Active surveillance of low-risk papillary thyroid microcarcinomas

BackgroundOvertreatment of papillary thyroid microcarcinoma (PTMC) has become a common concern. This study aimed to compare clinicopathological features between PTMC and papillary thyroid carcinoma (PTC) and to explore whether surgery can confer significant survival benefits in all patients with PTC or PTMC.MethodsData of 145,951 patients with PTC registered in Surveillance, Epidemiology, and End Results (SEER) database and 8,751 patients with PTC in our institution were retrospectively collected. Patients with tumors less than 10 mm in diameter were classified as PTMC cohort and the rest as PTC cohort. Clinicopathological features between PTMC and PTC were compared on the basis of SEER cohort and validated with institutional data. Survival analysis was conducted to explore the effect of surgery on the prognosis of patients. To minimize potential confounders and selection bias, we performed propensity score matching (PSM) analysis to match more comparable cohorts.ResultsCompared with PTC, PTMC exhibited the following characteristics: more common in women and whites, older age at diagnosis, lower proportion of follicular variants, intraglandular dissemination, extraglandular and capsular invasion, higher proportion of multifocality, fewer lymph node and distant metastases, and higher cancer-specific survival (CSS) and overall survival (OS) (all p-value < 0.05). Regarding treatment, patients with PTMC received a lower proportion of radiotherapy, chemotherapy, and total thyroidectomy but a higher proportion of lobectomy and/or isthmectomy. There was no significant difference in CSS for patients with PTMC at stage T1N0M0 with or without surgery (P = 0.36).ConclusionGenerally, PTMC showed higher biological indolence than PTC, which meant a higher survival rate for patients in both OS and CSS. For patients with PTMC at staged T1N0M0, active surveillance (AS) may be a potentially feasible management strategy. However, the maintenance of good medical compliance and the management of psychological burden cannot be ignored for patients included in AS.

Active surveillance (AS) for low-risk papillary thyroid microcarcinoma (PTMC), which was initiated at Kuma Hospital (Kobe, Japan) in 1993 and Cancer Institute Hospital (Tokyo) in 1995, is now gradually being adopted worldwide, and several prospective studies have described the favorable outcomes of PTMC patients who underwent AS. The most important factor predicting PTMC growth is young age, and PTMC enlargement in young patients may be affected by high serum levels of thyroid-stimulating hormone. This review notes that one patient showed lung metastasis after conversion surgery (CS) following AS, but there are no reports of patients dying of thyroid carcinoma during or after AS. Some PTMCs enlarge or show newly appeared metastatic nodes requiring CS, and findings on the postoperative prognosis and incidence of significant surgical complications (e.g., permanent vocal cord paralysis, hypoparathyroidism) do not differ significantly between patients who underwent CS after AS and those who underwent immediate surgery (IS). IS has been associated with significantly higher incidences of these complications compared to AS as the initial management. Several studies have examined the quality of life (QoL) of patients who underwent AS versus IS, and reported discrepant findings regarding various psychological conditions (including anxiety). Medical costs for AS and IS vary regionally, and in Japan, the 10-year total cost of IS was 4.1 times greater than that of AS in 2017. Taken together, the existing findings demonstrate that AS can be appropriate for the initial management of patients with PTMC.

We showed previously that subclinical low-risk papillary thyroid microcarcinoma (PTMC) could be observed without immediate surgery. Patient age is an important prognostic factor of clinical papillary thyroid carcinoma (PTC). In this study, we investigated how patient age influences the observation of low-risk PTMC. Between 1993 and 2011, 1235 patients with low-risk PTMC chose observation without immediate surgery. They were followed periodically with ultrasound examinations. These patients were enrolled in this study. We divided them into three subsets based on age at the beginning of observation: young (<40 years), middle-aged (40-59 years), and old patients (≥60 years). Observation periods ranged from 18 to 227 months (average 75 months). We set three parameters for the evaluation of PTMC progression: (i) size enlargement, (ii) novel appearance of lymph-node metastasis, and (iii) progression to clinical disease (tumor size reaching 12 mm or larger, or novel appearance of nodal metastasis). The proportion of patients with PTMC progression was lowest in the old patients and highest in the young patients. On multivariate analysis, young age was an independent predictor of PTMC progression. However, none of the 1235 patients showed distant metastasis or died of PTC during observation. Although only 51 patients (4%) underwent thyrotropin (TSH) suppression based on physician preference, the PTMC of all patients enrolled in this TSH suppression study, except one, were clinically stable. To date, 191 patients underwent surgery for various reasons after observation. None showed recurrence except for one in the residual thyroid, and none died of PTC after surgery. Old patients with subclinical low-risk PTMC may be the best candidates for observation. Although PTMC in young patients may be more progressive than in older patients, it might not be too late to perform surgery after subclinical PTMC has progressed to clinical disease, regardless of patient age.

Background: Active surveillance (AS) of low-risk papillary thyroid microcarcinoma (PMC) was adopted as a management modality in both the Japanese guidelines in 2011 and the American Thyroid Association guidelines in 2015. AS was initiated at Kuma Hospital in 1993 but was not immediately accepted by all physicians. This study investigated the history of acceptance of AS at Kuma Hospital over time. The results should assist in the implementation of AS at other hospitals in Japan and other countries.Methods: This study included 4023 patients who were cytologically diagnosed with low-risk PMC at Kuma Hospital during the 24-year period between October 1993 and June 2016. The trend in the frequency of AS use over time was analyzed, dividing the 24-year study period into five parts based on the change in frequency of AS use: 1993–1997, 1998–2002, 2003–2006, 2007–2013, and 2014–2016.Results: The frequency of AS use in the present cohort was 65%. The frequency gradually increased from 30% in 1993–1997 to 88% in 2014–2016, with a slight decrease from 51% in 1998–2002 to 42% in 2003–2006. Until 2007, patients were mostly seen by surgeons, and the frequency of AS use varied remarkably among individual surgeons. Since 2007, the number of patients whose therapeutic strategies are determined by endocrinologists has increased, and the frequency of AS use for low-risk PMC by endocrinologists has been higher than that by surgeons.Conclusions: At Kuma Hospital, acceptance of AS for low-risk PMC gradually increased over the 24-year study period, but AS was not equally accepted by all physicians. Such variations in the acceptance of AS among individual physicians are also expected to exist in other hospitals. However, due to increasing evidence of the safety and superiority of AS over immediate surgery for this indolent disease, it is expected that AS will gain faster acceptance in other hospitals in Japan and around the world.

Background:Active surveillance (AS) for low-risk papillary thyroid microcarcinoma (PTMC) was initiated at Kuma Hospital in 1993 and has gradually spread worldwide. We previously demonstrated that AS is associated with a much lower incidence of unfavorable events than immediate surgery (IS). However, conversion surgery (CS) raises concerns about increased surgical complications due to advanced disease. In this study, we conducted a comparative analysis of unfavorable events after IS and CS.Methods:Between 2005 and 2019, 4635 patients clinically diagnosed with low-risk PTMC at Kuma Hospital were enrolled. Of these, 2896 underwent AS (AS group), and the remaining 1739 underwent IS (IS group). To date, 242 patients (8.4%) in the AS group have undergone CS for various reasons (CS group).Results:The incidence of unfavorable events, such as levothyroxine administration after surgery, postoperative hematoma, transient/persistent hypoparathyroidism, and transient/persistent vocal cord paralysis, did not differ between the CS and IS groups. None of the patients in the CS group had permanent vocal cord paralysis; however, this occurred in 15 patients (0.9%) in the IS group and was caused by accidental injury in 4 patients and carcinoma invasion in 11 patients. The incidence of surgery, levothyroxine administration, postoperative hematoma, transient/permanent hypoparathyroidism, and vocal cord paralysis was significantly higher (p < 0.001) in the IS group than in the AS group. There were no differences in the incidence of lymph node recurrence and overall mortality between the AS and IS groups. None of the patients in the AS and IS groups showed distant metastasis or died from thyroid carcinoma.Conclusions:There were no differences in the incidence of unfavorable events between the CS group and the IS group. Although none of the CS and AS groups had permanent vocal cord paralysis, accidental injury of the recurrent laryngeal nerve occurred in four patients (0.2%) in the IS group. The IS group had a significantly higher incidence of unfavorable events than the AS group. The prognoses of patients in both the AS and IS groups were excellent. Therefore, we recommend AS as the first-line management for low-risk PTMC.Correction added on February 20, 2023 after first online publication of November 9, 2022: In the Methods section of the abstract, 242 patients (0.8%) has been corrected to 242 patients (8.4%).

ABSTRACTIntroduction: Active surveillance of low-risk papillary thyroid microcarcinomas (PTMCs) was initiated in Japan in 1993 and has since been adopted in many countries, especially after its approval by the American Thyroid Association in 2015.Areas covered: We performed a literature review in Medline/PubMed to identify studies that used active surveillance for PTMCs. Moreover, we performed a literature review about the increased incidence of thyroid microcarcinomas in relation to the relative stability of deaths due to thyroid carcinomas.Expert opinion: No patients showed life-threatening metastasis/recurrence or died of thyroid carcinoma during active surveillance or after conversion surgery following PTMC progression. Thus, active surveillance should be the first-line management of PTMCs without high-risk features. In the future, molecular testing of actively growing PTMCs using cytology specimens could be useful to guide the treatment plan.

Chapter 1 - Advances in the Diagnosis and Management of Papillary Thyroid Microcarcinoma

The clinical significance of papillary thyroid microcarcinoma (PTMC) tumors < or =1 cm is widely debated. The objective of this study was to compare conventional papillary thyroid carcinoma (PTC) (tumors >1 cm) to PTMC and assess for differences in tumor characteristics and patient outcome. A retrospective chart review of patients with PTC or PTMC who were followed for a minimum of 3 years postoperatively and managed at a single academic institute was performed. Of 202 patients in the study, 66 (32.7%) had PTMC and 136 (67.3%) had conventional PTC. Patient and tumor characteristics including tumor multifocality, extrathyroidal extension, angiolymphatic invasion, and lymph node metastasis were similar between both groups. Twenty-one percent of the PTMC tumors were discovered incidentally. Patients with conventional PTC were significantly more likely to undergo treatment with radioactive iodine therapy compared to PTMC patients (86.4% vs. 66.7%, respectively, p < 0.003). Disease recurrence was observed in 40 patients and was not statistically different between the two groups; 11 (16.7%) in PTMC and 29 (21.3%) in conventional PTC, p = 0.57. Within the PTMC group, tumors of patients that recurred were significantly larger than those who remained disease free (8.1 mm vs. 6.4 mm, p < 0.05). None of the patients with incidental PTMC had disease recurrence. Angiolymphatic invasion was the only significant prognostic indicator of recurrence on multivariate analysis (p < 0.02). Nonincidental PTMC can have aggressive tumor features and disease recurrence similar to conventional PTC. These tumors should be managed like any other papillary thyroid malignancy.

Background: Two Japanese prospective trials of active surveillance (AS) for adult patients with low-risk papillary thyroid carcinoma (PTC) ≤1 cm (cT1aN0M0 PTMC) have verified the safety of AS in oncological control and its superiority over immediate surgery with respect to unfavorable outcomes. Thus, AS has been accepted as an alternative to immediate surgery for asymptomatic papillary thyroid microcarcinomas (PTMCs). However, the real-world clinical approach for PTMC is unknown. Thus, this study aimed to investigate the current state of management of asymptomatic PTMCs in Japan.Methods: We conducted a questionnaire survey on the actual treatment patterns for adult patients with low-risk PTMCs. The subjects were member institutions of the Japan Association of Endocrine Surgery (JAES) or Japanese Society of Thyroid Surgery (JSTS), including the departments of surgery and head and neck surgery (HNS).Results: Responses were obtained from 134 institutes, where 72.4% of Japanese thyroid cancer cases operated by surgeons were treated. For suspicious tumors on ultrasound, 18 responders (13.4%) conducted cytological examination routinely, while 69 (51.5%) and 40 (27.8%) conducted it only for tumors >5 and >10 mm, respectively. After the diagnosis, 42 responders (31.3%) recommend AS, 35 (26.1%) recommend immediate surgery as the management, and 52 (38.8%) allowed patients to decide the treatment course. The present responders tended to recommend surgery for PTMCs that were located adjacent to the dorsal surface of the thyroid, were multiple, or measured almost 10 mm in size. At these institutions, 1176 patients with PTMC underwent surgery in 2017, accounting for 18.1% of surgeries for PTC. During the succeeding three months, 310 of 576 (53.8%) PTMC patients underwent AS. The treatment strategies did not differ between the departments (Surgery or HNS). The institutions that have six or more surgeons, that were located in metropolitan areas, or that were certified by JAES or JSTS performed AS more actively.Conclusion: More than 50% of low-risk PTMCs are on AS in Japan. However, the indication and recommendation for AS vary significantly between institutions. To improve the implementation of this management modality, physicians and patients should be further educated, and the sociomedical environment should be improved.

Background:It has been 30 years since the initiation of active surveillance (AS) for adult patients with low-risk papillary thyroid microcarcinoma (PTMC). This study compared the long-term oncological outcomes of patients who underwent AS or immediate surgery (IS).Methods:This is a retrospective review of extended follow-up data from patients enrolled in a single-center, prospective observational study in Japan. In total, 5646 patients diagnosed with low-risk PTMC at Kuma Hospital between 1993 and 2019 were enrolled in this study. Of these, 3222 patients underwent AS (AS group), whereas 2424 underwent IS (IS group). The patients were followed up regularly, at least once per year. Descriptive outcome data were presented according to the treatment group.Results:In the AS group, 124 patients (3.8%) had tumor enlargement of ≥3 mm, and the 10- and 20-year enlargement rates were 4.7% and 6.6%, respectively. Novel lymph node metastases occurred in 27 patients (0.8%), and the 10- and 20-year nodal metastasis occurrence rates were 1.0% and 1.6%, respectively. In the IS group, 13 patients (0.5%) experienced lymph node recurrence postoperatively, and the 10- and 20-year nodal recurrence rates were 0.4% and 0.7%, respectively. Eighteen (1.4%) of the 1327 patients who underwent hemithyroidectomy experienced recurrence in the residual thyroid. The rate of lymph node metastasis was significantly higher in the AS group than in the IS group (1.1% vs. 0.4% and 1.7% vs. 0.7% at 10 and 20 years, respectively; p = 0.009), but the differences were small. However, the proportion of patients who underwent one or more and two or more surgeries was significantly higher in the IS group than in the AS group (100% vs. 12.3% and 1.07% vs. 0.09%, p < 0.01). Distant metastatic recurrence was observed in one patient after AS and conversion surgery and another after IS; however, they were alive (18.4 and 18.8 years after diagnosis, respectively). None of the patients in this study died of thyroid carcinoma.Conclusions:Long-term oncological outcomes of patients with PTMC generally did not differ clinically significantly between those undergoing AS and IS. AS is a viable initial management option for patients with low-risk PTMC.

We appreciate the thoughtful and valuable comments by Dr. Coskun Ali from Turkey for our manuscript. Although papillary thyroid microcarcinoma (PTMC) has an indolent course, the central lymph node metastasis (CLNM) has been found with a high incidence in PTMCs at the time of diagnosis [1–3]. The role of therapeutic central lymph node dissection (CLND) for treatment of CLNM in PTMC is well accepted for cN1 disease by The American Thyroid Association (ATA) guidelines for differentiated thyroid cancer and 2014 updating version [4, 5]. However, given the undetermined effect on long-term survival and related morbidity in PTMC patients, the value of routinely prophylactic CLND for cN0 disease remains unclear. Therefore, we conducted a meta-analysis to investigate the clinicopathologic factors predictive of CLNM for guiding prophylactic CLND in PTMCs with risk factors. As noted from comments, the accurate preoperative imaging doesenable complete clearance of the primary tumor and affected lymph node in PTMC patients. Recently, Yeh et al. have published ‘‘American Thyroid Association Statement on Preoperative Imaging for Thyroid Cancer Surgery’’ and highlighted that ultrasonography (US) remained the most important imaging modality in the assessment for both the primary tumor and all associated cervical lymph node basins preoperatively [6]. Positive lymph nodes may be distinguished from normal nodes based upon size, shape, echogenicity, hypervascularity, loss of hilar architecture, and the presence of calcifications in US examination [6]. Actually, we had reviewed the clinicopathologic and imaging features in a total of 163 patients with thyroid micro-nodules, diagnosed as Bethesda classification V (44/163, 27.0 %) and VI (119/163, 73.0 %) for papillary carcinoma by preoperative cytology. All of them had received thyroidectomy, and PTMC was confirmed in 162 patients on histology. In the multivariate analysis, the US suspicious images for nodal metastasis (Figs. 1 and 2), as mentioned above, we reproved to be independent predictors for CLNM in PTMCs [7]. In addition, recent advances in research on thyroid carcinogenesis have yielded applications of diagnostic molecular biomarkers in the management of thyroid nodules [8]. Molecular markers have been reported to enhance the diagnostic sensitivity of fine-needle aspiration (FNA) cytology in detecting malignancy preoperatively [9], such as genetic alterations occur in the MAP kinase (MAPK) and PI3 K/AKT pathways, including BRAF and RAS point mutations, as well as translocations in the RET/PTC and PAX8/PPARc genes [8, 10]. In the latest 2014 ATA guidelines [5], it is pointed out that studies of the BRAF mutation have suggested an association between presence of the mutation and the risk of nodal disease [11–13]. However, BRAF mutation has a limited positive predictive value for recurrence and therefore BRAF mutation status in the primary tumor is not recommended on the decision for prophylactic CLND in the new guidelines [5]. We have reviewed the related studies and found that results across all patients on association between BRAF mutation status and the risk of & Qing-hai Ji jonathan_qn@163.com

The incidence of thyroid carcinoma has been increasing worldwide. This is interpreted as an increase in the incidental detection of papillary thyroid microcarcinomas (PTMCs). However, mortality has not changed, suggesting overdiagnosis and overtreatment. Prospective clinical trials of active surveillance for low-risk PTMC (T1aN0M0) have been conducted in two Japanese institutions since the 1990s. Based on the favorable outcomes of these trials, active surveillance has been gradually adopted worldwide. A task force on the management of PTMC in adults organized by the Japan Thyroid Association therefore conducted a systematic review and has produced the present position paper based on the scientific evidence concerning active surveillance. This paper indicates evidence for the increased incidence of PTMC, favorable surgical outcomes for low-risk PTMC, recommended criteria for diagnosis using fine needle aspiration cytology, and evaluation of lymph node metastasis (LNM), extrathyroidal extension (ETE) and distant metastasis. Active surveillance has also been reported with a low incidence of disease progression and no subsequent recurrence or adverse events on survival if conversion surgery was performed at a slightly advanced stage. Active surveillance is a safe and valid strategy for PTMC, because it might preserve physical quality of life and reduce 10-year medical costs. However, some points should be noted when performing active surveillance. Immediate surgery is needed for PTMC showing high-risk features, such as clinical LNM, ETE or distant metastasis. Active surveillance should be performed under an appropriate medical team and should be continued for life.

ABSTRACTObjective:We aimed to evaluate the patients diagnosed with papillary thyroid carcinoma (PTC) and papillary thyroid microcarcinoma (PTMC) in terms of clinical, ultrasonographical (US) and histopathological features and their relationships with tumor size.Subjects and methods:We retrospectively evaluated 881 patients who underwent thyroid surgery in our clinic and diagnosed with PTC histopathologically were enrolled the study. Demographic characteristics, US findings and histopathological features were evaluated.Results:In total, 1264 nodules were identified in the 881 patients. The incidentality rates were higher in the PTMC group and also in the ≤ 5 mm group. In total multifocality rate was 32.9%, and was significantly higher in PTMC group than the PTC group. PTC and > 5 mm PTMC groups compared to PTMC and ≤ 5 mm groups respectively, were more aggresive histopathological features.Conclusions:Since the incidentality rates were found significantly more common in our patients with PTMC and those with ≤ 5 mm, ultrasonographic features of the nodules should be evaluated carefully and for cases which are suspicious with US, US-guided fine needle aspiration biopsy (FNAB) should be considered in order to make the correct treatment strategy. Also our study revealed that PTC and > 5 mm PTMC groups compared to PTMC and ≤ 5 mm groups respectively, have more aggresive histopathological features.

Papillary thyroid microcarcinoma (PTMC) has an excellent prognosis; however, some PTMCs exhibit poor outcomes. Cancer-specific death from PTMC has been rarely reported, so we aimed to evaluate mortality rates and causes of death in patients who died with PTMC. We retrospectively reviewed 8969 PTMC patients treated at Samsung Medical Center from 1994 to 2017. Mortality rate and causes of death in PTMC patients were evaluated and compared with those of 7873 patients with papillary thyroid carcinoma (PTC) > 1 cm. In addition, we reviewed previous publications reporting cancer-specific deaths from PTMC. Among the 8969 PTMC patients, 107 (1.2%) patients died. Only two (0.02%) patients have died of PTMC, which was less than the cancer-specific deaths from PTC > 1 cm (0.71%). Among the deceased PTMC patients, 63 (58.9%) died of other malignancies, three (2.8%) died of cardiovascular diseases, and five (4.7%) died of other diseases. Compared with PTC > 1 cm, cancer-specific deaths was less (1.9% vs. 15.1%, P < 0.001), and deaths from other malignancies were higher in deceased PTMC patients (58.9% vs. 30.5%, P < 0.001). According to 18 studies, PTMC-specific mortality rates ranged from 0.05% to 14.3%, and 336 cancer-specific deaths (0.43%) occurred among 78,770 PTMC patients. The cancer-specific mortality rate of PTMC patients was extremely low (0.02%). More than half of deceased PTMC patients died of other malignancies, which was significantly more than those with PTC > 1 cm. These results support that active surveillance can be selected as a therapeutic option for PTMC.

Papillary thyroid carcinoma is the most common endocrine malignancy. Papillary thyroid microcarcinomas (PTMCs) are tumors with a size of ≤1 cm. The biological behavior of these tumors differs due to the presence of their aggressive features. The prognosis of PTMCs with high-risk features, such as clinical node metastasis, distant metastasis, and significant extrathyroidal extension to the tracheal or recurrent laryngeal nerve invasion, is poor, even if a sufficient immediate surgery is performed at diagnosis. However, PTMCs without these aggressive features are low-risk tumors because of their indolent and slow growth behaviors. The increase in thyroid cancer incidence is mostly a result of overdiagnosis of small low-risk PTMCs with indolent clinical course. Despite the sudden increase in thyroid cancer incidence worldwide, cancer mortality did not increase. Although the traditional treatment strategy for PTMC is immediate surgery at diagnosis, because of the rather low disease-specific mortality rate, low recurrence rate, and potential risk for postoperative complications, active surveillance has been proposed recently as an alternative option for PTMCs without invasion, metastasis, or cytological or molecular characteristics. The recent data support that active surveillance of low-risk PTMC should be the initial treatment modality, because only a small percentage of low-risk PTMCs show signs of progression, and delayed surgery has not caused significant recurrence. However, recent management guidelines are shifting toward more conservative treatments, such as active surveillance. Although there is an increase in the number of studies related to active surveillance, prospective studies have been mostly from academic referral centers in Japan. The world still needs class 1 evidence extended prospective studies originating from different geographic regions. Active surveillance may be a good alternative to immediate surgery for appropriately selected patients with PTMC.