Abstract
Graphical abstract
Abstract
Papillary and follicular thyroid carcinomas (PTC and FTC) are prominent malignancies that originate from thyroid follicular cells. PTC is usually diagnosed via preoperative cytology, and large tumor size, clinical node metastasis, and distant metastasis constitute preoperative prognostic factors. Gross extrathyroidal and extranodal tumor extensions have a significant prognostic impact, are evaluated intraoperatively, and are useful for determining the extent of surgery. Aggressive variants, such as tall cell and hobnail variants, a high Ki-67 labeling index (LI), and somatic gene mutations are prognostic factors in postoperative pathological and molecular examinations. In contrast, FTC is generally diagnosed based on postoperative pathology. Large tumor size and M factors have prognostic value; however, the findings of pathological examinations are very important. FTCs are classified as minimally invasive, encapsulated angioinvasive, and widely invasive FTCs. Widely invasive FTC with vascular invasion (VI) and encapsulated angioinvasive FTCs with extensive VI have a poor prognosis, whereas widely invasive FTC without VI has an excellent prognosis, which is similar to that of minimally invasive FTC. This indicates that VI is a considerably more important prognostic marker than capsular invasion. For postoperative follow-up, dynamic markers such as the thyroglobulin-doubling rate (DR), metastatic tumor volume-DR, and change in the neutrophil-to-lymphocyte ratio are important and are useful for evaluating the effectiveness of treatments, such as radioactive iodine therapy and molecular targeted therapy, for recurrent lesions. For clinicians, it is important to accurately evaluate prognostic markers of PTC and FTC in the pre-, intra-operative, and post-operative phases.
Introduction
Papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC) are major components of differentiated thyroid carcinoma (DTC) and are representative of malignancies that originate from the thyroid. Although both PTC and FTC originate from thyroid follicular cells, they have rather different characteristics. PTC frequently invades adjacent organs, such as the recurrent laryngeal nerve, esophagus, and trachea; however, this phenomenon is rare in FTC. Regarding metastases and recurrences, PTC frequently metastasizes to regional lymph nodes, whereas distant metastasis/recurrence is predominant for FTC. PTC is generally diagnosed by cytological examination, whereas FTC is normally diagnosed on postoperative pathological examination because of the difficulties associated with the cytological distinction between FTC and benign follicular adenoma.
Both carcinomas generally have a favorable prognosis if appropriately managed; however, in patients with certain clinicopathological features, the prognosis could be limited. The prognostic factors can be classified into two categories: static and dynamic. The former is further classified according to the periods when they are evaluated into three subcategories: pre-, intra-, and post-operative findings. They are useful in deciding therapeutic strategies, including the extent of surgery, adjuvant therapies such as radioactive iodine (RAI) administration, and postoperative follow-up imaging studies. Based on the 8th Edition of the American Joint Committee on Cancer (AJCC) staging (1), all data obtained within 4 months after surgery should be used for defining AJCC staging. This indicates that the ‘static period’ includes all preoperative and intraoperative findings, and postoperative findings detected up to 4 months after surgery. Furthermore, for PTC, some molecular markers, such as BRAF and TERT promoter gene mutations, have been identified. Although BRAF mutations are frequently detected in PTC, studies of the prognostic value of TERT promoter gene mutations have been published by only some institutions, especially in Japan. Dynamic factors are based on changes in blood markers and metastatic/recurrent tumors, which are useful for selecting postoperative therapies such as RAI therapy and molecular targeted therapy, to evaluate the effectiveness of these treatments, and to ascertain outcomes. In this review, we discuss both the static and dynamic prognostic factors for PTC and FTC.
Previously, there was no clear pathological distinction between PTC and FTC. However, this has changed with the reclassification of the PTC and FTC subtypes. For example, the follicular variant PTC, which was previously classified as FTC, has been reclassified as a PTC. Moreover, the invasive encapsulated follicular variant PTC has been separately classified from other PTC and FTC subtypes (1). Therefore, it is uncertain whether findings related to ‘FTC’ that were reported in previous studies (published 15–20 years ago) are relevant to our current classification system. In this review, we focused on recent studies reporting analyses of pathological specimens based on the current classification systems instituted in the previous 10–15 years.
Static prognostic factors of PTC
Factors based on preoperative findings
Age
Age is a well-known predominant prognostic factor. According to the current Tumor-Node-Metastasis (TNM) classification from the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC), all patients without distant metastasis (M0) are classified as stage I if they are younger than 55 years (1). As the AJCC staging system is designed to predict death from thyroid carcinoma, several previous studies have set the cutoff age for the endpoint of prognosis at disease-specific survival (DSS; Table 1). Although, in the previous version of the AJCC staging system, the age cutoff was 45 years, in 2010, Ito et al. reported that an age cutoff of 55 years more clearly reflected patient prognosis, including DSS (2). After the revision of the TNM classification system from the 7th to the 8th edition, the investigators showed that, among the 5892 patients with PTC, the number of patients with stage I disease increased from 3975 (79.0%) to 5034 (85.4%) mainly because of the revised age cutoff (3). Notably, the DSS rates of stage I patients did not differ before and after revision. Nixon et al. and Mazurat et al. concluded that for the DSS of patients with DTC, an age cutoff of 55 years was more robust than that of 45 years (4, 5). Furthermore, Trimboli et al. showed that the application of an age cutoff of 55 years to the American Thyroid Association (ATA) stratification system could help identify patients with the highest risk of relapse for disease-free survival (DFS) (6), whereas Sugitani et al. reported that 50 years was the optimal age cutoff for deriving DSS using their classification system (7). Recently, Sugino et al. showed that the DSS of patients with PTC without extrathyroidal extension was generally good regardless of age; however, the receiver operating characteristic (ROC) curve analysis showed that an age cutoff of 48 years was optimal for identifying patients with extrathyroidal extension and predicting a poor DSS (8). Some studies have proposed the following cutoff ages for DFS and DSS: 40 and 60 years, 35 and 62.5 years, and 30 and 60 years (9, 10, 11). The investigators showed that the prognostic significance of age in PTC is actually biphasic, wherein young patients are likely to show recurrence whereas older patients are likely to experience recurrence and die of thyroid carcinoma. Miyauchi et al. reported high proportions of patients with biochemically persistent disease among those with PTC who underwent total thyroidectomy and were younger than 40 years or older than 60 years; however, only the latter group had a short thyroglobulin-doubling time (9). This finding is consistent with the fact that carcinoma recurrence is more likely in young and old patients, although only older age is a mortality risk factor.
Cutoff age proposed in previous studies.
Studies | Optimal cutoff age (years) | Endpoint of prognosis |
---|---|---|
Ito et al. (2, 3) | 55 | DFS, DSS, OS |
Nixon et al. (4) | 55 | DSS (for DTC) |
Mazurat et al. (5) | 55 | DFS, DSS (for DTC) |
Trimboli et al. (6) | 55 | DFS (for DTC) |
Sugitani et al. (7) | 50 | DSS |
Sugino et al. (8) | 48 | DSS (for PTC with ETE) |
Miyauchi et al. (9) | 40 and 60 | BPD |
60 | Short Tg-DT | |
Cho et al. (10) | 35 and 62.5 | DFS |
62.5 | DSS | |
Ito et al. (11) | 30 and 60 | DFS |
60 | DSS |
BPD, biochemically persistent disease; DFS, disease-free survival; DSS, disease-specific survival; DTC, differentiated thyroid carcinoma; ETE, extrathyroidal extension; OS, overall survival; PTC, papillary thyroid carcinoma; Tg-DT, thyroglobulin doubling time.
Male sex
Although sex has not been incorporated into the UICC/AJCC TNM classification (1), AMES set sex-specific age cutoffs as ≤40 and ≤50 years for men and women, respectively (12). Ding et al. showed that PTC in male patients, compared to that in female patients, had more aggressive clinicopathological behaviors, such as large size, multiple tumors, bilateral tumors, and metastases-positive central and lateral nodes (13). Furthermore, Siraj et al. demonstrated that male patients had higher pT, pN, pM, and pTNM stages (14). A few single-institution studies and meta-analyses have shown that male sex is a predictor of poor prognosis (13, 14, 15, 16). In a single-institution study that enrolled 5897 patients with PTC, male sex was an independent prognostic factor for overall survival (OS) in patients aged <55 years (17).
Tumor size
The UICC/AJCC TNM classification has specified a 4-cm cutoff as the tumor size for upstaging of patients ≥55 years (1), and the current ATA guidelines recommend lobectomy for low-risk DTCs measuring 1–4 cm (18). Gordon et al. reported that, after the publication of these guidelines in 2015, the incidence of lobectomy increased from 13.7% to 22.9%, whereas that of adjuvant RAI administration decreased from 48.7% to 37.1% (19). Thus, previous clinical studies have shown that a tumor size >4 cm is a significant prognostic factor for DFS, DSS, and OS (17, 20).
Another noteworthy aspect is tumor-size-related differences in significant prognostic factors. Fukushima et al. reported that the prognostic significance of clinical lateral node metastasis (N1b) was higher than that of extrathyroidal extension in PTC ≤ 3.0 cm, whereas this significance was reversed in PTC > 3.0 cm (21). Ito et al. showed that extrathyroidal extension worsens the CSS in patients with PTC > 2 cm, but not in those with PTC ≤ 2 cm (22). Moreover, Liu et al. reported a higher recurrence rate of macroscopic extrathyroidal extension in PTC > 1 cm, but no significant value in PTC ≤ 1 cm (23).
Clinical lymph node (N1) metastasis: Importance of size of metastatic nodes
Numerous studies of the prognostic significance of N positivity have been published; however, the characteristics of N are also important. In 2004, Sugitani et al. evaluated the size of metastatic nodes and showed that N ≥ 3 cm was an important indicator of poor prognosis in patients aged ≥50 years with PTC (7). Subsequently, the authors reported that in patients with high-risk PTC without distant metastasis, N ≥ 3 cm, together with age ≥55 years, tumor size >4 cm, and massive extrathyroidal extension, were significantly associated with DSS (although the extent of thyroidectomy was unrelated to patient prognosis) (24). In 2012, Ito et al. analyzed 5768 patients with PTC and reported that N ≥ 3 cm had the strongest prognostic impact on lymph node, lung, and bone recurrences (25). Furthermore, N ≥ 3 cm was independently related to DSS and OS in patients with PTC (17). Therefore, in those aged ≥55 and <55 years, the investigators proposed the upstaging of M0 PTC with N ≥ 3 cm from stage II to stage III and stage I to stage II, respectively (26). The risk classification system recommended by the Japan Association of Endocrine Surgeons (JAES) classified patients with N ≥ 3 cm and N < 3 cm into high-risk and intermediate-risk categories, respectively (27). Another important N characteristic, extranodal tumor extension, is described in the ‘Extranodal tumor extension (LNEx)’ subsection of the ‘Factors based on intraoperative findings’ section.
Distant metastasis at diagnosis (M1)
To date, numerous reports have been published on M1, which indubitably is an important prognostic factor for FTC and PTC. Despite the small sample size, one study showed that a primary lesion >4 cm, age ≥55 years, and massive extrathyroidal extension of the primary lesion independently affected the DSS of M1 patients (28). This indicates that the biologically aggressive characteristics of the primary lesions and the patient background significantly affect prognosis in M1 patients. Although, in this series, the RAI uptake was unrelated to the DSS, a more recent large-sample study by the same investigators showed that RAI-refractory disease was an independent predictor of cancer-related mortality in patients who had DTC with distant metastasis/recurrence (29). Furthermore, in patients with distant recurrences, age ≥55 years and massive extrathyroidal extension were independent predictors of cancer-related mortality (30). Furthermore, Lee et al. showed that extensive extrathyroidal extension of the primary lesion resulted in poor outcomes in PTC with initial distant metastasis (31). Furthermore, Matsuzu et al. reported higher mortality rates in patients with distant metastasis other than to the lungs, or lung metastasis with ≥2 risk factors: age ≥55 years, RAI-refractory distant metastasis, and surgical non-curative conditions(32). However, there are limitations to the evaluation of the prognosis of patients with distant metastasis/recurrence based only on static prognostic markers. Notably, evaluations that use dynamic prognostic factors are important, and even essential, for accurately predicting the prognosis of patients with distant metastasis or recurrence (as stated in the ‘Dynamic prognostic factors of PTC and FTC’ section). Furthermore, the recent and future development of molecular-targeted medicines may significantly contribute to changes in the prognostic impact of distant metastasis and recurrence step-by-step.
Factors based on intraoperative findings
Extrathyroidal extension of PTC tumors
Extrathyroidal extension is an important predictive factor for the prognosis of PTC. In the present version of the TNM classification (1), extrathyroidal extension is reflected in T factor levels and is classified as follows: T3b, gross extrathyroidal extension invading only strap muscles (e.g. extension to sternothyroid, sternohyoid, thyrohyoid, or omohyoid muscles); T4a, gross extrathyroidal extension invading subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve; and T4b, gross extrathyroidal extension invading prevertebral fascia or encasing the carotid artery or mediastinal vessels. Curative surgery of T4b is often difficult, and even though it is possible, Moritani et al. reported a dire prognosis for stage IVA disease (T4b and ≥55 years) (33). Previous studies have shown controversial results regarding the prognosis of patients with T3b (34, 35, 36, 37), and recently, a study that enrolled 7811 M0 PTC patients with a median postoperative follow-up period of 10.0 years showed that in patients aged ≥55 years, the prognosis of stage II/T3b was significantly poorer than that of stage I and did not differ from that of stage III/T4a. However, stage II/T3b and stage III/T4a1 had significantly better prognoses than stage III/T4a2 (See below on T4a1 and T4a2) (38).
T4a is the most common and important type of tumor invasion. In the TNM classification, patients with T4aM0 aged ≥55 years are classified with stage III disease. However, the prognosis of T4a carcinoma differs according to the depth of PTC invasion. Notably, Ito et al. classified T4a into two categories (T4a1 and T4a2) according to the organs to which the PTC invades, as shown in Table 2. They reported that the DSS rate of patients with stage III/T4a2 disease was significantly lower than that of patients with T4a1 disease (26). Further, the DSS of patients with stage III/T4a1 did not differ from that of patients with stage II disease who were ≥55 years of age. In the subset of patients aged <55 years, the DSS rate of patients with stage I/T4a2 was poorer than that of those without T4a2 and did not significantly differ from that of patients with stage II disease (M1 patients). The investigators proposed that patients aged ≥55 years with T4a1 were likely down-staged to stage II (the same stage as T3bM0), and those aged <55 years with T4a2 were likely upstaged to stage II. The general rules for the description of thyroid cancer by the Japan Association of Endocrine Surgery and the Japanese Society of Thyroid Pathology also divide T4a into two categories, similar, although not identical, to Ito’s classification (39).
Ito’s subclassification of T4a. Based on Ito et al. (26).
Classification | Organs invaded by PTC |
---|---|
T4a1 | Tracheal adventitia and/or cartilage Esophageal muscle layer Recurrent laryngeal nerve Cricothyroid and inferior pharyngeal constrictor muscles |
T4a2 | Subcutaneous soft tissues Larynx Tracheal mucosa Esophageal mucosa Jugular vein Brachiocephalic vein Sternocleidomastoid muscle |
PTC, papillary thyroid carcinoma.
Extranodal tumor extension (LNEx)
PTC invasion occurs not only in primary lesions but also in metastatic lymph nodes. Moritani reported that although the DSS rate of patients with LNEx-positive PTC was poorer than that of patients with LNEx-negative PTC, LNEx was not regarded as an independent prognostic factor for carcinoma death (40). In contrast, in 2007, Ito et al. showed that LNEx significantly affected DFS and DSS, in both univariate and multivariate analyses (41). In 2018, LNEx was also reported to independently impact the OS of patients (26). Thereafter, studies published in other countries have reported the prognostic significance of LNEx in PTC (42, 43, 44, 45, 46). For example, LNEx was reported to be associated with recurrence (41) and lung metastasis (46). Furthermore, Suh et al. reported that LNEx should be considered a poor prognostic marker in their meta-analysis (44), and Kim et al. claimed that the incorporation of LNEx in the ATA classification improves the accuracy of risk stratification for patients with thyroid carcinoma (45). Additionally, Ito et al. also reported that patients with LNEx-positivity are appropriate to be upstaged to stage II when <55 years and to stage III when ≥55 years old (47). In the risk classification of PTC conducted by the Japan Association of Endocrine Surgery, LNEx was adopted as a high-risk feature (27). Recently, a few studies have reported the prognostic value of LNEx (48, 49, 50). des (39).
Factors based on postoperative findings
Aggressive variants
The pathological diagnosis of PTC and its subtypes is important for predicting the prognosis of PTC. To date, some aggressive variants have been identified, including tall cell, columnar cell, and hobnail variants (52, 53, 54). In the latest WHO classification, a new disease classification has been established, namely, high-grade follicular cell-derived non-anaplastic thyroid carcinoma, which is subdivided into poorly differentiated thyroid carcinoma and differentiated high-grade thyroid carcinoma (51). This type of malignancy was reported to be rare, at 1–6.7% of all thyroid carcinomas, with its incidence varying according to countries but showing a very dire prognosis (55). Clinicians should treat patients diagnosed with such variants carefully, even if no other high-risk features can be detected.
Cell proliferating activity (Ki-67 labeling index (LI))
In 2010, Ito et al. showed that high Ki-67 LI is associated with both DFS and DSS in patients with PTC (56). Thereafter, several studies have reported the prognostic value of Ki-67 LI alone or in combination with other factors (57, 58, 59, 60, 61, 62). For example, Matsuse et al. showed that the combination of high Ki-67 LI (cutoffs set at 5 and 10%) and TERT promoter mutations (stated later) keenly reflect patient DFS (57). Additionally, Miyauchi et al. reported that a high Ki-67 LI was significantly associated with short thyroglobulin-doubling time (stated later). The authors concluded that the evaluation of Ki-67 LI in primary tumors may allow the prediction of postoperative thyroglobulin status, thyroglobulin-doubling time, and prognosis of PTC (58).
TERT promoter mutations
To date, a few genetic mutations such as BRAF, RET fusion, and NTRK fusion mutations have been detected, and molecular-targeted medicines for these genes are available for advanced thyroid carcinoma therapy. However, the most important gene mutations that affect the prognosis are TERT promoter mutations. In 2014, Xing et al. reported that both BRAF V600E and TERT promoter mutations were predictors of PTC recurrence (63). Since then, a few other studies have investigated BRAF mutations and TERT promoter mutations; however, BRAF mutations were observed at high incidence and none of these studies showed that BRAF mutations alone significantly affect patients’ prognoses. In 2020, Ebina et al. showed that patients with PTC with TERT promoter mutations had poorer CSS than those without mutations (10-year CSS rates 73.7% vs 98.1%, and 10-year DFS rates 53.7% vs 93.3%). Notably, TERT promoter mutations are independent predictors of carcinoma mortality and recurrence. The investigators also showed that the DFS and DSS of patients with intrathyroidal PTCs that measured 1.1–4 cm without TERT promoter mutations, who underwent lobectomy, did not differ from those of patients who underwent total thyroidectomy (64). The researchers speculated that total thyroidectomy for PTCs measuring 1.1–4 cm may result in overtreatment if TERT promoter mutations are negative. Additional studies have been published on TERT promoter mutations and prognosis (54, 65, 66). Notably, Nakao et al. showed that preoperative detection of TERT promoter mutations using fine-needle aspiration is useful for predicting disease aggressiveness and determining PTC management strategy (67).
Brief summary
PTC can be diagnosed based on preoperative cytological examination. Since it often metastasizes to regional lymph nodes and invades adjacent organs, pre- and intra-operative evaluations are very important for deciding the surgical design (extent of thyroidectomy and prophylactic/therapeutic lymph node dissection) and whether postoperative adjuvant therapy, such as RAI administration, should be performed. In addition, pathological examination to accurately diagnose aggressive variants is important for predicting the recurrence of carcinoma and deciding how clinicians should follow patients postoperatively. Furthermore, if available, Ki-67 LI evaluation and molecular testing, including BRAF gene mutation and TERT promoter gene mutation analysis, could be considered, which may be helpful in predicting patient prognosis. Table 3 summarizes the static prognostic factors of PTC based on pre-, intra-, and post-operative findings. There are differences in prognostic factors according to the periods when they are evaluated, and clinicians should accurately evaluate the outcomes of patients in each period.
Static prognostic factors of PTC based on preoperative and intraoperative findings
Findings/Factors | Endpoint of prognosis |
---|---|
Preoperative findings | |
Young age (see Table 1) | DFS |
Old age (see Table 1) | DFS, DSS, OS |
Male sex | DFS, OS |
Tumor size >4 cm | DFS, DSS, OS |
N < 3 cm | DFS |
N ≥ 3 cm | DFS, DSS |
M1 | CSS |
Intraoperative findings | |
T4a1 (see Table 2) | DFS (≥55 years) |
T4a2 (see Table 2) | DFS, DSS |
T4b | DFS, DSS |
LNEx | DFS, DSS, OS |
Postoperative findings | |
Aggressive variants | DFS, DSS |
High Ki-67 LI | DFS, DSS |
DFS, disease-free survival; DSS, disease-specific survival; LI, labeling index; LNEx, extranodal tumor extension; OS, overall survival; PTC, papillary thyroid carcinoma.
Static prognostic factor of FTC
Factors based on preoperative findings
Similar to PTC, some prognostic factors based on preoperative findings, such as patient age, tumor size, and M factor, have been reported. A meta-analysis of 2075 patients from 13 studies published in 2023 found that age >45 years, male sex, tumor diameter >4 cm, multifocality, and distant metastasis at diagnosis were prognostic factors for carcinoma death (68). The most recent single-institution study also showed that nodule size >40 mm and M factor were independent prognostic factors for DSS (69). Regarding age, Ito et al. divided patient age into three categories; <20 years, 20–44 years, and ≥45 years. In the subsets of both of minimally invasive FTC and widely invasive FTC (based on the latest edition of WHO classification), DFS and DSS were the poorest in patients ≥45 years. Although this study enrolled only 12 patients <20 years, their DFS was poorer than those aged 20–44 (70) This trend was similar to that observed for the PTC. More recently, Yamazaki et al. showed that in patients with minimally invasive FTC, a cutoff age of 55 years better reflected patient prognoses than that of 45 years (71), and Ito et al. showed that age ≥55 years was an independent predictor of FTC distant recurrence (72).
Factors based on postoperative findings
Pathological findings: capsular and vascular invasions
The most recent WHO classification divides FTC into three categories based on capsular invasion (CI) and vascular invasion (VI): minimally invasive FTC (minimal CI only (detected only microscopically)), encapsulated angioinvasive (VI present with or without capsular penetration), and widely invasive FTC (extensive CI detected grossly) (55). Notably, the presence of VI is not required for the diagnosis of widely invasive FTC.
As for the prognostic impact of VI, Ito et al. showed that the number of VI events significantly affected distant recurrence (the number of VI, 0 vs. 1-3, vs ≥4) (72). Furthermore, Yamazaki et al. reported that the DFS, distant recurrence-free survival (DMFS), and DSS became poorer from VI = 0, VI = 1, to VI ≥ 2, but the prognoses did not differ between patients with VI = 1–3 and those with VI ≥ 4 (71). In a multivariate analysis, VI ≥ 2 was found to be an independent prognostic factor for DFS and DMFS. Further studies are necessary to set the optimal cutoff for the VI number; however, the prognosis of encapsulated angioinvasive FTC is not uniform but differs according to the degree of VI.
Ito et al. showed that the degree of CI (wide and minimal CI) did not affect DMFS of patients with FTC, because the DMFS of minimally invasive FTC and that of VI-negative widely invasive FTC did not significantly differ in their series (72). Furthermore, Yamazaki et al. reported an excellent prognosis of FTC with VI foci <2 (73) and subsequently showed that the DFS and DMFS of patients with VI-negative widely invasive FTC were similar to those of patients with minimally invasive FTC (74). Generally, widely invasive FTC is diagnosed based on the gross CI. Patients with FTC with a more extensive CI, for example, with significant invasion to adjacent organs, may have a poorer prognosis, but such incidences are very rare and, if they do occur, may be diagnosed as poorly differentiated carcinoma rather than FTC. Further investigation should be conducted to address this issue, but at least at present, the risk stratification of FTC is better based on VI than on CI, and the definition of widely invasive FTC should be reconsidered.
Ki-67 LI
Similar to PTC, the prognostic impact of Ki-67 LI on FTC has been previously reported. Ito et al. showed that high Ki-67 LI (≥5%) significantly affected DFS in patients with minimally invasive FTC and widely invasive FTC, using the former WHO classification criteria (75, 76). Furthermore, Hellgren et al. reported that the Ki-67 LI in FTC was significantly higher than that in follicular adenoma (FA); however, the LI did not significantly differ among FTC subgroups. The investigators showed that a high Ki-67 LI was an independent predictor of both carcinoma recurrence and death, together with patient age (77). Thus, an optimal Ki-67 LI cut-off of 4% was suggested, based on the ROC curve.
Brief summary
In contrast to PTC, most FTCs are diagnosed via postoperative pathological examination. Because most patients undergo hemithyroidectomy, a second surgery (completion total thyroidectomy) should be performed for patients with a poor prognosis; therefore, pathological examination is important. A second surgery is unnecessary and should not be performed for minimally invasive FTC, and patients with encapsulated angioinvasive FTC with extensive VI (at least ≥4 invasive foci) should undergo complete total thyroidectomy to allow RAI administration with the goal of decreasing the risk of distant recurrence. The prognosis of widely invasive FTC is twofold: poor in VI-positive patients and excellent in VI-negative patients. Total thyroidectomy and successive RAI administration are necessary for VI-positive patients; however, based on two Japanese studies, hemithyroidectomy should be adequate for VI-negative patients. Further studies and reports from other countries are needed to address this issue. Table 4 summarizes the static prognostic factors for FTC.
Static prognostic factors of FTC based on preoperative and postoperative findings
Findings/ Factors | Endpoint of prognosis |
---|---|
Preoperative findings | |
Young age (<20 years) | DFS |
Old age (≥45 or 55 years) | DFS, DSS |
Male sex | DFS |
Tumor size >4 cm | DFS, DSS |
M1 | DSS |
Postoperative findings | |
Vascular invasion (≥2 or ≥4)* | DFS, DSS |
High Ki-67 LI | DFS |
*Capsular invasion does not affect the prognosis of FTC. DFS, disease-free survival; DSS, disease-specific survival; FTC, follicular thyroid carcinoma; LI, labeling index.
Dynamic prognostic factors of PTC and FTC
In contrast to the static factors, a few dynamic factors have prognostic significance. The values of these factors change over time, and an evaluation of their changing values is useful for predicting patient outcomes.
Thyroglobulin-doubling rate (Tg-DR)/ thyroglobulin-doubling time (Tg-DT)
In 1984, Miyauchi et al. reported that the rate of increase in plasma calcitonin concentration, evaluated as calcitonin-doubling time (DT), was associated with survival in patients with medullary thyroid carcinoma (78). In 2011, the investigators found that short Tg-DT was significantly related to DSS in patients who underwent total thyroidectomy for PTC if their TgAbs were negative (79). Although the calculation formula is complicated, the Tg-DT calculator can be downloaded from the HP of Kuma Hospital (https://www.kuma-h.or.jp/kumapedia/kuma-medical/detail/?id=290). Notably, DT is a well-validated method for analyzing and expressing changes in tumor volume or serum tumor marker levels over time; however, it has two major limitations: if some patients show a decrease in tumor volume over time, their DTs are given negative values. This creates a discontinuity problem with the DTs of positive values. Secondly, the DT values are opposite to growth rate values, and an inverse DT value (1/DT) resolves this limitation. Miyauchi et al. named this index the doubling rate (DR) (80), which proved useful for evaluating changes in tumor volume over time in a cohort that included patients with decreased tumor volume over time. The DR indicates the number of doubling or halving events that occur per unit time.
Tumor volume-doubling rate (TV-DR)/ tumor volume-doubling time (TV-DT)
Similar to Tg, the change in TV of metastatic lesions has a prognostic impact on DSS and should be calculated for metastatic lesions that develop rapidly. The maximum diameter (D1) and the diameter in the direction perpendicular to the maximum diameter (D2) are measured, and the tumor volume is calculated using the formula: (π/6 × D1 × D2 × D2). The formula for TV-DT has been described previously (80), and the calculation software can be downloaded as described above. In 2017, Sabra et al. showed that the TV-DT of distant metastatic lesions was significantly related to DSS in patients with DTC (81). In 2021, Ito et al. showed that high TV-DR (>1/year), together with Tg-DR >1/year, was an independent predictor of cancer-related death in patients with DTC with distant metastasis (29).
Neutrophil-to-lymphocyte ratio
The neutrophil-to-lymphocyte ratio (NLR) is an inflammatory marker that reflects the imbalance between immune surveillance and tumor progression; an increased number of neutrophils and a decreased lymphocyte ratio are thought to reflect carcinoma progression and immunological surveillance, respectively (82, 83, 84). NLR has bilateral characteristics, as a static and dynamic prognostic factor. The prognostic impact of a high NLR in thyroid carcinomas has been investigated, but the study designs and results are rather fragmentary (82, 83, 84, 85, 86, 87, 88, 89, 90). In 2021, a study showed that NLR >3 at the time of detection of the distant recurrence of thyroid carcinoma was an independent predictor of CSS in patients with DTC (29). Furthermore, the investigators reported that the 5-year and 10-year DSS rates of patients with DTC with distant metastasis after NLR > 3 were low, at 50.4% and 23.9%, respectively. Additionally, Lee et al. showed that a significant increase in NLR was an independent risk factor for incomplete response to therapy (91); however, the NLR may change for reasons other than cancer status, and this limits its use.
Furthermore, a change in the NLR is useful for evaluating the effects of postoperative therapies for recurrent lesions. Ito et al. showed that changes in not only Tg levels but also NLRs of patients with DTC who underwent sorafenib or lenvatinib treatment strongly reflected the therapeutic efficacy (92). Additionally, Fukuda et al. showed that patients with DTC with a median NLR < 3 at the initiation of lenvatinib therapy had a longer OS and that the median NLR values decreased when the best tumor response was achieved, whereas they increased again at disease progression (93).
Brief summary and comments
Dynamic factors are very useful for estimating the recurrence and disease progression of patients during postoperative follow-up and for deciding if and when any treatment intervention is necessary. Both Tg-DR and TV-DR < 1 significantly predict poor patient DSS (28, 79). These parameters provide an indication for the treatment of recurrent lesions, such as external beam radiotherapy and molecular targeted therapies.
Conclusions
In this review, we discussed the pre-, intra-, and post-operative prognostic factors of PTC and FTC. Pre- and intra-operative factors are useful for planning surgical design and postoperative management, including adjuvant treatment. Postoperative findings should be evaluated carefully to avoid oversight of important pathological or molecular findings. During postoperative follow-up, clinicians should consider changing dynamic factors to appropriately implement adjuvant/therapeutic RAI administration and, if needed, molecular-targeted therapy.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the study reported.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.
References
- 1↑
Tuttle M, Morris LF, Haugen B, Shah J, Sosa JA, Rohren E, Subramanian RM, Hunt JL, & Perrier ND. Thyroid-differentiated and anaplastic carcinoma (Chapter 73). In AJCC Cancer Staging Manual, 8th ed. Eds Amin MB, Edge SB, Greene F, Byrd D, Brookland RK, Washington MK, Gershenwald JE, Compton CC, Hess KR, Sullivan DC, et al.. New York City: Springer International Publishing.
- 2↑
Ito Y, Miyauchi A, Hirokawa M, Yamamoto M, Oda H, Masuoka H, Sasai H, Fukushima M, Higashiyama T, Kihara M, et al.Prognostic value of the 8th edition of the tumor-node-metastasis classification for patients with papillary thyroid carcinoma: a single-institution study at a high-volume center in Japan. Endocrine Journal 2018 65 707–716. (https://doi.org/10.1507/endocrj.EJ18-0019)
- 3↑
Ito Y, Ichihara K, Masuoka H, Fukushima M, Inoue H, Kihara M, Tomoda C, Higashiyama T, Takamura Y, Kobayashi K, et al.Establishment of an intraoperative staging system (iStage) by improving UICC TNM classification system for papillary thyroid carcinoma. World Journal of Surgery 2010 34 2570–2580. (https://doi.org/10.1007/s00268-010-0710-2)
- 4↑
Nixon IJ, Kuk D, Wreesmann V, Morris L, Palmer FL, Ganly I, Patel SG, Singh B, Tuttle RM, Shaha AR, et al.Defining a valid age cutoff in staging of well-differentiated thyroid cancer. Annals of Surgical Oncology 2016 23 410–415. (https://doi.org/10.1245/s10434-015-4762-2)
- 5↑
Mazurat A, Torroni A, Hendrickson-Rebizant J, Benning H, Nason RW, & Pathak KA. The age factor in survival of a population cohort of well-differentiated thyroid cancer. Endocrine Connections 2013 2 154–160. (https://doi.org/10.1530/EC-13-0056)
- 6↑
Trimboli P, Piccardo A, Signore A, Valabrega S, Barnabei A, Santolamazza G, Di Paolo A, Stati V, Chiefari A, Vottari S, et al.Patient age is an independent risk factor of relapse of differentiated thyroid carcinoma and improves the performance of the American Thyroid Association Stratification System. Thyroid 2020 30 713–719. (https://doi.org/10.1089/thy.2019.0688)
- 7↑
Sugitani I, Kasai N, Fujimoto Y, & Yanagisawa A. A novel classification system for patients with PTC: addition of the new variables of large (3 cm or greater) nodal metastases and reclassification during the follow-up period. Surgery 2004 135 139–148. (https://doi.org/10.1016/s0039-6060(0300384-2)
- 8↑
Sugino K, Matsuzu K, Nagahama M, Kitagawa W, Suzuki A, Tomoda C, Hames KY, Akaishi J, Masaki C, Yoshioka K, et al.Impact of age on prognosis in papillary thyroid carcinoma: how should age be incorporated into the treatment strategy? World Journal of Surgery 2023 47 674–681. (https://doi.org/10.1007/s00268-022-06843-z)
- 9↑
Miyauchi A, Kudo T, Kihara M, Higashiyama T, Ito Y, Kobayashi K, & Miya A. Relationship of biochemically persistent disease and thyroglobulin-doubling time to age at surgery in patients with papillary thyroid carcinoma. Endocrine Journal 2013 60 415–421. (https://doi.org/10.1507/endocrj.EJ12-0363)
- 10↑
Cho JS, Yoon JH, Park MH, Shin SH, Jegal YJ, Lee JS, & Kim HK. Age and prognosis of papillary thyroid carcinoma: retrospective stratification into three groups. Journal of the Korean Surgical Society 2012 83 259–266. (https://doi.org/10.4174/jkss.2012.83.5.259)
- 11↑
Ito Y, Miyauchi A, Kihara M, Higashiyama T, Kobayashi K, & Miya A. Prognostic significance of young age in papillary thyroid carcinoma: analysis of 5,733 patients with 150 months' median follow-up. Endocrine Journal 2014 61 491–497. (https://doi.org/10.1507/endocrj.ej13-0529)
- 12↑
Cady B, & Rossi R. An expanded view of risk-group definition in differentiated thyroid carcinoma. Surgery 1988 104 947–953.
- 13↑
Ding J, Wu W, Fang J, Zhao J, & Jiang L. Male sex is associated with aggressive behaviour and poor prognosis in Chinese papillary thyroid carcinoma. Scientific Reports 2020 10 4141. (https://doi.org/10.1038/s41598-020-60199-9)
- 14↑
Mao J, Zhang Q, Zhang H, Zheng K, Wang R, & Wang G. Risk factors for lymph node metastasis in papillary thyroid carcinoma: a systematic review and meta-analysis. Frontiers in Endocrinology 2020 11 265. (https://doi.org/10.3389/fendo.2020.00265)
- 15↑
Siraj AK, Parvathareddy SK, Annaiyappanaidu P, Siraj N, Al-Sobhi SS, Al-Dayel F, & Al-Kuraya KS. Male sex is an independent predictor of recurrence-free survival in middle eastern papillary thyroid carcinoma. Frontiers in Endocrinology 2022 13 777345. (https://doi.org/10.3389/fendo.2022.777345)
- 16↑
Sun W, Lan X, Zhang H, Dong W, Wang Z, He L, Zhang T, & Liu S. Risk Factors for Central lymph node metastasis in CN0 papillary thyroid carcinoma: a systematic review and meta-analysis. PLoS One 2015 10 e0139021. (https://doi.org/10.1371/journal.pone.0139021)
- 17↑
Ito Y, Miyauchi A, Kihara M, Fukushima M, Higashiyama T, & Miya A. Overall survival of papillary thyroid carcinoma patients: a single-institution long-term follow-up of 5897 patients. World Journal of Surgery 2018 42 615–622. (https://doi.org/10.1007/s00268-018-4479-z)
- 18↑
Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, Pacini F, Randolph GW, Sawka AM, Schlumberger M, et al.2015 American thyroid association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American thyroid association guidelines task force on thyroid nodules and differentiated thyroid cancer. Thyroid 2016 26 1–133. (https://doi.org/10.1089/thy.2015.0020)
- 19↑
Gordon AJ, Dublin JC, Patel E, Papazian M, Chow MS, Persky MJ, Jacobson AS, Patel KN, Suh I, Morris LGT, et al.American Thyroid association guidelines and national trends in management of papillary thyroid carcinoma . JAMA Otolaryngology– Head and Neck Surgery 2022 148 1156–1163. (https://doi.org/10.1001/jamaoto.2022.3360)
- 20↑
Shin CH, Roh JL, Song DE, Cho KJ, Choi SH, Nam SY, & Kim SY. Prognostic value of tumor size and minimal extrathyroidal extension in papillary thyroid carcinoma. American Journal of Surgery 2020 220 925–931. (https://doi.org/10.1016/j.amjsurg.2020.02.020)
- 21↑
Fukushima M, Ito Y, Hirokawa M, Miya A, Shimizu K, & Miyauchi A. Prognostic impact of extrathyroid extension and clinical lymph node metastasis in papillary thyroid carcinoma depend on carcinoma size. World Journal of Surgery 2010 34 3007–3014. (https://doi.org/10.1007/s00268-010-0776-x)
- 22↑
Ito Y, Fukushima M, Kihara M, Takamura Y, Kobayashi K, Miya A, & Miyauchi A. Investigation of the prognosis of patients with papillary thyroid carcinoma by tumor size. Endocrine Journal 2012 59 457–464. (https://doi.org/10.1507/endocrj.ej12-0013)
- 23↑
Liu L, Oh C, Heo JH, Park HS, Lee K, Chang JW, Jung SN, & Koo BS. Clinical significance of extrathyroidal extension according to primary tumor size in papillary thyroid carcinoma. European Journal of Surgical Oncology 2018 44 1754–1759. (https://doi.org/10.1016/j.ejso.2018.05.009)
- 24↑
Sugitani I, Kazusaka H, Ebina A, Shimbashi W, Toda K, & Takeuchi K. Long-term outcomes after lobectomy for patients with high-risk papillary thyroid carcinoma. World Journal of Surgery 2023 47 382–391. (https://doi.org/10.1007/s00268-022-06705-8)
- 25↑
Ito Y, Kudo T, Kobayashi K, Miya A, Ichihara K, & Miyauchi A. Prognostic factors for recurrence of papillary thyroid carcinoma in the lymph nodes, lung, and bone: analysis of 5,768 patients with average 10-year follow-up. World Journal of Surgery 2012 36 1274–1278. (https://doi.org/10.1007/s00268-012-1423-5)
- 26↑
Ito Y, Miyauchi A, Kihara M, Masuoka H, Higashiyama T, & Miya A. Subclassification of tumor extension and nodal metastasis in papillary thyroid cancer to improve prognostic accuracy of the Eighth Edition of the tumor-node-metastasis classification. World Journal of Surgery 2020 44 336–345. (https://doi.org/10.1007/s00268-019-05120-w)
- 27↑
Japan Association of Endocrine Surgery. Clinical practice guidelines on the management of thyroid tumors by the Japan Associations. (in Japanese). Official Journal of the Japan Association of Endocrine Surgery 2024 41(Supplement 2).
- 28↑
Ito Y, Masuoka H, Fukushima M, Inoue H, Kihara M, Tomoda C, Higashiyama T, Takamura Y, Kobayashi K, Miya A, et al.Prognosis and prognostic factors of patients with papillary carcinoma showing distant metastasis at surgery (M1 patients) in Japan. Endocrine Journal 2010 57 523–531. (https://doi.org/10.1507/endocrj.k10e-019)
- 29↑
Ito Y, Onoda N, Kihara M, Miya A, & Miyauchi A. Prognostic significance of neutrophil-to-lymphocyte ratio in differentiated thyroid carcinoma having distant metastasis: a comparison with thyroglobulin-doubling rate and tumor volume-doubling rate. In Vivo 2021 35 1125–1132. (https://doi.org/10.21873/invivo.12358)
- 30↑
Ito Y, Higashiyama T, Takamura Y, Kobayashi K, Miya A, & Miyauchi A. Clinical outcomes of patients with papillary thyroid carcinoma after the detection of distant recurrence. World Journal of Surgery 2010 34 2333–2337. (https://doi.org/10.1007/s00268-010-0712-0)
- 31↑
Lee YK, Kim D, Shin DY, Lee CR, Lee EJ, Kang SW, Lee J, Jeong JJ, Nam KH, Chung WY, et al.The prognosis of papillary thyroid cancer with initial distant metastasis is strongly associated with extensive extrathyroidal extension: a retrospective cohort study. Annals of Surgical Oncology 2019 26 2200–2209. (https://doi.org/10.1245/s10434-019-07314-x)
- 32↑
Matsuzu K, Sugino K, Masudo K, Mori K, Ono R, Yamazaki H, Masaki C, Akaishi J, Kiyomi Yamada H, Tomoda C, et al.Clinical outcomes and risk stratification for papillary thyroid carcinoma presenting with distant metastasis before the era of tyrosine kinase inhibitors. Endocrine Journal 2020 67 869–876. (https://doi.org/10.1507/endocrj.EJ20-0081)
- 33↑
Moritani S. Impact of gross extrathyroidal extension into major neck structures on the prognosis of papillary thyroid carcinoma according to the American Joint Committee on Cancer eighth edition. Endocrine Journal 2020 67 941–948. (https://doi.org/10.1507/endocrj.EJ19-0523)
- 34↑
Kim M, Kim WG, Jeon MJ, Kim HK, Yi HS, Kim ES, Kim BH, Kim WB, Shong YK, Kang HC, et al.Modification of the tumor-node-metastasis staging system for differentiated thyroid carcinoma by considering extra-thyroidal extension and lateral cervical lymph node metastasis. Endocrinology and Metabolism (Seoul, Korea) 2020 35 149–156. (https://doi.org/10.3803/EnM.2020.35.1.149)
- 35↑
Li G, Li R, Song L, Chen W, Jiang K, Tang H, Wei T, Li Z, Gong R, Lei J, et al.Implications of extrathyroidal extension invading only the strap muscles in papillary thyroid carcinomas. Thyroid 2020 30 57–64. (https://doi.org/10.1089/thy.2018.0801)
- 36↑
Amit M, Boonsripitayanon M, Goepfert RP, Tam S, Busaidy NL, Cabanillas ME, Dadu R, Varghese J, Waguespack SG, Gross ND, et al.Extrathyroidal extension: does strap muscle invasion alone influence recurrence and survival in patients with differentiated thyroid cancer? Annals of Surgical Oncology 2018 25 3380–3388. (https://doi.org/10.1245/s10434-018-6563-x)
- 37↑
Song E, Kim WW, Jeon MJ, Sung TY, Song DE, Kim TY, Chung KW, Kim WB, Shong YK, Hong SJ, et al.Clinical significance of gross invasion of strap muscles in patients with 1- to 4-cm-sized papillary thyroid carcinoma undergoing lobectomy. Annals of Surgical Oncology 2019 26 4466–4471. (https://doi.org/10.1245/s10434-019-07778-x)
- 38↑
Ito Y, Miyauchi A, Kawakami M, Kihara M, & Miya A. Prognostic significance of T3b in papillary thyroid carcinoma: appropriateness of classifying T3bN0M0 in patients aged 55 years or older into stage II. World Journal of Surgery 2024. (https://doi.org/10.1002/wjs.12307)
- 39↑
Japan A ssociation of E ndocrine S urgery and the Japanese S ociety of T hyroid P athology eds. General Rules for the Description of Thyroid Cancer, 9th ed. Tokyo, Japan: Kanehara Shuppan 2023.
- 40↑
Moritani S. Impact of invasive extranodal extension on the prognosis of patients with papillary thyroid carcinoma. Thyroid 2014 24 1779–1783. (https://doi.org/10.1089/thy.2014.0167)
- 41↑
Ito Y, Hirokawa M, Jikuzono T, Higashiyama T, Takamura Y, Miya A, Kobayashi K, Matsuzuka F, Kuma K, & Miyauchi A. Extranodal tumor extension to adjacent organs predicts a worse cause-specific survival in patients with papillary thyroid carcinoma. World Journal of Surgery 2007 31 1194–1201. (https://doi.org/10.1007/s00268-007-9042-2)
- 42↑
Randolph GW, Duh QY, Heller KS, LiVolsi VA, Mandel SJ, Steward DL, Tufano RP, Tuttle RM & American Thyroid Association Surgical Affairs Committee’s Taskforce on Thyroid Cancer Nodal Surgery. The prognostic significance of nodal metastases from papillary thyroid carcinoma can be stratified based on the size and number of metastatic lymph nodes, as well as the presence of extranodal extension. Thyroid 2012 22 1144–1152. (https://doi.org/10.1089/thy.2012.0043)
- 43↑
Lango M, Flieder D, Arrangoiz R, Veloski C, Yu JQ, Li T, Burtness B, Mehra R, Galloway T, & Ridge JA. Extranodal extension of metastatic papillary thyroid carcinoma: correlation with biochemical endpoints, nodal persistence, and systemic disease progression. Thyroid 2013 23 1099–1105. (https://doi.org/10.1089/thy.2013.0027)
- 44↑
Suh S, Pak K, Seok JW, & Kim IJ. Prognostic value of extranodal extension in thyroid cancer: A meta-analysis. Yonsei Medical Journal 2016 57 1324–1328. (https://doi.org/10.3349/ymj.2016.57.6.1324)
- 45↑
Kim HI, Hyeon J, Park SY, Ahn HS, Kim K, Han JM, Bae JC, Shin JH, Kim JS, Kim SW, et al.Impact of extranodal extension on risk stratification in papillary thyroid carcinoma. Thyroid 2019 29 963–970. (https://doi.org/10.1089/thy.2018.0541)
- 46↑
Hei H, Gong W, Zheng C, Zhou B, & Qin J. Macroscopic extranodal extension is an independent predictor of lung metastasis in papillary thyroid cancer. Endocrine 2022 77 73–79. (https://doi.org/10.1007/s12020-022-03045-4)
- 47↑
Ito Y, Miyauchi A, Masuoka H, Higashiyama T, Kihara M, & Miya A. Prognostic value of extranodal tumor extension in papillary thyroid carcinoma: proposal for upstaging of cases with extranodal tumor extension. World Journal of Surgery 2020 44 638–643. (https://doi.org/10.1007/s00268-019-05232-3)
- 48↑
Roh JL, Park JW, Jeong J, Gong G, Cho KJ, Choi SH, Nam SY, & Kim SY. Extranodal extension of lymph node metastasis as a prognostic indicator of recurrence and survival in papillary thyroid carcinoma. Journal of Surgical Oncology 2017 116 450–458. (https://doi.org/10.1002/jso.24713)
- 49↑
Zhou TH, Lin B, Wu F, Lu KN, Mao LL, Zhao LQ, Jiang KC, Zhang Y, Zheng WJ, & Luo DC. Extranodal extension is an independent prognostic factor in papillary thyroid cancer: a propensity score matching analysis. Frontiers in Endocrinology 2021 12 759049. (https://doi.org/10.3389/fendo.2021.759049)
- 50↑
Genpeng L, Pan Z, Tao W, Rixiang G, Jingqiang Z, Zhihui L, & Jianyong L. Prognostic implications of extranodal extension in papillary thyroid carcinomas: A propensity score matching analysis and proposal for incorporation into current tumor, lymph node, metastasis staging. Surgery 2022 171 368–376. (https://doi.org/10.1016/j.surg.2021.07.018)
- 51↑
WHO Classification of Tumours Editorial Board Endocrine and Neuroendocrine Tumours, Vol. 8, 5th ed. Lyon, France: International Agency for Research on Cancer 2022. Available at: https://tumourclassification.iarc.who.int.
- 52↑
Wang S, Xiong Y, Zhao Q, Song H, Yi P, & Liu C. Columnar cell papillary thyroid carcinoma prognosis: findings from the SEER database using propensity score matching analysis. American Journal of Translational Research 2019 11 6262–6270.
- 53↑
Spyroglou A, Kostopoulos G, Tseleni S, Toulis K, Bramis K, Mastorakos G, Konstadoulakis M, Vamvakidis K, & Alexandraki KI. Hobnail papillary thyroid carcinoma, a systematic review and meta-analysis. Cancers 2022 14 2785. (https://doi.org/10.3390/cancers14112785)
- 54↑
Morris LGT, Shaha AR, Tuttle RM, Sikora AG, & Ganly I. Tall-cell variant of papillary thyroid carcinoma: a matched-pair analysis of survival. Thyroid 2010 20 153–158. (https://doi.org/10.1089/thy.2009.0352)
- 55↑
Baloch ZW, Asa SL, Barletta JA, Ghossein RA, Juhlin CC, Jung CK, LiVolsi VA, Papotti MG, Sobrinho-Simões M, Tallini G, et al.Overview of the 2022 WHO classification of thyroid neoplasms. Endocrine Pathology 2022 33 27–63. (https://doi.org/10.1007/s12022-022-09707-3)
- 56↑
Ito Y, Miyauchi A, Kakudo K, Hirokawa M, Kobayashi K, & Miya A. Prognostic significance of Ki-67 labeling index in papillary thyroid carcinoma. World Journal of Surgery 2010 34 3015–3021. (https://doi.org/10.1007/s00268-010-0746-3)
- 57↑
Matsuse M, Yabuta T, Saenko V, Hirokawa M, Nishihara E, Suzuki K, Yamashita S, Miyauchi A, & Mitsutake N. TERT promoter mutations and Ki-67 labeling index as a prognostic marker of papillary thyroid carcinomas: combination of two independent factors. Scientific Reports 2017 7 41752. (https://doi.org/10.1038/srep41752)
- 58↑
Miyauchi A, Kudo T, Hirokawa M, Ito Y, Kihara M, Higashiyama T, Yabuta T, Masuoka H, Shindo H, Kobayashi K, et al.Ki-67 labeling index is a predictor of postoperative persistent disease and cancer growth and a prognostic indicator in papillary thyroid carcinoma. European Thyroid Journal 2013 2 57–64. (https://doi.org/10.1159/000347148)
- 59↑
Viana AOR, Gonçalves Filho J, Francisco ALN, Pinto CAL, & Kowalski LP. Ki-67 and CK-19 are predictors of locoregional recurrence in papillary thyroid carcinoma. Acta Otorhinolaryngologica Italica 2020 40 190–197. (https://doi.org/10.14639/0392-100X-N0311)
- 60↑
Lindfors H, Ihre Lundgren C, Zedenius J, Juhlin CC, & Shabo I. The clinical significance of lymph node ratio and Ki-67 expression in papillary thyroid cancer. World Journal of Surgery 2021 45 2155–2164. (https://doi.org/10.1007/s00268-021-06070-y)
- 61↑
Lindfors H, Karlsen M, Karlton E, Zedenius J, Larsson C, Ihre Lundgren C, Juhlin CC, & Shabo I. Thyroglobulin expression, Ki-67 index, and lymph node ratio in the prognostic assessment of papillary thyroid cancer. Scientific Reports 2023 13 1070. (https://doi.org/10.1038/s41598-023-27684-3)
- 62↑
Lei Y, Zhao X, Feng Y, He D, Hu D, & Min Y. The value of Ki-67 labeling index in central lymph node metastasis and survival of papillary thyroid carcinoma: evidence from the clinical and molecular analyses. Cancer Control 2023 30 10732748231155701. (https://doi.org/10.1177/10732748231155701)
- 63↑
Xing M, Liu R, Liu X, Murugan AK, Zhu G, Zeiger MA, Pai S, & Bishop J. BRAF V600E and TERT promoter mutations cooperatively identify the most aggressive papillary thyroid cancer with highest recurrence. Journal of Clinical Oncology 2014 32 2718–2726. (https://doi.org/10.1200/JCO.2014.55.5094)
- 64↑
Ebina A, Togashi Y, Baba S, Sato Y, Sakata S, Ishikawa M, Mitani H, Takeuchi K, & Sugitani I. TERT promoter mutation and extent of thyroidectomy in patients with 1–4 cm intrathyroidal papillary carcinoma. Cancers 2020 12 2115. (https://doi.org/10.3390/cancers12082115)
- 65↑
Tanaka A, Matsuse M, Saenko V, Nakao T, Yamanouchi K, Sakimura C, Yano H, Nishihara E, Hirokawa M, Suzuki K, et al.TERT mRNA expression as a novel prognostic marker in papillary thyroid carcinomas. Thyroid 2019 29 1105–1114. (https://doi.org/10.1089/thy.2018.0695)
- 66↑
Choi YS, Choi SW, & Yi JW. Prospective analysis of TERT promoter mutations in papillary thyroid carcinoma at a single institution. Journal of Clinical Medicine 2021 10 2179. (https://doi.org/10.3390/jcm10102179)
- 67↑
Nakao T, Matsuse M, Saenko V, Rogounovitch T, Tanaka A, Suzuki K, Higuchi M, Sasai H, Sano T, Hirokawa M, et al.Preoperative detection of the TERT promoter mutations in papillary thyroid carcinomas. Clinical Endocrinology 2021 95 790–799. (https://doi.org/10.1111/cen.14567)
- 68↑
Zhang T, He L, Wang Z, Dong W, Sun W, Zhang P, & Zhang H. Risk factors for death of follicular thyroid carcinoma: a systematic review and meta-analysis. Endocrine 2023 82 457–466. (https://doi.org/10.1007/s12020-023-03466-9)
- 69↑
Shen J, Yan M, Chen L, Ou D, Yao J, Feng N, Zhou X, Lei Z, & Xu D. Prognosis and influencing factors of follicular thyroid cancer. Cancer Medicine 2024 13 e6727. (https://doi.org/10.1002/cam4.6727)
- 70↑
Ito Y, Miyauchi A, Tomoda C, Hirokawa M, Kobayashi K, & Miya A. Prognostic significance of patient age in minimally and widely invasive follicular thyroid carcinoma: investigation of three age groups. Endocrine Journal 2014 61 265–271. (https://doi.org/10.1507/endocrj.ej13-0512)
- 71↑
Yamazaki H, Sugino K, Katoh R, Matsuzu K, Masaki C, Akaishi J, Yamada Hames K, Tomoda C, Suzuki A, Ohkuwa K, et al.Outcomes for minimally invasive follicular thyroid carcinoma in relation to the change in age stratification in the AJCC 8th edition. Annals of Surgical Oncology 2021 28 3576–3583. (https://doi.org/10.1245/s10434-020-09397-3)
- 72↑
Ito Y, Hirokawa M, Masuoka H, Higashiyama T, Kihara M, Onoda N, Miya A, & Miyauchi A. Prognostic factors for follicular thyroid carcinoma: the importance of vascular invasion. Endocrine Journal 2022 69 1149–1156. (https://doi.org/10.1507/endocrj.EJ22-0077)
- 73↑
Yamazaki H, Sugino K, Katoh R, Matsuzu K, Kitagawa W, Nagahama M, Rino Y, & Ito K. New insights on the importance of the extent of vascular invasion in widely invasive follicular thyroid carcinoma. World Journal of Surgery 2023 47 2767–2775. (https://doi.org/10.1007/s00268-023-07127-w)
- 74↑
Yamazaki H, Sugino K, Katoh R, Matsuzu K, Kitagawa W, Nagahama M, Rino Y, Saito A, & Ito K. Role of the degree of vascular invasion in predicting prognosis of follicular thyroid carcinoma. Journal of Clinical Endocrinology and Metabolism 2024 109 1291–1300. (https://doi.org/10.1210/clinem/dgad689)
- 75↑
Ito Y, Hirokawa M, Miyauchi A, Masuoka H, Yabuta T, Fukushima M, Kihara M, Higashiyama T, Kobayashi K, & Miya A. Prognostic impact of Ki-67 labeling index in minimally invasive follicular thyroid carcinoma. Endocrine Journal 2016 63 913–917. (https://doi.org/10.1507/endocrj.EJ16-0277)
- 76↑
Ito Y, Hirokawa M, Fujishima M, Masuoka H, Higashiyama T, Kihara M, Onoda N, Miya A, & Miyauchi A. Prognostic significance of vascular invasion and cell-proliferation activity in widely invasive follicular carcinoma of the thyroid. Endocrine Journal 2021 68 881–888. (https://doi.org/10.1507/endocrj.EJ21-0064)
- 77↑
Hellgren LS, Stenman A, Paulsson JO, Höög A, Larsson C, Zedenius J, & Juhlin CC. Prognostic utility of the Ki-67 labeling index in follicular thyroid tumors: a 20-year experience from a tertiary thyroid center. Endocrine Pathology 2022 33 231–242. (https://doi.org/10.1007/s12022-022-09714-4)
- 78↑
Miyauchi A, Onishi T, Morimoto S, Takai S, Matsuzuka F, Kuma K, Maeda M, & Kumahara Y. Relation of doubling time of plasma calcitonin levels to prognosis and recurrence of medullary thyroid carcinoma. Annals of Surgery 1984 199 461–466. (https://doi.org/10.1097/00000658-198404000-00014)
- 79↑
Miyauchi A, Kudo T, Miya A, Kobayashi K, Ito Y, Takamura Y, Higashiyama T, Fukushima M, Kihara M, Inoue H, et al.Prognostic impact of serum thyroglobulin doubling-time under thyrotropin suppression in patients with papillary thyroid carcinoma who underwent total thyroidectomy. Thyroid 2011 21 707–716. (https://doi.org/10.1089/thy.2010.0355)
- 80↑
Miyauchi A, Kudo T, Ito Y, Oda H, Yamamoto M, Sasai H, Higashiyama T, Masuoka H, Fukushima M, Kihara M, et al.Natural history of papillary thyroid microcarcinoma: kinetic analyses on tumor volume during active surveillance and before presentation. Surgery 2019 165 25–30. (https://doi.org/10.1016/j.surg.2018.07.045)
- 81↑
Sabra MM, Sherman EJ, & Tuttle RM. Tumor volume doubling time of pulmonary metastases predicts overall survival and can guide the initiation of multikinase inhibitor therapy in patients with metastatic, follicular cell-derived thyroid carcinoma. Cancer 2017 123 2955–2964. (https://doi.org/10.1002/cncr.30690)
- 82↑
Coussens LM, & Werb Z. Inflammation and cancer. Nature 2002 420 860–867. (https://doi.org/10.1038/nature01322)
- 83↑
Whiteside TL. The tumor microenvironment and its role in promoting tumor growth. Oncogene 2008 27 5904–5912. (https://doi.org/10.1038/onc.2008.271)
- 84↑
Nozawa H, Chiu C, & Hanahan D. Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis. Proceedings of the National Academy of Sciences of the United States of America 2006 103 12493–12498. (https://doi.org/10.1073/pnas.0601807103)
- 85↑
Liu CL, Lee JJ, Liu TP, Chang YC, Hsu YC, & Cheng SP. Blood neutrophil-to-lymphocyte ratio correlates with tumor size in patients with differentiated thyroid cancer. Journal of Surgical Oncology 2013 107 493–497. (https://doi.org/10.1002/jso.23270)
- 86↑
Seretis C, Gourgiotis S, Gemenetzis G, Seretis F, Lagoudianakis E, & Dimitrakopoulos G. The significance of neutrophil/lymphocyte ratio as a possible marker of underlying papillary microcarcinomas in thyroidal goiters: a pilot study. American Journal of Surgery 2013 205 691–696. (https://doi.org/10.1016/j.amjsurg.2012.08.006)
- 87↑
Kim SM, Kim EH, Kim BH, Kim JH, Park SB, Nam YJ, Ahn KH, Oh MY, Kim WJ, Jeon YK, et al.Association of the preoperative neutrophil-to-lymphocyte count ratio and platelet-to-lymphocyte count ratio with clinicopathological characteristics in patients with papillary thyroid cancer. Endocrinology and Metabolism (Seoul, Korea) 2015 30 494–501. (https://doi.org/10.3803/EnM.2015.30.4.494)
- 88↑
Lang BHH, Ng CPC, Au KB, Wong KP, Wong KKC, & Wan KY. Does preoperative neutrophil lymphocyte ratio predict risk of recurrence and occult central nodal metastasis in papillary thyroid carcinoma? World Journal of Surgery 2014 38 2605–2612. (https://doi.org/10.1007/s00268-014-2630-z)
- 89↑
Kim JY, Park T, Jeong SH, Jeong CY, Ju YT, Lee YJ, Hong SC, Ha WS, Choi SK, & Jung EJ. Prognostic importance of baseline neutrophil to lymphocyte ratio in patients with advanced papillary thyroid carcinomas. Endocrine 2014 46 526–531. (https://doi.org/10.1007/s12020-013-0089-6)
- 90↑
Cheong TY, Hong SD, Jung KW, & So YK. The diagnostic predictive value of neutrophil-to-lymphocyte ratio in thyroid cancer adjusted for tumor size. PLOS ONE 2021 16 e0251446. (https://doi.org/10.1371/journal.pone.0251446)
- 91↑
Lee F, Yang PS, Chien MN, Lee JJ, Leung CH, & Cheng SP. An increased neutrophil-to-lymphocyte ratio predicts incomplete response to therapy in differentiated thyroid cancer. International Journal of Medical Sciences 2018 15 1757–1763. (https://doi.org/10.7150/ijms.28498)
- 92↑
Ito Y, Onoda N, Kudo T, Masuoka H, Higashiyama T, Kihara M, Miya A, & Miyauchi A. Sorafenib and lenvatinib treatment for metastasis/recurrence of radioactive iodine-refractory differentiated thyroid carcinoma . In Vivo 2021 35 1057–1064. (https://doi.org/10.21873/invivo.12350)
- 93↑
Fukuda N, Wang X, Ohmoto A, Urasaki T, Sato Y, Nakano K, Nishizawa M, Yunokawa M, Ono M, Tomomatsu J, et al.Sequential analysis of neutrophil-to-lymphocyte ratio for differentiated thyroid cancer patients treated with lenvatinib . In Vivo 2020 34 709–714. (https://doi.org/10.21873/invivo.11828)