were the
only two independent prognostic factors in patients
with MTC. Patient gender approached statistical significance in univariate analysis and probably represents a minor risk factor. Some,12,13,16,18 but not
all,11,15,19,20 studies have also reported gender to be a
significant prognostic factor. The type of MTC (familial MTC, MEN 2A, sporadic MTC, and MEN 2B, in
increasing order of mortality rates) has been reported
to be an important prognostic factor in some studies.12,17,18 However, when controlling for the stage of
disease or multivariate analysis was done, the type of
MTC was not an independent prognostic factor.11,13,17,18,20,32 This is consistent with our finding.
Although patients with cervical lymph node metastasis were more likely to have persistent or recurrent
MTC, the presence of cervical lymph node metastasis
was not associated with significantly higher mortality.
Although this is in conflict with some studies,11,15,16
others have reported that cervical lymph node metastasis was not an independent prognostic factor.12,19,33,39
Previous studies of patients with differentiated
thyroid carcinoma have demonstrated the importance
of the prognostic staging systems.9,22–25,27 To our
knowledge, however, the utility and predictive value of
these staging systems have not been addressed regarding patients with MTC. The rationale for comparing these staging systems was 1) to determine the
most accurate staging system that best predicts survival, and 2) to evaluate the influence of the individual
prognostic factors on survival in these prognostic staging models. We recognize that some of these retrospective risk models involving patients with MTC have
been originally derived from a single population and
might not necessarily apply to another population.40
Their utility, however, has been validated in follow-up
studies or by other investigators who have evaluated
such staging systems in different cohorts, or in prospective studies.21,22,23,41 It is noteworthy that the
EORTC staging system had the highest PVE value and
that age, gender, and distant metastasis are included
in this system. This is consistent with our observation
that age and stage (mainly the presence of distant
metastasis) were the main determinants of survival in
our multivariate analysis. The apparent higher PVE of
the EORTC compared with the TNM system may also
be due to the absence of patient age in the TNM
system for MTC, which has been observed to be an
important prognostic factor in most studies, including
ours.1,11,12,13,16,17,39 This suggests that a similar TNM
staging system should be used for MTC as is used for
papillary and follicular thyroid carcinoma, in which
patient age is included in the TNM staging system. It is
interesting that the PVE value was lower for the
NTCTCS staging system than for the TNM system
because both are based on the same pathologic data,
with distinction between the two systems only in the
stage distribution (Table 1). The inclusion of otherthan-distant metastasis (i.e., extrathyroidal invasive
tumors) into the Stage IV group of the NTCTCS system
may account for this apparent difference, which did
not portend a poor prognosis in our cohort (Table 1).
Furthermore, the higher PVE and mortality rates by
stage (for Stage ⱖII) observed in the TNM staging
system compared with the NTCTCS system suggest a
more meaningful stage classification for the TNM system, at least in our cohort. Because the PVE is sensitive to the number of categories in a particular staging
system, it is not surprising, then, that the SEER extentof-disease staging system (local, regional, and distant)
had the least predictive value for patient survival.
In summary, the initial clinical presentation of
patients with MTC was useful in determining which
patients were at risk for poor outcome or for persistent
or recurrent MTC. Patients with familial MTC and
MEN 2A who were diagnosed at an early age and had
total thyroidectomy with central neck lymph node
clearance had an excellent prognosis. Patient age and
stage of disease were independent prognostic factors
in all patients with MTC. The model that included the
greatest number of significant prognostic factors
yielded a higher predictive value for survival. Although
the EORTC scoring system had the highest PVE value
in our cohort, the more commonly used TNM staging
system should probably be used to report treatment
outcome, for uniform comparison of treatment and
outcomes of patients with MTC. Furthermore, our
findings suggest that patients with persistent hypercalcitoninemia and no clinical or radiographic evidence of residual tumor may have long survival time.
These findings should be reassuring to those patients
with persistently elevated serum calcitonin levels after
apparent curative surgical resection and who are without clinical evidence of MTC.
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