Thyroid papillary microcarcinoma: A descriptive and meta-analysis study

Article (PDF Available)inEuropean Journal of Endocrinology 159(6):659-73 · September 2008with81 Reads
DOI: 10.1530/EJE-07-0896 · Source: PubMed
Abstract
The authors review anatomical, clinical characteristics and prevalence of thyroid microcarcinoma. Diagnostic procedures and risk factors of aggressiveness at diagnosis and during follow-up are also covered. The possible clinical, pathologic and therapeutic risk factors are analyzed by meta-analysis study. Treatment procedures by different authors and guidelines suggested by societies are reported.
REVIEW
Thyroid papillary microcarcinoma: a descriptive and meta-
analysis study
Elio Roti, Ettore C degli Uberti
1
, Marta Bondanelli
1
and Lewis E Braverman
2
Institute of Endocrinology, University of Milan, 20133 Milan, Italy,
1
Section of Endocrinology, Department of Biochemical Sciences and Advanced
Therapies, University of Ferrara, 44100 Ferrara, Italy and
2
Section of Endocrinology, Diabetes, and Nutrition, Boston Medical Center, Boston University
School of Medicine, Boston, Massachusetts 02118, USA
(Correspondence should be addressed to E Roti; Email: elio.roti@unimi.it)
Abstract
The authors review anatomical, clinical characteristics and prevalence of thyroid microcarcinoma.
Diagnostic procedures and risk factors of aggressiveness at diagnosis and during follow-up are also
covered. The possible clinical, pathologic and therapeutic risk factors are analyzed by meta-analysis
study. Treatment procedures by different authors and guidelines suggested by societies are reported.
European Journal of Endocrinology 159 659–673
Introduction
Thyroid microcarcinoma has been defined as thyroid
cancer %10 mm in diameter, usually papillary (papil-
lary thyroid microcarcinoma, PTMC) (1). In the past,
the term occult thyroid carcinoma was used to define
cancers with local metastases without a definite
presurgical diagnosis and those detected at histologic
examination. The diameter of these apparently un-
identified thyroid cancers was set %15 mm (2). A recent
study did not separate cancers with a diameter
%10 mm from those with %15 mm, all defined as
small papillary thyroid carcinomas (3).
However, in the present review, we will analyze some
clinical and histological characteristics of PTMC
(Table 1), mentioning some aspects of small thyroid
carcinomas, when appropriate, for a more comprehen-
sive evaluation. The uncertainty of the literature
concerning the possible risk factors at diagnosis for
recurrent disease as well as the treatment to adopt in
patients with PTMC has led us to conduct the present
review, including a meta-analysis of the clinical,
pathologic, and therapeutic characteristics of PTMC
related to cancer recurrence.
Selection of relevant studies for review
We have searched the key words ‘thyroid microcarci-
noma’ and ‘papillary microcarcinoma’ on the electronic
database Medline with a temporal limit, 1966–March,
2008. Through PubMed, 243 and 207 articles related
to the former and latter keywords respectively have
been retrieved. The former group of articles included, as
well, all the articles related to the latter item ‘papillary
microcarcinoma’ except four articles. These four articles
were not included in the present review: two articles
were not related to thyroid pathology and two did not
describe the characteristics of PTMC. Thus, 243
abstracts were read by two authors (ER, MB). These
authors agreed to discard from the present analysis
22 articles of medullary carcinoma, 23 only dealing
with histological aspects, 23 with immunochemistry,
7 related to surgical technique only, 21 editorials/reviews,
53 case reports/letters, 15 discussing cancer in general,
and 3 because the abstracts were not reported or
insufficient for evaluation. Articles from the same group
of authors updating their series of PTMC were reported
once or pooled, as appropriate. To describe the general
characteristics of PTMC, 76 articles were examined.
For analyzing the risk factors for recurrence, we
further restricted the selection to articles in English and
Italian, each article containing a number of cases O35
and reporting data on PTMC recurrence and possible
risk factors for tumor recurrence, such as age, sex,
discover modality, tumor size and extension, lymph
node involvement at diagnosis, distant metastases at
diagnosis, type of surgery, and ablative 131-iodine
therapy. Thus, in total, 17 articles met the inclusion/
exclusion criteria for the meta-analysis study.
Data pooling and statistics
The primary analysis consisted in evaluating an effect
size for each of the studies by calculating the odds ratio
(OR) for dichotomous events. The effect sizes of all trials
were tested for heterogeneity using the Q statistics,
which were an adaptation of the c
2
goodness-of-fit test.
The OR was the ratio across different groups for the odds
European Journal of Endocrinology (2008) 159 659–673 ISSN 0804-4643
q 2008 European Society of Endocrinology DOI: 10.1530/EJE-07-0896
Online version via www.eje-online.org
that the event would occur. A 95% confidence interval
(CI) was constructed around the effect size to establish
its significance. If the 95% CI of an OR included 1, the
two groups were not considered statistically different.
Statistical analysis was performed using the Compre-
hensive Meta-analysis software (v. 2.0, Biostat, Engle-
wood,NJ,USA).AP value less than 0.05 was
considered statistically significant.
Size
The diameter of PTMC is more than 5 mm in 35.2–79%
of the cases, with a median size in each study ranging
from 4.1 to 8 mm in diameter (4–26). In some patients,
cancers as small as 1 mm in diameter have been
diagnosed (4, 5, 9, 27).
An autopsy study on survivors of the atomic bomb in
Hiroshima and Nagasaki, revealed that among 2035
thyroid glands examined, 141 harbored a papillary
cancer !1.0 mm in diameter (28). In Finland, an
autopsy study found that the size of occult papillary
carcinoma was !1.0 mm in diameter in 77% of the
cases (29). Another autopsy study of thyroid glands
collected in different geographical areas of the world
reported that thyroid microcarcinomas 1–3 mm in
diameter were more prevalent than those 3–9 and
10–15 mm in diameter, 50.4, 27.3 and 3.6% respect-
ively, suggesting an arrest of the growth of PTMC (30).
Histology
Thyroid microcarcinoma is most often papillary, 65–99%
of the cases (5, 9, 10, 15, 17, 18, 24, 30–32).The
follicular variant of papillary thyroid cancer has been
observed in 9.7 (30),13.1(9) and 31% (15) of the cases
and follicular cancer has been found in 0.3–23.6% of the
cases (5, 9, 10, 17, 18, 24, 30–34). This latter finding is
in agreement with the observation that 11% of follicular
cancers are %10 mm in diameter (35). The more virulent
oncocytic and tall cell variants of PTMC have been
observed, with a prevalence of 0.8% of the cases (9).The
sclerosing variant has been found in 5–11.7% of thyroid
carcinomas with a diameter %10 mm (9, 24) and in
only 1.1% of cancers with a diameter of 11–20 mm (36).
The decreased prevalence of the sclerosing variant with
the larger tumors might indicate, as suggested by
Fukunaga & Yatani (37), that the sclerosing is a defensive
mechanism preventing tumor growth. Also, a recent study
(3) confirmed that the sclerosing variant is more frequent
in cancers %10 mm in diameter than those with a
diameter of 1.1–1.5 mm (P!0.015). However, in patients
with smaller cancers, the prevalence of distant metastases
was increased compared with those of larger cancers.
Age at the time of the diagnosis PTMC
The mean age at diagnosis of patients with thyroid
microcarcinoma has been reported by different studies
to be 41.9–55 years (4–6, 8–12, 15–26, 30, 31, 34,
38–53) with a range of 4–85 years (4–6, 8, 11, 12, 15,
17–20, 24, 30, 31, 34, 38, 39, 42, 44–46, 48, 51, 53).
The age range of larger thyroid cancers %15 mm in
diameter at diagnosis did not change, 13–79 years with
a median value of 41.9 years (3). Two studies reported
that 25.9 and 52.8% of cases of thyroid microcarci-
noma occurred in patients older than 45 years (54, 55).
Autopsy studies demonstrated that thyroid microcarci-
nomas occurred at the same rate in each decade in
adults (29, 37, 56, 57). In only one study, patients with
thyroid microcarcinoma with metastases had a mean
age higher than those without metastases, 54G16.9
and 37.7G12.3 years respectively (58).
Sex
Combining the results of different studies, among 6653
patients with thyroid microcarcinoma, 5516 (82.9%)
were women and 1137 (17%) were men with a ratio
of 4.85/1 (4–6, 8, 10, 12, 15–19, 21, 25, 30–32, 34,
38–42, 44–47, 49, 50, 52–55). Similarly, in patients
with small thyroid carcinomas, %15 mm in diameter,
85% were women and 15% were men (3). This striking
sex difference was not observed in autopsy studies.
Among 198 cases of microcarcinoma, 109 (55%) were
men and 89 (45%) were women (29, 37, 56, 59).Ina
single study describing 141 cases of thyroid micro-
carcinoma !10 mm in diameter, 82 (58%) were men
and 59 (42%) were women (28). It is likely that the
Table 1 Some clinical and pathologic characteristics of papillary thyroid microcarcinoma (PTMC).
Reference nos
Size %10 mm (1)
Mean size (range) 4.1–8 (4–26)
Papillary type (range) 65–99% (5, 9, 10, 15, 17, 18, 24, 30–32)
Age (years; range) 41.9–55 (4–6, 8–12, 15–26, 30, 34, 38–55)
Sex F/M ratio 4.8/1 (4–6, 8, 10, 12, 15–19, 21, 25, 30–32, 34, 38–42, 44–47, 49, 50, 52–57)
Autopsy prevalence O35.6% (29)
Clinical prevalence O95.3% of all cancers (23)
Incidental prevalence O100% of all PTMC (7)
Range values refer to the results of different studies.
660 E Roti and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2008) 159
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higher prevalence of thyroid microcarcinoma in living
women may be due to their higher prevalence of thyroid
disease and, therefore, greater access to diagnostic
procedures resulting in increased identification of PTMC.
Familial prevalence of PTMC
PTMC has been reported in members of the same family.
Lupoli et al. (60) reported seven familial cases out of 119
patients with PTMC. Pellegriti et al. (3) observed 18 familial
cases among 299 small papillary thyroid cancers (size
%15 mm in diameter); of these, 10 were true micro-
carcinomas. Roti et al. (12) reported 13 familial cases
in their series of 243 PTMC patients. Thus, familial cases
of PTMC have an overall prevalence of 4.5%. Similarly,
5–10% of all thyroid carcinoma are familial (61). Familial
cases of PTMC have occasionally been reported (62, 63).
One study reported that familial PTMC are more aggressive
than the nonhereditary types (60). However, this finding
was not confirmed by others (3, 12) likely due to the
fact that familial papillary thyroid carcinoma (PTC)
consists of different syndromes with heterogeneous gene-
tic susceptibility to thyroid cancer (61).
Molecular events in PTMC
Papillary carcinomas frequently harbor activating
mutations of genes coding for proteins that signal
along the MAP kinase pathway.
It has been reported that RET/PTC rearrangement is
present not only in large papillary thyroid cancers but also
in micropapillary thyroid carcinoma in up to 52% of the
cases (64–66), but this finding does not seem to be a sign
of cancer aggressiveness (67). In contrast, RET/PTC3-
positive papillary thyroid carcinoma has a more aggres-
sive behavior (68). BRAF mutations may occur in
papillary thyroid carcinoma and have also been reported
in PTMC (65, 69–71). Furthermore, it has recently been
reported that BRAF mutations enhance the capacity of
BRAF mutated cells to proliferate and transform (72).It
has also been suggested that lymph node metastases of
papillary cancer are accompanied by a new BRAF
mutation, different from that observed in the matched
primary thyroid cancer, confirming the progression model
of cancer where metastatic foci have a new mutational
event (73). These results suggesting that PTMC harboring
an activating mutation of the gene for BRAF might have a
more aggressive behavior have not been confirmed by
another study in Korean patients (74).
Prevalence
Autopsy prevalence
The autopsy prevalence of thyroid microcarcinoma is
largely ranging between 0.01% in USA (37) and 35.6% in
Finland (29), the highest value reported in the literature.
This striking difference may be due to genetic and
environmental factors and to the methods employed in
the histologic examination of the thyroid gland.
An elevated prevalence of thyroid microcarcinoma
has consistently been observed in the Japanese popu-
lation, 13.7–28.4% (37, 75–78). This may be related to
radiation exposure during the bombing of Hiroshima
and Nagasaki, but is probably due to ethnicity since
Japanese residing in Hawaii, not exposed to bomb
radiation, have a similar prevalence of thyroid micro-
carcinoma, 24% (37, 79). In 4620 autopsy cases, PTMC
was observed in 9.9% when only a suspected lesion was
examined and in 15.5% of 1262 autopsy cases when
the entire gland was examined (13, 29, 37, 59, 75, 76,
80–85). Therefore, the prevalence of occult thyroid
microcarcinoma increases with the extent of the
examination of the thyroid, in particular with the
thinness of the anatomical slices of the thyroid speci-
mens (29).
Iodine intake has been suggested as a possible factor
affecting the prevalence of thyroid cancer (86).Ina
single ethnic group, it has been observed that the
autopsy prevalence of PTMC was not affected by iodine
intake (80).
Clinical prevalence
The prevalence of thyroid nodules is variable in different
populations and within the same population. In the USA,
the prevalence of nodules detected by ultrasound
examination (US) varies between 13 and 67% (86).US
diagnosed nodules with a diameter of 0.5–1.0 cm have
been found in 10% of the population of Germany (87).Tan
et al. (88) reported that 48% of patients with a palpable
nodule had more than one nodule detected by US
examination and, in these patients, 72% of the nodules
had a diameter of %1 cm. Similar results have been
reported by others (89, 90). Obviously, the increased
accuracy in the clinical and laboratory evaluation since
the introduction of US-guided fine needle aspiration biopsy
(FNAB) of patients with suspected thyroid diseases has led
to a dramatic increase in the incidence of thyroid cancer.
Recently, it has been reported that the prevalence of PTMC
is 1.24% in 8203 patients who underwent FNAB (21).
In France, during the last two decades, the prevalence of
PTMC among all thyroid cancers increased from 18.4
(1983–1987) to 43.1% (1998–2001) (91).TheGeneva
Cancer Registry showed an increase in PTMC/all papillary
thyroid cancers from 17 to 24% in 1970–1974 and
1995–1998 respectively (92). In the USA, the incidence
of PTMC has consistently increased over the course of
years; in 1968, PTMC had an incidence of 1.5 per
100 000, whereas in 2002 it was w3.5 per 100 000
subjects, accounting for 49% of all thyroid cancers (93).
Similarly, in Tasmania, the prevalence of PTMC among
all thyroid cancers almost doubled during 1992–1998 in
comparison with 1978–1984 (94). In Hong Kong, the
Thyroid papillary microcarcinoma 661EUROPEAN JOURNAL OF ENDOCRINOLOGY (2008) 159
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proportion of PTMC among all differentiated thyroid
cancers was 5.1% before 1980, 16.1% during 1981
1990, and 21.7% during 1991–2000 (95).InTable 2,we
report the prevalence of PTMC in patients with different
thyroid diseases (6, 10–12, 15–17, 20, 23, 31, 38, 43, 45,
46, 49, 50, 52, 54, 55, 96–118). As shown, PTMC
accounts for approximately a quarter of thyroid malignant
diseases. Furthermore, it has been reported that 14.2%
of 551 patients operated upon for thyroid papillary
carcinoma had a cancer %5mm(119, 122).
Thus, the increased prevalence of PTMC at surgery
reflects the prevalence of occult thyroid carcinoma in
autopsy series.
Incidental prevalence
PTMC is often diagnosed during thyroidectomy for benign
thyroid and parathyroid diseases. The results of different
studies of 5035 patients with PTMC, demonstrated that
71% were incidentally discovered at surgery for other
thyroid disorders (4–7, 11–15, 18, 23–27, 32, 43, 44, 46,
49, 96–99, 102, 103, 112–116, 118, 119–125).The
prevalence of incidental cases of PTMC is very variable
ranging in large series between 4.6 (23) and 100% (7).
Even in the same institution, the prevalence of incidental
PTMC varied at different periods of time from 10.9 to
55.4% (9, 55, 123, 126). Recent studies reported a
prevalence of incidental PTMC ranging from 3.1% in
385 (121) to 21% in 386 patients (99) operated upon
for benign diseases of the thyroid. In multinodular
goiter/nodules, PTMC has been observed in 2–15.2% of
the cases (96, 125). In patients operated upon for nodules
measuring O1andO4 cm in diameter, the presence of
PTMC occurred in 3.1 and 15.2% of the cases respectively
(120, 125). The different results in the prevalence of
incidental PTMC are likely due to the variable use and
expertise in the use of US and US-guided FNAB.
Diagnosis of PTMC
The use of US examination of the thyroid gland has
greatly increased the number of small benign and
malignant nodules diagnosed before surgery. Some US
nodule characteristics appear suspicious for malig-
nancy. Microcalcifications within malignant nodules
have been observed in many studies (76, 127–130) and
were present in 7.1–59% of patients with PTMC (76,
127–131). Irregular margins of the nodules have been
observed in 21.5–77% of PTMC (11, 127, 130, 133).
A taller-than wider dimension and antero-posterior
diameter larger than the transverse diameter of non-
palpable thyroid nodules have also been suggested as
a diagnostic feature for the presence of malignancy
(76, 101). An increase in the size of small thyroid
nodules at US follow-up was not a reliable marker in the
differential diagnosis between malignant and benign
nodules (132). In one study, US examination of the
thyroid led to a correct preoperative diagnosis in 20 out
of 36 PTMC patients (110).
US-guided FNAB is a very accurate diagnostic
procedure in evaluating patients with thyroid nodules
%10 mm in diameter. Under US guidance, sufficient
cytological material has been obtained from nodules as
small as 2 mm in diameter (53). Inadequate cytologic
samples obtained by US-guided FNAB in nonpalpable
nodules was w18.5% of all cases (127, 133, 134) and
22.5 and 33% in nodules %10 mm (127, 130, 135,
138). To our knowledge, no systematic studies have
been conducted to evaluate the diagnostic precision of
FNAB in nodules with a diameter %10 mm. PTMC was
detected in 12 (9.2%) out of 131 nodules that are
8–10 mm in diameter (127) and in 24 (13.5%) out of
178 nodules that are 2–10 mm in diameter (135).
US-guided FNAB is performed in patients with small
nodules with variable frequency, primarily due to the
decision of the physician and to patient preference.
The American Thyroid Association (ATA) (136) and
the American Association of Clinical Endocrinologists
(AACE) (137) suggested that nodules %10 mm should
be examined by US-guided FNAB only in the presence of
suspicious features at US examination, a history of neck
irradiation and a positive family history of thyroid
cancer. The guidelines of the Society of Radiologists in
Ultrasound (138) recommended that only nodules with
a diameter of at least 10 mm with microcalcifications
should undergo FNAB.
It has been reported that the presence of malignancy
was not different between nodules with a diameter
of 8–10 and 11–15 mm (127) and that the risk of
malignancy was not significantly increased by the
presence of more than one nodule (127). This nding
Table 2 Prevalence of papillary thyroid microcarcinoma (PTMC) among malignant and benign thyroid diseases in different studies.
PTMC (%) Reference nos
Papillary thyroid cancer (10 981) 28.8 (10, 11, 15, 16, 20, 23, 31, 38, 50, 54, 55, 99–105)
Differentiated thyroid cancer (4776) 24.8 (52, 105–111)
All thyroid cancer (10 628) 22.9 (13, 17, 43, 45, 50, 99, 100, 112–114)
Nodular goiter/nodule (2157) 7.7 (13, 26, 43, 99, 118, 120)
Graves’/hyperthyroidism (1789) 4.1 (105, 115, 117)
All thyroidectomy (10 422) 3.8 (46, 49, 101, 116, 119)
The prevalence of PTMC has been calculated as the mean of the percentage values in different studies (Reference nos). In parenthesis are reported the sum of
cases of the different thyroid conditions in the studies indicating the prevalence of PTMC.
662 E Roti and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2008) 159
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is similar to that observed in patients with larger
nodules (138).
Thyroid scans should not be used in the diagnostic work
up of PTMC, since it does not have sufficient sensitivity and
specificity in detecting small cancers (!1.5 cm) (139).
PET imaging with [18F] uorodeoxyglucose failed to
detect extrathyroid invasion in patients with PTMC (140).
Clinical and pathologic characteristics of
PTMC at diagnosis
The clinical and pathologic characteristics of PTMC at
the time of diagnosis are variable in different studies.
Bilateral and multiple foci have been observed in 2.9
(125) to 48% (26) and 7.1 (14) to 56.8% (104)
respectively. The prevalence of extracapsular invasion
and lymph node metastasis at diagnosis ranged between
2 (4) and 62.1% (112) and 0 (113) and 64% (8)
respectively. In one study, it was reported that lymph
node metastases were present in 40.5% of patients with
microcarcinoma, even though the patients were
diagnosed as node negative before surgery (141).
Distant metastases at diagnosis have rarely been
observed in patients with PTMC, occurring in only 35
cases (0.37%) of 9313 patients described in different
studies published between 1966 and 2008
(3–8, 10–12, 13–18, 20, 21, 23–27, 30, 31, 34, 38–
40, 42, 45–52, 58, 98, 103, 109, 112–114, 116, 121,
123–125, 141–143). In one study, multifocality,
extrathyroidal extension, and lymph node metastasis at
diagnosis were similarly prevalent in patients with PTMC
and in those with larger papillary thyroid carcinomas
(21). In three studies (5, 12, 130), the clinical and
histologic characteristics of incidental and nonincidental
PTMC were compared. It was observed that the
prevalence of multifocality/bilaterality, extracapsular
invasion, and lymph node metastases at diagnosis were
more frequent in patients with nonincidental PTMC.
Furthermore, distant metastases at diagnosis were
observed in only 9 cases out of 283 nonincidental and
in 3 out of 241 incidental PTMC (5, 12).
Risk factors for the presence of lymph
node metastases at diagnosis
Some studies have identified risk factors for the presence
of lymph node metastases at diagnosis. Nonincidental
PTMC appears to have a higher risk for lymph node
metastases at diagnosis (12, 131). Lymph node
metastases were more frequent in patients with larger
PTMC, O5 (8, 144) and O8mm (12). Lymph node
metastases and extrathyroid extension were observed in
only 4.4 and 25.7%, respectively, of patients with PTMC
%5 mm in diameter (42). The follicular variant of
PTMC and extracapsular invasion were associated with
a higher prevalence of lymph node metastases (12).
The presence of Hashimoto’s thyroiditis appeared to be
protective for the presence of lymph node metastases at
diagnosis (12). Recently, it has been reported that the
absence of epidermal growth factor receptor expression
was positively correlated with the presence of lymph
node metastases (23). Some studies evaluated whether
the expression of cyclin D1 and galectin-3 in PTMC
could be a marker of lymph node metastases (145–
147). Overexpression of cyclin D1 was present in PTMC
with lymph node metastases. However, similar results
were observed in patients without lymph node metas-
tases (148). Similarly, the expression of galectin in
PTMC was not significantly correlated with the presence
of lymph node metastases (148, 149).
Risk factors for the presence of distant
metastases at diagnosis
Distant metastases at diagnosis are a rare event.
Therefore, only few studies have statistically analyzed
possible risk factors. Distant metastases at diagnosis
correlated positively with the diameter of PTMC
(P%0.05) (12), advancing age (P%0.01), lymph node
metastasis at diagnosis (P!0.01), and follicular variant
of PTMC (P!0.008) (58). In one study, it was observed
that all patients with distant metastases had lymph
node invasion at diagnosis (5).
Treatment of PTMC
Surgical procedures
Surgical procedures in patients with PTMC were extre-
mely different among the studies. Total/near total
thyroidectomy was carried out in 100% of the cases in
17 (11, 12, 14, 15, 18, 24, 26, 27, 39, 46, 49, 52, 97,
104, 106, 117, 150) out of 44 studies that reported the
type of surgery (4–6, 8, 11, 12, 14–18, 20, 23–27,
30–32, 34, 38–40, 42, 45, 46, 48–50, 58, 97, 98,
104–106, 114, 117, 121, 123, 124, 143, 148, 150).
Combining the results of different studies that clearly
reported the extent of surgery in 9259 patients with
PTMC, total/near total thyroidectomy was performed in
the 72%, subtotal thyroidectomy in the 11% and
lobectomy in the 17% of the cases (4–6, 8, 11, 12,
14–18, 20, 23–27, 30–32, 34, 38–40, 42, 45, 46,
48–50, 58, 97, 98, 104–106, 114, 117, 121, 123, 124,
143, 148, 150). In these studies, therapeutic lymph node
excision was carried out in an extremely variable
proportion of patients, ranging from 0 to 46.9% of the
cases, with a mean value of 9.8%, whereas prophylactic
lymph node excision was performed in 11 studies (4–8,
17, 30, 34, 39, 48, 148) with a mean value of 55.7% of
the patients. The presence of metastases in the excised
nodes was found in 1104 (58%) out of 1895 cases (3, 5, 7,
8, 12, 22, 30, 41, 42, 56).
Thyroid papillary microcarcinoma 663EUROPEAN JOURNAL OF ENDOCRINOLOGY (2008) 159
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Table 3 Characteristics of the studies included in the meta-analysis on possible risk factors for recurrence of thyroid papillary microcarcinoma.
Authors
No of patients
(M/F) Age (yr)
Period of
study (yr)
Mean follow-up
(yr or mo; range)
Lymph
node meta-
stases at
diagnosis
(no)
Distant
metastases
at diagnosis
(no)
Locoregional
recurrence
(no)
Distant
recurrence
(no)
Total
recurrence
(no)
Besic et al. 2008 (152) 228 (39/189) 14–85 1975–2006 84 mo (1–385) 56 0 6 1 7
Baudin et al. 1998 (5) 273 (69/204) 6–65 1962–1995 7.3 yr (0.6–33.7) 121 3 11 1 11
Sugitani et al. 1998 (51) 190 1976–1996 8 yr (2–21) 34 0 11 4
Roti et al. 2006 (12) 243 (46/197) 16–85 1993–2002 4.4 yr (2.4–10.6) 32 4 4 0 4
Pelizzo et al. 2006 (55) 403 (66/337) 1990–2004 8.5 yr (9 mo–14 yr) 47 1 6 1 (C)24
a
Lo et al. 2006 (20) 185 (37/148) 11–84 1964–2003 8.2 yr (0.1–38) 43 3 NR NR 13 (C4 died of disease)
Ku
¨
c¸u
¨
k et al.2007(22) 120 (15/105) 17–67 1997–2005 45 mo (16–86) 7 0 2 0 2
Ito et al. 2004 (48) 590 (38/552) 18–83 1993–2003 (0–140 mo) 67 NR 10 NR
Ito et al 2003 (41) 626 (39/587) 16–83 1993–2003 48.7 mo (0–120) 300 0 16 0 16
Rodriguez et al. 1997 (31) 36 (6/30) 4–65 1970–1990 7 yr 6 ? 0 3 0 3
Appetecchia et al. 2002 (40) 120 (24/96) 23–77 NR 8 yr (5–15) 26 0 2 0 2
Chow et al. 2003 (42) 203 (27/176) 7.7–77.2 1960–1999 8.4 yr 50 4 12 4
Wada et al. 2003 (8) 259 (29/230) 17–72 1988–1998 61.6 mo (13–144) 93 0 7 0 7
Gu
¨
lben et al. 2008 (151) 81 (15/66) 16–61 1990–2003 7 yr (28–192) 10 0 1 0 1
Scho
¨
nberger et al. 2007 (25) 67 (19/48) 22–88 1993–2003 55.5 mo (14–169) 10 2 1 2
b
1
Yamashita et al. 1999
c
(7) 1743
(186/1557)
1970–1994 11.2 202 0 35 5 31
Monacelli et al.2006
c
(18) 74 (16/58) 24–73 2001–2004 6 0 4 0 4
6 ?, six patients presented with enlarged cervical lymph node without a palpable lesion, histology of these lymph node has not been specified. NR, not reported; mo, months; yr, years.
a
Living with disease: 24 patients with increased serum thyroglobulin levels; during follow-up, six of these patients experienced locoregional macroscopic recurrent disease. Moreover, one patient (C)was
deceased due to metastatic thyroid cancer.
b
These patients had distant metastases also at diagnosis.
c
These studies also included some follicular and/or medullary thyroid microcarcinomas.
664 E Roti and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2008) 159
www.eje-online.org
131
I treatment following thyroidectomy
131
I treatment following surgical treatment was done in
some studies (4, 5, 12, 16, 20, 25, 22, 26, 39, 40, 45,
50, 97, 98, 106, 123, 124, 142, 143) with a variable
proportion of patients, 10.3 (4) to 100% (22, 106).In
total, 1594 (17%) out of 9379 patients were treated
with
131
I.
L-T
4
(L-thyroxine) treatment following
thyroidectomy
Many studies on PTMC failed to mention whether L-T
4
was given after surgery. However, it seems likely that L-
T
4
therapy was administered in patients with extensive
thyroidectomy. In some studies (3, 8, 12, 21, 32, 38, 39,
55, 142), suppressive doses of
L-T
4
were recommended
in patients operated upon for PTMC, but in one study it
was discontinued within several years (30).
L-T
4
suppressive therapy was prescribed in 95.8% of patients
who underwent prophylactic lymph node excision,
87.2% of patients who had therapeutic lymph node
excision and 47.1% of those who did not have lymph
node excision (8). Another study reported that either
suppressive or substitutive
L-T
4
therapy was rec-
ommended for an unknown period of time and later
substitutive therapy only (42). Finally, substitutive
L-T
4
therapy was the treatment of choice in some patients
with PTMC (26, 27, 42).
Follow-up
Recurrence
One study has provided information on the natural
course of PTMC (41). In this study, it was observed that
in 162 patients with PTMC who did not undergo
surgical excision, cancer size increased in 27.5%,
decreased in 12.1%, and remained stable in 60.3%,
and lymph-node metastases were diagnosed in 5.5% of
the cases over 5 years of follow-up (41).
Local/lymph node recurrent disease has been
observed with variable prevalence, with values ranging
between 0.3 and 37% (97, 104). Combining the results
of different studies, local/lymph node recurrence has
been observed in 231 (2.4%) out of 9379 patients (4–6,
8, 11, 12, 14–18, 20, 22, 23–27, 30–32, 34, 38–40,
42, 45, 46, 48–50, 58, 97, 98, 104–106, 114, 117,
121, 123, 124, 143, 148, 150). In these studies, distant
metastases were clearly reported in 26 cases (4, 16, 20,
30, 34, 42, 48, 51, 58, 105) corresponding to 0.27% of
9379 cases (4–6, 8, 11, 12, 14–18, 20, 22, 23–27, 30–
32, 34, 38–40, 42, 45, 46, 48–50, 58, 97, 98, 104–
106, 114, 117, 121, 123, 124, 143, 148, 150).
Mortality
Cancer-related death has rarely been reported in
patients with PTMC, 32 (0.34%) of 9379 patients
(4–6, 8, 11, 12, 14–18, 20, 22, 23–27, 30–32, 34,
38–40, 42, 45, 46, 48–50, 58, 97, 98, 104–106, 114,
117, 121, 123, 124, 143, 148, 150).
Risk factors for recurrence and mortality
In the present study, possible risk factors at diagnosis for
recurrent disease have been studied by meta-analysis.
Table 3 reports the studies utilized for the analysis; the
studies by Gu
¨
lben et al. (151) and Besic et al. (152) were
not included since we had direct access to the full text
after the calculations of our study were completed.
Recurrence was not statistically related to gender. In
contrast, younger age (!45 years) was significantly
(P!0.04) associated with cancer recurrence (Fig. 1).
Also, clinically overt cancer was significantly related
(P!0.001) to recurrence (Fig. 2). Among the pathologic
characteristics of PTMC, cancer size was not associated
with recurrence. In contrast, cancer multifocality
(Fig. 3) and lymph node involvement at diagnosis
Figure 1 Pooled data for the association of tumor recurrence and age. OR in patients aged !45 years was 1.846 (95% CI 1.036–3.291;
PZ0.038). There was no statistical heterogeneity (PZ0.783). Tumor recurrence was significantly associated to younger age (!45 years).
Thyroid papillary microcarcinoma
665EUROPEAN JOURNAL OF ENDOCRINOLOGY (2008) 159
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(Fig. 4) were highly significantly (P!0.000) associated
with recurrence. The presence of extrathyroid extension
was not related to cancer progression. The presence of
distant metastases at diagnosis suggests a higher cancer
recurrence rate; however, in this analysis, some patients
had only persistent disease rather than new metastases
(Fig. 5). Among the therapeutic option for treatment of
PTMC, we found that patients who had total/near total
thyroidectomy, as well those with lymph node excision
had a lower cancer recurrence rate, but these values
were not statistically significant because of the hetero-
geneity of the data. Again,
131
I treatment was not
associated with progression of the disease.
Analyzing different studies (4, 30, 34, 42, 55, 153),a
total of 14 patients with PTMC died, of whom 11 had
extensive thyroidectomy and the other 3 had partial
thyroidectomy.
Guidelines for the treatment of PTMC
Specific recommendations for the treatment of patients
with PTMC have been published by some Scientific
Societies. The ATA (136) recommends that total/near
total thyroidectomy should be performed in patients with
thyroid cancer of O1.5 cm in diameter. In patients with
small, low-risk, isolated, intrathyroidal papillary carci-
nomas in the absence of cervical nodal metastases,
thyroid lobectomy may be sufficient treatment. The
presence of positive contralateral thyroid nodules or
regional or distant metastases, if the patient has a history
of radiation therapy to the head and neck or a first-degree
member with differentiated thyroid cancer or older than
45 years of age, near-total or total thyroidectomy is the
treatment of choice for PTMC. The European Thyroid
Association (ETA) (154) and the British Thyroid
Figure 2 Pooled data for the association of tumor recurrence and modality of diagnosis. OR in incidentally discovered tumors was 0.210
(95% CI 0.086–0.517; PZ0.001). There was no statistical heterogeneity (PZ0.675). Tumor recurrence was significantly higher in patients
with overt tumors.
Figure 3 Pooled data for the association of tumor recurrence and tumor focality at diagnosis. OR in patients with unifocal tumor was 0.174
(95% CI 0.105–0290; PZ0.000). There was no statistical heterogeneity (PZ0.535). Positive association was found between tumor
recurrence and multifocal tumors at diagnosis.
666 E Roti and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2008) 159
www.eje-online.org
Association (BTA) (155) recommend partial thyroid-
ectomy and lobectomy respectively, in the presence of
PTMC N0M0 without a history of neck irradiation. The
AACE (137) suggests that lobectomy plus isthmectomy is
the surgical procedure of choice in cases of PTMC
without evidence of lymph node involvement.
131
I treatment, according to the ATA guidelines (136),
is indicated in patients with PTMC (any N, M1) younger
than 45 years (stage II disease) and in patients older than
45 years, N1a,Mo (stage III) and N1b, Mo (stage IVa) and
any N,M1 (stage IVc), according to the TNM 6th edition
classification for differentiated thyroid carcinoma (156).
The ETA recommendations (154) state that patients with
unifocal microcarcinoma (%1 cm) with no extension
beyond the thyroid capsule and without lymph node
metastases will not benefit from postoperative
131
I
treatment. Also, in patients with documented persistent
disease or at high risk of persistent or recurrent post-
operative disease,
131
I treatment reduces the recurrence
rate and possibly prolongs survival (154). The BTA (155)
recommends
131
I treatment in patients with a tumor size
O1cmindiameter.
Suppressive or substitutive
L-T
4
treatment in patients
with PTMC has not been clearly stated by the different
Societies. The ATA (136) recommends that low-risk
patients, a category that includes the majority of PTMC,
be treated with
L-T
4
to reach serum thyroid stimulating
hormone (TSH) concentrationsZ0.1 mU/l in the early
follow-up period; for maintenance treatment, the goal is
to have serum TSH values 0.1–0.5 mU/l and in the long-
term follow-up of patients free of disease and low-risk at
diagnosis, a serum TSH concentration of 0.3–2.0 mU/l
is recommended. In contrast, the BTA recommends
TSH-suppressive doses of
L-T
4
for patients with PTMC !
1 cm in diameter and negative nodes treated by a
lobectomy (155). These recommendations seem accep-
table for the large majority of patients with PTMC.
A recent Belgian survey conducted among the members
of the Belgian Thyroid Club (157) found that in the case
of nodules 0.9 cm in diameter, suspicious of PTC by FNA
Figure 4 Pooled data for the association of tumor recurrence and positive lymph node at diagnosis. OR in patients with no lymph node
involvement at diagnosis was 0.213 (95% CI 0.136–0.336; PZ0.000). There was no statistical heterogeneity (PZ0.195). Positive
association was found between tumor recurrence and lymph node involvement at diagnosis.
Figure 5 Pooled data for the association of tumor recurrence and distant metastases at diagnosis. OR in patients with distant metastases
at diagnosis was 0.007 (95% CI 0.001–0.036; P!0.0000). There was no statistical heterogeneity (PZ0.078). Positive association was
found between tumor recurrence and presence of distant metastases at diagnosis. Please note that some patients had persistent rather
than recurrent disease.
Thyroid papillary microcarcinoma
667EUROPEAN JOURNAL OF ENDOCRINOLOGY (2008) 159
www.eje-online.org
without lymph node enlargement, 41% of the respon-
dents favored a total thyroidectomy and 37% a total
thyroidectomy with lymph node dissection; only 17%
favored lobectomy. This study indicates that the large
majority of Belgian endocrinologists did not follow the
American, European, or BTA recommendations (136,
154, 155). Similarly, Mazzaferri (158) recently rec-
ommended total or near total thyroidectomy for
preoperatively diagnosed low-risk PTMC.
Recently, Jonklaas et al. (159) reported no impact,
positive or negative, of total/near total thyroidectomy,
radioactive iodine treatment and
L-T
4
suppressive
therapy in patients with stage I differentiated thyroid
carcinoma. The large majority of patients with PTMC
are stage I. However, the same study showed that the
above-mentioned specific therapies were beneficial in
stage III patients. We have recently observed (36)
that 17% of patients with PTMC were classified as
stage III, according to the TNM 6th edition
classification (105). Similarly, Cappelli et al. (21)
reported that 15.7% of PTMC were stage III cancers.
At present, it is not possible to discriminate patients
with aggressive PTMC from those with an indolent
clinical course. Future prospective studies carried out
according to the recommendations of the above-
mentioned Societies might determine the adequate
treatment for patients with PTMC. After the com-
pletion of this manuscript, Pacini’s group published a
review on the same topic (160). However, we have
added to the description of clinical and pathologic
characteristics of PTMC a meta-analysis study of the
risk factors for recurrence.
In conclusion, PTMC is diagnosed with increased
frequency, mainly due to the widespread use of
ultrasound-guided FNAB, and an increased percentage
of all thyroid cancers are PTMC.
The diagnosis and treatment reported in the different
studies are, in general, increased in contrast to the
guidelines suggested by some Scientific Societies; in
some studies, a more aggressive treatment than that
recommended has been adopted. In the present study, a
meta-analysis showed some clinical and pathologic
characteristics associated with increased aggressive-
ness. Probably, a more aggressive treatment should be
reserved to PTMC showing these characteristics. Despite
the increased prevalence of PTMC, thyroid cancer-
related mortality did not change over the years (93).
This finding suggests that PTMC has, in general, a
benign clinical course; therefore, increasingly sophis-
ticated diagnostic procedures and aggressive treatment
procedures appear unnecessary. However, the scientific
perception and the patient perception of the problem are
different.
Declaration of interest
The authors declare that there is no conflict of interest that would
prejudice the impartiality of this scientific work.
Funding
Grant support: This work was supported by grants from the Italian
Ministry of University and Scientific and Technological Research
(MIUR 2005060839-004), Fondazione Cassa di Risparmio di Ferrara,
and Associazione Ferrarese dell’Ipertensione Arteriosa to the
University of Ferrara. It was also supported by NIH grant
5K23DK4611.
References
1 Lloyd R, De Lellis R, Heitz P & Eng C. World Health Organization
Classification of Tumours: Pathology and Genetics of Tumours of the
Endocrine Organs Lyon, France: IARC Press International Agency
for Research on Cancer, 2004.
2 Woolner LB, Lemmon ML, Beahrs OH, Black BM & Keating FR.
Occult papillary carcinoma of the thyroid gland: a study of 140
cases observed in 30 year period. Journal of Clinical Endocrinology
and Metabolism 1960 20 89–105.
3 Pellegriti G, Scollo C, Lumera G, Regalbuto C, Vigneri R &
Belfiore A. Clinical behavior and outcome of papillary thyroid
cancers smaller than 1.5 cm in diameter: study of 299 cases.
Journal of Clinical Endocrinology and Metabolism 2004 89
3713–3720.
4 Hay ID, Grant CS, van Heerden JA, Goellner JR, Ebersold JR &
Bergstralh EJ. Papillary thyroid microcarcinoma: a study of 535
cases observed in a 50-year period. Surgery 1992 112 1139–1146.
5 Baudin E, Travagli JP, Ropers J, Mancusi F, Bruno-Bossio G,
Caillou B, Cailleux AF, Lumbroso JD, Parmentier C &
Schlumberger M. Microcarcinoma of the thyroid gland: the
Gustave Roussy Institute experience. Cancer 1998 83 553–559.
6 Sugino K, Ito K Jr, Ozaki O, Mimura T, Iwasaki H & Ito K. Papillary
microcarcinoma of the thyroid. Journal of Endocrinological
Investigation 1998 21 445–448.
7 Yamashita H, Noguchi S, Murakami N, Toda M, Uchino S,
Watanabe S & Kawamoto H. Extracapsular invasion of lymph
node metastasis. A good indicator of disease recurrence and poor
prognosis in patients with thyroid microcarcinoma. Cancer 1999
86 842–849.
8 Wada N, Duh QY, Sugino K, Iwasaki H, Kameyama K, Mimura T,
Ito K, Takami H & Takanashi Y. Lymph node metastasis from 259
papillary thyroid microcarcinomas: frequency, pattern of occur-
rence, and optimal strategy for neck dissection. Annals of Surgery
2003 237 399–407.
9 Pelizzo MR, Boschin IM, Toniato A, Pagetta C, Piotto A,
Bernante P, Casara D, Pennelli G & Rubello D. Natural history,
diagnosis, treatment and outcome of papillary thyroid micro-
carcinoma (PTMC): a mono-institutional 12-year experience.
Nuclear Medicine Communications 2004 25 547–552.
10 Fardella C, Jime
´
nez M, Gonza
´
lez H, Leo
´
n A, Gon˜ i I, Cruz F,
Solar A, Torres J, Mosso L, Gonza
´
lez G, Rodrı´guez JA,
Campusano C, Lo
´
pez JM & Arteaga E. Pathological characteristics
of thyroid microcarcinoma. A review of 402 biopsies. Revista
Me
`
dica de Chile 2005 133 1305–1310 (Spanish).
11 Barbaro D, Simi U, Meucci G, Lapi P, Orsini P & Pasquini C.
Thyroid papillary cancers: microcarcinoma and carcinoma,
incidental cancers and non-incidental cancers – are they different
diseases? Clinical Endocrinology 2005 63 577–581.
12 Roti E, Rossi R, Trasforini G, Bertelli F, Ambrosio MR, Busutti L,
Pearce EN, Braverman LE & degli Uberti EC. Clinical and
histological characteristics of papillary thyroid microcarcinoma:
results of a retrospective study in 243 patients. Journal of Clinical
Endocrinology and Metabolism 2006 91 2171–2178.
13 de Matos PS, Ferreira AP & Ward LS. Prevalence of papillary
microcarcinoma of the thyroid in Brazilian autopsy and surgical
series. Endocrine Pathology 2006 17 165–173.
668 E Roti and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2008) 159
www.eje-online.org
14 Sacco R, Aversa S, Innaro N, Carpino A, Bolognini S &
Amorosi A. Thyroid microcarcinoma and multinodular struma.
Personal experience and considerations regarding surgical
therapy. Chirurgia Italiana 2006 58 69–75 (Italian).
15 Antonaci A, Anello A, Aucello A, Consorti F, Della Rocca C,
Giovannone G & Scardella L. Microcarcinoma and incidental
carcinoma of the thyroid in a clinical series: clinical behaviour
and surgical management. La Clinica Terapeutica 2006 157
225–229.
16 Cheema Y, Olson S, Elson D & Chen H. What is the biology and
optimal treatment for papillary microcarcinoma of the thyroid?
Journal of Surgical Research 2006 134 160–162.
17 Lee J, Rhee Y, Lee S, Ahn CW, Cha BS, Kim KR, Lee HC, Kim SI,
Park CS & Lim SK. Frequent, aggressive behaviors of thyroid
microcarcinomas in korean patients. Endocrinology Journal 2006
53 627–632.
18 Monacelli M, Sperlongano P, D’Ajello M, Calzolari F, Piatto A,
Lucchini R, Misso C, Parmeggiani D, Pisaniello D, Sordelli I,
Sperlongano R & Avenia N. Thyroid microcarcinoma: our
experience. Il Giornale di Chirurgia 2006 27 158–160 (Italian).
19 Torlontano M, Crocetti U, Augello G, D’Aloiso L, Bonfitto N,
Varraso A, Dicembrino F, Modoni S, Frusciante V, Di Giorgio A,
Bruno R, Filetti S & Trischitta V. Comparative evaluation of
recombinant human thyrotropin-stimulated thyroglobulin
levels,
131
I whole-body scintigraphy, and neck ultrasonography
in the follow-up of patients with papillary thyroid microcarci-
noma who have not undergone radioiodine therapy. Journal of
Clinical Endocrinology and Metabolism 2006 91 60–63.
20 Lo CY, Chan WF, Lang BH, Lam KY & Wan KY. Papillary
microcarcinoma: is there any difference between clinically overt
and occult tumors? World Journal of Surgery 2006 30 759–766.
21 Cappelli C, Castellano M, Braga M, Gandossi E, Pirola I, De
Martino E, Agosti B & Agabiti Rosei E. Aggressiveness and
outcome of papillary thyroid carcinoma (PTC) versus micro-
carcinoma (PMC): a mono-institutional experience. Journal of
Surgical Oncology 2007 95 555–560.
22 Ku
¨
c¸u
¨
k NO, Tari P, Tokmak E & Aras G. Treatment for
microcarcinoma of the thyroid clinical experience. Clinical
Nuclear Medicine 2007 32 279–281.
23 Lim DJ, Baek KH, Lee YS, Park WC, Kim MK, Kang MI, Jeon HM,
Lee JM, Yun-Cha B, Lee KW, Son HY & Kang SK. Clinical,
histopathological, and molecular characteristics of papillary
thyroid microcarcinoma. Thyroid 2007 17 883–888.
24 Pisello F, Geraci G, Sciume
`
C, Li Volsi F & Modica G. Total
thyroidectomy of choice in papillary microcarcinoma. Il Giornale
di Chirurgia 2007 28 13–19 (Italian).
25 Scho¨nberger J, Marienhagen J, Agha A, Rozeboom S,
Bachmeier E, Schlitt H & Eilles C. Papillary microcarcinoma
and papillary cancer of the thyroid !orZ1 cm: modified
definition of the WHO and the therapeutic dilemma. Nuklearme-
dizin 2007 46 115–120.
26 Sakorafas GH, Stafyla V, Kolettis T, Tolumis G, Kassaras G &
Peros G. Microscopic papillary thyroid cancer as an incidental
finding in patients treated surgically for presumably benign
thyroid disease. Journal of Postgraduate Medicine 2007 53 23–26.
27 Carlini M, Giovannini C, Castaldi F, Mercadante E, Dell’Avanzato R,
Zazza S, Nania A, Santeusanio G, Passeri M & Di Perna P. High risk
for microcarcinoma in thyroid benign diseases. Incidence in a one
year period of total thyroidectomies. Journal of Experimental and
Clinical Cancer Research 2005 24 231–236.
28 Sampson RJ, Key CR, Buncher CR & Iijima S. Smallest forms of
papillary carcinoma of the thyroid. A study of 141 micro-
carcinomas less than 0.1 cm in greatest dimension. Archives of
Pathology 1971 91 334–339.
29 Harach HR, Franssila KO & Wasenius VM. Occult papillary
carcinoma of the thyroid. A ‘normal’ finding in Finland. A
systematic autopsy study. Cancer 1985 56 531–538.
30 Noguchi S, Yamashita H, Murakami N, Nakayama I, Masakatsu T
& Kawamoto H. Small carcinomas of the thyroid. A long-
term follow-up of 867 patients. Archives of Surgery 1996 131
187–191.
31 Rodriguez JM, Moreno A, Parrilla P, Sola J, Soria T, Tebar FJ &
Aranda F. Papillary thyroid microcarcinoma: clinical study and
prognosis. European Journal of Surgery 1997 163 255–259.
32 Ruggieri M, Genderini M, Gargiulo P, Del Grammastro A,
Mascaro A, Luongo B & Paolini A. Surgical treatment of
differentiated microcarcinomas of the thyroid. European Review
for Medical and Pharmacological Sciences 2001 5 85–89.
33 Simpson WJ, McKinney SE, Carruthers JS, Gospodarowicz MK,
Sutcliffe SB & Panzarella T. Papillary follicular thyroid cancer:
prognostic factors in 1578 patients. American Journal of Medicine
1987 83 479–488.
34 Sugitani I & Fujimoto Y. Symptomatic versus asymptomatic
papillary thyroid microcarcinoma: a retrospective analysis of
surgical outcome and prognostic factors. Endocrine Journal 1999
46 209–216.
35 Emerick GT, Duh QY, Siperstein AE, Burrow GN & Clark OH.
Diagnosis, treatment, and outcome of follicular thyroid carci-
noma. Cancer 1993 72 3287–3291.
36 Rossi R, Roti E, Trasforini G, Bertelli F, Cavazzini L, Zatelli MC,
Pearce EN, Braverman LE & degli Uberti EC. Histological and
clinical differences in thyroid cancers %10 mm and 11–20 mm
in diameter: results of a retrospective study of 426 patients.
Thyroid 2008 18 309–315.
37 Fukunaga FH & Yatani R. Geographic pathology of occult thyroid
carcinomas. Cancer 1975 36 1095–1099.
38 Tournaire J, Bernard MH, Bizollon-Roblin MH, Bertholon-
Gre
´
goire M & Berger-Dutrieux N. Le micro-carcinome papillaire
du corps thyroı
¨
de. 179 cas observe
`
s depuis 1973. Presse Me
´
dicale
1998 27 1467–1469.
39 Falvo I, D’Ercole C, Sorrenti S, D’Andrea V, Catania A, Berni A,
Grilli P & De Antoni E. Papillary microcarcinoma of the thyroid
gland: analysis of prognostic factors including histological subtype.
European Journal of Surgery 2002 168 (Suppl 588) 28–32.
40 Appetecchia M, Scarcello G, Pucci E & Procaccini A. Outcome
after treatment of papillary thyroid microcarcinoma. Journal of
Experimental & Clinical Cancer Research 2002 21 159–164.
41 Ito Y, Uruno T, Nakano K, Takamura Y, Miya A, Kobayeshi K,
Yokozawa T, Matsuzuka F, Kuma S, Kuma K & Miyauchi A.
An observation trial without surgical treatment in patients
with papillary microcarcinoma of the thyroid. Thyroid 2003 13
381–387.
42 Chow SM, Law SCK, Chan JKC, Au SK, Yau S & Lau WH. Papillary
microcarcinoma of the thyroid prognostic significance of lymph
node metastasis and multifocality. Cancer 2003 98 31–40.
43 Barroeta JE, Wang H, Shiina N, Gupta PK, Livolsi VA &
Baloch ZW. Is ne-needle aspiration (FNA) of multiple thyroid
nodules justified? Endocrine Pathology 2006 17 61–65.
44 Biscolla RP, Ugolini C, Sculli M, Bottici V, Castagna MG, Romei C,
Cosci B, Molinaro E, Faviana P, Basolo F, Miccoli P, Pacini F,
Pinchera A & Elisei R. Medullary and papillary tumors are
frequently associated in the same thyroid gland without evidence
of reciprocal influence in their biologic behavior. Thyroid 2004
14 946–952.
45 Bonnin C, Trojani M, Corcuff JB & Bonichon F. Outcome of 111
thyroid papillary carcinomas. Retrospective study from 1953 to
1994. Experience of Bergonie
´
Institute. Annales d’Endocrinologie
1997 58 318–325 (Review. French).
46 Farina GP, Baccoli A, Pisano M, Pani C, Di Ninni S, Marcello A &
Cagetti M. Papillary microcarcinoma of the thyroid. Clinical
implications and therapeutic strategy. Il Giornale di Chirurgia
2003 24 11–17 (Italian).
47 Ito Y, Higashiyama T, Takamura Y, Miya A, Kobayashi K,
Matsuzuka F, Kuma K & Miyauchi A. Prognosis of patients with
benign thyroid diseases accompanied by incidental papillary
carcinoma undetectable on preoperative imaging tests. World
Journal of Surgery 2007 31 1672–1676.
48 Ito Y, Tomoda C, Uruno T, Takamura Y, Miya A, Kobayashi K,
Matsuzuka F, Kuma K & Miyauchi A. Preoperative ultrasono-
graphic examination for lymph node metastasis: usefulness when
designing lymph node dissection for papillary microcarcinoma of
the thyroid. World Journal of Surgery 2004 28 498–501.
Thyroid papillary microcarcinoma
669EUROPEAN JOURNAL OF ENDOCRINOLOGY (2008) 159
www.eje-online.org
49 Jacquot-Laperrie
`
re S, Timoshenko AP, Dumollard JM, Peoc’h M,
Estour B, Martin C & Prades JM. Papillary thyroid micro-
carcinoma: incidence and prognostic factors. European Archives
of Oto-Rhino-Laryngology 2007 264 935–939.
50 Lin JD, Chen ST, Chao TC, Hsueh C & Weng HF. Diagnosis and
therapeutic strategy for papillary thyroid microcarcinoma.
Archives of Surgery 2005 140 940–945.
51 Sugitani I, Yanagisawa A, Shimizu A, Kato M & Fujimoto Y.
Clinicopathologic and immunohistochemical studies of papillary
thyroid microcarcinoma presenting with cervical lymphadeno-
pathy. World Journal of Surgery 1998 22 731–737.
52 Wang J, Qiu X, Zhou L, Deng X, Zhang C & Zhou C. Differentiated
microcarcinoma of the thyroid gland in 45 cases. Lin Chuang Er
Bi Yan Hou Ke Za Zhi 2001 15 542–543 (Chinese).
53 Yang GC, LiVolsi VA & Baloch ZW. Thyroid microcarcinoma: fine-
needle aspiration diagnosis and histologic follow-up. International
Journal of Surgical Pathology 2002 10 133–139.
54 Miccoli P, Minuto MN, Ugolini C, Panicucci E, Massi M, Berti P &
Basolo F. Papillary thyroid cancer: pathological parameters as
prognostic factors in different classes of age. Archives of
Otolaryngology Head and Neck Surgery 2008 138 200–203.
55 Pelizzo MR, Boschin LM, Toniato A, Piotto A, Bernante P,
Pagetta C, Rampin L & Rubello D. Papillary thyroid micro-
carcinoma (PTMC): prognostic factors, management and out-
come in 403 patients. European Journal of Surgical Oncology 2006
32 1144–1148.
56 Nishiyama RH, Ludwig GK & Thompson NW. The prevalence of
small papillary thyroid carcinomas in 100 consecutive necropsies
in an American population. In Radiation-Associated Thyroid
Carcinoma, pp 123–135. Eds LJ De Groot, LA Frohman,
EL Kaplan & S Refetoff, New York: Grune & Stratton, 1977.
57 Sampson RJ. Comment on Dr. Edis’s presentation on natural
history of occult thyroid carcinoma. In Radiation-Associated
Thyroid Carcinoma, pp 171–181. Eds LJ De Groot, LA Frohman,
EL Kaplan & S Refetoff, New York: Grune & Stratton, 1977.
58 Lin KD, Lin JD, Huang J, Huang HS, Jeng LB & Chao TC. Clinical
presentations and predictive variables of thyroid microcarci-
noma with distant metastasis. International Surgery 1997 82
378–381.
59 Neuhold N, Kaiser H & Kaserer K. Latent carcinoma of the
thyroid in Austria: a systematic autopsy study. Endocrine
Pathology 2001 12 23–31.
60 Lupoli G, Vitale G, Caraglia M, Fittipaldi MR, Abbruzzese A,
Tagliaferri P & Bianco AR. Familial papillary thyroid micro-
carcinoma: a new clinical entity. Lancet 1999 353 637–639.
61 Eng C. Familial papillary thyroid cancer: many syndromes, too
many genes? Journal of Clinical Endocrinology and Metabolism
2000 85 1755–1757.
62 ´os A, Rodrı´guez JM, Illana J, Torregrosa NM & Parrilla P.
Familial papillary carcinoma of the thyroid: report of three
families. European Journal of Surgery 2001 167 339–343.
63 Ferna
´
ndez-Real JM & Ricart W. Familial papillary thyroid
microcarcinoma. Lancet 1999 353 1973–1974.
64 Viglietto G, Chiappetta G, Martinez-Tello FJ, Fukunaga FH,
Tallini G, Rigoupoulou D, Visconti R, Mastro A, Santoro M &
Fusco A. RET/PTC oncogene activation is an early event in
thyroid carcinogenesis. Oncogene 1995 11 1207–1210.
65 Adeniran AJ, Zhu Z, Gandhi M, Steward DL, Fidler JP,
Giordano TJ, Biddinger PW & Nikiforov YE. Correlation between
genetic alterations and microscopic features, clinical mani-
festations, and prognostic characteristics of thyroid papillary
carcinomas. American Journal of Surgical Pathology 2006 30
216–222.
66 Corvi R, Martinez-Alfaro M, Harach HR, Zini M, Papotti M &
Romeo G. Frequent RET rearrangements in thyroid papillary
microcarcinoma detected by interphase uorescence in situ
hybridization. Laboratory Investigation; A Journal of Technical
Methods and Pathology 2001 81 1639–1645.
67 Tallini G, Santoro M, Helie M, Carlomagno F, Salvatore G,
Chiappetta G, Carcangiu ML & Fusco A. RET/PTC oncogene
activation defines a subset of papillary thyroid carcinomas
lacking evidence of progression to poorly or undifferentiated
tumor phenotypes. Clinical Cancer Research 1998 4 287–294.
68 Sugg SL, Zheng L, Rosen IB, Freeman JL, Ezzat S & Asa SL.
RET/PTC1, 2 and 3 oncogene rearrangements in human thyroid
carcinomas: implications for metastatic potential? Journal of
Clinical Endocrinology and Metabolism 1996 81 3360–3365.
69 Namba H, Nakashima M, Hayashi T, Hayashida N, Maeda S,
Rogounovitch TI, Ohtsuru A, Saenko VA, Kanematsu T &
Yamashita S. Clinical implication of hot spot BRAF mutation,
V599E, in papillary thyroid cancers. Journal of Clinical Endo-
crinology and Metabolism 2003 88 4393–4397.
70 Nikiforova MN, Kimura ET, Gandhi M, Biddinger PW, Knauf JA,
Basolo F, Zhu Z, Giannini R, Salvatore G, Fusco A, Santoro M,
Fagin JA & Nikiforov YE. BRAF mutations in thyroid tumors are
restricted to papillary carcinomas and anaplastic or poorly
differentiated carcinomas. Journal of Clinical Endocrinology and
Metabolism 2003 88 5399–5404.
71 Puxeddu E, Moretti S, Elisei R, Romei C, Pascucci R, Martinelli M,
Marino C, Avenia N, Rossi ED, Fadda G, Cavaliere A, Ribacchi R,
Falorni A, Pontecorvi A, Pacini F, Pinchera A & Santeusanio F.
BRAF(V599E) mutation is the leading genetic event in adult
sporadic papillary thyroid carcinomas. Journal of Clinical
Endocrinology and Metabolism 2004 89 2414–2420.
72 Liu D, Liu Z, Condouris S & Xing M. BRAF V600E maintains
proliferation, transformation, and tumorigenicity of BRAF-
mutant papillary thyroid cancer cells. Journal of Clinical
Endocrinology and Metabolism 2007 92 2264–2271.
73 Oler G, Ebina KN, Mchaluart P, Rimura ET & Cerutti J.
Investigation of BRAF mutation in a series of papillary thyroid
carcinoma and matched lymph node metastasis reveals a new
mutation in metastasis. Clinical Endocrinology 2005 62
509–511.
74 Kim EK, Park CS, Chung WY, Oh KK, Kim DI, Lee JT & Yoo HS.
New sonographic criteria for recommending ne-needle aspira-
tion biopsy of nonpalpable solid nodules of the thyroid. American
Journal of Roentgenology 2002 178 687–691.
75 Sampson RJ, Woolner LB, Bahn RC & Kurland LT. Occult thyroid
carcinoma in Olmsted County, Minnesota: prevalence at autopsy
compared with that in Hiroshima and Nagasak, Japan. Cancer
1974 34 2072–2076.
76 Yamamoto Y, Maeda T, Izumi K & Otsuka H. Occult papillary
carcinoma of the thyroid. Cancer 1990 65 1173–1179.
77 Brierre I & Dickson LG. Clinically unsuspected thyroid disease.
American Family Physician/GP 1964 30 94–98.
78 Yagawa K, Takahashi S & Murata T. Clinico-pathological study
of latent thyroid carcinoma. In Proceedings of the Japanese
Cancer Association, the 25th Annual Meeting, 106 (abstract).
December, 1966.
79 Fukunaga FH & Lockett IJ. Thyroid carcinoma in Japanese in
Hawaii. Archives of Pathology 1971 92 6–13.
80 Kovacs GL, Gonda G, Vadasz G, Ludmany E, Uhrin K, Gorombey Z,
Kovacs L, Hubina E, Bodo M, Goth MI & Szabolcs I. Epidemiologyof
thyroid microcarcinoma found in autopsy series conducted in
areas of different iodine intake. Thyroid 2005 15 152–157.
81 Balazs GY & Krasznai G. Occult pajzsmirigyrak post mortem
vizsgalata [in Hungarian]. Orvosi Hetilap 1974 115 2856–2860.
82 Sobrinho-Simoes MA, Sambade MC & Goncalves V. Latent
thyroid carcinoma at autopsy. Cancer 1979 43 1702–1706.
83 Bondeson L & Ljungberg O. Occult thyroid carcinoma at autopsy
in Malmo¨, Sweden. Cancer 1981 47 319–323.
84 Lang W, Borrusch H & Bauer L. Evaluation of 1020 sequential
autopsies. American Journal of Clinical Pathology 1988 90 72–76.
85 Ottino A, Pianzola HM & Castelletto RH. Occult papillary thyroid
carcinoma at autopsy in La Plata, Argentina. Cancer 1989 64
547–551.
86 Tan GH & Gharib H. Thyroid incidentalomas: management
approaches to nonpalpable nodules discovered incidentally on
thyroid imaging. Annals of Internal Medicine 1997 126 226–231.
87 Reiners C, Wegscheider K, Schicha H, Theissen P, Vaupel R,
Wrbitzky R & Schumm-Draeger PM. Prevalence of thyroid
670 E Roti and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2008) 159
www.eje-online.org
disorders in the working population of Germany: ultrasonogra-
phy screening in 96,278 unselected employees. Thyroid 2004 14
926–932.
88 Tan GH, Gharib H & Reading CC. Solitary thyroid nodule.
Comparison between palpation and ultrasonography. Archives of
Internal Medicine 1995 155 2418–2423.
89 Brander A, Viikinkoski P, Tuuhea J, Voutilainen L & Kivisaari L.
Clinical versus ultrasound examination of the thyroid gland in
common clinical practice. Journal of Clinical Ultrasound 1992 20
37–42.
90 Walker J, Findlay D, Amar SS, Small PG, Wastie ML & Pegg CA.
A prospective study of thyroid ultrasound scan in the clinically
solitary thyroid nodule. British Journal of Radiology 1985 58
617–619.
91 Leenhardt L, Grosclaude P & Che
´
rie
´
-Challine L. Thyroid Cancer
Committee. Increased incidence of thyroid carcinoma in France:
a true epidemic or thyroid nodule management effects? Report
from the French thyroid cancer committee Thyroid 2004 14
1056–1106.
92 Verkooijen HM, Fioretta G, Pache JC, Franceschi S, Raymond L,
Schubert H & Bouchardy C. Diagnostic changes as a reason for
the increase in papillary thyroid cancer incidence in Geneva,
Switzerland. Cancer Causes and Control 2003 14 13–17.
93 Davies L & Welch HG. Increasing incidence of thyroid cancer in
the United States, 1973–2002. Journal of the American Medical
Association 2006 295 2164–2167.
94 Burgess JR, Dwyer T, McArdle K, Tucker P & Shugg D. The
changing incidence and spectrum of thyroid carcinoma in
Tasmania (1978–1998) during a transition from iodine
sufficiency to iodine deficiency. Journal of Clinical Endocrinology
and Metabolism 2000 85 1513–1517.
95 Chow SM, Law SC, Au SK, Mang O, Yau S, Yuen KT & Lau WH.
Changes in clinical presentation, management and outcome in
1348 patients with differentiated thyroid carcinoma: experience
in a single institute in Hong Kong, 1960–2000. Clinical Oncology
2003 15 329–336.
96 Abdulmughni YA, Al-Hureibi MA, Al-Hureibi KA, Ghafoor MA,
Al-Wadan AH & Al-Hureibi YA. Thyroid cancer in Yemen. Saudi
Medical Journal 2004 25 55–59.
97 Ardito G, Revelli L, Lucci C, Giacinto O & Praquin B. Papillary
microcarcinoma [correction of carcinoma] of the thyroid: clinical
experience and prognosis factors. Annali Italiani di Chirurgia 2001
72 261–265 (Italian. Erratum in: Annali Italiani di Chirurgia
2001 72: 390).
98 Garrel R, Cartier C, Marvaso V, Corpelet D, Makeieff M,
Crampette L & Guerrier B. Our experience with papillary
microcarcinoma of the thyroid. Revue de Laryngologie Otologie
Rhinologie 2002 123 239–242 (French).
99 Deveci MS, Deveci G, LiVolsi VA, Gupta PK & Baloch ZW.
Concordance between thyroid nodule sizes measured by
ultrasound and gross pathology examination: effect on patient
management. Diagnostic Cytopathology 2007 35 579–583.
100 Lam AK, Lo CY & Lam KS. Papillary carcinoma of thyroid: a
30-yr clinicopathological review of the histological variants.
Endocrine Pathology 2005 16 323–330 (Review).
101 Cappelli C, Pirola I, Cumetti D, Micheletti L, Tironi A, Gandossi E,
Martino E, Cherubini L, Agosti B, Castellano M, Mattanza C &
Agabiti Rosei E. Is the anteroposterior and transverse diameter
ratio of nonpalpable thyroid nodules a sonographic criteria for
recommending fine-needle aspiration cytology? Clinical Endo-
crinology 2005 63 689–693.
102 Gemsenja¨ ger E & Schweizer I. Small thyroid carcinomas:
biological characteristics, diagnosis and therapy. Schweizerische
Medizinische Wochenschrift 1999 129 681–690.
103 Leprat F, Trouette H, Cochet C, Saumthally B, Masson B,
de Mascarel A & Latapie JL. Papillary microcarcinoma of the
thyroid. Annales d’Endocrinologie 1994 54 343–346 (French).
104 Melliere D, Hindie E, Becquemin JP, Desgranges P, Allaire E &
Geachan E. Differentiated thyroid carcinoma how to improve
the long-term results? Twenty-five-year outcomes of 850 patients
Bulletin de l’Acade
`
mie Nationale de Me
`
decine 2006 190 89–106
(discussion 106–109. French).
105 Orsenigo E, Beretta E, Fiacco E, Scaltrinia F, Veronesi P,
Invernizzi L, Gini P, Fiorina P & Di Carlo V. Management of
papillary microcarcinoma of the thyroid gland. European
Journal of Surgical Oncology 2004 30 1104–1106.
106 Jukkola A, Bloigu R, Ebeling T, Salmela P & Blanco G. Prognostic
factors in differentiated thyroid carcinomas and their impli-
cations for current staging classifications. Endocrine-Related
Cancer 2004 11 571–579.
107 Passler C, Scheuba C, Prager G, Kaczirek K, Kaserer K, Zettinig G
& Niederle B. Prognostic factors of papillary and follicular thyroid
cancer: differences in an iodine replete endemic goiter region.
Endocrine-Related Cancer 2004 11 131–139.
108 Eustatia-Rutten CF, Corssmit EP, Biermasz NR, Pereira AM,
Romijn JA & Smit JW. Survival and death causes in differentiated
thyroid carcinoma. Journal of Clinical Endocrinology and Metab-
olism 2006 91 313–319.
109 Piraino P, Sepu´ lveda A, Lillo R, Pineda P & Liberman C. Thyroid
cancer. Report of 85 cases. Revista Me
`
dica de Chile 2000 128
405–410 (Spanish).
110 Yokozawa T. Evaluation of the clinical usefulness of ultrasono-
graphy in making a preoperative diagnosis of thyroid carcinoma.
Nippon Geka Gakkai Zasshi 1988 89 582–594 (Japanese).
111 Hundahl SA, Cady B, Cunningham MP, Mazzaferri E, McKee RF,
Rosai J, Shah JP, Fremgen AM, Stewart AK & Ho¨lzer S. Initial
results from a prospective cohort study of 5583 cases of thyroid
carcinoma treated in the United States during 1996. US and
German Thyroid Cancer Study Group. An American College of
Surgeons Commission on Cancer Patient Care Evaluation study.
Cancer 2000 89 202–217.
112 Chigot JP, Me
´
ne
´
gaux F, Keopadabsy K, Hoang C, Aurengo A,
Leenhardt L & Turpin G. Thyroid cancer in patients with
hyperthyroidism. Presse Me
´
dicale 2000 29 1969–1972 (French).
113 Dietlein M, Luyken WA, Schicha H & Larena-Avellaneda A.
Incidental multifocal papillary microcarcinomas of the thyroid: is
subtotal thyroidectomy combined with radioiodine ablation
enough? Nuclear Medicine Communications 2005 26 3–8.
114 Kasuga Y, Sugenoya A, Kobayashi S, Masuda H & Iida F. The
outcome of patients with thyroid carcinoma and Graves’ disease.
Surgery Today 1993 23 9–12.
115 Klofanda J, Krska Z & Trca S. Total tyroidectomy in malignant
goiter, significance and problems. Rozhledy v Chirurgii 2002 81
5–7 (Czech).
116 Lokey JS, Palmer RM & Macfie JA. Unexpected ndings during
thyroid surgery in a regional community hospital: a 5-year
experience of 738 consecutive cases. American Surgeon 2005 71
911–913 (discussion 913–915).
117 Costanzo M, Caruso LA, Messina DC, Cavallaro A, Palumbo A,
Marziani A & Cannizzaro MA. Thyroid microcarcinoma in
benign thyroid diseases. Annali Italiani di Chirurgia 2005 76
119–121 (discussion 121–122. Italian).
118 Stulak JM, Grant CS, Farley DR, Thompson GB, van Heerden JA,
Hay ID, Reading CC & Charboneau JW. Value of preoperative
ultrasonography in the surgical management of initial and
reoperative papillary thyroid cancer. Archives of Surgery 2006
141 489–496.
119 Yassa L, Cibas ES, Benson CB, Frates MC, Doubilet PM,
Gawande AA, Moore FD, Kim BW, Marqusee E, Larsen PR &
Alexander EK. Long-term assessment of a multidisciplinary
approach to thyroid nodule diagnostic evaluation. Cancer 2007
111 508–516.
120 ´os A, Rodrı´guez JM, Canteras M, Galindo PJ, Balsalobre MD &
Parrilla P. Risk factors for malignancy in multinodular goitres.
European Journal of Surgical Oncology 2004 30 58–62.
121 Russo F, Barone Adesi TL, Arturi A, Stolfi VM, Spina C, Savio A,
De Majo A, Uccioli L & Gentileschi P. Clinico-pathological study of
microcarcinoma of the thyroid. Minerva Chirurgica 1997 52
891–900 (Italian).
Thyroid papillary microcarcinoma
671EUROPEAN JOURNAL OF ENDOCRINOLOGY (2008) 159
www.eje-online.org
122 Ortiz S, Rodriguez JM, Torregrosa N, Balsalobre M, Rios A &
Parrilla P. Relation between clinical presentation and prognosis
of patients with papillary thyroid microcarcinoma (article in
spain). Medicina Clinica 2003 120 773–774.
123 Pelizzo MR, Merante Boschin I, Toniato A, Piotto A, Bernante P,
Pagetta C, Casal Ide E, Mazzarotto R, Casara D & Rubello D.
Papillary thyroid microcarcinoma. Long-term outcome in 587
cases compared with published data. Minerva Chirurgica 2007
62 315–325.
124 Giles Y, Boztepe H, Terzioglu T & Tezelman S. The advantage of
total thyroidectomy to avoid reoperation for incidental thyroid
cancer in multinodular goiter. Archives of Surgery 2004 139
179–182.
125 McCoy KL, Jabbour N, Ogilvie JB, Ohori NP, Carty SE & Yim JH.
The incidence of cancer and rate of false-negative cytology in
thyroid nodules greater than or equal to 4 cm in size. Surgery
2007 142 837–844.
126 Pelizzo MR, Piotto A, Rubello D, Casara D, Fassina A &
Busnardo B. High prevalence of occult papillary thyroid
carcinoma in a surgical series for benign thyroid disease. Tumori
2000 76 255–257.
127 Papini E, Guglielmi R, Bianchini A, Crescenzi A, Taccogna S,
Nardi F, Panunzi C, Rinaldi R, Toscano V & Pacella CM. Risk of
malignancy in nonpalpable thyroid nodules: predictive value of
ultrasound and color Doppler features. Journal of Clinical
Endocrinology and Metabolism 2002 87 1941–1946.
128 Khoo ML, Asa SL, Witterick IJ & Freeman JL. Thyroid
calcification and its association with thyroid carcinoma. Head
and Neck 2002 24 651–655.
129 Peccin S, de Castro JA, Furlanetto TW, Furtado AP, Brasil BA &
Czepielewski MA. Ultrasonography: is it useful in the diagnosis of
cancer in thyroid nodules? Journal of Endocrinological Investigation
2002 25 39–43.
130 Chan BK, Desser TS, McDougall IR, Weigel RJ & Jeffrey RB Jr.
Common and uncommon sonographic features of papillary
thyroid carcinoma. Journal of Ultrasound in Medicine 2003 22
1083–1090.
131 Ito Y, Kobayashi K, Tomoda C, Uruno T, Takamura Y, Miya A,
Matsuzuka F, Kuma K & Miyauchi A. Ill-defined edge on
ultrasonographic examination can be a marker of aggressive
characteristic of papillary thyroid microcarcinoma. World
Journal of Surgery 2005 29 1007–1011.
132 Asanuma K, Kobayashi S, Shingu K, Hama Y, Yokoama S,
Fujimori M & Amano J. The rate of tumour growth does not
distinguish between malignant and benign thyroid nodules.
European Journal of Surgery 2001 167 102–105.
133 Leenhardt L, Hejblum G, Franc B, Fediaevsky LD, Delbot T,
Le Guillouzic D, Menegaux F, Guillausseau C, Hoang C, Turpin G
& Aurengo A. Indications and limits of ultrasound-guided
cytology in the management of nonpalpable thyroid nodules.
Journal of Clinical Endocrinology and Metabolism 1999 84 24–28.
134 Hagag P, Strauss S & Weiss M. Role of ultrasound-guided ne-
needle aspiration biopsy in evaluation of nonpalpable thyroid
nodules. Thyroid 1998 8 989–995.
135 Nam-Goong IL, Kim HY, Gong G, Lee HK, Hong SJ, Kim WB &
Shong YK. Ultrasonographically-guided fine needle aspirations
of thyroid incidentaloma: correlation with pathologic findings.
Clinical Endocrinology 2004 60 21–28.
136 Cooper DS, Doherty GM, Haugen BR, Kloos RT, StLee SL,
Mandel SJ, Mazzaferri EL, McIver B, Sherman SI & Tuttle RM. The
American Thyroid Association Guidelines Taskforce. Manage-
ment guidelines for patients with thyroid nodules and differ-
entiated thyroid cancer. Thyroid 2006 16 109–141.
137 AACE/AME Task Force on Thyroid Nodules. American Associ-
ation of Clinical Endocrinologists and Associazione Medici
Endocrinologi medical guidelines for clinical practice for the
diagnosis and management of thyroid nodules. Endocrine Practice
2006 12 63–102.
138 Frates MC, Benson CB, Charboneau JW, Cibas ES, Clark OH,
Coleman BG, Cronan JJ, Doubilet PM, Evans DB, Goellner JR,
Hay ID, Hertzberg BS, Intenzo CM, Jeffrey RB, Langer JE,
Larsen PR, Mandel SJ, Middleton WD, Reading CC, Sherman SI
& Tessler FN. Society of Radiologists in Ultrasound. Management
of thyroid nodules detected at US: Society of Radiologists in
Ultrasound consensus conference statement. Radiology 2005
237 794–800.
139 Kang HW, No JH, Chung JH, Min YK, Lee MS, Lee MK, Yang JH &
Kim KW. Prevalence, clinical and ultrasonographic charac-
teristics of thyroid inciden-talomas. Thyroid 2004 14 29–33.
140 Jeong HS, Chung M, Baek CH, Ko YH, Choi JY & Son YI. Can [18F]
fluorodeoxyglucose standardized uptake values of PET imaging
predict pathologic extrathyroid invasion of thyroid papillary
microcarcinomas? Laryngoscope 2006 116 2133–2137.
141 Ito Y, Higashiyama T, Takamura Y, Miya A, Kobayashi K,
Matsuzuka F, Kuma K & Miyauchi A. Risk factors for recurrence
to the lymph node in papillary thyroid carcinoma patients
without preoperatively detectable lateral node metastasis:
validity of prophylactic modified radical neck dissection. Wo rl d
Journal of Surgery 2007 31 2085–2091.
142 Oueslati Z, Aloui M, Gritli S, Touati S, el-May A, Gamoudi A, Ben
Slimene F & Ladgham A. Thyroid papillary microcarcinoma.
Salah Azaiz Institute experience. Revue de Laryngologie Otologie
Rhinologie 2002 123 39–42 (French).
143 Rosa
´
rio PW, Fagundes TA & Purisch S. Treatment of papillary
microcarcinoma of the thyroid. Arquivos Brasileiros de Endocri-
nologia e Metabologia 2004 48 855–860 (Portuguese).
144 Machens A, Holzhausen HJ & Dralle H. The prognostic value of
primary tumor size in papillary and follicular thyroid carcinoma.
Cancer 2005 103 2269–2273.
145 Lantsov D, Meirmanov S, Nakashima M, Kondo H, Saenko V,
Naruke Y, Namba H, Ito M, Abrosimov A, Lushnikov E, Sekine I
& Yamashita SH. Cyclin D1 overexpression in thyroid papillary
microcarcinoma: its association with tumour size and aberrant
beta-catenin expression. Histopathology 2005 47 248–256.
146 Khoo ML, Ezzat S, Freeman JL & Asa SL. Cyclin D1 protein
expression predicts metastatic behavior in thyroid papillary
microcarcinomas but is not associated with gene amplification.
Journal of Clinical Endocrinology and Metabolism 2002 87
1810–1813.
147 Ito Y, Uruno T, Takamura Y, Miya A, Kobayashi K, Matsuzuka F,
Kuma K & Miyauchi A. Papillary microcarcinomas of the thyroid
with preoperatively detectable lymph node metastasis show
significantly higher aggressive characteristics on immunohisto-
chemical examination. Oncology 2005 68 87–96.
148 Londero SC, Godballe C, Krogdahl A, Bastholt L, Specht L,
Sørensen CH, Pedersen HB, Pedersen U & Christiansen P. Papillary
microcarcinoma of the thyroid gland: is the immunohistochem-
ical expression of cyclin D1 or galectin-3 in primary tumour an
indicator of metastatic disease? Acta Oncologica 2007 28 1–7.
149 Cvejic D, Savin S, Petrovic I, Paunovic I, Tatic S, Krgovic K &
Havelca M. Galectin-3 expression in papillary microcarcinoma of
the thyroid. Histopathology 2005 47 209–214.
150 Cotellese R, Dell’Osa A, Francomano F, Cieri M & Innocenti P.
Thyroid microcarcinoma: our experience. Tumori 2005 4
S155–S156 (Italian).
151 Gu
¨
lben K, Berberog
˘
lu U, Celen O & Mersin HH. Incidental
papillary microcarcinoma of the thyroid-factors affecting lymph
node metastasis. Langenbeck’s Archives of Surgery 2008 393
25–29.
152 Besic N, Pilko G, Petric R, Hocevar M & Zgajnar J. Papillary
thyroid microcarcinoma: prognostic factors and treatment.
Journal of Surgical Oncology 2008 97 221–225.
153 Rouxel A, Hejblum G, Bernier MO, Boelle PY, Menegaux F,
Mansour G, Hoang C, Aurengo A & Leenhardt L. Prognostic
factors associated with the survival of patients developing loco-
regional recurrences of differentiated thyroid carcinomas.
Journal of Clinical Endocrinology and Metabolism 2004 89
5362–5368.
154 Pacini F, Schlumberger M, Dralle H, Elisei R, Smit JWA,
Wiersinga W & the European Thyroid Cancer Taskforce .
672 E Roti and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2008) 159
www.eje-online.org
European consensus for the management of patients with
differentiated thyroid carcinoma of the follicular epithelium.
European Journal of Endocrinology 2006 154 787–803.
155 British Thyroid Association and Royal College of Physicians.
Guidelines for the management of thyroid cancer in adults.
www.british-thyroid-association.org, 2002.
156 Shah JP, Kian K, Forastiere A, Garden A, Hoffman HT, Jack
Lee J, Lydiatt W, Medina JE, Mukherji S, Oliva ME, O’Sullivan
B, Paulino A, Singh B, Weber R & Weymuller E. American
Joint Committee on Cancer. In Cancer Staging Manual, edn 6,
pp 77–87. New York: Springer-Verlag, 2002.
157 Van den Bruel A, Moreno-Reyes R, Bex M, Daumerie C & Glinoer D.
Is the management of thyroid nodules and differentiated thyroid
cancer in accordance with recent consensus guidelines? results of
a national survey Clinical Endocrinology 2008 68 599–604.
158 Mazzaferri EL. Management of low-risk differentiated thyroid
cancer. Endocrine Practice 2007 5 498–512.
159 Jonklaas J, Sarlis NJ, Litofsky D, Ain KB, Thomas Bigos T,
Brierley JD, Cooper DS, Haugen BR, Ladenson PW, Magner J,
Robbins J, Ross DS, Skarulis M, Maxon HR & Sherman SI.
Outcomes of patients with differentiated thyroid carcinoma
following initial therapy. Thyroid 2006 16 1229–1242.
160 Pazaitou-Panayiotou K, Capezzone M & Pacini F. Clinical features
and therapeutic implication of papillary thyroid microcarci-
noma. Thyroid 2007 17 1085–1092.
Received 27 July 2008
Accepted 5 August 2008
Thyroid papillary microcarcinoma
673EUROPEAN JOURNAL OF ENDOCRINOLOGY (2008) 159
www.eje-online.org
    • "A meta-analysis study performed by Roti et al. has shown that the prevalence of PTMCs was correlated to the sampling method: PTMC was detected in 9.9% of cases if only one suspected macroscopic lesion was examined and on the contrary, PTMC was found in 15.5% cases when the entire gland was examined [15]. The female/male ratio in PTMC cases was 9.7/1, a much higher value compared to the 4.2/1 ratio reported by Roti E et al [15] or Besic N et al [24]. This can be related to their higher prevalence of thyroid disease in women compared with men and, therefore, greater access to diagnostic procedures resulting in increased identification of PTMC. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Papillary thyroid microcarcinoma (PTMC) defines a group of papillary thyroid carcinomas, incidentally discovered, measuring 1 cm or less. The aim of our study was to evaluate the incidence and the pathological characteristics of PTMCs in our institution in the last 25 years, with special emphasis on the prognostic factors related to PTMCs. Material and methods: We performed a retrospective, cohort study on 255 PTMCs, registered in the Department of Pathology, Tîrgu-Mureş Emergency County Hospital between 1990 and 2014. Results: A significant increase in the incidence of PTMCs was observed in the 2004-2014 period, compared to 1990-2003 (7.6%, 229 PTMCs/3005 thyroid specimens vs. 1.2%, 23 PTMCs/1885 thyroid specimens). Conventional PTMCs accounted for most of PTMC cases (n=123 cases, 48.2%), followed by the follicular variant of PTC (n=117 cases, 45.9%). The increasing incidence of PTMCs was associated with a significant increase in the routine number of blocks sampled per case over the study period (R2 =0.72, p < 0.001). By means of the univariate and multivariate analysis, three risk factors were predictive for extrathyroidal extension in PTMCs: multifocality (Odds ratio [OR] 4.97, p-0.002), tumor size ≥ 5mm (OR 8.97, p-0.008) and lymph node involvement (OR 17.66 p
    Full-text · Article · Mar 2016
    • "В связи с этим был сделан вывод, что лечение пациентов с папиллярными микрокарциномами не должно отличаться от лечения пациентов с папиллярным раком большего размера. По данным различных авторов, мультифокальность обнаруживается в 15–35,6% случаев микрокарцином и является важным прогностическим фактором персистенции [5, 6, 10, 19,383940. Учитывая, что при мультифокальности высока вероятность билатерального поражения (25–27% случаев), при микрокарциномах рекомендуют проведение тотальной ти- реоидэктомии. "
    Full-text · Article · Jun 2015
    • "For unilateral multifocal PT- MCs, the extent of surgery is still not determined clearly [15,19]. Although the prognosis of PTMCs is excellent [20,21] , we suggest total thyroidectomy for preoperatively diagnosed multifocal PTMCs and completion thyroidectomy for multifocal PTMCs incidentally diagnosed after lobectomy, because of the high probability of contralateral tumor foci and the poor prognosis of multifocal PTCs. Though lobectomy alone may be performed, thorough and meticulous follow-up is necessary for those multifocal cases. "
    [Show abstract] [Hide abstract] ABSTRACT: Papillary thyroid carcinomas frequently occur as two or more separate foci within the thyroid gland (18%-87%). However, those multifocal tumors are easy to be undetected by preoperative radiologic evaluations, which lead to remnant disease after initial surgery. We aimed to study the incidence of multifocal papillary thyroid microcarcinomas (PTMCs), diagnostic accuracy of preoperative radiologic evaluation, predictive factors, and the chance of bilateral tumors. Two hundred and seventy-seven patients with PTMC were included in this study. All patients underwent total thyroidectomy as an initial treatment. Medical records, pathologic reports, and radiological reports were reviewed for analysis. Multifocal PTMCs were detected in 100 of 277 patients (36.1%). The mean number of tumors in each patient was 1.6±1.1, ranging from 1 to 10. The additional tumor foci were significantly smaller (0.32±0.18 cm) than the primary tumors (0.63±0.22 cm) (P<0.001). There was no significant relationship between primary tumor size and the presence of contralateral tumors. With more tumors detected in one lobe, there was greater chance of contralateral tumors; 18.8% with single tumor focus, 30.2% with 2 tumor foci, and 46.2% with 3 or more tumor foci in one lobe. Sensitivity of preoperative sonography was 42.7% for multifocal tumors and 49.0% for bilateral tumors. With multivariate analysis, nodular hyperplasia was the only significant factor for multifocal tumors. In cases of PTMCs, the incidence of multifocal tumors is high. However, additional tumor foci are too small to be diagnosed preoperatively, especially under the recent guidelines on radiologic screening tests for papillary thyroid carcinoma. Multifocal PTMCs have high risk of bilateral tumors, necessitating more extensive surgery or more thorough follow-up.
    Full-text · Article · Jun 2015
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