Thyroid papillary microcarcinoma: A descriptive and meta-analysis study
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.
Thyroid papillary microcarcinoma: a descriptive and meta-
Elio Roti, Ettore C degli Uberti
, Marta Bondanelli
and Lewis E Braverman
Institute of Endocrinology, University of Milan, 20133 Milan, Italy,
Section of Endocrinology, Department of Biochemical Sciences and Advanced
Therapies, University of Ferrara, 44100 Ferrara, Italy and
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: firstname.lastname@example.org)
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
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
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.
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).
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).
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).
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
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).
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-
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
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
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
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 ﬁnding
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
is similar to that observed in patients with larger
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] ﬂuorodeoxyglucose 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 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
Table 3 Characteristics of the studies included in the meta-analysis on possible risk factors for recurrence of thyroid papillary microcarcinoma.
No of patients
(M/F) Age (yr)
(yr or mo; range)
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
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)
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
lben et al. 2008 (151) 81 (15/66) 16–61 1990–2003 7 yr (28–192) 10 0 1 0 1
nberger et al. 2007 (25) 67 (19/48) 22–88 1993–2003 55.5 mo (14–169) 10 2 1 2
Yamashita et al. 1999
1970–1994 11.2 202 0 35 5 31
Monacelli et al.2006
(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.
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.
These patients had distant metastases also at diagnosis.
These studies also included some follicular and/or medullary thyroid microcarcinomas.
664 E Roti and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2008) 159
I treatment following thyroidectomy
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
(L-thyroxine) treatment following
Many studies on PTMC failed to mention whether L-T
was given after surgery. However, it seems likely that L-
therapy was administered in patients with extensive
thyroidectomy. In some studies (3, 8, 12, 21, 32, 38, 39,
55, 142), suppressive doses of
in patients operated upon for PTMC, but in one study it
was discontinued within several years (30).
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
therapy was rec-
ommended for an unknown period of time and later
substitutive therapy only (42). Finally, substitutive
therapy was the treatment of choice in some patients
with PTMC (26, 27, 42).
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).
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
(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,
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
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
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.
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
treatment. Also, in patients with documented persistent
disease or at high risk of persistent or recurrent post-
I treatment reduces the recurrence
rate and possibly prolongs survival (154). The BTA (155)
I treatment in patients with a tumor size
Suppressive or substitutive
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
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
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
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
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
Declaration of interest
The authors declare that there is no conﬂict of interest that would
prejudice the impartiality of this scientiﬁc work.
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
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Received 27 July 2008
Accepted 5 August 2008
Thyroid papillary microcarcinoma
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