Thyroid Cancers: From Surgery to Current and Future Systemic Therapies through Their Molecular Identities.

Differentiated thyroid cancers (DTC) are commonly and successfully treated with total thyroidectomy plus/minus radioiodine therapy (RAI). Medullary thyroid cancer (MTC) is only treated with surgery but only intrathyroidal tumors are cured. The worst prognosis is for anaplastic (ATC) and poorly differentiated thyroid cancer (PDTC). Whenever a local or metastatic advanced disease is present, other treatments are required, varying from local to systemic therapies. In the last decade, the efficacy of the targeted therapies and, in particular, tyrosine kinase inhibitors (TKIs) has been demonstrated. They can prolong the disease progression-free survival and represent the most important therapeutic option for the treatment of advanced and progressive thyroid cancer. Currently, lenvatinib and sorafenib are the approved drugs for the treatment of RAI-refractory DTC and PDTC while advanced MTC can be treated with either cabozantinib or vandetanib. Dabrafenib plus trametinib is the only approved treatment by FDA for BRAFV600E mutated ATC. A new generation of TKIs, specifically for single altered oncogenes, is under evaluation in phase 2 and 3 clinical trials. The aim of this review was to provide an overview of the current and future treatments of thyroid cancer with regards to the advanced and progressive cases that require systemic therapies that are becoming more and more targeted on the molecular identity of the tumor.

Nonthyroidal second primary malignancies in differentiated thyroid cancer patients: Is the incidence increased comparing to the general population and could it be a radioiodine therapy consequence?

The long-term survival of differentiated thyroid cancer (DTC) patients and the need to perform several treatments with radioiodine (131-I) lead to the question if the lifetime risk of developing a nonthyroidal second primary cancer (NTSPC) is increased in these patients. In our study, we assessed the prevalence of NTSPCs in thyroid cancer population and evaluated the possible causative role of 131-I treatment. We analyzed 1096 consecutive patients followed at our institution from 1964 to 1998. A total of 101 NTSPCs were observed in 92/1096 patients (8.4%) among which 17/101 (16.8%) diagnosed before DTC and 84/101 (83.2%) diagnosed after. The most frequent tumor sites observed were breast and bladder/urinary tract in the post-DTC group and breast and hematological system in the pre-DTC group. Regarding 131-I treatment, we did not observe any significant differences regarding either the number of treatments or the cumulative activity. The only significant parameter associated with an increased incidence of NTSPC was follow-up (P = .02): a longer follow-up period was associated with a higher number of NTSPCs. The mean latency between 131-I and NTSPC was 10.52 ± 7.69 years. Comparing with the general Italian population, independent of radioiodine treatment, the standard incidence ratio in our cohort was similar to that of the general population (SIR 1.07) and this result was confirmed by analyzing only the treated group. In conclusion, these results show that the risk of NTSPCs in the DTC patients' population is similar to that in the general population and 131-I treatment was not associated with an increased risk.

DELAYED 131-I FIRST TREATMENT AFTER SURGERY HAS NO IMPACT ON THE MEDIAN TERM OUTCOME OF PATIENTS WITH INTERMEDIATE RISK DIFFERENTIATED THYROID CANCER.

Objective: In intermediate risk (IR) differentiated thyroid cancer (DTC) patients, selective use of radioiodine (131-I) for remnant ablation and/or as adjuvant therapy (RRA) is advocated. The recently suggested postoperative evaluation could delay the use of RRA. The aim of this study was to evaluate if a delayed RRA can worsen the clinical outcome of IR-DTC patients. Methods: Four hundred and fourteen consecutive IR-DTC patients were divided according to the time elapsed from surgery to RRA, <6 months (group A, 186/414 [44.9%]), or ≥6 months (group B, 228/414 [55.1%]). Clinical and biochemical data were collected, and clinical outcome was analyzed at the first evaluation (EV) after RRA (first-EV) and after a median of 6 years of follow-up (last-EV). Results: No difference in the clinical outcome of group A and B was found. Since a different activity of 131-I could have an impact on the outcome, we separately analyzed the groups according to the 131-I activity (low-activity group: 1,110 MBq/30 mCi [n = 320], and high-activity group: 3,700 MBq/100 mCi [n = 94]), further subdivided according to the time elapsed from surgery to RRA. No major differences were found in both the low- and high-activity groups when comparing the features of their subgroups A and B, as far as in their clinical outcome. Conclusion: The time elapsed between surgery and the first 131-I treatment does not influence the clinical outcome of IR-DTC patients. This finding allows a more relaxed attitude in the decision making process whether to perform the RRA in IR-DTC cases in which a selective use of 131-I is recommended. Abbreviations: ATA = American Thyroid Association; DTC = differentiated thyroid cancer; EV = evaluation; HR = high risk; 131-I = radioiodine; IR = intermediate risk; LR = low risk; rhTSH = recombinant human thyroid-stimulating hormone; RRA = radioiodine for remnant ablation; Tg = thyroglobulin; TgAb = thyroglobulin autoantibody; US = ultrasound.

Twenty years of lesson learning: how does the RET genetic screening test impact the clinical management of medullary thyroid cancer?

OBJECTIVE: Medullary thyroid carcinoma (MTC) is a rare disease that can be inherited or sporadic; its pathogenesis is related to activating mutations in the RET gene. DESIGN: This study describes our 20-year experience regarding RET genetic screening in MTC. PATIENTS AND METHODS: We performed RET genetic screening in 1556 subjects, 1007 with an apparently sporadic MTC, 95 with a familial form and 454 relatives of RET-positive patients with MTC. RESULTS: A germline RET mutation was found in 68 of 1007 (6·7%) patients with sporadic MTC, while 939 patients with MTC were negative for germline RET mutations. We then identified a total of 137 gene carriers (GC). These subjects initiated a clinical evaluation for the diagnosis of MEN 2. A total of 139 MEN 2 families have been followed: 94 FMTC, 33 MEN 2A and 12 MEN 2B. Thirty-three different germline RET mutations were identified. Codon 804 was the most frequently altered codon particularly in FMTC (32/94, 34%), while codon 634 was the most frequently altered codon in MEN 2A (31/33, 94%); MEN 2B cases were exclusively associated with an M918T mutation at exon 16. CONCLUSIONS: Our 20-year study demonstrated that RET genetic screening is highly specific and sensitive, and it allows the reclassification as hereditary of apparently sporadic cases and the identification of GC who require an adequate follow-up. We confirmed that FMTC is the most prevalent MEN 2 syndrome and that it is strongly correlated with noncysteine RET mutations. According to these findings, a new paradigm of follow-up of hereditary MTC cases might be considered in the next future.

Treatment of advanced thyroid cancer with axitinib: Phase 2 study with pharmacokinetic/pharmacodynamic and quality-of-life assessments.

BACKGROUND: In a previous phase 2 trial, axitinib was active and well tolerated in patients with advanced thyroid cancer. In this second phase 2 trial, the efficacy and safety of axitinib were evaluated further in this population, and pharmacokinetic/pharmacodynamic relationships and patient-reported outcomes were assessed. METHODS: Patients (N = 52) with metastatic or unresectable, locally advanced medullary or differentiated thyroid cancer that was refractory or not amenable to iodine-131 received a starting dose of axitinib 5 mg twice daily. The primary endpoint was the objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), safety, pharmacokinetic parameters, and patient-reported outcomes assessed with the MD Anderson Symptom Inventory questionnaire. RESULTS: The overall ORR was 35% (18 partial responses), and 18 patients had stable disease for ≥16 weeks. The median PFS was 16.1 months, and the median OS was 27.2 months. All-causality, grade ≥3 adverse events (>5%) were fatigue, dyspnea, diarrhea, decreased weight, pain in extremity, hypertension, decreased appetite, palmar-plantar erythrodysesthesia, hypocalcemia, and myalgia. Patients who had greater axitinib exposure had a longer median PFS. Quality of life was maintained during treatment with axitinib, and no significant deterioration in symptoms or interference in daily life caused by symptoms, assessed on MD Anderson Symptom Inventory subscales, were observed. CONCLUSIONS: Axitinib has activity and a manageable safety profile while maintaining quality of life, and it represents an additional treatment option for patients with advanced thyroid cancer.

Detection of metastases from differentiated thyroid cancer by different imaging techniques (neck ultrasound, computed tomography and [18F]-FDG positron emission tomography) in patients with negative post-therapeutic ¹³¹I whole-body scan and detectable serum thyroglobulin levels.

INTRODUCTION: DTC patients having detectable Tg and negative post-therapeutic (131)I-WBS have to be investigated by different imaging techniques to detect metastases. PURPOSE: Comparison of neck US, CT and [18F]-FDG PET scan. METHODS: In 49 DTC patients with biochemical disease, neck was examined by US, CT and [18F]-FDG PET. FNA was performed and Tg was determined by FNA-Tg in selected cases of suspicious lymph nodes. Thorax was examined by CT and PET. Serum Tg was measured on LT4 therapy (basal Tg) and after the stimulation with recombinant human TSH (peak Tg). RESULTS: A thyroid remnant was seen by US, CT and PET in eight patients; recurrences were seen by US, CT and PET in six, five and five patients, respectively. Two metastatic nodes were identified by US and CT but not by PET. Lung micronodules were detected by CT in 7/49 (14.3 %) patients and by FDG PET in three of them. Basal Tg ranged from 0.5-1,725 ng/ml while peak Tg ranged from 0.5 to 2,135 ng/ml: the distribution between positive and negative patients was similar. Bone scan was negative in all cases. CONCLUSIONS: In DTC patients with detectable Tg and negative I-131 post-therapy WBS, imaging examination revealed remnant or metastases in 43 % of cases. Remnant and recurrences were equally detected by the three techniques; US was better than [18F]-FDG PET for lymph node metastases since this latter method can give false both positive and negative results; chest examination is best made by CT versus FDG PET due to its higher spatial resolution.

HAND-FOOT SYNDROME IN SORAFENIB AND LENVATINIB TREATMENT FOR ADVANCED THYROID CANCER.

OBJECTIVE: The aim of this study was to assess the clinical impact of hand-foot syndrome (HFS) during treatment with two multikinase inhibitors, sorafenib and lenvatinib, in a large group of patients with advanced thyroid cancer. Moreover, we looked for possible associations between HFS occurrence and clinical and pathological features. METHODS: We retrospectively evaluated 239 patients with advanced thyroid cancer: 165 treated with lenvatinib and 74 with sorafenib. Statistical analysis was performed to verify which features could be correlated with HFS development. RESULTS: HFS was observed in 35/74 (47.4%) and in 43/165 (26.7%) patients treated with sorafenib or lenvatinib, respectively. The median latency from the drug beginning and HFS appearance was 27 days for sorafenib and 2.9 months for lenvatinib. G3/G4 toxicity was observed in 16/35 (45.7%) patients treated with sorafenib and only in 3/43 (7%) treated with lenvatinib. Drug dose reduction due to HFS was required in 19/74 (25.7%) and 3/165 (1.8%) patients treated with sorafenib and lenvatinib, respectively. HFS occurrence was significantly associated with a longer duration of therapy in both groups. CONCLUSIONS: HFS was a frequent adverse event during both lenvatinib and sorafenib therapy, with a higher frequency and toxicity grade during sorafenib treatment. HFS was the most frequent reason for drug reduction or discontinuation in patient treated with sorafenib. Early diagnosis of HFS is important to allow early intervention, possibly in a multidisciplinary setting, and to avoid treatment discontinuation, which is highly relevant to obtain the maximum effectiveness of systemic therapy.

Pros and cons of an aggressive initial treatment with surgery and radioiodine treatment in minimally invasive follicular thyroid carcinoma.

BACKGROUND: Currently, surgery alone is the gold standard treatment for minimally invasive follicular thyroid cancer (mi-FTC). CASE PRESENTATION: A case of a mi-FTC diagnosed in 1994 was treated with total thyroidectomy and radioiodine (RAI) ablation, according to the therapeutic algorithm used at that time. Nevertheless, he had a recurrence with distant metastasis after 24 years from the initial treatment. CONCLUSION: Total thyroidectomy and RAI ablation might have delayed the development of distant metastasis but they were not sufficient to avoid disease recurrence. Certainly, remnant ablation simplified the follow-up and the monitoring of serum thyroglobulin allowed the early detection of the biochemical recurrence, but didn't change the outcome of the disease. Moreover, because of this early detection the patient was exposed to useless biochemical and imaging examinations. The aim of this report is to discuss the pros and cons of an aggressive treatment of a patient with mi-FTC.

Enlargement of a metastatic lymph node from differentiated thyroid cancer after COVID-19 vaccination.

BACKGROUND: The massive vaccination campaign against COVID-19 has granted a high level of protection against the severe forms of the disease at the price of some mild adverse events. OBJECTIVE: To underline that COVID-19 vaccination can induce a transient enlargement of lymph-node metastases in differentiated thyroid cancer patients. CASE PRESENTATION: We describe the clinical, laboratory, and imaging features of a 60-year-old woman affected by paratracheal lymph-node relapse of Hurtle Cell Carcinoma who came to our attention after full COVID-19 vaccination because of neck swelling and pain. In April 2021, after 5 years of stable structural disease, the patient presented an enlargement of the metastatic lymph node, associated with a rise of serum thyroglobulin (from 4.6 to 14.7 pg/mL). Anti-inflammatory treatment was started and pain and swelling remitted after 15 days. At the subsequent evaluation, at neck ultrasound, the right paratracheal lesion was smaller and thyroglobulin dropped to 3.9 pg/mL. CONCLUSIONS: We report the case of an enlargement of metastatic lymph node from differentiated thyroid cancer after COVID-19 vaccination. We warn clinicians to identify features of inflammatory response due to COVID-19 vaccination in order to prevent unwarranted surgical treatment.

Significance of Thyroglobulin Autoantibodies in Patients With Thyroid Cancer Treated With Lenvatinib.

Context: Serum thyroglobulin (Tg) is a highly sensitive and specific tumor marker, employed in post-operative management of patients with differentiated thyroid carcinomas. Tumor shrinkage of radioiodine-refractory thyroid cancer (RAIR-DTC) treated with multitarget kinase inhibitors as lenvatinib, expressed according to the Response Evaluation Criteria in Solid Tumors (RECIST), is also associated with a drastic reduction of Tg levels. However, interference caused by circulating thyroglobulin autoantibodies (TgAb) represents the main limitation in the clinical use of Tg. Objective: To evaluate if in RAIR-DTC TgAb could be considered a surrogate marker of Tg in monitoring response to treatment with lenvatinib. Design: We retrospectively evaluated patients who had started lenvatinib and correlated serum Tg and TgAb with the radiological response across visits. Setting: University of Pisa, Italy. Patients: We selected 9/97 RAIR-DTC patients with detectable TgAb. Intervention: None. Main Outcome Measures: None. Results: Tg values correlated neither with TgAb title nor with radiological response across visits. Greater decreases in TgAb titer correlated with favorable radiological response to lenvatinib after 1 month (Spearman's correlation = 0.74, P = .021) and 6 months (correlation = 0.61, P = .079). According to RECIST, patients with partial response showed a ∼10-fold greater decrease in TgAb compared to those with stable disease at 1 month (median TgAb decrease: -142 vs -14 IU/mL, P = .01) and those with progressive disease at 6 months (median TgAb decrease: -264 vs-24 IU/mL, P = .04). Conclusion: TgAb evaluation may represent a reliable surrogate marker for Tg trend in evaluating response of RAIR-DTC to treatment with lenvatinib. A multicentric study would be useful to confirm our results.

Clinical Evolution of Sporadic Medullary Thyroid Carcinoma With Biochemical Incomplete Response After Initial Treatment.

CONTEXT: The clinical response after surgery is a determinant in the management of patients with medullary thyroid carcinoma (MTC). In case of excellent or structural incomplete response, the follow-up strategies are well designed. Conversely, in case of biochemical incomplete response (BiR) the management is not clearly defined. OBJECTIVE: This work aimed to evaluate the overall and per-site prevalence of structural disease detection in sporadic MTC patients with BiR and to assess the predictive value of various clinical, biochemical, and genetic features. METHODS: We evaluated data of 599 consecutive patients surgically treated for sporadic MTC (2000-2018) and followed-up at the endocrine unit of the University Hospital of Pisa. RESULTS: After a median of 5 months from surgery, 145 of 599 (24.2%) patients were classified as BiR. Structural disease was detected in 64 of 145 (44.1%), after a median time of 3.3 years. In 73.6%, structural disease was detected at a single site, prevalently cervical lymph nodes. Among several others, at the time of first evaluation after surgery, only basal calcitonin (bCTN) and stage IVa/b were independent predictive factors. Also, structural disease was more frequent in patients with shorter CTN doubling time and somatic RET mutation. CONCLUSION: In sporadic MTC patients with BiR, the risk of detection of structural disease was about 50% at 10 years. Higher bCTN levels and staging predicted the risk of detecting structural disease. According to these findings, stricter follow-up should be reserved for MTC with BiR and elevated values of bCTN and to those with an advanced stage. Long follow-up should be considered for all BiR patients since 50% of them develop structural disease within 10 years.

Active surveillance in differentiated thyroid cancer: a strategy applicable to all treatment categories response.

Currently, the differentiated thyroid cancer (DTC) management is shifted toward a tailored approach based on the estimated risks of recurrence and disease-specific mortality. While the current recommendations on the management of metastatic and progressive DTC are clear and unambiguous, the management of slowly progressive or indeterminate disease varies according to different centers and different physicians. In this context, active surveillance (AS) becomes the main tool for clinicians, allowing them to plan a personalized therapeutic strategy, based on the risk of an unfavorable prognosis, and to avoid unnecessary treatment. This review analyzes the main possible scenarios in treated DTC patients who could take advantage of AS.

Thyroid autoimmunity, thyroglobulin autoantibodies, and thyroid cancer prognosis.

The relevance of thyroid autoimmunity to the prognosis of papillary thyroid carcinoma is still unsettled. We decided to investigate the impact of thyroid autoimmunity on the prognosis of papillary thyroid carcinoma and the handling of TgAbs. We evaluated the clinical course of a large group of patients according to the presence (PTC-LT) or absence (PTC) of lymphocytic thyroiditis at histology. We studied 194 consecutive patients with a diagnosis of PTC and treated them with total thyroidectomy plus ¹³¹I ablation between 2007 and 2009. Median follow-up (with 25th-75th percentiles) was 84.0 (56.4-118.0) months. The remission criteria were: basal Tg < 0.2 ng/mL (or stimulated Tg: < 1), TgAbs < 8 IU/mL (otherwise 'decreasing TgAb trend', a decline of ≥20% in sequential TgAb measurements) and unremarkable imaging. PTC-LT and PTC patients had comparable treatment.TgAbs were detectable in 72.5% of PTC-LT and 16.5% of PTC patients. Time to remission was longer in the detectable than in the undetectable TgAb cohort (28.5 vs· 7.5 months (median); HR: 0.54, CI: 0.35-0.83, P = 0.005). When comparing PTC-LT to PTC patients, the difference was maintained in the detectable TgAb (29.3 vs 13.0 months; HR: 0.38, CI: 0.18-0.80; P = 0.01) but not in the undetectable TgAb cohort (7.7 vs 7.3 months; HR: 0.90, CI: 0.55-1.47; P = 0.68). Using the decreasing TgAb trend, the influence of detectable TgAbs on time to remission was abolished. Thyroid autoimmunity does not influence the prognosis of papillary thyroid carcinoma. A decreasing TgAb trend seems an appropriate criterion to establish the remission of papillary thyroid carcinoma.

Nutrition in Advanced Thyroid Cancer Patients.

In the last decade, multikinase inhibitors (MKIs) have changed the paradigm of treatment of advanced and progressive thyroid cancer. Compared with the traditional treatment with chemotherapy and radiotherapy, these new drugs have shown a good efficacy in controlling the neoplastic disease, and also a different toxicity profile compared to traditional chemotherapy, milder but still present and involving mainly the nutritional profile. Weight loss, nausea, anorexia, stomatitis, diarrhea may be associated with malnutrition and cancer-related cachexia. The latter is characteristic of the advanced cancer stage and may be present before starting MKIs, or may develop afterwards. Adverse events with nutritional impact may cause a significant impairment of quality of life, often requiring dose reduction and sometimes drug discontinuation, but with a lower efficacy on the neoplastic disease. The aim of this paper was to discuss the role of nutritional therapy in advanced thyroid cancer and the importance of prevention, early recognition and careful management of malnutrition and cachexia during systemic therapy with MKIs.

Yttrium-90 transarterial radioembolization for liver metastases from medullary thyroid cancer.

Objectives: Liver metastases occur in 45% of patients with advanced metastatic medullary thyroid cancer (MTC). Transarterial radioembolization (TARE) has been proposed to treat liver metastases (LM), especially in neuroendocrine tumors. The aim of this study was to investigate the biochemical (calcitonin and carcino-embryonic antigen) and objective response of liver metastases from MTC to TARE. Methods: TARE is an internal radiotherapy in which microspheres loaded with ß-emitting yttrium-90 (90Y) are delivered into the hepatic arteries that supply blood to LM. Eight patients with progressive multiple LM underwent TARE and were followed prospectively. They were clinically, biochemically and radiologically evaluated at 1, 4, 12 and 18 months after TARE. Results: Two patients were excluded from the analysis due to severe liver injury and death due to extrahepatic disease progression, respectively. One month after TARE, a statistically significant (P = 0.02) reduction of calcitonin was observed in all patients and remained clinically relevant during follow-up; reduction of CEA, although not significant, was found in all patients. Significant reduction of liver tumor mass was observed 1, 4 and 12 months after TARE (P = 0.007, P = 0.004, P = 0.002, respectively). After 1 month, three of six patients showed partial response (PR) and three of six stable disease (SD) according to RECIST 1.1, while five of six patients had a PR and one of six a SD according to mRECIST. The clinical response remained relevant 18 months after TARE. Excluding one patient, all others showed only a slight and transient increase in liver enzymes. Conclusions: TARE is effective in LM treatment of MTC. The absence of severe complications and the good tolerability make TARE a valid therapeutic strategy when liver LM are multiple and progressive.

Ca19.9 Positivity and Doubling Time Are Prognostic Factors of Mortality in Patients with Advanced Medullary Thyroid Cancer with No Evidence of Structural Disease Progression According to Response Evaluation Criteria in Solid Tumors.

Background: Serum Ca19.9 positivity is a prognostic factor for mortality in patients with advanced medullary thyroid cancer (aMTC), independently from calcitonin doubling time (DT). However, it is unknown whether aMTC patients who become positive for Ca19.9 also have progressive disease (PD) according to response evaluation criteria in solid tumors (RECIST) and whether Ca19.9 DT has a role in the management of aMTC patients. The aims of this study were to evaluate whether in aMTC, when serum Ca19.9 becomes positive, PD develops, and to determine the role of Ca19.9 DT in predicting mortality and PD. Patients and Methods: Serum Ca19.9 was periodically measured in 107 aMTC patients, and the DTs were calculated. Restaging of the disease was radiologically performed in 104 of 107 patients and PD was evaluated according to RECIST. Results: At the end of follow-up, 25 of 107 patients were Ca19.9 positive and PD was identified in 30 of 104 patients. No significant association was found between Ca19.9 positivity and PD, while there was a significant association between Ca19.9 positivity and mortality (p < 0.0001). Ca19.9 DTs <6 months and <1 year were not associated with PD but were associated with mortality (p < 0.0001 and p < 0.0001, respectively). In particular, 3 patients who had a Ca19.9 DT <6 months with no evidence of PD according to RECIST died of their disease after 6, 5, and 3 months, respectively. Conclusions: Serum Ca19.9 positivity and DTs <6 months and <1 year are prognostic factors for mortality but not for PD. Serum Ca19.9 positivity and DTs <6 months and <1 year should be considered in the decision-making process of whether to initiate systemic therapy even if there is no evidence of PD according to RECIST.

Assessing mPTC Progression during Active Surveillance: Volume or Diameter Increase?

Active surveillance (AS) is considered an alternative to immediate surgery in micropapillary thyroid carcinoma (mPTC). However, the definition of clinical mPTC progression during AS is controversial. We evaluated changes in tumor size using both tumor diameters and volume in 109 patients with mPTC followed in an AS protocol for a mean period of 31 ± 18 months. At the time of data lock, 19/109 (17.4%) mPTC reached and maintained a volume increase of ≥50%. However, only 3/19 (15.7%) showed progression, according to the diameter increase. The remaining 16 showed a slight diameter growth without reaching the original protocol progression criteria. The mean mPTC growth rate in stable cases was 0.37 mm3/month, while it was significantly greater in the mPTC, which achieved a volume change ≥50% with respect to the other. The two mPTC that developed a significant diameter increase had a growth rate of 41 and 18 mm3/month. Instead, the growth rates of the three mPTC that developed lymph node metastases were 0, 2.5 and 16 mm3/month. The ≥50% volume increase appears to be a too sensitive marker of disease progression, with a downstream higher surgery rate. The assessment of growth rate could distinguish mPTC with high and low growth rates, which would allow us to tailor the algorithm of the evaluations to a more appropriate timing.

Prevalence and Risk Factors of Developing Fistula or Organ Perforation in Patients Treated with Lenvatinib for Radioiodine-Refractory Thyroid Cancer.

INTRODUCTION: Tyrosine kinase inhibitors represent a better treatment in patients with radioiodine-refractory differentiated thyroid cancer (RAI-R DTC). Lenvatinib is usually well-tolerated, but sometimes, it is associated with serious and even life-threatening side effects. The aim of this study was to evaluate the prevalence of and the potential risk factors for fistula and/or organ perforation in RAI-R DTC patients treated with lenvatinib. METHODS: This study included data from advanced and progressive RAI-R DTC patients treated with lenvatinib from February 2011 to February 2020 who were followed up at a single center. The clinical-pathological features and the biochemical and morphological results of the patients were collected at the time of starting lenvatinib and during the follow-up. RESULTS: Fourteen of 95 (14.7%) locally advanced or metastatic RAI-R DTC patients treated with lenvatinib developed a fistula or organ perforation. Nine of 14 (64.3%) patients had tumor infiltration of the trachea, bronchus, esophagus, pleura, or bladder. Five of 14 (35.7%) had a bowel perforation, but only 2 had preexisting diverticulosis. Evaluation of the risk factors for developing a fistula or organ perforation showed that the presence of tumor infiltration and the tumor histology (papillary and poorly differentiated vs. follicular and Hurthle thyroid cancer) were significantly correlated with the development of a fistula or organ perforation (p = 0.003 and p = 0.02, respectively). In the subgroup of patients with tumor infiltration, we found that the papillary thyroid cancer histotype was the only potential predictor of fistula development. External beam radiation therapy (EBRT), the starting dose of lenvatinib, and the duration of treatment were not relevant for the development of fistula. CONCLUSIONS: In metastatic thyroid cancer patients treated with lenvatinib, the presence of tumor infiltration and histological type should be considered as potential risk factors for the development of fistula or organ perforation, although they do not represent an absolute contraindication. Although EBRT and the presence of diverticulosis were not significantly associated with the development of fistula and organ perforation, they should be regarded as potential additional reasons for the development of these complications. According to our findings, there is no reason to start lenvatinib at a lower daily dose when tumor infiltration is present.

Thyroid cancer and COVID-19: experience at one single thyroid disease referral center.

PURPOSE: Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) is challenging health systems all over the world. Cancer patients have a higher risk of being infected by SARS-Cov-2 and higher coronavirus disease 2019 (COVID-19) severity and mortality. Up to date, there were no data about COVID-19 in patients with thyroid cancer (TCs). The aim of the study was to describe the prevalence of COVID-19 in a well-characterized series of TC patients evaluated for the persistence of the neoplastic disease from March to September 2020; as secondary objective, we looked for the COVID-19 disease severity in a subgroup of multimetastatic TC patients. METHODS: We evaluated 1464 patients affected by persistent TC: 67 patients who were taking multikinase inhibitors (MKIs) and 1397 under active surveillance for a persistent but stable disease. During the clinical evaluation, all patients were specifically investigated about a positive history of Sars-Cov-2 infection. RESULTS: SARS-Cov-2 infection was identified in 4/1464 (0.3%) cases of patients affected by TC. We identified three cases among patients under active surveillance (0.2%), and one case among patients treated with MKI systemic therapy (1/67, 1.5%). This patient was taking vandetanib for metastatic medullary thyroid cancer (MTC), when he came to our attention referring severe fatigue, dyspnea for light physical activities. He presented a mild COVID-19 and he received exclusively supportive care. After a multidisciplinary consultation, we decided against the discontinuation of vandetanib. After 2 months from the infection, he did not present any signs of active infection, and the MTC metastatic disease was stable. CONCLUSIONS: We showed that COVID-19 is not more frequent in TC patients than in general population, although a relatively higher prevalence in the group of TC patients treated with MKIs. A single patient with advanced TC and SARS-Cov-2 infection during MKIs treatment had a mild COVID-19 and did not require the discontinuation of MKI therapy. In cases of more severe COVID-19, an accurate evaluation from a multidisciplinary team would consider risks and benefits in taking the decision to continue or stop MKI treatment.

Whole Tumor Capsule Is Prognostic of Very Good Outcome in the Classical Variant of Papillary Thyroid Cancer.

CONTEXT: Tumor capsule integrity is becoming a relevant issue to predict the biological behavior of human tumors, including thyroid cancer. OBJECTIVE: This work aims to verify whether a whole tumor capsule in the classical variant of papillary thyroid carcinoma (CVPTC) could have as a predictive role of a good outcome as for follicular variant (FVPTC). METHODS: FVPTC (n = 600) and CVPTC (n = 554) cases were analyzed. We distinguished between encapsulated-FVPTC (E-FVPTC) and encapsulated-CVPTC (E-CVPTC) and, thereafter, invasive (Ei-FVPTC and Ei-CVPTC) and noninvasive (En-FVPTC and En-CVPTC) tumors, according to the invasion or integrity of the tumor capsule, respectively. Cases without a tumor capsule were indicated as invasive-FVPTC (I-FVPTC) and invasive-CVPTC (I-CVPTC). The subgroup of each variant was evaluated for BRAF mutations. RESULTS: E-FVPTC was more frequent than E-CVPTC (P < .001). No differences were found between En-FVPTC and En-CVPTC or between Ei-FVPTC and Ei-CVPTC. After 18 years of follow-up, a greater number of not-cured cases were observed in Ei-CVPTC with respect to Ei-FVPTC, but not in En-CVPTC to En-FVPTC. Multivariate clustering analysis showed that En-FVPTC, En-CVPTC, and Ei-FVPTC have similar features but different from I-FVPTC and I-CVPTC and, to a lesser extent, from Ei-CVPTC. A total of 177 of 614 (28.8%) cases were BRAFV600E mutated, and 10 of 614 (1.6%) carried BRAF-rare alterations. A significantly higher rate of En-CVPTC (22/49, 44.9%) than En-FVPTC (15/195, 7.7%) (P < .0001) were BRAFV600E mutated. CONCLUSION: En-CVPTC is less prevalent than En-FVPTC. However, it has good clinical/ pathological behavior comparable to En-FVPTC. This finding confirms the good prognostic role of a whole tumor capsule in CVPTC as well. New nomenclature for En-CVPTC, similar to that introduced for En-FVPTC (ie, noninvasive follicular thyroid neoplasm with papillary-like nuclear features; NIFTP) could be envisaged.