Thyroid cancer runs the gamut from indolent micropapillary carcinoma to highly aggressive metastatic disease. Today, using prognostic algorithms, treatment and follow-up can be tailored to each ...patient in order to decrease overtreatment and over-medicalization of indolent disease. Active surveillance of papillary thyroid carcinoma less than 1cm avoids surgery and thyroid hormone replacement in a large proportion of patient whose tumors remain stable for years. Total thyroidectomy, once a dogma in the treatment of all thyroid cancer, is being supplanted by thyroid lobectomy for low-risk cancers, thereby decreasing the surgical risks involved and improving patients' quality of life. Indications for prophylactic central neck dissection, once mandatory, are now being adapted to the risk of cancer recurrence. Radioactive iodine therapy, also previously mandatory for all, is now only employed according to risk factors and expected outcomes. Follow-up is also being tailored to risk factors for recurrence, with less frequent visits and less use of ultrasound and scintigraphy. For more advanced disease, molecular therapies tailored to somatic mutations are opening opportunities for redifferentiation of aggressive tumors which become amenable to radioactive iodine therapy which carries fewer side effects than other systemic therapies. These advances in the management of thyroid cancer with a personalized approach and de-escalation of treatment and follow-up are improving the way we treat thyroid cancer, avoiding overtreatment and improving patients' quality of life.
Medullary thyroid carcinoma (MTC) is an aggressive neuroendocrine tumor (NET) arising from the calcitonin-producing C cells. Unlike other NETs, there is no widely accepted pathologic grading scheme. ...In 2020, two groups separately developed slightly different schemes (the Memorial Sloan Kettering Cancer Center and Sydney grade) on the basis of proliferative activity (mitotic index and/or Ki67 proliferative index) and tumor necrosis. Building on this work, we sought to unify and validate an internationally accepted grading scheme for MTC.
Tumor tissue from 327 patients with MTC from five centers across the United States, Europe, and Australia were reviewed for mitotic activity, Ki67 proliferative index, and necrosis using uniform criteria and blinded to other clinicopathologic features. After reviewing different cutoffs, a two-tiered consensus grading system was developed. High-grade MTCs were defined as tumors with at least one of the following features: mitotic index ≥ 5 per 2 mm
, Ki67 proliferative index ≥ 5%, or tumor necrosis.
Eighty-one (24.8%) MTCs were high-grade using this scheme. In multivariate analysis, these patients demonstrated decreased overall (hazard ratio HR = 11.490; 95% CI, 3.118 to 32.333;
< .001), disease-specific (HR = 8.491; 95% CI, 1.461 to 49.327;
= .017), distant metastasis-free (HR = 2.489; 95% CI, 1.178 to 5.261;
= .017), and locoregional recurrence-free (HR = 2.114; 95% CI, 1.065 to 4.193;
= .032) survivals. This prognostic power was maintained in subgroup analyses of cohorts from each of the five centers.
This simple two-tiered international grading system is a powerful predictor of adverse outcomes in MTC. As it is based solely on morphologic assessment in conjunction with Ki67 immunohistochemistry, it brings the grading of MTCs in line with other NETs and can be readily applied in routine practice. We therefore recommend grading of MTCs on the basis of mitotic count, Ki67 proliferative index, and tumor necrosis.
Persistent/recurrent disease in the neck is frequent in patients with differentiated thyroid cancer (DTC).
Assess efficacy, safety, and prognostic factors of first neck reoperation in DTC.
...Retrospective study of consecutive patients undergoing neck reoperation for recurrent/persistent DTC in a referral cancer center. Response after reoperation was defined according to the 2015 American Thyroid Association guidelines.
One hundred sixty-one DTC patients were enrolled (64% females, median age 35 years, 96% papillary DTC). Initial stage was pT3 in 43% and pT4 in 10%, pN1 in 74%. Aggressive histology was present in 25% of the patients, in both primary and persistent/recurrent tumor. Four patients had no malignancy in the reoperative specimen, and 1 patient died due to postoperative hematoma and was excluded from further analysis. Following reoperation, 15 patients (10%) had persistent structural disease, 16 (10%) had biochemical incomplete response, 26 (17%) had indeterminate response, and 99 (63%) had complete response (CR), among whom 24 relapsed later. After a median follow-up of 5 years, only 83 patients (53%) had CR without the need for further treatments. The rate of permanent complications was: hypoparathyroidism 2%, laryngeal nerve palsy 0.6%, other 6%. Age ≥45 years, aggressive histology, and lymph node ratio ≥0.6 at initial surgery were independent risk factors for incomplete response after reoperation. Male sex, aggressive histology, and ≥10 metastases at reoperation were independent risk factors of secondary relapse following CR achieved with reoperation.
A careful risk-benefit analysis should guide surgical decision, particularly in patients with risk factors for incomplete response.
Anaplastic thyroid carcinoma (ATC) is a rare tumor, with poorly defined oncogenic molecular mechanisms and limited therapeutic options contributing to its poor prognosis. The aims of this ...retrospective study were to determine the frequency of anaplastic lymphoma kinase (ALK) translocations and to identify the mutational profile of ATC including TERT promoter mutations.
One hundred and forty-four ATC cases were collected from 10 centers that are a part of the national French network for management of refractory thyroid tumors. Fluorescence in situ hybridization analysis for ALK rearrangement was performed on tissue microarrays. A panel of 50 genes using next-generation sequencing and TERT promoter mutations using Sanger sequencing were also screened.
Fluorescence in situ hybridization was interpretable for 90 (62.5%) cases. One (1.1%) case was positive for an ALK rearrangement with a borderline threshold (15% positive cells). Next-generation sequencing results were interpretable for 94 (65.3%) cases, and Sanger sequencing (TERT) for 98 (68.1%) cases. A total of 210 mutations (intronic and exonic) were identified. TP53 alterations were the most frequent (54.4%). Forty-three percent harbored a mutation in the (H-K-N)RAS genes, 13.8% a mutation in the BRAF gene (essentially p.V600E), 17% a PI3K-AKT pathway mutation, 6.4% both RAS and PI3K pathway mutations, and 4.3% both TP53 and PTEN mutations. Nearly 10% of the cases showed no mutations of the RAS, PI3K-AKT pathways, or TP53, with mutations of ALK, ATM, APC, CDKN2A, ERBB2, RET, or SMAD4, including mutations not yet described in thyroid tumors. Genes encoding potentially druggable targets included: mutations in the ATM gene in four (4.3%) cases, in ERBB2 in one (1.1%) case, in MET in one (1.1%) case, and in ALK in one (1.1%) case. A TERT promoter alteration was found in 53 (54.0%) cases, including 43 C228T and 10 C250T mutations. Three out of our cases did not harbor mutations in the panel of genes with therapeutic interest.
This study confirms that ALK rearrangements in ATC are rare and that the mutational landscape of ATC is heterogeneous, with many genes implicated in the follicular epithelial cell dedifferentiation process. This may explain the limited effectiveness of targeted therapeutic options tested so far.
Background
The incidence of cancer in thyroglossal duct cysts (TDC) is low and management is controversial. The objective was to report the rate of multifocality, lymph node metastases, and long-term ...results for TDC carcinomas in adults.
Materials and Methods
Files from 1979 to 2008 were reviewed for tumor stage, multifocality in the lobes, lymph node metastases, treatment, and follow-up.
Results
A total of 18 patients (13 females, 5 males, average age 41.5 years) were treated for papillary carcinoma arising in a TDC. Of these, 15 underwent total thyroidectomy, 1 isthmusectomy and 2 a Sistrunk procedure only. Also, 16 patients underwent neck dissection of the central and/or lateral compartments. Tumors were staged pT1 (
n
= 15), pT3 (
n
= 3), pN0 (
n
= 4), pN1a (
n
= 3), pN1b (
n
= 9), Nx (
n
= 2), M0 (
n
= 17), and M1 (
n
= 1, lung metastases). Tumor foci were found in the thyroid lobes in 9 of 16 patients(56%). Lymph node metastases were found in 12 of 16 (75%). Nodes were positive in 6 of 15 central compartment dissections (40%) and in 9 of 15 lateral neck dissections (60%). Metastases to the lateral compartment, with no central compartment metastasis, were found in 6 of 15 patients (40%). Radioiodine was administered to 12 patients. Median follow-up was 12 years (range 1–22 years). All had negative ultrasound. Stimulated Tg levels available for 11 patients were undetectable for 10 and 2 ng/mL for the remaining patient.
Conclusions
This series shows a high rate of thyroid lobe foci and lymph node metastases but an excellent long-term outcome, characteristics shared with classic papillary carcinoma. Lateral neck metastases seem to be more frequent. These findings are in favor of following the current guidelines for differentiated thyroid cancer in general for the treatment of these rare tumors.
Purpose
Presence of venous vascular invasion is a criterion of intermediate risk of recurrence in papillary thyroid carcinoma (PTC). However, the presence and type of vascular invasion (lymphatic or ...venous) is often underreported and its impact on PTCs without other risk features remains unknown. The aim of this study was to evaluate the impact of both lymphatic and venous invasion on the risk of recurrence/persistence on otherwise low-risk PTCs.
Methods
Retrospective study including patients with otherwise low-risk PTCs but with vascular invasion, diagnosed between 2013 and 2019. The persistence/recurrence during the follow-up was evaluated. Pathology was reviewed to confirm the presence of lymphovascular invasion and determine the type of invasion.
Results
A total of 141 patients were included. Lymphovascular invasion was confirmed in 20.6%. After surgery, 48.9% (
N
= 69) of the patients received radioactive iodine (RAI). The median follow-up time was 4 3–6 years. Overall, 6 (4.2%) patients experienced persistent/recurrent disease in the neck, including 3 with lymphovascular invasion, confirmed as “only lymphatic”. Overall, patients with tumors harboring lymphovascular invasion had sensibly more persistent/recurrence disease compared with those without lymphovascular invasion (10.3% vs 2.7%,
p
= 0.1), especially in the subgroup of patients not treated with RAI (20% vs 1.6%,
p
= 0.049) OR 15.25, 95% CI 1.24-187.85,
p
= 0.033.
Conclusion
Lymphovascular invasion, including lymphatic invasion only, is associated with a sensibly higher risk of persistent/recurrent disease in otherwise low-risk PTCs, namely in patients not treated with RAI. Lymphatic invasion could have a role in risk-stratification systems for decision making.
Purpose
Adrenocortical carcinoma (ACC) is a very rare and aggressive malignant disease. Therefore, overall survival (OS) has long been considered as the best endpoint. Yet, a unique endpoint is not ...optimal to take into account the heterogeneity in tumor profile and the diversification of therapeutic option. The purpose of this mini review was to describe endpoints used in the past, present and future in the field of ACC.
Methods
Pubmed and Clinicaltrial.gov were used to identify relevant studies.
Results
Before year 2000 only three endpoints were regularly used: OS, recurrence-free survival (RFS) and response rate. These endpoints were used because ACC was seen as a homogeneous diseases with a high recurrence rate and low rate of long-term survival. Since 2000; along with the apparition of new class of drug, progression-free survival (PFS) has been more and more used. Other endpoints as “time to chemotherapy” or “Progression-free survival 2” were used to evaluate multimodal therapies or treatment with a delayed action. Finally, there is a hope that in the near future, quality of life along with other patient-reported outcomes may be used more frequently.
Conclusion
While OS and PFS are currently the most used endpoints in ACC, new endpoints are needed to better take into account the challenges offered by different situations and treatment strategies.
Abstract Even though tumor progression under neoadjuvant chemotherapy is uncommon, its locoregional management remains absolutely unclear. What is the best time for radical surgery or radiotherapy? ...“Rescue” chemo-radiotherapy could be a suitable radiosensitizing strategy to further reduce tumor progression and allow curative surgery while maintaining systemic therapy.
The International Medullary Thyroid Carcinoma Grading System, introduced in 2022, mandates evaluation of the Ki67 proliferation index to assign a histological grade for medullary thyroid carcinoma. ...However, manual counting remains a tedious and time-consuming task.
We aimed to evaluate the performance of three other counting techniques for the Ki67 index, eyeballing by a trained experienced investigator, a machine learning-based deep learning algorithm (DeepLIIF) and an image analysis software with internal thresholding compared to the gold standard manual counting in a large cohort of 260 primarily resected medullary thyroid carcinoma. The Ki67 proliferation index generated by all three methods correlate near-perfectly with the manual Ki67 index, with kappa values ranging from 0.884 to 0.979 and interclass correlation coefficients ranging from 0.969 to 0.983. Discrepant Ki67 results were only observed in cases with borderline manual Ki67 readings, ranging from 3 to 7%. Medullary thyroid carcinomas with a high Ki67 index (≥ 5%) determined using any of the four methods were associated with significantly decreased disease-specific survival and distant metastasis-free survival.
We herein validate a machine learning-based deep-learning platform and an image analysis software with internal thresholding to generate accurate automatic Ki67 proliferation indices in medullary thyroid carcinoma. Manual Ki67 count remains useful when facing a tumour with a borderline Ki67 proliferation index of 3-7%. In daily practice, validation of alternative evaluation methods for the Ki67 index in MTC is required prior to implementation.
Aims
Recently, there have been attempts to improve prognostication and therefore better guide treatment for patients with medullary thyroid carcinoma (MTC). In 2022, the International MTC Grading ...System (IMTCGS) was developed and validated using a multi‐institutional cohort of 327 patients. The aim of the current study was to build upon the findings of the IMTCGS to develop and validate a prognostic nomogram to predict recurrence‐free survival (RFS) in MTC.
Methods and Results
Data from 300 patients with MTC from five centres across the USA, Europe, and Australia were used to develop a prognostic nomogram that included the following variables: age, sex, AJCC stage, tumour size, mitotic count, necrosis, Ki67 index, lymphovascular invasion, microscopic extrathyroidal extension, and margin status. A process of 10‐fold cross‐validation was used to optimize the model's performance. To assess discrimination and calibration, the area‐under‐the‐curve (AUC) of a receiver operating characteristic (ROC) curve, concordance‐index (C‐index), and dissimilarity index (D‐index) were calculated. Finally, the model was externally validated using a separate cohort of 87 MTC patients. The model demonstrated very strong performance, with an AUC of 0.94, a C‐index of 0.876, and a D‐index of 19.06. When applied to the external validation cohort, the model had an AUC of 0.9.
Conclusions
Using well‐established clinicopathological prognostic variables, we developed and externally validated a robust multivariate prediction model for RFS in patients with resected MTC. The model demonstrates excellent predictive capability and may help guide decisions on patient management. The nomogram is freely available online at https://nomograms.shinyapps.io/MTC_ML_DFS/.
Building upon the International Medullary Thyroid Carcinoma (MTC) Grading System (IMTCGS) developed in 2022, this study presents a prognostic nomogram to predict recurrence‐free survival in MTC. The model was created using data from 300 MTC patients and was externally validated in a separate cohort. The nomogram is available at https://nomograms.shinyapps.io/MTC_ML_DFS/.
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