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DOI: 10.1530/EJE-07-0896
European Journal of Endocrinology, Vol 159, Issue 6, 659-673
Copyright © 2008 by European Society of Endocrinology
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REVIEW

Thyroid papillary microcarcinoma: a descriptive and meta-analysis study

Elio Roti, Ettore C degli Uberti1, Marta Bondanelli1 and Lewis E Braverman2

Institute of Endocrinology, University of Milan, 20133 Milan, Italy1 Section of Endocrinology, Department of Biochemical Sciences and Advanced Therapies, University of Ferrara, 44100 Ferrara, Italy2 Section of Endocrinology, Diabetes, and Nutrition, Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts 02118, USA

(Correspondence should be addressed to E Roti; Email: elio.roti{at}unimi.it)

Abstract

The authors review anatomical, clinical characteristics and prevalence of thyroid microcarcinoma. Diagnostic procedures and risk factors of aggressiveness at diagnosis and during follow-up are also covered. The possible clinical, pathologic and therapeutic risk factors are analyzed by meta-analysis study. Treatment procedures by different authors and guidelines suggested by societies are reported.

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.


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  		Table 1 Some clinical and pathologic characteristics of papillary thyroid microcarcinoma (PTMC).

 
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 {chi}2 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).


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  		Table 2 Prevalence of papillary thyroid microcarcinoma (PTMC) among malignant and benign thyroid diseases in different studies.

 
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.


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  		Table 3 Characteristics of the studies included in the meta-analysis on possible risk factors for recurrence of thyroid papillary microcarcinoma.

 
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
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  		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).

 

Figure 2
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  		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.

 

Figure 3
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  		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.

 

Figure 4
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  		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.

 

Figure 5
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  		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.

 
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.

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Received 27 July 2008
Accepted 5 August 2008





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