Thyroid papillary microcarcinoma: a descriptive and meta-analysis study

in European Journal of Endocrinology
(Correspondence should be addressed to E Roti; Email: elio.roti@unimi.it)

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.

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.

Introduction

Thyroid microcarcinoma has been defined as thyroid cancer ≤10 mm in diameter, usually papillary (papillary 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 unidentified 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 comprehensive 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.

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, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26)
Papillary type (range)65–99%(5, 9, 10, 15, 17, 18, 24, 30, 31, 32)
Age (years; range)41.9–55(4, 5, 6, 8, 9, 10, 11, 12, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 30, 34, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55)
Sex F/M ratio4.8/1(4, 5, 6, 8, 10, 12, 15, 16, 17, 18, 19, 21, 25, 30, 31, 32, 34, 38, 39, 40, 41, 42, 44, 45, 46, 47, 49, 50, 52, 53, 54, 55, 56, 57)
Autopsy prevalence>35.6%(29)
Clinical prevalence>95.3% of all cancers(23)
Incidental prevalence>100% of all PTMC(7)

Range values refer to the results of different studies.

Selection of relevant studies for review

We have searched the key words ‘thyroid microcarcinoma’ 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 >35 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 χ2 goodness-of-fit test. The OR was the ratio across different groups for the odds 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 Comprehensive Meta-analysis software (v. 2.0, Biostat, Englewood, NJ, USA). A P 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, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 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% respectively, 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, 31, 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, 31, 32, 33, 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, 5, 6, 8, 9, 10, 11, 12, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 30, 31, 34, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53) with a range of 4–85 years (4, 5, 6, 8, 11, 12, 15, 17, 18, 19, 20, 24, 30, 31, 34, 38, 39, 42, 44, 45, 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 microcarcinoma occurred in patients older than 45 years (54, 55). Autopsy studies demonstrated that thyroid microcarcinomas 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, 54±16.9 and 37.7±12.3 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, 5, 6, 8, 10, 12, 15, 16, 17, 18, 19, 21, 25, 30, 31, 32, 34, 38, 39, 40, 41, 42, 44, 45, 46, 47, 49, 50, 52, 53, 54, 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). In a single study describing 141 cases of thyroid microcarcinoma <10 mm in diameter, 82 (58%) were men and 59 (42%) were women (28). It is likely that the 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 microcarcinomas. 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 genetic 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, 65, 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 aggressive behavior (68). BRAF mutations may occur in papillary thyroid carcinoma and have also been reported in PTMC (65, 69, 70, 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 population, 13.7–28.4% (37, 75, 76, 77, 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 microcarcinoma, 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, 81, 82, 83, 84, 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 specimens (29).

Iodine intake has been suggested as a possible factor affecting the prevalence of thyroid cancer (86). In a 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). The Geneva 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 ∼3.5 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 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). In Table 2, we report the prevalence of PTMC in patients with different thyroid diseases (6, 10, 11, 12, 15, 16, 17, 20, 23, 31, 38, 43, 45, 46, 49, 50, 52, 54, 55, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 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 ≤5 mm (119, 122).

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, 100, 101, 102, 103, 104, 105)
Differentiated thyroid cancer (4776)24.8(52, 105, 106, 107, 108, 109, 110, 111)
All thyroid cancer (10 628)22.9(13, 17, 43, 45, 50, 99, 100, 112, 113, 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.

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, 5, 6, 7, 11, 12, 13, 14, 15, 18, 23, 24, 25, 26, 27, 32, 43, 44, 46, 49, 96, 97, 98, 99, 102, 103, 112, 113, 114, 115, 116, 118, 119, 120, 121, 122, 123, 124, 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 >1 and >4 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 malignancy. Microcalcifications within malignant nodules have been observed in many studies (76, 127, 128, 129, 130) and were present in 7.1–59% of patients with PTMC (76, 127, 128, 129, 130, 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 ∼18.5% 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 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] 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, 4, 5, 6, 7, 8, 10, 11, 12, 13, 14, 15, 16, 17, 18, 20, 21, 23, 24, 25, 26, 27, 30, 31, 34, 38, 39, 40, 42, 45, 46, 47, 48, 49, 50, 51, 52, 58, 98, 103, 109, 112, 113, 114, 116, 121, 123, 124, 125, 141, 142, 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, >5 (8, 144) and >8 mm (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, 146, 147). Overexpression of cyclin D1 was present in PTMC with lymph node metastases. However, similar results were observed in patients without lymph node metastases (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 extremely 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, 5, 6, 8, 11, 12, 14, 15, 16, 17, 18, 20, 23, 24, 25, 26, 27, 30, 31, 32, 34, 38, 39, 40, 42, 45, 46, 48, 49, 50, 58, 97, 98, 104, 105, 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, 5, 6, 8, 11, 12, 14, 15, 16, 17, 18, 20, 23, 24, 25, 26, 27, 30, 31, 32, 34, 38, 39, 40, 42, 45, 46, 48, 49, 50, 58, 97, 98, 104, 105, 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, 5, 6, 7, 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).

131I treatment following thyroidectomy

131I 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 131I.

l-T4 (l-thyroxine) treatment following thyroidectomy

Many studies on PTMC failed to mention whether l-T4 was given after surgery. However, it seems likely that l-T4 therapy was administered in patients with extensive thyroidectomy. In some studies (3, 8, 12, 21, 32, 38, 39, 55, 142), suppressive doses of l-T4 were recommended in patients operated upon for PTMC, but in one study it was discontinued within several years (30). l-T4 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-T4 therapy was recommended for an unknown period of time and later substitutive therapy only (42). Finally, substitutive l-T4 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, 5, 6, 8, 11, 12, 14, 15, 16, 17, 18, 20, 22, 23, 24, 25, 26, 27, 30, 31, 32, 34, 38, 39, 40, 42, 45, 46, 48, 49, 50, 58, 97, 98, 104, 105, 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, 5, 6, 8, 11, 12, 14, 15, 16, 17, 18, 20, 22, 23, 24, 25, 26, 27, 30, 31, 32, 34, 38, 39, 40, 42, 45, 46, 48, 49, 50, 58, 97, 98, 104, 105, 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, 5, 6, 8, 11, 12, 14, 15, 16, 17, 18, 20, 22, 23, 24, 25, 26, 27, 30, 31, 32, 34, 38, 39, 40, 42, 45, 46, 48, 49, 50, 58, 97, 98, 104, 105, 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 Gülben 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.

Table 3

Characteristics of the studies included in the meta-analysis on possible risk factors for recurrence of thyroid papillary microcarcinoma.

AuthorsNo of patients (M/F)Age (yr)Period of study (yr)Mean follow-up (yr or mo; range)Lymph node metastases 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)14–851975–200684 mo (1–385)560617
Baudin et al. 1998 (5)273 (69/204)6–651962–19957.3 yr (0.6–33.7)121311111
Sugitani et al. 1998 (51)1901976–19968 yr (2–21)340114
Roti et al. 2006 (12)243 (46/197)16–851993–20024.4 yr (2.4–10.6)324404
Pelizzo et al. 2006 (55)403 (66/337)1990–20048.5 yr (9 mo–14 yr)47161 (+)24a
Lo et al. 2006 (20)185 (37/148)11–841964–20038.2 yr (0.1–38)433NRNR13 (+4 died of disease)
Küçük et al. 2007 (22)120 (15/105)17–671997–200545 mo (16–86)70202
Ito et al. 2004 (48)590 (38/552)18–831993–2003(0–140 mo)67NR10NR
Ito et al 2003 (41)626 (39/587)16–831993–200348.7 mo (0–120)300016016
Rodriguez et al. 1997 (31)36 (6/30)4–651970–19907 yr6 ?0303
Appetecchia et al. 2002 (40)120 (24/96)23–77NR8 yr (5–15)260202
Chow et al. 2003 (42)203 (27/176)7.7–77.21960–19998.4 yr504124
Wada et al. 2003 (8)259 (29/230)17–721988–199861.6 mo (13–144)930707
Gülben et al. 2008 (151)81 (15/66)16–611990–20037 yr (28–192)100101
Schönberger et al. 2007 (25)67 (19/48)22–881993–200355.5 mo (14–169)10212b1
Yamashita et al. 1999c(7)1743 (186/1557)1970–199411.2202035531
Monacelli et al. 2006c(18)74 (16/58)24–732001–200460404

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.

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 (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 heterogeneity of the data. Again, 131I treatment was not associated with progression of the disease.

Figure 1
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; P=0.038). There was no statistical heterogeneity (P=0.783). Tumor recurrence was significantly associated to younger age (<45 years).

Citation: European Journal of Endocrinology 159, 6; 10.1530/EJE-07-0896

Download Figure

Figure 2
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; P=0.001). There was no statistical heterogeneity (P=0.675). Tumor recurrence was significantly higher in patients with overt tumors.

Citation: European Journal of Endocrinology 159, 6; 10.1530/EJE-07-0896

Download Figure

Figure 3
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; P=0.000). There was no statistical heterogeneity (P=0.535). Positive association was found between tumor recurrence and multifocal tumors at diagnosis.

Citation: European Journal of Endocrinology 159, 6; 10.1530/EJE-07-0896

Download Figure

Figure 4
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; P=0.000). There was no statistical heterogeneity (P=0.195). Positive association was found between tumor recurrence and lymph node involvement at diagnosis.

Citation: European Journal of Endocrinology 159, 6; 10.1530/EJE-07-0896

Download Figure

Figure 5
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 (P=0.078). 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.

Citation: European Journal of Endocrinology 159, 6; 10.1530/EJE-07-0896

Download Figure

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 >1.5 cm in diameter. In patients with small, low-risk, isolated, intrathyroidal papillary carcinomas 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 Association (BTA) (155) recommend partial thyroidectomy 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.

131I 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 131I treatment. Also, in patients with documented persistent disease or at high risk of persistent or recurrent postoperative disease, 131I treatment reduces the recurrence rate and possibly prolongs survival (154). The BTA (155) recommends 131I treatment in patients with a tumor size >1 cm in diameter.

Suppressive or substitutive l-T4 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-T4 to reach serum thyroid stimulating hormone (TSH) concentrations=0.1 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-T4 for patients with PTMC <1 cm in diameter and negative nodes treated by a lobectomy (155). These recommendations seem acceptable 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 without lymph node enlargement, 41% of the respondents 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 recommended 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-T4 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 completion 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 aggressiveness. 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 sophisticated 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

    LloydRDe LellisRHeitzPEngC, Lyon, France: IARC Press International Agency for Research on Cancer, 2004

  • 2

    WoolnerLBLemmonMLBeahrsOHBlackBMKeatingFR. Occult papillary carcinoma of the thyroid gland: a study of 140 cases observed in 30 year period. Journal of Clinical Endocrinology and Metabolism1960 ;20:89105.

  • 3

    PellegritiGScolloCLumeraGRegalbutoCVigneriRBelfioreA. Clinical behavior and outcome of papillary thyroid cancers smaller than 1.5 cm in diameter: study of 299 cases. Journal of Clinical Endocrinology and Metabolism2004 ;89:37133720.

  • 4

    HayIDGrantCSvan HeerdenJAGoellnerJREbersoldJRBergstralhEJ. Papillary thyroid microcarcinoma: a study of 535 cases observed in a 50-year period. Surgery1992 ;112:11391146.

  • 5

    BaudinETravagliJPRopersJMancusiFBruno-BossioGCaillouBCailleuxAFLumbrosoJDParmentierCSchlumbergerM. Microcarcinoma of the thyroid gland: the Gustave Roussy Institute experience. Cancer1998 ;83:553559.

  • 6

    SuginoKItoKJrOzakiOMimuraTIwasakiHItoK. Papillary microcarcinoma of the thyroid. Journal of Endocrinological Investigation1998 ;21:445448.

  • 7

    YamashitaHNoguchiSMurakamiNTodaMUchinoSWatanabeSKawamotoH. Extracapsular invasion of lymph node metastasis. A good indicator of disease recurrence and poor prognosis in patients with thyroid microcarcinoma. Cancer1999 ;86:842849.

  • 8

    WadaNDuhQYSuginoKIwasakiHKameyamaKMimuraTItoKTakamiHTakanashiY. Lymph node metastasis from 259 papillary thyroid microcarcinomas: frequency, pattern of occurrence, and optimal strategy for neck dissection. Annals of Surgery2003 ;237:399407.

  • 9

    PelizzoMRBoschinIMToniatoAPagettaCPiottoABernantePCasaraDPennelliGRubelloD. Natural history, diagnosis, treatment and outcome of papillary thyroid microcarcinoma (PTMC): a mono-institutional 12-year experience. Nuclear Medicine Communications2004 ;25:547552.

  • 10

    FardellaCJiménezMGonzálezHLeónAGoñiICruzFSolarATorresJMossoLGonzálezGRodríguezJACampusanoCLópezJMArteagaE. Pathological characteristics of thyroid microcarcinoma. A review of 402 biopsies. Revista Mèdica de Chile2005 ;133:13051310(Spanish)

  • 11

    BarbaroDSimiUMeucciGLapiPOrsiniPPasquiniC. Thyroid papillary cancers: microcarcinoma and carcinoma, incidental cancers and non-incidental cancers – are they different diseases?Clinical Endocrinology2005 ;63:577581.

  • 12

    RotiERossiRTrasforiniGBertelliFAmbrosioMRBusuttiLPearceENBravermanLEdegli UbertiEC. Clinical and histological characteristics of papillary thyroid microcarcinoma: results of a retrospective study in 243 patients. Journal of Clinical Endocrinology and Metabolism2006 ;91:21712178.

  • 13

    de MatosPSFerreiraAPWardLS. Prevalence of papillary microcarcinoma of the thyroid in Brazilian autopsy and surgical series. Endocrine Pathology2006 ;17:165173.

  • 14

    SaccoRAversaSInnaroNCarpinoABologniniSAmorosiA. Thyroid microcarcinoma and multinodular struma. Personal experience and considerations regarding surgical therapy. Chirurgia Italiana2006 ;58:6975(Italian)

  • 15

    AntonaciAAnelloAAucelloAConsortiFDella RoccaCGiovannoneGScardellaL. Microcarcinoma and incidental carcinoma of the thyroid in a clinical series: clinical behaviour and surgical management. La Clinica Terapeutica2006 ;157:225229.

  • 16

    CheemaYOlsonSElsonDChenH. What is the biology and optimal treatment for papillary microcarcinoma of the thyroid?Journal of Surgical Research2006 ;134:160162.

  • 17

    LeeJRheeYLeeSAhnCWChaBSKimKRLeeHCKimSIParkCSLimSK. Frequent, aggressive behaviors of thyroid microcarcinomas in korean patients. Endocrinology Journal2006 ;53:627632.

  • 18

    MonacelliMSperlonganoPD'AjelloMCalzolariFPiattoALucchiniRMissoCParmeggianiDPisanielloDSordelliISperlonganoRAveniaN. Thyroid microcarcinoma: our experience. Il Giornale di Chirurgia2006 ;27:158160(Italian)

  • 19

    TorlontanoMCrocettiUAugelloGD'AloisoLBonfittoNVarrasoADicembrinoFModoniSFruscianteVDi GiorgioABrunoRFilettiSTrischittaV. Comparative evaluation of recombinant human thyrotropin-stimulated thyroglobulin levels, 131I whole-body scintigraphy, and neck ultrasonography in the follow-up of patients with papillary thyroid microcarcinoma who have not undergone radioiodine therapy. Journal of Clinical Endocrinology and Metabolism2006 ;91:6063.

  • 20

    LoCYChanWFLangBHLamKYWanKY. Papillary microcarcinoma: is there any difference between clinically overt and occult tumors?World Journal of Surgery2006 ;30:759766.

  • 21

    CappelliCCastellanoMBragaMGandossiEPirolaIDe MartinoEAgostiBAgabiti RoseiE. Aggressiveness and outcome of papillary thyroid carcinoma (PTC) versus microcarcinoma (PMC): a mono-institutional experience. Journal of Surgical Oncology2007 ;95:555560.

  • 22

    KüçükNOTariPTokmakEArasG. Treatment for microcarcinoma of the thyroid – clinical experience. Clinical Nuclear Medicine2007 ;32:279281.

  • 23

    LimDJBaekKHLeeYSParkWCKimMKKangMIJeonHMLeeJMYun-ChaBLeeKWSonHYKangSK. Clinical, histopathological, and molecular characteristics of papillary thyroid microcarcinoma. Thyroid2007 ;17:883888.

  • 24

    PiselloFGeraciGSciumèCLi VolsiFModicaG. Total thyroidectomy of choice in papillary microcarcinoma. Il Giornale di Chirurgia2007 ;28:1319(Italian)

  • 25

    SchönbergerJMarienhagenJAghaARozeboomSBachmeierESchlittHEillesC. Papillary microcarcinoma and papillary cancer of the thyroid <or=1 cm: modified definition of the WHO and the therapeutic dilemma. Nuklearmedizin2007 ;46:115120.

  • 26

    SakorafasGHStafylaVKolettisTTolumisGKassarasGPerosG. Microscopic papillary thyroid cancer as an incidental finding in patients treated surgically for presumably benign thyroid disease. Journal of Postgraduate Medicine2007 ;53:2326.

  • 27

    CarliniMGiovanniniCCastaldiFMercadanteEDell'AvanzatoRZazzaSNaniaASanteusanioGPasseriMDi PernaP. High risk for microcarcinoma in thyroid benign diseases. Incidence in a one year period of total thyroidectomies. Journal of Experimental and Clinical Cancer Research2005 ;24:231236.

  • 28

    SampsonRJKeyCRBuncherCRIijimaS. Smallest forms of papillary carcinoma of the thyroid. A study of 141 microcarcinomas less than 0.1 cm in greatest dimension. Archives of Pathology1971 ;91:334339.

  • 29

    HarachHRFranssilaKOWaseniusVM. Occult papillary carcinoma of the thyroid. A ‘normal’ finding in Finland. A systematic autopsy study. Cancer1985 ;56:531538.

  • 30

    NoguchiSYamashitaHMurakamiNNakayamaIMasakatsuTKawamotoH. Small carcinomas of the thyroid. A long-term follow-up of 867 patients. Archives of Surgery1996 ;131:187191.

  • 31

    RodriguezJMMorenoAParrillaPSolaJSoriaTTebarFJArandaF. Papillary thyroid microcarcinoma: clinical study and prognosis. European Journal of Surgery1997 ;163:255259.

  • 32

    RuggieriMGenderiniMGargiuloPDel GrammastroAMascaroALuongoBPaoliniA. Surgical treatment of differentiated microcarcinomas of the thyroid. European Review for Medical and Pharmacological Sciences2001 ;5:8589.

  • 33

    SimpsonWJMcKinneySECarruthersJSGospodarowiczMKSutcliffeSBPanzarellaT. Papillary follicular thyroid cancer: prognostic factors in 1578 patients. American Journal of Medicine1987 ;83:479488.

  • 34

    SugitaniIFujimotoY. Symptomatic versus asymptomatic papillary thyroid microcarcinoma: a retrospective analysis of surgical outcome and prognostic factors. Endocrine Journal1999 ;46:209216.

  • 35

    EmerickGTDuhQYSipersteinAEBurrowGNClarkOH. Diagnosis, treatment, and outcome of follicular thyroid carcinoma. Cancer1993 ;72:32873291.

  • 36

    RossiRRotiETrasforiniGBertelliFCavazziniLZatelliMCPearceENBravermanLEdegli UbertiEC. Histological and clinical differences in thyroid cancers ≤10 mm and 11–20 mm in diameter: results of a retrospective study of 426 patients. Thyroid2008 ;18:309315.

  • 37

    FukunagaFHYataniR. Geographic pathology of occult thyroid carcinomas. Cancer1975 ;36:10951099.

  • 38

    TournaireJBernardMHBizollon-RoblinMHBertholon-GrégoireMBerger-DutrieuxN. Le micro-carcinome papillaire du corps thyroïde. 179 cas observès depuis 1973. Presse Médicale1998 ;27:14671469.

  • 39

    FalvoID'ErcoleCSorrentiSD'AndreaVCataniaABerniAGrilliPDe AntoniE. Papillary microcarcinoma of the thyroid gland: analysis of prognostic factors including histological subtype. European Journal of Surgery168Suppl 58820022832.

  • 40

    AppetecchiaMScarcelloGPucciEProcacciniA. Outcome after treatment of papillary thyroid microcarcinoma. Journal of Experimental & Clinical Cancer Research2002 ;21:159164.

  • 41

    ItoYUrunoTNakanoKTakamuraYMiyaAKobayeshiKYokozawaTMatsuzukaFKumaSKumaKMiyauchiA. An observation trial without surgical treatment in patients with papillary microcarcinoma of the thyroid. Thyroid2003 ;13:381387.

  • 42

    ChowSMLawSCKChanJKCAuSKYauSLauWH. Papillary microcarcinoma of the thyroid – prognostic significance of lymph node metastasis and multifocality. Cancer2003 ;98:3140.

  • 43

    BarroetaJEWangHShiinaNGuptaPKLivolsiVABalochZW. Is fine-needle aspiration (FNA) of multiple thyroid nodules justified?Endocrine Pathology2006 ;17:6165.

  • 44

    BiscollaRPUgoliniCSculliMBotticiVCastagnaMGRomeiCCosciBMolinaroEFavianaPBasoloFMiccoliPPaciniFPincheraAEliseiR. Medullary and papillary tumors are frequently associated in the same thyroid gland without evidence of reciprocal influence in their biologic behavior. Thyroid2004 ;14:946952.

  • 45

    BonninCTrojaniMCorcuffJBBonichonF. Outcome of 111 thyroid papillary carcinomas. Retrospective study from 1953 to 1994. Experience of Bergonié Institute. Annales d'Endocrinologie1997 ;58:318325(Review. French)

  • 46

    FarinaGPBaccoliAPisanoMPaniCDi NinniSMarcelloACagettiM. Papillary microcarcinoma of the thyroid. Clinical implications and therapeutic strategy. Il Giornale di Chirurgia2003 ;24:1117(Italian)

  • 47

    ItoYHigashiyamaTTakamuraYMiyaAKobayashiKMatsuzukaFKumaKMiyauchiA. Prognosis of patients with benign thyroid diseases accompanied by incidental papillary carcinoma undetectable on preoperative imaging tests. World Journal of Surgery2007 ;31:16721676.

  • 48

    ItoYTomodaCUrunoTTakamuraYMiyaAKobayashiKMatsuzukaFKumaKMiyauchiA. Preoperative ultrasonographic examination for lymph node metastasis: usefulness when designing lymph node dissection for papillary microcarcinoma of the thyroid. World Journal of Surgery2004 ;28:498501.

  • 49

    Jacquot-LaperrièreSTimoshenkoAPDumollardJMPeoc'hMEstourBMartinCPradesJM. Papillary thyroid microcarcinoma: incidence and prognostic factors. European Archives of Oto-Rhino-Laryngology2007 ;264:935939.

  • 50

    LinJDChenSTChaoTCHsuehCWengHF. Diagnosis and therapeutic strategy for papillary thyroid microcarcinoma. Archives of Surgery2005 ;140:940945.

  • 51

    SugitaniIYanagisawaAShimizuAKatoMFujimotoY. Clinicopathologic and immunohistochemical studies of papillary thyroid microcarcinoma presenting with cervical lymphadenopathy. World Journal of Surgery1998 ;22:731737.

  • 52

    WangJQiuXZhouLDengXZhangCZhouC. Differentiated microcarcinoma of the thyroid gland in 45 cases. Lin Chuang Er Bi Yan Hou Ke Za Zhi2001 ;15:542543(Chinese)

  • 53

    YangGCLiVolsiVABalochZW. Thyroid microcarcinoma: fine-needle aspiration diagnosis and histologic follow-up. International Journal of Surgical Pathology2002 ;10:133139.

  • 54

    MiccoliPMinutoMNUgoliniCPanicucciEMassiMBertiPBasoloF. Papillary thyroid cancer: pathological parameters as prognostic factors in different classes of age. Archives of Otolaryngology – Head and Neck Surgery2008 ;138:200203.

  • 55

    PelizzoMRBoschinLMToniatoAPiottoABernantePPagettaCRampinLRubelloD. Papillary thyroid microcarcinoma (PTMC): prognostic factors, management and outcome in 403 patients. European Journal of Surgical Oncology2006 ;32:11441148.

  • 56

    NishiyamaRHLudwigGKThompsonNW. The prevalence of small papillary thyroid carcinomas in 100 consecutive necropsies in an American population. In Radiation-Associated Thyroid Carcinoma In Eds pp. 123135. Eds. De GrootLJFrohmanLAKaplanELRefetoffS, New YorkGrune & Stratton1977

  • 57

    SampsonRJ. Comment on Dr. Edis's presentation on natural history of occult thyroid carcinoma. In Radiation-Associated Thyroid Carcinoma In Eds pp. 171181. Eds. De GrootLJFrohmanLAKaplanELRefetoffS, New YorkGrune & Stratton1977

  • 58

    LinKDLinJDHuangJHuangHSJengLBChaoTC. Clinical presentations and predictive variables of thyroid microcarcinoma with distant metastasis. International Surgery1997 ;82:378381.

  • 59

    NeuholdNKaiserHKasererK. Latent carcinoma of the thyroid in Austria: a systematic autopsy study. Endocrine Pathology2001 ;12:2331.

  • 60

    LupoliGVitaleGCaragliaMFittipaldiMRAbbruzzeseATagliaferriPBiancoAR. Familial papillary thyroid microcarcinoma: a new clinical entity. Lancet1999 ;353:637639.

  • 61

    EngC. Familial papillary thyroid cancer: many syndromes, too many genes?Journal of Clinical Endocrinology and Metabolism2000 ;85:17551757.

  • 62

    RíosARodríguezJMIllanaJTorregrosaNMParrillaP. Familial papillary carcinoma of the thyroid: report of three families. European Journal of Surgery2001 ;167:339343.

  • 63

    Fernández-RealJMRicartW. Familial papillary thyroid microcarcinoma. Lancet1999 ;353:19731974.

  • 64

    VigliettoGChiappettaGMartinez-TelloFJFukunagaFHTalliniGRigoupoulouDViscontiRMastroASantoroMFuscoA. RET/PTC oncogene activation is an early event in thyroid carcinogenesis. Oncogene1995 ;11:12071210.

  • 65

    AdeniranAJZhuZGandhiMStewardDLFidlerJPGiordanoTJBiddingerPWNikiforovYE. Correlation between genetic alterations and microscopic features, clinical manifestations, and prognostic characteristics of thyroid papillary carcinomas. American Journal of Surgical Pathology2006 ;30:216222.

  • 66

    CorviRMartinez-AlfaroMHarachHRZiniMPapottiMRomeoG. Frequent RET rearrangements in thyroid papillary microcarcinoma detected by interphase fluorescence in situ hybridization. Laboratory Investigation; A Journal of Technical Methods and Pathology2001 ;81:16391645.

  • 67

    TalliniGSantoroMHelieMCarlomagnoFSalvatoreGChiappettaGCarcangiuMLFuscoA. RET/PTC oncogene activation defines a subset of papillary thyroid carcinomas lacking evidence of progression to poorly or undifferentiated tumor phenotypes. Clinical Cancer Research1998 ;4:287294.

  • 68

    SuggSLZhengLRosenIBFreemanJLEzzatSAsaSL. RET/PTC1, 2 and 3 oncogene rearrangements in human thyroid carcinomas: implications for metastatic potential?Journal of Clinical Endocrinology and Metabolism1996 ;81:33603365.

  • 69

    NambaHNakashimaMHayashiTHayashidaNMaedaSRogounovitchTIOhtsuruASaenkoVAKanematsuTYamashitaS. Clinical implication of hot spot BRAF mutation, V599E, in papillary thyroid cancers. Journal of Clinical Endocrinology and Metabolism2003 ;88:43934397.

  • 70

    NikiforovaMNKimuraETGandhiMBiddingerPWKnaufJABasoloFZhuZGianniniRSalvatoreGFuscoASantoroMFaginJANikiforovYE. BRAF mutations in thyroid tumors are restricted to papillary carcinomas and anaplastic or poorly differentiated carcinomas. Journal of Clinical Endocrinology and Metabolism2003 ;88:53995404.

  • 71

    PuxedduEMorettiSEliseiRRomeiCPascucciRMartinelliMMarinoCAveniaNRossiEDFaddaGCavaliereARibacchiRFalorniAPontecorviAPaciniFPincheraASanteusanioF. BRAF(V599E) mutation is the leading genetic event in adult sporadic papillary thyroid carcinomas. Journal of Clinical Endocrinology and Metabolism2004 ;89:24142420.

  • 72

    LiuDLiuZCondourisSXingM. BRAF V600E maintains proliferation, transformation, and tumorigenicity of BRAF-mutant papillary thyroid cancer cells. Journal of Clinical Endocrinology and Metabolism2007 ;92:22642271.

  • 73

    OlerGEbinaKNMchaluartPRimuraETCeruttiJ. Investigation of BRAF mutation in a series of papillary thyroid carcinoma and matched lymph node metastasis reveals a new mutation in metastasis. Clinical Endocrinology2005 ;62:509511.

  • 74

    KimEKParkCSChungWYOhKKKimDILeeJTYooHS. New sonographic criteria for recommending fine-needle aspiration biopsy of nonpalpable solid nodules of the thyroid. American Journal of Roentgenology2002 ;178:687691.

  • 75

    SampsonRJWoolnerLBBahnRCKurlandLT. Occult thyroid carcinoma in Olmsted County, Minnesota: prevalence at autopsy compared with that in Hiroshima and Nagasak, Japan. Cancer1974 ;34:20722076.

  • 76

    YamamotoYMaedaTIzumiKOtsukaH. Occult papillary carcinoma of the thyroid. Cancer1990 ;65:11731179.

  • 77

    BrierreIDicksonLG. Clinically unsuspected thyroid disease. American Family Physician/GP1964 ;30:9498.

  • 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

    FukunagaFHLockettIJ. Thyroid carcinoma in Japanese in Hawaii. Archives of Pathology1971 ;92:613.

  • 80

    KovacsGLGondaGVadaszGLudmanyEUhrinKGorombeyZKovacsLHubinaEBodoMGothMISzabolcsI. Epidemiology of thyroid microcarcinoma found in autopsy series conducted in areas of different iodine intake. Thyroid2005 ;15:152157.

  • 81

    BalazsGYKrasznaiG. Occult pajzsmirigyrak post mortem vizsgalata [in Hungarian]. Orvosi Hetilap1974 ;115:28562860.

  • 82

    Sobrinho-SimoesMASambadeMCGoncalvesV. Latent thyroid carcinoma at autopsy. Cancer1979 ;43:17021706.

  • 83

    BondesonLLjungbergO. Occult thyroid carcinoma at autopsy in Malmö, Sweden. Cancer1981 ;47:319323.

  • 84

    LangWBorruschHBauerL. Evaluation of 1020 sequential autopsies. American Journal of Clinical Pathology1988 ;90:7276.

  • 85

    OttinoAPianzolaHMCastellettoRH. Occult papillary thyroid carcinoma at autopsy in La Plata, Argentina. Cancer1989 ;64:547551.

  • 86

    TanGHGharibH. Thyroid incidentalomas: management approaches to nonpalpable nodules discovered incidentally on thyroid imaging. Annals of Internal Medicine1997 ;126:226231.

  • 87

    ReinersCWegscheiderKSchichaHTheissenPVaupelRWrbitzkyRSchumm-DraegerPM. Prevalence of thyroid disorders in the working population of Germany: ultrasonography screening in 96,278 unselected employees. Thyroid2004 ;14:926932.

  • 88

    TanGHGharibHReadingCC. Solitary thyroid nodule. Comparison between palpation and ultrasonography. Archives of Internal Medicine1995 ;155:24182423.

  • 89

    BranderAViikinkoskiPTuuheaJVoutilainenLKivisaariL. Clinical versus ultrasound examination of the thyroid gland in common clinical practice. Journal of Clinical Ultrasound1992 ;20:3742.

  • 90

    WalkerJFindlayDAmarSSSmallPGWastieMLPeggCA. A prospective study of thyroid ultrasound scan in the clinically solitary thyroid nodule. British Journal of Radiology1985 ;58:617619.

  • 91

    LeenhardtLGrosclaudePChérié-ChallineL. 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. Thyroid2004 ;14:10561106.

  • 92

    VerkooijenHMFiorettaGPacheJCFranceschiSRaymondLSchubertHBouchardyC. Diagnostic changes as a reason for the increase in papillary thyroid cancer incidence in Geneva, Switzerland. Cancer Causes and Control2003 ;14:1317.

  • 93

    DaviesLWelchHG. Increasing incidence of thyroid cancer in the United States, 1973–2002. Journal of the American Medical Association2006 ;295:21642167.

  • 94

    BurgessJRDwyerTMcArdleKTuckerPShuggD. 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 Metabolism2000 ;85:15131517.

  • 95

    ChowSMLawSCAuSKMangOYauSYuenKTLauWH. 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 Oncology2003 ;15:329336.

  • 96

    AbdulmughniYAAl-HureibiMAAl-HureibiKAGhafoorMAAl-WadanAHAl-HureibiYA. Thyroid cancer in Yemen. Saudi Medical Journal2004 ;25:5559.

  • 97

    ArditoGRevelliLLucciCGiacintoOPraquinB. Papillary microcarcinoma [correction of carcinoma] of the thyroid: clinical experience and prognosis factors. Annali Italiani di Chirurgia2001 ;72:261265(Italian. Erratum in: Annali Italiani di Chirurgia 2001 72: 390)

  • 98

    GarrelRCartierCMarvasoVCorpeletDMakeieffMCrampetteLGuerrierB. Our experience with papillary microcarcinoma of the thyroid. Revue de Laryngologie – Otologie – Rhinologie2002 ;123:239242(French)

  • 99

    DeveciMSDeveciGLiVolsiVAGuptaPKBalochZW. Concordance between thyroid nodule sizes measured by ultrasound and gross pathology examination: effect on patient management. Diagnostic Cytopathology2007 ;35:579583.

  • 100

    LamAKLoCYLamKS. Papillary carcinoma of thyroid: a 30-yr clinicopathological review of the histological variants. Endocrine Pathology2005 ;16:323330(Review)

  • 101

    CappelliCPirolaICumettiDMichelettiLTironiAGandossiEMartinoECherubiniLAgostiBCastellanoMMattanzaCAgabiti RoseiE. Is the anteroposterior and transverse diameter ratio of nonpalpable thyroid nodules a sonographic criteria for recommending fine-needle aspiration cytology?Clinical Endocrinology2005 ;63:689693.

  • 102

    GemsenjägerESchweizerI. Small thyroid carcinomas: biological characteristics, diagnosis and therapy. Schweizerische Medizinische Wochenschrift1999 ;129:681690.

  • 103

    LepratFTrouetteHCochetCSaumthallyBMassonBde MascarelALatapieJL. Papillary microcarcinoma of the thyroid. Annales d'Endocrinologie1994 ;54:343346(French)

  • 104

    MelliereDHindieEBecqueminJPDesgrangesPAllaireEGeachanE. Differentiated thyroid carcinoma – how to improve the long-term results? Twenty-five-year outcomes of 850 patients. Bulletin de l'Acadèmie Nationale de Mèdecine2006 ;190:89106(discussion 106–109. French)

  • 105

    OrsenigoEBerettaEFiaccoEScaltriniaFVeronesiPInvernizziLGiniPFiorinaPDi CarloV. Management of papillary microcarcinoma of the thyroid gland. European Journal of Surgical Oncology2004 ;30:11041106.

  • 106

    JukkolaABloiguREbelingTSalmelaPBlancoG. Prognostic factors in differentiated thyroid carcinomas and their implications for current staging classifications. Endocrine-Related Cancer2004 ;11:571579.

  • 107

    PasslerCScheubaCPragerGKaczirekKKasererKZettinigGNiederleB. Prognostic factors of papillary and follicular thyroid cancer: differences in an iodine replete endemic goiter region. Endocrine-Related Cancer2004 ;11:131139.

  • 108

    Eustatia-RuttenCFCorssmitEPBiermaszNRPereiraAMRomijnJASmitJW. Survival and death causes in differentiated thyroid carcinoma. Journal of Clinical Endocrinology and Metabolism2006 ;91:313319.

  • 109

    PirainoPSepúlvedaALilloRPinedaPLibermanC. Thyroid cancer. Report of 85 cases. Revista Mèdica de Chile2000 ;128:405410(Spanish)

  • 110

    YokozawaT. Evaluation of the clinical usefulness of ultrasonography in making a preoperative diagnosis of thyroid carcinoma. Nippon Geka Gakkai Zasshi1988 ;89:582594(Japanese)

  • 111

    HundahlSACadyBCunninghamMPMazzaferriEMcKeeRFRosaiJShahJPFremgenAMStewartAKHölzerS. 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. Cancer2000 ;89:202217.

  • 112

    ChigotJPMénégauxFKeopadabsyKHoangCAurengoALeenhardtLTurpinG. Thyroid cancer in patients with hyperthyroidism. Presse Médicale2000 ;29:19691972(French)

  • 113

    DietleinMLuykenWASchichaHLarena-AvellanedaA. Incidental multifocal papillary microcarcinomas of the thyroid: is subtotal thyroidectomy combined with radioiodine ablation enough?Nuclear Medicine Communications2005 ;26:38.

  • 114

    KasugaYSugenoyaAKobayashiSMasudaHIidaF. The outcome of patients with thyroid carcinoma and Graves' disease. Surgery Today1993 ;23:912.

  • 115

    KlofandaJKrskaZTrcaS. Total tyroidectomy in malignant goiter, significance and problems. Rozhledy v Chirurgii2002 ;81:57(Czech)

  • 116

    LokeyJSPalmerRMMacfieJA. Unexpected findings during thyroid surgery in a regional community hospital: a 5-year experience of 738 consecutive cases. American Surgeon2005 ;71:911913(discussion 913–915)

  • 117

    CostanzoMCarusoLAMessinaDCCavallaroAPalumboAMarzianiACannizzaroMA. Thyroid microcarcinoma in benign thyroid diseases. Annali Italiani di Chirurgia2005 ;76:119121(discussion 121–122. Italian)

  • 118

    StulakJMGrantCSFarleyDRThompsonGBvan HeerdenJAHayIDReadingCCCharboneauJW. Value of preoperative ultrasonography in the surgical management of initial and reoperative papillary thyroid cancer. Archives of Surgery2006 ;141:489496.

  • 119

    YassaLCibasESBensonCBFratesMCDoubiletPMGawandeAAMooreFDKimBWMarquseeELarsenPRAlexanderEK. Long-term assessment of a multidisciplinary approach to thyroid nodule diagnostic evaluation. Cancer2007 ;111:508516.

  • 120

    RíosARodríguezJMCanterasMGalindoPJBalsalobreMDParrillaP. Risk factors for malignancy in multinodular goitres. European Journal of Surgical Oncology2004 ;30:5862.

  • 121

    RussoFBarone AdesiTLArturiAStolfiVMSpinaCSavioADe MajoAUccioliLGentileschiP. Clinico-pathological study of microcarcinoma of the thyroid. Minerva Chirurgica1997 ;52:891900(Italian)

  • 122

    OrtizSRodriguezJMTorregrosaNBalsalobreMRiosAParrillaP. Relation between clinical presentation and prognosis of patients with papillary thyroid microcarcinoma (article in spain). Medicina Clinica2003 ;120:773774.

  • 123

    PelizzoMRMerante BoschinIToniatoAPiottoABernantePPagettaCCasal IdeEMazzarottoRCasaraDRubelloD. Papillary thyroid microcarcinoma. Long-term outcome in 587 cases compared with published data. Minerva Chirurgica2007 ;62:315325.

  • 124

    GilesYBoztepeHTerziogluTTezelmanS. The advantage of total thyroidectomy to avoid reoperation for incidental thyroid cancer in multinodular goiter. Archives of Surgery2004 ;139:179182.

  • 125

    McCoyKLJabbourNOgilvieJBOhoriNPCartySEYimJH. The incidence of cancer and rate of false-negative cytology in thyroid nodules greater than or equal to 4 cm in size. Surgery2007 ;142:837844.

  • 126

    PelizzoMRPiottoARubelloDCasaraDFassinaABusnardoB. High prevalence of occult papillary thyroid carcinoma in a surgical series for benign thyroid disease. Tumori2000 ;76:255257.

  • 127

    PapiniEGuglielmiRBianchiniACrescenziATaccognaSNardiFPanunziCRinaldiRToscanoVPacellaCM. Risk of malignancy in nonpalpable thyroid nodules: predictive value of ultrasound and color – Doppler features. Journal of Clinical Endocrinology and Metabolism2002 ;87:19411946.

  • 128

    KhooMLAsaSLWitterickIJFreemanJL. Thyroid calcification and its association with thyroid carcinoma. Head and Neck2002 ;24:651655.

  • 129

    PeccinSde CastroJAFurlanettoTWFurtadoAPBrasilBACzepielewskiMA. Ultrasonography: is it useful in the diagnosis of cancer in thyroid nodules?Journal of Endocrinological Investigation2002 ;25:3943.

  • 130

    ChanBKDesserTSMcDougallIRWeigelRJJeffreyRBJr. Common and uncommon sonographic features of papillary thyroid carcinoma. Journal of Ultrasound in Medicine2003 ;22:10831090.

  • 131

    ItoYKobayashiKTomodaCUrunoTTakamuraYMiyaAMatsuzukaFKumaKMiyauchiA. Ill-defined edge on ultrasonographic examination can be a marker of aggressive characteristic of papillary thyroid microcarcinoma. World Journal of Surgery2005 ;29:10071011.

  • 132

    AsanumaKKobayashiSShinguKHamaYYokoamaSFujimoriMAmanoJ. The rate of tumour growth does not distinguish between malignant and benign thyroid nodules. European Journal of Surgery2001 ;167:102105.

  • 133

    LeenhardtLHejblumGFrancBFediaevskyLDDelbotTLe GuillouzicDMenegauxFGuillausseauCHoangCTurpinGAurengoA. Indications and limits of ultrasound-guided cytology in the management of nonpalpable thyroid nodules. Journal of Clinical Endocrinology and Metabolism1999 ;84:2428.

  • 134

    HagagPStraussSWeissM. Role of ultrasound-guided fine-needle aspiration biopsy in evaluation of nonpalpable thyroid nodules. Thyroid1998 ;8:989995.

  • 135

    Nam-GoongILKimHYGongGLeeHKHongSJKimWBShongYK. Ultrasonographically-guided fine needle aspirations of thyroid incidentaloma: correlation with pathologic findings. Clinical Endocrinology2004 ;60:2128.

  • 136

    CooperDSDohertyGMHaugenBRKloosRTStLeeSLMandelSJMazzaferriELMcIverBShermanSITuttleRM. The American Thyroid Association Guidelines Taskforce. Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid2006 ;16:109141.

  • 137

    AACE/AME Task Force on Thyroid NodulesAmerican Association of Clinical Endocrinologists and Associazione Medici Endocrinologi medical guidelines for clinical practice for the diagnosis and management of thyroid nodules. Endocrine Practice2006 ;12:63102.

  • 138

    FratesMCBensonCBCharboneauJWCibasESClarkOHColemanBGCronanJJDoubiletPMEvansDBGoellnerJRHayIDHertzbergBSIntenzoCMJeffreyRBLangerJELarsenPRMandelSJMiddletonWDReadingCCShermanSITesslerFN. Society of Radiologists in Ultrasound. Management of thyroid nodules detected at US: Society of Radiologists in Ultrasound consensus conference statement. Radiology2005 ;237:794800.

  • 139

    KangHWNoJHChungJHMinYKLeeMSLeeMKYangJHKimKW. Prevalence, clinical and ultrasonographic characteristics of thyroid inciden-talomas. Thyroid2004 ;14:2933.

  • 140

    JeongHSChungMBaekCHKoYHChoiJYSonYI. Can [18F] fluorodeoxyglucose standardized uptake values of PET imaging predict pathologic extrathyroid invasion of thyroid papillary microcarcinomas?Laryngoscope2006 ;116:21332137.

  • 141

    ItoYHigashiyamaTTakamuraYMiyaAKobayashiKMatsuzukaFKumaKMiyauchiA. 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. World Journal of Surgery2007 ;31:20852091.

  • 142

    OueslatiZAlouiMGritliSTouatiSel-MayAGamoudiABen SlimeneFLadghamA. Thyroid papillary microcarcinoma. Salah Azaiz Institute experience. Revue de Laryngologie – Otologie – Rhinologie2002 ;123:3942(French)

  • 143

    RosárioPWFagundesTAPurischS. Treatment of papillary microcarcinoma of the thyroid. Arquivos Brasileiros de Endocrinologia e Metabologia2004 ;48:855860(Portuguese)

  • 144

    MachensAHolzhausenHJDralleH. The prognostic value of primary tumor size in papillary and follicular thyroid carcinoma. Cancer2005 ;103:22692273.

  • 145

    LantsovDMeirmanovSNakashimaMKondoHSaenkoVNarukeYNambaHItoMAbrosimovALushnikovESekineIYamashitaSH. Cyclin D1 overexpression in thyroid papillary microcarcinoma: its association with tumour size and aberrant beta-catenin expression. Histopathology2005 ;47:248256.

  • 146

    KhooMLEzzatSFreemanJLAsaSL. Cyclin D1 protein expression predicts metastatic behavior in thyroid papillary microcarcinomas but is not associated with gene amplification. Journal of Clinical Endocrinology and Metabolism2002 ;87:18101813.

  • 147

    ItoYUrunoTTakamuraYMiyaAKobayashiKMatsuzukaFKumaKMiyauchiA. Papillary microcarcinomas of the thyroid with preoperatively detectable lymph node metastasis show significantly higher aggressive characteristics on immunohistochemical examination. Oncology2005 ;68:8796.

  • 148

    LonderoSCGodballeCKrogdahlABastholtLSpechtLSørensenCHPedersenHBPedersenUChristiansenP. Papillary microcarcinoma of the thyroid gland: is the immunohistochemical expression of cyclin D1 or galectin-3 in primary tumour an indicator of metastatic disease?Acta Oncologica2007 ;28:17.

  • 149

    CvejicDSavinSPetrovicIPaunovicITaticSKrgovicKHavelcaM. Galectin-3 expression in papillary microcarcinoma of the thyroid. Histopathology2005 ;47:209214.

  • 150

    CotelleseRDell'OsaAFrancomanoFCieriMInnocentiP. Thyroid microcarcinoma: our experience. Tumori2005 ;4:S155S156(Italian)

  • 151

    GülbenKBerberoğluUCelenOMersinHH. Incidental papillary microcarcinoma of the thyroid-factors affecting lymph node metastasis. Langenbeck's Archives of Surgery2008 ;393:2529.

  • 152

    BesicNPilkoGPetricRHocevarMZgajnarJ. Papillary thyroid microcarcinoma: prognostic factors and treatment. Journal of Surgical Oncology2008 ;97:221225.

  • 153

    RouxelAHejblumGBernierMOBoellePYMenegauxFMansourGHoangCAurengoALeenhardtL. Prognostic factors associated with the survival of patients developing loco-regional recurrences of differentiated thyroid carcinomas. Journal of Clinical Endocrinology and Metabolism2004 ;89:53625368.

  • 154

    PaciniFSchlumbergerMDralleHEliseiRSmitJWAWiersingaWthe European Thyroid Cancer Taskforce. European consensus for the management of patients with differentiated thyroid carcinoma of the follicular epithelium. European Journal of Endocrinology2006 ;154:787803.

  • 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 BruelAMoreno-ReyesRBexMDaumerieCGlinoerD. Is the management of thyroid nodules and differentiated thyroid cancer in accordance with recent consensus guidelines? – results of a national survey. Clinical Endocrinology2008 ;68:599604.

  • 158

    MazzaferriEL. Management of low-risk differentiated thyroid cancer. Endocrine Practice2007 ;5:498512.

  • 159

    JonklaasJSarlisNJLitofskyDAinKBThomas BigosTBrierleyJDCooperDSHaugenBRLadensonPWMagnerJRobbinsJRossDSSkarulisMMaxonHRShermanSI. Outcomes of patients with differentiated thyroid carcinoma following initial therapy. Thyroid2006 ;16:12291242.

  • 160

    Pazaitou-PanayiotouKCapezzoneMPaciniF. Clinical features and therapeutic implication of papillary thyroid microcarcinoma. Thyroid2007 ;17:10851092.

 

Official journal of

European Society of Endocrinology

Sections

Figures

  • 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; P=0.038). There was no statistical heterogeneity (P=0.783). Tumor recurrence was significantly associated to younger age (<45 years).

    View in gallery
  • 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; P=0.001). There was no statistical heterogeneity (P=0.675). Tumor recurrence was significantly higher in patients with overt tumors.

    View in gallery
  • 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; P=0.000). There was no statistical heterogeneity (P=0.535). Positive association was found between tumor recurrence and multifocal tumors at diagnosis.

    View in gallery
  • 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; P=0.000). There was no statistical heterogeneity (P=0.195). Positive association was found between tumor recurrence and lymph node involvement at diagnosis.

    View in gallery
  • 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 (P=0.078). 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.

    View in gallery

References

1

LloydRDe LellisRHeitzPEngC, Lyon, France: IARC Press International Agency for Research on Cancer, 2004

2

WoolnerLBLemmonMLBeahrsOHBlackBMKeatingFR. Occult papillary carcinoma of the thyroid gland: a study of 140 cases observed in 30 year period. Journal of Clinical Endocrinology and Metabolism1960 ;20:89105.

3

PellegritiGScolloCLumeraGRegalbutoCVigneriRBelfioreA. Clinical behavior and outcome of papillary thyroid cancers smaller than 1.5 cm in diameter: study of 299 cases. Journal of Clinical Endocrinology and Metabolism2004 ;89:37133720.

4

HayIDGrantCSvan HeerdenJAGoellnerJREbersoldJRBergstralhEJ. Papillary thyroid microcarcinoma: a study of 535 cases observed in a 50-year period. Surgery1992 ;112:11391146.

5

BaudinETravagliJPRopersJMancusiFBruno-BossioGCaillouBCailleuxAFLumbrosoJDParmentierCSchlumbergerM. Microcarcinoma of the thyroid gland: the Gustave Roussy Institute experience. Cancer1998 ;83:553559.

6

SuginoKItoKJrOzakiOMimuraTIwasakiHItoK. Papillary microcarcinoma of the thyroid. Journal of Endocrinological Investigation1998 ;21:445448.

7

YamashitaHNoguchiSMurakamiNTodaMUchinoSWatanabeSKawamotoH. Extracapsular invasion of lymph node metastasis. A good indicator of disease recurrence and poor prognosis in patients with thyroid microcarcinoma. Cancer1999 ;86:842849.

8

WadaNDuhQYSuginoKIwasakiHKameyamaKMimuraTItoKTakamiHTakanashiY. Lymph node metastasis from 259 papillary thyroid microcarcinomas: frequency, pattern of occurrence, and optimal strategy for neck dissection. Annals of Surgery2003 ;237:399407.

9

PelizzoMRBoschinIMToniatoAPagettaCPiottoABernantePCasaraDPennelliGRubelloD. Natural history, diagnosis, treatment and outcome of papillary thyroid microcarcinoma (PTMC): a mono-institutional 12-year experience. Nuclear Medicine Communications2004 ;25:547552.

10

FardellaCJiménezMGonzálezHLeónAGoñiICruzFSolarATorresJMossoLGonzálezGRodríguezJACampusanoCLópezJMArteagaE. Pathological characteristics of thyroid microcarcinoma. A review of 402 biopsies. Revista Mèdica de Chile2005 ;133:13051310(Spanish)

11

BarbaroDSimiUMeucciGLapiPOrsiniPPasquiniC. Thyroid papillary cancers: microcarcinoma and carcinoma, incidental cancers and non-incidental cancers – are they different diseases?Clinical Endocrinology2005 ;63:577581.

12

RotiERossiRTrasforiniGBertelliFAmbrosioMRBusuttiLPearceENBravermanLEdegli UbertiEC. Clinical and histological characteristics of papillary thyroid microcarcinoma: results of a retrospective study in 243 patients. Journal of Clinical Endocrinology and Metabolism2006 ;91:21712178.

13

de MatosPSFerreiraAPWardLS. Prevalence of papillary microcarcinoma of the thyroid in Brazilian autopsy and surgical series. Endocrine Pathology2006 ;17:165173.

14

SaccoRAversaSInnaroNCarpinoABologniniSAmorosiA. Thyroid microcarcinoma and multinodular struma. Personal experience and considerations regarding surgical therapy. Chirurgia Italiana2006 ;58:6975(Italian)

15

AntonaciAAnelloAAucelloAConsortiFDella RoccaCGiovannoneGScardellaL. Microcarcinoma and incidental carcinoma of the thyroid in a clinical series: clinical behaviour and surgical management. La Clinica Terapeutica2006 ;157:225229.

16

CheemaYOlsonSElsonDChenH. What is the biology and optimal treatment for papillary microcarcinoma of the thyroid?Journal of Surgical Research2006 ;134:160162.

17

LeeJRheeYLeeSAhnCWChaBSKimKRLeeHCKimSIParkCSLimSK. Frequent, aggressive behaviors of thyroid microcarcinomas in korean patients. Endocrinology Journal2006 ;53:627632.

18

MonacelliMSperlonganoPD'AjelloMCalzolariFPiattoALucchiniRMissoCParmeggianiDPisanielloDSordelliISperlonganoRAveniaN. Thyroid microcarcinoma: our experience. Il Giornale di Chirurgia2006 ;27:158160(Italian)

19

TorlontanoMCrocettiUAugelloGD'AloisoLBonfittoNVarrasoADicembrinoFModoniSFruscianteVDi GiorgioABrunoRFilettiSTrischittaV. Comparative evaluation of recombinant human thyrotropin-stimulated thyroglobulin levels, 131I whole-body scintigraphy, and neck ultrasonography in the follow-up of patients with papillary thyroid microcarcinoma who have not undergone radioiodine therapy. Journal of Clinical Endocrinology and Metabolism2006 ;91:6063.

20

LoCYChanWFLangBHLamKYWanKY. Papillary microcarcinoma: is there any difference between clinically overt and occult tumors?World Journal of Surgery2006 ;30:759766.

21

CappelliCCastellanoMBragaMGandossiEPirolaIDe MartinoEAgostiBAgabiti RoseiE. Aggressiveness and outcome of papillary thyroid carcinoma (PTC) versus microcarcinoma (PMC): a mono-institutional experience. Journal of Surgical Oncology2007 ;95:555560.

22

KüçükNOTariPTokmakEArasG. Treatment for microcarcinoma of the thyroid – clinical experience. Clinical Nuclear Medicine2007 ;32:279281.

23

LimDJBaekKHLeeYSParkWCKimMKKangMIJeonHMLeeJMYun-ChaBLeeKWSonHYKangSK. Clinical, histopathological, and molecular characteristics of papillary thyroid microcarcinoma. Thyroid2007 ;17:883888.

24

PiselloFGeraciGSciumèCLi VolsiFModicaG. Total thyroidectomy of choice in papillary microcarcinoma. Il Giornale di Chirurgia2007 ;28:1319(Italian)

25

SchönbergerJMarienhagenJAghaARozeboomSBachmeierESchlittHEillesC. Papillary microcarcinoma and papillary cancer of the thyroid . Nuklearmedizin2007 ;46:115120.

26

SakorafasGHStafylaVKolettisTTolumisGKassarasGPerosG. Microscopic papillary thyroid cancer as an incidental finding in patients treated surgically for presumably benign thyroid disease. Journal of Postgraduate Medicine2007 ;53:2326.

27

CarliniMGiovanniniCCastaldiFMercadanteEDell'AvanzatoRZazzaSNaniaASanteusanioGPasseriMDi PernaP. High risk for microcarcinoma in thyroid benign diseases. Incidence in a one year period of total thyroidectomies. Journal of Experimental and Clinical Cancer Research2005 ;24:231236.

28

SampsonRJKeyCRBuncherCRIijimaS. Smallest forms of papillary carcinoma of the thyroid. A study of 141 microcarcinomas less than 0.1 cm in greatest dimension. Archives of Pathology1971 ;91:334339.

29

HarachHRFranssilaKOWaseniusVM. Occult papillary carcinoma of the thyroid. A ‘normal’ finding in Finland. A systematic autopsy study. Cancer1985 ;56:531538.

30

NoguchiSYamashitaHMurakamiNNakayamaIMasakatsuTKawamotoH. Small carcinomas of the thyroid. A long-term follow-up of 867 patients. Archives of Surgery1996 ;131:187191.

31

RodriguezJMMorenoAParrillaPSolaJSoriaTTebarFJArandaF. Papillary thyroid microcarcinoma: clinical study and prognosis. European Journal of Surgery1997 ;163:255259.

32

RuggieriMGenderiniMGargiuloPDel GrammastroAMascaroALuongoBPaoliniA. Surgical treatment of differentiated microcarcinomas of the thyroid. European Review for Medical and Pharmacological Sciences2001 ;5:8589.

33

SimpsonWJMcKinneySECarruthersJSGospodarowiczMKSutcliffeSBPanzarellaT. Papillary follicular thyroid cancer: prognostic factors in 1578 patients. American Journal of Medicine1987 ;83:479488.

34

SugitaniIFujimotoY. Symptomatic versus asymptomatic papillary thyroid microcarcinoma: a retrospective analysis of surgical outcome and prognostic factors. Endocrine Journal1999 ;46:209216.

35

EmerickGTDuhQYSipersteinAEBurrowGNClarkOH. Diagnosis, treatment, and outcome of follicular thyroid carcinoma. Cancer1993 ;72:32873291.

36

RossiRRotiETrasforiniGBertelliFCavazziniLZatelliMCPearceENBravermanLEdegli UbertiEC. Histological and clinical differences in thyroid cancers ≤10 mm and 11–20 mm in diameter: results of a retrospective study of 426 patients. Thyroid2008 ;18:309315.

37

FukunagaFHYataniR. Geographic pathology of occult thyroid carcinomas. Cancer1975 ;36:10951099.

38

TournaireJBernardMHBizollon-RoblinMHBertholon-GrégoireMBerger-DutrieuxN. Le micro-carcinome papillaire du corps thyroïde. 179 cas observès depuis 1973. Presse Médicale1998 ;27:14671469.

39

FalvoID'ErcoleCSorrentiSD'AndreaVCataniaABerniAGrilliPDe AntoniE. Papillary microcarcinoma of the thyroid gland: analysis of prognostic factors including histological subtype. European Journal of Surgery168Suppl 58820022832.

40

AppetecchiaMScarcelloGPucciEProcacciniA. Outcome after treatment of papillary thyroid microcarcinoma. Journal of Experimental & Clinical Cancer Research2002 ;21:159164.

41

ItoYUrunoTNakanoKTakamuraYMiyaAKobayeshiKYokozawaTMatsuzukaFKumaSKumaKMiyauchiA. An observation trial without surgical treatment in patients with papillary microcarcinoma of the thyroid. Thyroid2003 ;13:381387.

42

ChowSMLawSCKChanJKCAuSKYauSLauWH. Papillary microcarcinoma of the thyroid – prognostic significance of lymph node metastasis and multifocality. Cancer2003 ;98:3140.

43

BarroetaJEWangHShiinaNGuptaPKLivolsiVABalochZW. Is fine-needle aspiration (FNA) of multiple thyroid nodules justified?Endocrine Pathology2006 ;17:6165.

44

BiscollaRPUgoliniCSculliMBotticiVCastagnaMGRomeiCCosciBMolinaroEFavianaPBasoloFMiccoliPPaciniFPincheraAEliseiR. Medullary and papillary tumors are frequently associated in the same thyroid gland without evidence of reciprocal influence in their biologic behavior. Thyroid2004 ;14:946952.

45

BonninCTrojaniMCorcuffJBBonichonF. Outcome of 111 thyroid papillary carcinomas. Retrospective study from 1953 to 1994. Experience of Bergonié Institute. Annales d'Endocrinologie1997 ;58:318325(Review. French)

46

FarinaGPBaccoliAPisanoMPaniCDi NinniSMarcelloACagettiM. Papillary microcarcinoma of the thyroid. Clinical implications and therapeutic strategy. Il Giornale di Chirurgia2003 ;24:1117(Italian)

47

ItoYHigashiyamaTTakamuraYMiyaAKobayashiKMatsuzukaFKumaKMiyauchiA. Prognosis of patients with benign thyroid diseases accompanied by incidental papillary carcinoma undetectable on preoperative imaging tests. World Journal of Surgery2007 ;31:16721676.

48

ItoYTomodaCUrunoTTakamuraYMiyaAKobayashiKMatsuzukaFKumaKMiyauchiA. Preoperative ultrasonographic examination for lymph node metastasis: usefulness when designing lymph node dissection for papillary microcarcinoma of the thyroid. World Journal of Surgery2004 ;28:498501.

49

Jacquot-LaperrièreSTimoshenkoAPDumollardJMPeoc'hMEstourBMartinCPradesJM. Papillary thyroid microcarcinoma: incidence and prognostic factors. European Archives of Oto-Rhino-Laryngology2007 ;264:935939.

50

LinJDChenSTChaoTCHsuehCWengHF. Diagnosis and therapeutic strategy for papillary thyroid microcarcinoma. Archives of Surgery2005 ;140:940945.

51

SugitaniIYanagisawaAShimizuAKatoMFujimotoY. Clinicopathologic and immunohistochemical studies of papillary thyroid microcarcinoma presenting with cervical lymphadenopathy. World Journal of Surgery1998 ;22:731737.

52

WangJQiuXZhouLDengXZhangCZhouC. Differentiated microcarcinoma of the thyroid gland in 45 cases. Lin Chuang Er Bi Yan Hou Ke Za Zhi2001 ;15:542543(Chinese)

53

YangGCLiVolsiVABalochZW. Thyroid microcarcinoma: fine-needle aspiration diagnosis and histologic follow-up. International Journal of Surgical Pathology2002 ;10:133139.

54

MiccoliPMinutoMNUgoliniCPanicucciEMassiMBertiPBasoloF. Papillary thyroid cancer: pathological parameters as prognostic factors in different classes of age. Archives of Otolaryngology – Head and Neck Surgery2008 ;138:200203.

55

PelizzoMRBoschinLMToniatoAPiottoABernantePPagettaCRampinLRubelloD. Papillary thyroid microcarcinoma (PTMC): prognostic factors, management and outcome in 403 patients. European Journal of Surgical Oncology2006 ;32:11441148.

56

NishiyamaRHLudwigGKThompsonNW. The prevalence of small papillary thyroid carcinomas in 100 consecutive necropsies in an American population. In Radiation-Associated Thyroid Carcinoma In Eds pp. 123135. Eds. De GrootLJFrohmanLAKaplanELRefetoffS, New YorkGrune & Stratton1977

57

SampsonRJ. Comment on Dr. Edis's presentation on natural history of occult thyroid carcinoma. In Radiation-Associated Thyroid Carcinoma In Eds pp. 171181. Eds. De GrootLJFrohmanLAKaplanELRefetoffS, New YorkGrune & Stratton1977

58

LinKDLinJDHuangJHuangHSJengLBChaoTC. Clinical presentations and predictive variables of thyroid microcarcinoma with distant metastasis. International Surgery1997 ;82:378381.

59

NeuholdNKaiserHKasererK. Latent carcinoma of the thyroid in Austria: a systematic autopsy study. Endocrine Pathology2001 ;12:2331.

60

LupoliGVitaleGCaragliaMFittipaldiMRAbbruzzeseATagliaferriPBiancoAR. Familial papillary thyroid microcarcinoma: a new clinical entity. Lancet1999 ;353:637639.

61

EngC. Familial papillary thyroid cancer: many syndromes, too many genes?Journal of Clinical Endocrinology and Metabolism2000 ;85:17551757.

62

RíosARodríguezJMIllanaJTorregrosaNMParrillaP. Familial papillary carcinoma of the thyroid: report of three families. European Journal of Surgery2001 ;167:339343.

63

Fernández-RealJMRicartW. Familial papillary thyroid microcarcinoma. Lancet1999 ;353:19731974.

64

VigliettoGChiappettaGMartinez-TelloFJFukunagaFHTalliniGRigoupoulouDViscontiRMastroASantoroMFuscoA. RET/PTC oncogene activation is an early event in thyroid carcinogenesis. Oncogene1995 ;11:12071210.

65

AdeniranAJZhuZGandhiMStewardDLFidlerJPGiordanoTJBiddingerPWNikiforovYE. Correlation between genetic alterations and microscopic features, clinical manifestations, and prognostic characteristics of thyroid papillary carcinomas. American Journal of Surgical Pathology2006 ;30:216222.

66

CorviRMartinez-AlfaroMHarachHRZiniMPapottiMRomeoG. Frequent RET rearrangements in thyroid papillary microcarcinoma detected by interphase fluorescence in situ hybridization. Laboratory Investigation; A Journal of Technical Methods and Pathology2001 ;81:16391645.

67

TalliniGSantoroMHelieMCarlomagnoFSalvatoreGChiappettaGCarcangiuMLFuscoA. RET/PTC oncogene activation defines a subset of papillary thyroid carcinomas lacking evidence of progression to poorly or undifferentiated tumor phenotypes. Clinical Cancer Research1998 ;4:287294.

68

SuggSLZhengLRosenIBFreemanJLEzzatSAsaSL. RET/PTC1, 2 and 3 oncogene rearrangements in human thyroid carcinomas: implications for metastatic potential?Journal of Clinical Endocrinology and Metabolism1996 ;81:33603365.

69

NambaHNakashimaMHayashiTHayashidaNMaedaSRogounovitchTIOhtsuruASaenkoVAKanematsuTYamashitaS. Clinical implication of hot spot BRAF mutation, V599E, in papillary thyroid cancers. Journal of Clinical Endocrinology and Metabolism2003 ;88:43934397.

70

NikiforovaMNKimuraETGandhiMBiddingerPWKnaufJABasoloFZhuZGianniniRSalvatoreGFuscoASantoroMFaginJANikiforovYE. BRAF mutations in thyroid tumors are restricted to papillary carcinomas and anaplastic or poorly differentiated carcinomas. Journal of Clinical Endocrinology and Metabolism2003 ;88:53995404.

71

PuxedduEMorettiSEliseiRRomeiCPascucciRMartinelliMMarinoCAveniaNRossiEDFaddaGCavaliereARibacchiRFalorniAPontecorviAPaciniFPincheraASanteusanioF. BRAF(V599E) mutation is the leading genetic event in adult sporadic papillary thyroid carcinomas. Journal of Clinical Endocrinology and Metabolism2004 ;89:24142420.

72

LiuDLiuZCondourisSXingM. BRAF V600E maintains proliferation, transformation, and tumorigenicity of BRAF-mutant papillary thyroid cancer cells. Journal of Clinical Endocrinology and Metabolism2007 ;92:22642271.

73

OlerGEbinaKNMchaluartPRimuraETCeruttiJ. Investigation of BRAF mutation in a series of papillary thyroid carcinoma and matched lymph node metastasis reveals a new mutation in metastasis. Clinical Endocrinology2005 ;62:509511.

74

KimEKParkCSChungWYOhKKKimDILeeJTYooHS. New sonographic criteria for recommending fine-needle aspiration biopsy of nonpalpable solid nodules of the thyroid. American Journal of Roentgenology2002 ;178:687691.

75

SampsonRJWoolnerLBBahnRCKurlandLT. Occult thyroid carcinoma in Olmsted County, Minnesota: prevalence at autopsy compared with that in Hiroshima and Nagasak, Japan. Cancer1974 ;34:20722076.

76

YamamotoYMaedaTIzumiKOtsukaH. Occult papillary carcinoma of the thyroid. Cancer1990 ;65:11731179.

77

BrierreIDicksonLG. Clinically unsuspected thyroid disease. American Family Physician/GP1964 ;30:9498.

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

FukunagaFHLockettIJ. Thyroid carcinoma in Japanese in Hawaii. Archives of Pathology1971 ;92:613.

80

KovacsGLGondaGVadaszGLudmanyEUhrinKGorombeyZKovacsLHubinaEBodoMGothMISzabolcsI. Epidemiology of thyroid microcarcinoma found in autopsy series conducted in areas of different iodine intake. Thyroid2005 ;15:152157.

81

BalazsGYKrasznaiG. Occult pajzsmirigyrak post mortem vizsgalata [in Hungarian]. Orvosi Hetilap1974 ;115:28562860.

82

Sobrinho-SimoesMASambadeMCGoncalvesV. Latent thyroid carcinoma at autopsy. Cancer1979 ;43:17021706.

83

BondesonLLjungbergO. Occult thyroid carcinoma at autopsy in Malmö, Sweden. Cancer1981 ;47:319323.

84

LangWBorruschHBauerL. Evaluation of 1020 sequential autopsies. American Journal of Clinical Pathology1988 ;90:7276.

85

OttinoAPianzolaHMCastellettoRH. Occult papillary thyroid carcinoma at autopsy in La Plata, Argentina. Cancer1989 ;64:547551.

86

TanGHGharibH. Thyroid incidentalomas: management approaches to nonpalpable nodules discovered incidentally on thyroid imaging. Annals of Internal Medicine1997 ;126:226231.

87

ReinersCWegscheiderKSchichaHTheissenPVaupelRWrbitzkyRSchumm-DraegerPM. Prevalence of thyroid disorders in the working population of Germany: ultrasonography screening in 96,278 unselected employees. Thyroid2004 ;14:926932.

88

TanGHGharibHReadingCC. Solitary thyroid nodule. Comparison between palpation and ultrasonography. Archives of Internal Medicine1995 ;155:24182423.

89

BranderAViikinkoskiPTuuheaJVoutilainenLKivisaariL. Clinical versus ultrasound examination of the thyroid gland in common clinical practice. Journal of Clinical Ultrasound1992 ;20:3742.

90

WalkerJFindlayDAmarSSSmallPGWastieMLPeggCA. A prospective study of thyroid ultrasound scan in the clinically solitary thyroid nodule. British Journal of Radiology1985 ;58:617619.

91

LeenhardtLGrosclaudePChérié-ChallineL. 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. Thyroid2004 ;14:10561106.

92

VerkooijenHMFiorettaGPacheJCFranceschiSRaymondLSchubertHBouchardyC. Diagnostic changes as a reason for the increase in papillary thyroid cancer incidence in Geneva, Switzerland. Cancer Causes and Control2003 ;14:1317.

93

DaviesLWelchHG. Increasing incidence of thyroid cancer in the United States, 1973–2002. Journal of the American Medical Association2006 ;295:21642167.

94

BurgessJRDwyerTMcArdleKTuckerPShuggD. 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 Metabolism2000 ;85:15131517.

95

ChowSMLawSCAuSKMangOYauSYuenKTLauWH. 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 Oncology2003 ;15:329336.

96

AbdulmughniYAAl-HureibiMAAl-HureibiKAGhafoorMAAl-WadanAHAl-HureibiYA. Thyroid cancer in Yemen. Saudi Medical Journal2004 ;25:5559.

97

ArditoGRevelliLLucciCGiacintoOPraquinB. Papillary microcarcinoma [correction of carcinoma] of the thyroid: clinical experience and prognosis factors. Annali Italiani di Chirurgia2001 ;72:261265(Italian. Erratum in: Annali Italiani di Chirurgia 2001 72: 390)

98

GarrelRCartierCMarvasoVCorpeletDMakeieffMCrampetteLGuerrierB. Our experience with papillary microcarcinoma of the thyroid. Revue de Laryngologie – Otologie – Rhinologie2002 ;123:239242(French)

99

DeveciMSDeveciGLiVolsiVAGuptaPKBalochZW. Concordance between thyroid nodule sizes measured by ultrasound and gross pathology examination: effect on patient management. Diagnostic Cytopathology2007 ;35:579583.

100

LamAKLoCYLamKS. Papillary carcinoma of thyroid: a 30-yr clinicopathological review of the histological variants. Endocrine Pathology2005 ;16:323330(Review)

101

CappelliCPirolaICumettiDMichelettiLTironiAGandossiEMartinoECherubiniLAgostiBCastellanoMMattanzaCAgabiti RoseiE. Is the anteroposterior and transverse diameter ratio of nonpalpable thyroid nodules a sonographic criteria for recommending fine-needle aspiration cytology?Clinical Endocrinology2005 ;63:689693.

102

GemsenjägerESchweizerI. Small thyroid carcinomas: biological characteristics, diagnosis and therapy. Schweizerische Medizinische Wochenschrift1999 ;129:681690.

103

LepratFTrouetteHCochetCSaumthallyBMassonBde MascarelALatapieJL. Papillary microcarcinoma of the thyroid. Annales d'Endocrinologie1994 ;54:343346(French)

104

MelliereDHindieEBecqueminJPDesgrangesPAllaireEGeachanE. Differentiated thyroid carcinoma – how to improve the long-term results? Twenty-five-year outcomes of 850 patients. Bulletin de l'Acadèmie Nationale de Mèdecine2006 ;190:89106(discussion 106–109. French)

105

OrsenigoEBerettaEFiaccoEScaltriniaFVeronesiPInvernizziLGiniPFiorinaPDi CarloV. Management of papillary microcarcinoma of the thyroid gland. European Journal of Surgical Oncology2004 ;30:11041106.

106

JukkolaABloiguREbelingTSalmelaPBlancoG. Prognostic factors in differentiated thyroid carcinomas and their implications for current staging classifications. Endocrine-Related Cancer2004 ;11:571579.

107

PasslerCScheubaCPragerGKaczirekKKasererKZettinigGNiederleB. Prognostic factors of papillary and follicular thyroid cancer: differences in an iodine replete endemic goiter region. Endocrine-Related Cancer2004 ;11:131139.

108

Eustatia-RuttenCFCorssmitEPBiermaszNRPereiraAMRomijnJASmitJW. Survival and death causes in differentiated thyroid carcinoma. Journal of Clinical Endocrinology and Metabolism2006 ;91:313319.

109

PirainoPSepúlvedaALilloRPinedaPLibermanC. Thyroid cancer. Report of 85 cases. Revista Mèdica de Chile2000 ;128:405410(Spanish)

110

YokozawaT. Evaluation of the clinical usefulness of ultrasonography in making a preoperative diagnosis of thyroid carcinoma. Nippon Geka Gakkai Zasshi1988 ;89:582594(Japanese)

111

HundahlSACadyBCunninghamMPMazzaferriEMcKeeRFRosaiJShahJPFremgenAMStewartAKHölzerS. 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. Cancer2000 ;89:202217.

112

ChigotJPMénégauxFKeopadabsyKHoangCAurengoALeenhardtLTurpinG. Thyroid cancer in patients with hyperthyroidism. Presse Médicale2000 ;29:19691972(French)

113

DietleinMLuykenWASchichaHLarena-AvellanedaA. Incidental multifocal papillary microcarcinomas of the thyroid: is subtotal thyroidectomy combined with radioiodine ablation enough?Nuclear Medicine Communications2005 ;26:38.

114

KasugaYSugenoyaAKobayashiSMasudaHIidaF. The outcome of patients with thyroid carcinoma and Graves' disease. Surgery Today1993 ;23:912.

115

KlofandaJKrskaZTrcaS. Total tyroidectomy in malignant goiter, significance and problems. Rozhledy v Chirurgii2002 ;81:57(Czech)

116

LokeyJSPalmerRMMacfieJA. Unexpected findings during thyroid surgery in a regional community hospital: a 5-year experience of 738 consecutive cases. American Surgeon2005 ;71:911913(discussion 913–915)

117

CostanzoMCarusoLAMessinaDCCavallaroAPalumboAMarzianiACannizzaroMA. Thyroid microcarcinoma in benign thyroid diseases. Annali Italiani di Chirurgia2005 ;76:119121(discussion 121–122. Italian)

118

StulakJMGrantCSFarleyDRThompsonGBvan HeerdenJAHayIDReadingCCCharboneauJW. Value of preoperative ultrasonography in the surgical management of initial and reoperative papillary thyroid cancer. Archives of Surgery2006 ;141:489496.

119

YassaLCibasESBensonCBFratesMCDoubiletPMGawandeAAMooreFDKimBWMarquseeELarsenPRAlexanderEK. Long-term assessment of a multidisciplinary approach to thyroid nodule diagnostic evaluation. Cancer2007 ;111:508516.

120

RíosARodríguezJMCanterasMGalindoPJBalsalobreMDParrillaP. Risk factors for malignancy in multinodular goitres. European Journal of Surgical Oncology2004 ;30:5862.

121

RussoFBarone AdesiTLArturiAStolfiVMSpinaCSavioADe MajoAUccioliLGentileschiP. Clinico-pathological study of microcarcinoma of the thyroid. Minerva Chirurgica1997 ;52:891900(Italian)

122

OrtizSRodriguezJMTorregrosaNBalsalobreMRiosAParrillaP. Relation between clinical presentation and prognosis of patients with papillary thyroid microcarcinoma (article in spain). Medicina Clinica2003 ;120:773774.

123

PelizzoMRMerante BoschinIToniatoAPiottoABernantePPagettaCCasal IdeEMazzarottoRCasaraDRubelloD. Papillary thyroid microcarcinoma. Long-term outcome in 587 cases compared with published data. Minerva Chirurgica2007 ;62:315325.

124

GilesYBoztepeHTerziogluTTezelmanS. The advantage of total thyroidectomy to avoid reoperation for incidental thyroid cancer in multinodular goiter. Archives of Surgery2004 ;139:179182.

125

McCoyKLJabbourNOgilvieJBOhoriNPCartySEYimJH. The incidence of cancer and rate of false-negative cytology in thyroid nodules greater than or equal to 4 cm in size. Surgery2007 ;142:837844.

126

PelizzoMRPiottoARubelloDCasaraDFassinaABusnardoB. High prevalence of occult papillary thyroid carcinoma in a surgical series for benign thyroid disease. Tumori2000 ;76:255257.

127

PapiniEGuglielmiRBianchiniACrescenziATaccognaSNardiFPanunziCRinaldiRToscanoVPacellaCM. Risk of malignancy in nonpalpable thyroid nodules: predictive value of ultrasound and color – Doppler features. Journal of Clinical Endocrinology and Metabolism2002 ;87:19411946.

128

KhooMLAsaSLWitterickIJFreemanJL. Thyroid calcification and its association with thyroid carcinoma. Head and Neck2002 ;24:651655.

129

PeccinSde CastroJAFurlanettoTWFurtadoAPBrasilBACzepielewskiMA. Ultrasonography: is it useful in the diagnosis of cancer in thyroid nodules?Journal of Endocrinological Investigation2002 ;25:3943.

130

ChanBKDesserTSMcDougallIRWeigelRJJeffreyRBJr. Common and uncommon sonographic features of papillary thyroid carcinoma. Journal of Ultrasound in Medicine2003 ;22:10831090.

131

ItoYKobayashiKTomodaCUrunoTTakamuraYMiyaAMatsuzukaFKumaKMiyauchiA. Ill-defined edge on ultrasonographic examination can be a marker of aggressive characteristic of papillary thyroid microcarcinoma. World Journal of Surgery2005 ;29:10071011.

132

AsanumaKKobayashiSShinguKHamaYYokoamaSFujimoriMAmanoJ. The rate of tumour growth does not distinguish between malignant and benign thyroid nodules. European Journal of Surgery2001 ;167:102105.

133

LeenhardtLHejblumGFrancBFediaevskyLDDelbotTLe GuillouzicDMenegauxFGuillausseauCHoangCTurpinGAurengoA. Indications and limits of ultrasound-guided cytology in the management of nonpalpable thyroid nodules. Journal of Clinical Endocrinology and Metabolism1999 ;84:2428.

134

HagagPStraussSWeissM. Role of ultrasound-guided fine-needle aspiration biopsy in evaluation of nonpalpable thyroid nodules. Thyroid1998 ;8:989995.

135

Nam-GoongILKimHYGongGLeeHKHongSJKimWBShongYK. Ultrasonographically-guided fine needle aspirations of thyroid incidentaloma: correlation with pathologic findings. Clinical Endocrinology2004 ;60:2128.

136

CooperDSDohertyGMHaugenBRKloosRTStLeeSLMandelSJMazzaferriELMcIverBShermanSITuttleRM. The American Thyroid Association Guidelines Taskforce. Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid2006 ;16:109141.

137

AACE/AME Task Force on Thyroid NodulesAmerican Association of Clinical Endocrinologists and Associazione Medici Endocrinologi medical guidelines for clinical practice for the diagnosis and management of thyroid nodules. Endocrine Practice2006 ;12:63102.

138

FratesMCBensonCBCharboneauJWCibasESClarkOHColemanBGCronanJJDoubiletPMEvansDBGoellnerJRHayIDHertzbergBSIntenzoCMJeffreyRBLangerJELarsenPRMandelSJMiddletonWDReadingCCShermanSITesslerFN. Society of Radiologists in Ultrasound. Management of thyroid nodules detected at US: Society of Radiologists in Ultrasound consensus conference statement. Radiology2005 ;237:794800.

139

KangHWNoJHChungJHMinYKLeeMSLeeMKYangJHKimKW. Prevalence, clinical and ultrasonographic characteristics of thyroid inciden-talomas. Thyroid2004 ;14:2933.

140

JeongHSChungMBaekCHKoYHChoiJYSonYI. Can [18F] fluorodeoxyglucose standardized uptake values of PET imaging predict pathologic extrathyroid invasion of thyroid papillary microcarcinomas?Laryngoscope2006 ;116:21332137.

141

ItoYHigashiyamaTTakamuraYMiyaAKobayashiKMatsuzukaFKumaKMiyauchiA. 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. World Journal of Surgery2007 ;31:20852091.

142

OueslatiZAlouiMGritliSTouatiSel-MayAGamoudiABen SlimeneFLadghamA. Thyroid papillary microcarcinoma. Salah Azaiz Institute experience. Revue de Laryngologie – Otologie – Rhinologie2002 ;123:3942(French)

143

RosárioPWFagundesTAPurischS. Treatment of papillary microcarcinoma of the thyroid. Arquivos Brasileiros de Endocrinologia e Metabologia2004 ;48:855860(Portuguese)

144

MachensAHolzhausenHJDralleH. The prognostic value of primary tumor size in papillary and follicular thyroid carcinoma. Cancer2005 ;103:22692273.

145

LantsovDMeirmanovSNakashimaMKondoHSaenkoVNarukeYNambaHItoMAbrosimovALushnikovESekineIYamashitaSH. Cyclin D1 overexpression in thyroid papillary microcarcinoma: its association with tumour size and aberrant beta-catenin expression. Histopathology2005 ;47:248256.

146

KhooMLEzzatSFreemanJLAsaSL. Cyclin D1 protein expression predicts metastatic behavior in thyroid papillary microcarcinomas but is not associated with gene amplification. Journal of Clinical Endocrinology and Metabolism2002 ;87:18101813.

147

ItoYUrunoTTakamuraYMiyaAKobayashiKMatsuzukaFKumaKMiyauchiA. Papillary microcarcinomas of the thyroid with preoperatively detectable lymph node metastasis show significantly higher aggressive characteristics on immunohistochemical examination. Oncology2005 ;68:8796.

148

LonderoSCGodballeCKrogdahlABastholtLSpechtLSørensenCHPedersenHBPedersenUChristiansenP. Papillary microcarcinoma of the thyroid gland: is the immunohistochemical expression of cyclin D1 or galectin-3 in primary tumour an indicator of metastatic disease?Acta Oncologica2007 ;28:17.

149

CvejicDSavinSPetrovicIPaunovicITaticSKrgovicKHavelcaM. Galectin-3 expression in papillary microcarcinoma of the thyroid. Histopathology2005 ;47:209214.

150

CotelleseRDell'OsaAFrancomanoFCieriMInnocentiP. Thyroid microcarcinoma: our experience. Tumori2005 ;4:S155S156(Italian)

151

GülbenKBerberoğluUCelenOMersinHH. Incidental papillary microcarcinoma of the thyroid-factors affecting lymph node metastasis. Langenbeck's Archives of Surgery2008 ;393:2529.

152

BesicNPilkoGPetricRHocevarMZgajnarJ. Papillary thyroid microcarcinoma: prognostic factors and treatment. Journal of Surgical Oncology2008 ;97:221225.

153

RouxelAHejblumGBernierMOBoellePYMenegauxFMansourGHoangCAurengoALeenhardtL. Prognostic factors associated with the survival of patients developing loco-regional recurrences of differentiated thyroid carcinomas. Journal of Clinical Endocrinology and Metabolism2004 ;89:53625368.

154

PaciniFSchlumbergerMDralleHEliseiRSmitJWAWiersingaWthe European Thyroid Cancer Taskforce. European consensus for the management of patients with differentiated thyroid carcinoma of the follicular epithelium. European Journal of Endocrinology2006 ;154:787803.

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 BruelAMoreno-ReyesRBexMDaumerieCGlinoerD. Is the management of thyroid nodules and differentiated thyroid cancer in accordance with recent consensus guidelines? – results of a national survey. Clinical Endocrinology2008 ;68:599604.

158

MazzaferriEL. Management of low-risk differentiated thyroid cancer. Endocrine Practice2007 ;5:498512.

159

JonklaasJSarlisNJLitofskyDAinKBThomas BigosTBrierleyJDCooperDSHaugenBRLadensonPWMagnerJRobbinsJRossDSSkarulisMMaxonHRShermanSI. Outcomes of patients with differentiated thyroid carcinoma following initial therapy. Thyroid2006 ;16:12291242.

160

Pazaitou-PanayiotouKCapezzoneMPaciniF. Clinical features and therapeutic implication of papillary thyroid microcarcinoma. Thyroid