Kate Hasal

The incidence of thyroid cancer, which is now the most rapidly increasing endocrine malignancy, has been increasing at a rate of 3% to 5% per year, resulting in a near doubling in the past 30 years. Although improved detection and increased diagnosis have certainly played a role in the increasing incidence of thyroid cancer, other contributing factors have not yet been established.

With the emergence of geostatistics and geographic information system (GIS) tools, geospatial techniques have gained prominence as a way to use geolocated data to visualize, analyze, interpret, and map disease clusters, patterns, and trends, and as a method to assess the impact of ecological and socioeconomic factors on the spatial distribution of diseases. Together, these tools help to identify new drivers of public health concerns, which was one of the aims of a study at the University of Vermont.

&ldquo;In this study, we postulated that geospatial and temporal analyses would reveal novel patterns of thyroid cancer incidence in a rural population,&rdquo; said John P. Hanley, of the School of Engineering, College of Engineering and Mathematical Sciences at the University of Vermont in Burlington. Hanley made his comments at the Endocrine Society&rsquo;s 97th Annual Meeting & Expo. For the study by Hanley and colleagues, the Vermont Department of Health provided data, including the year of initial diagnosis, age at diagnosis, gender, primary site of disease at diagnosis, histology code, histological grade, behavior code, size of tumor, postal code at diagnosis, year last contacted, vital status, and death place code, for the period 1994 to 2007.

The thyroid cancer incidence rate in rural Vermont was 8.0 per 100,000 and comparable to the national incidence rate of 8.4 per 100,000. However, the annual percentage change (APC) in rural Vermont was 8.3% compared with a nationwide APC of 5.7%. Similar to national estimates, about 3 times as many women as men were diagnosed with thyroid cancer (3.1:1 females to males), and 0.5 deaths occurred per 100,000 cases. For women, the thyroid cancer incidence peaked in the 30- to 59-year-old age group and rose significantly between 2001 and 2007, while the incidence of thyroid cancer in men did not vary significantly by age.

Tumor size did not vary over time for men or women, with 38% of tumors being <1.0 cm, 22% between 1 and 2 cm, and 40% >2.0 cm. For women, 89% of cases were papillary thyroid cancer (PTC), 8% were follicular thyroid cancer (FTC), 2% were medullary thyroid cancer (MTC), and 0.6% were anaplastic thyroid cancer. For men, 77% of cases were PTC, 15% were FTC, 1% were MTC, and 3% were ATC.

Using geospatial analyses, the data provided evidence of an increased incidence of thyroid cancerincluding both large and small tumors&mdash;in a rural population and in both women and men.

&ldquo;Our data indicate that factors other than increased diagnostic scrutiny are drivers of the increase in thyroid cancer incidence. These data provide evidence of increased thyroid cancer incidence in a rural population that is likely due to environmental drivers and socioeconomic factors,&rdquo; Hanley concluded.

Geospatial modeling can provide an important framework for evaluation of additional associative risk factors. Future studies will focus on expanding these analyses to the household level and elucidating associated risk factors in nonrandom clusters of patients.

Carr FE, Hanley JP, Jackson E, et al. Geospatial and temporal analysis of thyroid cancer incidence in a rural population. Presented at the 2015 Endocrine Society Annual Meeting; March 5-8, 2015; San Diego, CA. Poster Board FRI-026.

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The incidence of thyroid cancer, which is now the most rapidly increasing endocrine malignancy, has been increasing at a rate of 3% to 5% per year, resulting in a near doubling in the past 30 years. 

Geospatial and Temporal Analysis Show Increased Thyroid Cancer Incidence in Rural Population

After treatment with ipilimumab, a monoclonal antibody againstcytotoxic T lymphocyte-associated antigen 4 (CTLA-4), patients with metastatic melanoma may be treated with pembrolizumab, a monoclonal antibody that binds to the programmed cell death-1 (PD-1) receptor.

Pembrolizumab was approved by the US Food and Drug Administration (FDA) in September 2014 for the treatment of unresectable or metastatic melanoma with disease progression following ipilimumab and, in patients who are

Another PD-1 inhibitor, nivolumab, was previously approved for use in Japan. Anti-PD-1 agents use a unique approach to chemotherapy in that they serve as checkpoint inhibitors that enhance or de novo stimulate antitumor immune responses to eliminate cancer cells rather than directly acting on the tumor cell to induce tumor cell death.

Unfortunately, immune checkpoint inhibitors can also cause side effects, described as immune-related adverse events (IRAEs). In a comprehensive retrospective review of endocrine-related AEs following treatment of patients with advanced melanoma with ipilimumab and nivolumab, combination therapy was associated with a 22% incidence of either thyroiditis or hypothyroidism and a 9% incidence of hypophysitis.

&ldquo;We describe a patient who developed thyroiditis and pancreatitis following treatment with ipilimumab and pembrolizumab,&rdquo; said Joseph James Fallon Jr, MD, of Inspira Medical Center in Woodbury and Marlton, New Jersey, on March 5, 2014, at the Endocrine Society&rsquo;s 97th Annual Meeting and Expo.

Fallon presented the case of a 45-year-old Caucasian female with a history of stage III melanoma of the scalp, whichhad been excised, and hypertriglyceridemia. She presented to the emergency department with a 2-week history of abdominal pain, intractable nausea, vomiting, and watery diarrhea. Additionally, she reported significant fatigue, decreased oral intake, and a 16-lb weight loss. Her melanoma had recurred after wide excision, and she had undergone chemotherapy, including 3 of 4 cycles of ipilimumab and, subsequently, 5 cycles of pembrolizumab. Her last infusion of pembrolizumab had been administered 1 week before her presentation in the emergency department. She was taking fenofibrate 136 mg daily.

On examination, her body mass index was 25.4 kg/m

, blood pressure was 106/51 mmHg, and her heart rate was 103 bpm. She exhibited multiple scalp lesions, but no thyroid enlargement or tenderness was observed, and she exhibited no hand tremors.

Her laboratory tests revealed an erythrocyte sedimentation rate of 52 (0-20 mm/h), C-reactive protein value of 12.0 (0-0.9 mg/L), bicarbonate value of 15 (24-32 mEq/L), alkaline phosphatase value of 131 (38-126 U/L), aspartate aminotransferase value of 64 (14-36 U/L), triglyceride value of 168 (10-150 mg/dL), and a lipase value of 1880 (23-300 U/L). Her thyroid-stimulating hormone level was 0.015 (0.465-4.68 &micro;U/mL) with a free T4 value of 3.81 (0.78-2.19 ng/dL), and a free T

value of 8.9 (2.77-5.77 pg/mL). Thyroperoxidase antibodies were 4.7 (0-9 IU/cc), thyroglobulin antibodies were <0.9 (0-4 IU/cc), and her thyroid-stimulating immunoglobulin level was 105% (<125%).

Thyroid ultrasound revealed a normally textured gland. The patient was admitted to the hospital and received intravenous (IV) fluids. A computed tomography scan of the abdomen and pelvis demonstrated mild thickening of the right colon wall. A positron emission scan showed mild increased uptake in the right thyroid and pancreas.

Based on her clinical symptoms and laboratory and imaging results, the patient was diagnosed with thyroiditis and pancreatitis, presumably attributable to an autoimmune response to the chemotherapy that she received. The patient significantly improved with the initiation of IV methylprednisone treatment, and she was discharged with metoprolol and prednisone taper.

Autoimmune thyroiditis has been noted to occur in ipilimumab-treated patients at an incidence of less than 1%.

Immune-mediated adverse reactions, including changes in thyroid activity (hyperthyroidism or hypothyroidism), have been observed with pembrolizumab.

Therefore, although rare, thyroiditis has been described as a side effect of anticancer immunotherapy with these agents.

&ldquo;The exact mechanism of IRAEs from pembrolizumab still remains to be elucidated; however, they are inflammatory in nature and may represent a breakdown of tolerance to self-antigens. Monitoring of thyroid and pituitary function at baseline and before each cycle is required, and medication discontinuation may be required,&rdquo; concluded Fallon.

Keytruda&reg; Injection [package insert]. Whitehouse Station, NJ. Merck & Co., Inc.; 2014.

Ryder M, Callahan M, Postow MA, Wolchok J, Fagin JA. Endocrine-related adverse events following ipilimumab in patients with advanced melanoma: a comprehensive retrospective review from a single institution.

Somasundaram A, Ukrainski M, Ahmed I, et al. Ipilimumab and pembrolizumab induced thyroiditis. Presented at the 2015 Endocrine Society Annual Meeting; March 5-8, 2015; San Diego, CA. Abstract THR 024-043. Poster Board THR-032.

In an analysis of adverse events following treatment of patients with advanced melanoma with ipilimumab and nivolumab, combination therapy was associated with a 22% incidence of either thyroiditis or hypothyroidism and a 9% incidence of hypophysitis.

Kate Hasal | Authors

Articles

Geospatial and Temporal Analysis Show Increased Thyroid Cancer Incidence in Rural Population

Thyroiditis in Melanoma Patient Treated With Ipilimumab and Pembrolizumab