Kotwal, Anupam

The NCCN Guidelines for Thyroid Carcinoma address the management of different types of thyroid carcinoma, including papillary, follicular, oncocytic, medullary, and anaplastic carcinoma. The NCCN Thyroid Carcinoma Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights focus on the panel’s most recent recommendations regarding systemic therapies for thyroid carcinoma as well as the supporting clinical data.

Immune checkpoint inhibitors (ICIs) can cause pituitary dysfunction due to hypophysitis. We aimed to characterize ICI-induced hypophysitis and examine its association with overall survival in this single-center retrospective cohort study of adult patients with cancer who received an ICI from January 1, 2012 through December 31, 2016. A total of 896 patients were identified who received ipilimumab alone (n=120); ipilimumab and nivolumab (n=50); ipilimumab before or after pembrolizumab (n=70); pembrolizumab alone (n=406); and nivolumab alone (n=250). Twenty-six patients (2.9%) developed hypophysitis after a median of 2.3 months. Median age at the start of ICI was 57.9 years and 54% were men. Hypophysitis occurred in 7.9% of patients receiving ipilimumab alone or in combination or sequence with a programmed cell death protein 1 inhibitor; 1.7% after pembrolizumab alone, never after nivolumab alone. Secondary adrenal insufficiency occurred in all hypophysitis cases. Use of ipilimumab alone or in combination was associated with pituitary enlargement on imaging and mass effects more frequently than pembrolizumab alone. Occurrence of hypophysitis was associated with improved overall survival by univariate analysis (median 50.7 vs 16.5 months; p=0.015) but this association was not observed in multivariable landmark survival analysis (HR for mortality 0.75; 95% CI 0.38 to 1.30; p=0.34) after adjusting for age, sex and malignancy type. To conclude, hypophysitis occurred most frequently after ipilimumab and manifested as anterior hypopituitarism affecting the corticotrophs more commonly than thyrotrophs and gonadotrophs. Mass effects and pituitary enlargement occurred more frequently in ipilimumab-induced hypophysitis. The association of hypophysitis with overall survival needs further investigation.

Purpose of review Our goal is to review pertinent data evaluating the association between immune checkpoint inhibitor (ICI)-induced endocrine dysfunction and survival in cancer patients as well as to understand the potential molecular links between these. Recent findings ICIs have revolutionized cancer therapy but have also led to multiple immune-related adverse events (irAEs). Studies have demonstrated a link between the development of irAEs and improved survival, suggesting that ICI-induced antitumor immunity and autoimmunity are coupled. Thyroid irAEs are most frequently and strongly associated with improved survival, particularly in the context of overt thyroid dysfunction. Other endocrine irAEs, such as hypophysitis and diabetes are quite rare wherein the treatment approach or the disease process itself may mitigate improvement in survival. Preclinical and translational data indicate a role for CD4+ T cells, regulatory T cells and/or cytokines mediating irAEs, including thyroiditis. Summary The development of irAEs is associated with improved tumor responses and survival in cancer patients. Thyroid irAEs, alone or in combination with other irAEs, are most strongly associated with improved outcomes. Biomarkers of response to ICIs are lacking, despite well-characterized pathologic and genomic susceptibilities predicting ICI efficacy. Early detection of thyroid irAEs may identify patients most likely to have durable antitumor response to ICIs. Although irAEs and antitumor immunity appear ‘coupled’, translational studies indicate the potential for their ‘uncoupling’, which could enable antitumor efficacy with greater safety margins.

Abstract Introduction: The influence of the immune system on follicular cell-derived thyroid cancer behavior has been suggested by various studies but this information has not been comprehensively translated into a prediction for thyroid cancer prognosis. We aimed to identify circulating immune cell profiles associated with thyroid cancer prognosis. This information would be a significant advance in the field of thyroid cancer management. Methods: We performed a single-center prospective cohort study of 32 follicular-cell derived thyroid cancer patients enrolled at the time of initial or subsequent surgery. We performed peripheral blood multi-parameter flow cytometry and collected relevant clinicopathologic, biochemical and radiologic data. We classified patients based on the AJCC TNM cancer stage, American Thyroid Association (ATA) initial risk of recurrence, and status of disease during follow-up. Results: On initial immunophenotyping, patients with aggressive/advanced thyroid cancer (ATA high risk vs. intermediate/low risk; AJCC stage 3/4 vs. 1/2; recurrence or distant metastases vs. no evidence of disease during follow-up) demonstrated increased circulating monocytes and granulocytes but decreased all lymphocytes, T cells (specifically CD4+ and gamma delta) and natural killer (NK) T-like cells. Further immunophenotyping revealed that aggressive/advanced thyroid cancer had increased circulating CD4+CD45+RO effector memory but decreased CD4+CD45+RA central memory T cells and increased regulatory T cells. Stage 3/4 thyroid cancer patients additionally had increased circulating CD33+HLADR- myeloid-derived suppressor cells (MDSCs) as compared to stage1/2. Conclusions: Aggressive thyroid cancer at presentation (AJCC stage, ATA risk category) or during follow-up (distant metastases) is characterized by a circulating immunophenotype comprising of increased immune suppressor cells (regulatory T cells, MDSCs, effector memory T cells) but decreased immune activator cells (CD4+ T cells, gamma delta T cells, NK T-like cells, central memory T cells) as compared to less aggressive thyroid cancer. This circulating immunophenotype may serve as a biomarker for cancer prognosis and guide the selection and development of novel immunotherapies for advanced thyroid cancer.

Background: Medullary thyroid cancer (MTC) can be associated with significant morbidity and mortality in advanced cases. Hence, we aimed to identify factors at the time of MTC surgery that predict overall survival (OS), disease-specific survival (DSS), locoregional recurrence/persistence (LR), and distant metastases (DM). Methods: We performed a retrospective study of clinicopathologic, radiological, and laboratory data in MTC patients who underwent thyroidectomy at Mayo Clinic from January 1995 to December 2015. Results: We identified 163 patients (mean age 48.4 years, 48% males), 102 with sporadic MTC and 61 with hereditary disease ( n = 46 multiple endocrine neoplasia [MEN] 2A, n = 3 MEN 2B, n = 12 familial MTC) with a median follow-up time of 5.5 years. On univariate analysis, age >55 years, male sex, DM at the time of surgery (M1), lateral neck lymph node (LN) involvement (N1b), gross extrathyroidal extension (ETE), American Joint Committee on Cancer (AJCC) stage 3/4, tumor size (T) 3/4, tumor size, and postoperative calcitonin (Ctn) and carcinoembryonic antigen (CEA) were significant predictors of worse OS and DSS. On multivariable analysis, both gross ETE (hazard ratio [HR] 4.62, 6.58) and M1 (HR 5.11, 10.45) remained significant predictors of worse OS as well as DSS, while age >55 years (HR 3.21), male sex (HR 2.42), and postoperative Ctn (HR 1.002 for every 100 pg/mL increase) were significant only for worse OS. On univariate analysis, male sex, M1, N1b, gross ETE, stage 3/4, T 3/4, tumor size, number of LNs involved, and postoperative Ctn were significant predictors of LR and DM; age >55 years was additionally significant for DM. On multivariable analysis, gross ETE (HR 3.16, 5.93) and N1b (HR 4.31, 4.64) remained significant predictors of LR and DM; ratio of resected/involved LN (HR 10.91) was additionally predictive for LR and postoperative Ctn (HR 1.003 for every 100 pg/mL increase) for DM. Conclusions: Disease burden at initial surgery, especially gross ETE, lateral neck LN involvement, and DM, as well as the biochemical response to surgery appear to be more important than demographic factors in terms of MTC prognosis. These findings highlight the importance of rigorous perioperative assessment to better predict MTC outcomes.

Abstract Context Hyperthyroidism is associated with low levels of cholesterol and triglycerides, and hypothyroidism is associated with hypercholesterolemia and hypertriglyceridemia. Objective The aim of this systematic review was to investigate the impact of therapy for overt and subclinical hyper- and hypothyroidism on serum lipids. Data Sources We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and Scopus from 1970 through April 5, 2018. Study Selection Pairs of independent reviewers selected randomized and observational studies evaluating lipid parameters in patients undergoing treatment for hyper- or hypothyroidism. Data Extraction Pairs of independent reviewers extracted data and appraised studies. Data Synthesis Treatment of overt hyperthyroidism showed a significant increase in total cholesterol (TC) by 44.50 mg/dL (95% confidence interval [CI]: 37.99, 51.02), low-density lipoprotein cholesterol (LDL-C) by 31.13 mg/dL (95% CI: 24.33, 37.93), high-density lipoprotein cholesterol (HDL-C) by 5.52 mg/dL (95% CI: 1.48, 9.56), apolipoprotein A (Apo A) by 15.6 mg/dL (95% CI: 10.38, 20.81), apolipoprotein B (apo B) by 26.12 mg/dL (95% CI: 22.67, 29.57), and lipoprotein (Lp[a]) by 4.18 mg/dL (95% CI: 1.65, 6.71). There was no significant change in triglyceride (TG) levels. Treatment of subclinical hyperthyroidism did not change any lipid parameters significantly. Levothyroxine therapy in overt hypothyroidism showed a statistically significant decrease in TC by -58.4 mg/dL (95% CI: -64.70, -52.09), LDL-C by -41.11 mg/dL (95% CI: -46.53, -35.69), HDL-C by -4.14 mg/dL (95% CI: -5.67, -2.61), TGs by -7.25 mg/dL (95% CI: -36.63, 17.87), apo A by -12.59 mg/dL (95% CI: -17.98, -7.19), apo B by -33.96 mg/dL (95% CI: 41.14, -26.77), and Lp(a) by -5.6 mg/dL (95% CI: -9.06, -2.14). Levothyroxine therapy in subclinical hypothyroidism showed similar changes but with a smaller magnitude. The studies contained varied population characteristics, severity of thyroid dysfunction, and follow-up duration. Conclusions Treatment of overt but not subclinical hyperthyroidism is associated with worsening of the lipid profile. Levothyroxine therapy in both overt and subclinical hypothyroidism leads to improvement in the lipid profile, with a smaller magnitude of improvement in subclinical hypothyroidism.

Abstract Context: Immune checkpoint inhibitors (ICIs) are monoclonal antibodies against checkpoints namely CTLA-4, PD-1 and PD-L1. These can cause pituitary dysfunction due to hypophysitis in addition to other endocrinopathies. While the prevalence and course of hypophysitis have been described extensively, the relationship between hypophysitis and cancer prognosis has only been investigated in melanoma patients on ipilimumab. Additionally, the impact of high dose glucocorticoids for hypophysitis treatment on survival has been unclear. Objective: In order to address these important questions, we aimed to characterize the frequency and course of hypophysitis from various ICIs, and to investigate a possible impact on overall survival in cancer patients.Design and Methods: We conducted a single center retrospective cohort study of adult cancer patients that received an ICI from 1/1/2012 - 12/31/2016, followed for a median of 14.8 months. A total of 896 patients were identified that received ipilimumab alone (n=120); ipilimumab and nivolumab (n=50); ipilimumab followed or preceded by pembrolizumab (n=70), pembrolizumab alone (n=406), and nivolumab alone (n=250). Results: Twenty-six patients (2.9%) developed hypophysitis after a median of 2.3 months (range 0.8 to 11.7). Their median age at initiation of ICI was 57.9 years (range 42.4 to 78.5), 54% were males, and the most common malignancy was melanoma (81%). All had hypopituitarism showing secondary adrenal insufficiency (100%), central hypothyroidism (38.5%) and central hypogonadism (28.5% in men, 25% in premenopausal women). Sixty-four percent demonstrated pituitary enlargement on imaging which resolved on follow-up. Mass effects occurred in 50% and were managed by initial high dose glucocorticoids. Thyroiditis occurred in 19.2% of those with hypophysitis. Occurrence of hypophysitis was associated with better overall survival (median 50.7 vs 16.5 months; p value 0.015) and reduced mortality (RR 0.52, 95% CI 0.28 to 0.99; p value 0.036) after adjusting for age, sex and malignancy type. Conclusions: Hypophysitis, usually but not always accompanied by classic MRI features, occurrs within a few weeks in cancer patients most frequently after ipilimumab alone or in combination with a PD-1 inhibitor, rarely after pembrolizumab and never after nivolumab alone. ICI-induced hypophysitis presents as mass effects in half and as hypopituitarism in all patients involving the corticotrophs more commonly than thyrotrophs and gonadotrophs. The improved survival with a 48% lower mortality rate in patients with hypophysitis suggests its possible role as a marker for better efficacy of ICIs against malignancy.

Background: Immune checkpoint inhibitors (ICIs) frequently cause thyroid dysfunction but their underlying mechanism remains unclear. We have previously demonstrated increased circulating natural killer (NK) cells and human leukocyte antigen (HLA)-DR surface expression on inflammatory intermediate CD14 + CD16 + monocytes in programmed cell death protein-1 (PD-1) inhibitor-treated patients. This study characterizes intrathyroidal and circulating immune cells and class II HLA in ICI-induced thyroiditis. Methods: This is a single-center prospective cohort study of 10 patients with ICI-induced thyroiditis by flow cytometry of thyroid fine needle aspirates ( n = 9) and peripheral blood ( n = 7) as compared with healthy thyroid samples ( n = 5) and healthy volunteer blood samples ( n = 44); HLA class II was tested in n = 9. Results: ICI-induced thyroiditis samples demonstrated overall increased T lymphocytes (61.3% vs. 20.1%, p = 0.00006), CD4 − CD8 − T lymphocytes (1.9% vs. 0.7%, p = 0.006), and, as a percent of T lymphocytes, increased CD8 + T lymphocytes (38.6% vs. 25.7%; p = 0.0259) as compared with healthy thyroid samples. PD-1 inhibitor-induced thyroiditis had increased CD4 + PD1 + T lymphocytes (40.4% vs. 0.8%; p = 0.021) and CD8 + PD1 + T lymphocytes (28.8% vs. 1.5%; p = 0.038) in the thyroid compared with the blood. Circulating NK cells, certain T lymphocytes (CD4 + CD8 + , CD4 − CD8 − T, gamma – delta), and intermediate monocytes were increased in ICI-induced thyroiditis. Six patients typed as HLA-DR4-DR53 and three as HLA-DR15. Conclusions: ICI-induced thyroiditis is a T lymphocyte-mediated process with intra-thyroidal predominance of CD8 + and CD4 − CD8 − T lymphocytes. The HLA haplotypes may be involved but need further evaluation. These findings expand the limited understanding of ICI-induced thyroiditis, which could be further translated to guide immunomodulatory therapies for advanced thyroid cancer.