Christian Nasr

Circulating thyrotropin receptor mRNA as a novel marker of thyroid cancer: clinical applications learned from 1758 samples.

Objectives:Since thyroglobulin, no new blood tests for differentiated thyroid cancer (DTC) have been introduced into routine clinical practice. In initial studies, the detection of circulating DTC cells by thyrotropin receptor (TSHR) mRNA measurement distinguished benign from malignant thyroid diseases. This prospective validation study tests the ability of TSHR mRNA to diagnose DTC preoperatively and to detect cancer recurrence. Methods:TSHR mRNA was measured by quantitative RT-PCR from blood drawn perioperatively in patients undergoing thyroid surgery (n = 526), postoperatively in patients undergoing DTC follow-up (n = 418) and in patients monitored for known benign disease (n = 151). The reference range and applications for TSHR mRNA were previously defined from 663 samples from patients with normal, benign, and malignant thyroid disease. Results:In patients with follicular neoplasms or suspicious cytology, preoperative TSHR mRNA >1 ng/&mgr;g had 96% predictive value for DTC, whereas 95% of patients with undetectable mRNA and benign thyroid sonography had benign disease. In patients with DTC, elevated TSHR mRNA levels became undetectable in all patients (n = 64) on the first postoperative day, except in 5 who manifested persistent or recurrent cervical disease within the year. In long-term follow-up of DTC patients with thyroglobulin antibodies, 96% with undetectable TSHR mRNA also had no evidence of cancer recurrence. Conclusions:TSHR mRNA provides an additional clinical tool for the evaluation of patients with thyroid nodules. It is particularly useful in guiding appropriate initial surgery for follicular neoplasms. TSHR mRNA also represents a new blood test to aid assessment of disease status in thyroid cancer follow-up.

Co-Occurrence of Papillary Thyroid Carcinoma and Primary Lymphoma of the Thyroid in a Patient with Long-Standing Hashimoto's Thyroiditis

BACKGROUND Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer, whereas mucosa-associated lymphoid tissue (MALT) lymphoma of the thyroid gland is uncommon. Simultaneous occurrence of both disease entities is very rare. PATIENT FINDINGS A 59-year-old man with known hypothyroidism from Hashimotos thyroiditis (HT) was seen for thyroid nodules. A thyroid ultrasound revealed a heterogeneous thyroid gland with two hypoechoic nodules, one in the right aspect of the isthmus measuring 2.0 cm×3.2 cm×1.7 cm and another one in the left lobe measuring 1.4 cm×1.3 cm×1.2 cm. A fine-needle aspiration (FNA) of the right-sided nodule revealed atypical epithelial cells and atypical lymphoid cells in a background of lymphocytic thyroiditis; FNA of the left-sided nodule showed findings of PTC. A total thyroidectomy was performed. Lymph node dissection was not performed. Pathology showed extranodal marginal zone B-cell lymphoma of MALT type with extreme plasmacytic differentiation in the right nodule and PTC in the left nodule (pT1b Nx Mx). Postoperatively, he underwent radioactive iodine ablation treatment. There was only minimal neck uptake on the post-treatment scan. Further work-up did not show any evidence of extrathyroidal lymphoma. Seven years after the surgery, the patient had no evidence of recurrence of either malignancy. SUMMARY PTC is the most prevalent thyroid cancer and has an excellent prognosis. Primary thyroid lymphoma is rare and accounts for <5% of all thyroid cancers. Among the primary thyroid lymphomas, MALT lymphoma tends to have a more indolent course and a better prognosis. PTC and MALT lymphoma have been associated with HT. FNA has been validated in several studies for the diagnosis of MALT lymphoma; however, distinguishing MALT lymphoma from HT remains a challenge due to their histological similarities. The treatment of MALT lymphoma remains controversial; however, surgery is generally accepted in the early-stage MALT lymphoma as was performed in the present case. CONCLUSION Since HT is associated with PTC and MALT lymphoma, patients with HT deserve careful surveillance for both disease entities. In our patient, the management of one malignancy did not affect the management of the other, and the prognosis did not seem to be affected.

Approach to a low TSH level: patience is a virtue.

Confronted with a low serum level of thyrotropin (thyroid- stimulating hormone, TSH), physicians should not jump to the conclusion that it is due to a hyperthyroid state, as other conditions and some drugs can be associated with a TSH level that is slightly low (0.1–0.4 μIU/mL) or frankly suppressed (< 0.1 μIU/mL). This review discusses how to approach a low TSH, stressing the frequent need to reassess thyroid function before making a diagnosis, the underlying processes and the drugs that can be responsible, and the degree of TSH suppression and its role in the evaluation. Confronted with a low TSH level, physicians should not jump to the conclusion that it is due to a hyperthyroid state.

Risk of Hematologic Malignancies After Radioiodine Treatment of Well-Differentiated Thyroid Cancer

Purpose To investigate the risk and outcomes of second hematologic malignancies (SHMs) in a population-based cohort of patients with well-differentiated thyroid cancer (WDTC) treated or not with radioactive iodine (RAI). Methods Patients with WDTC were identified from SEER registries. Competing risk regression analysis was performed to calculate the risks of SHMs that occurred after WDTC treatment and outcomes after SHM development were assessed. Results Of 148,215 patients with WDTC, 53% received surgery alone and 47% received RAI. In total, 783 patients developed an SHM after a median interval of 6.5 years (interquartile range, 3.3 to 11.2 years) from WDTC diagnosis. In multivariable analysis, compared with those undergoing thyroidectomy alone, RAI treatment was associated with an increased early risk of developing acute myeloid leukemia (AML; hazard ratio, 1.79; 95% CI, 1.13 to 2.82; P = .01) and chronic myeloid leukemia (CML; hazard ratio, 3.44; 95% CI, 1.87 to 6.36; P < .001). This increased risk of AML and CML after RAI treatment was seen even in low-risk and intermediate-risk WDTC tumors. Occurrence of AML but not CML in patients with WDTC was associated with shorter median overall survival compared with matched controls (8.0 years v 31.0 years; P = .001). In addition, AML developing after RAI trended toward inferior survival compared with matched controls with de novo AML (median overall survival, 1.2 years v 2.9 years; P = .06). Conclusion Patients with WDTC treated with RAI had an increased early risk of developing AML and CML but no other hematologic malignancies. AML that arises after RAI treatment has a poor prognosis. RAI use in patients with WDTC should be limited to patients with high-risk disease features, and patients with WDTC treated with adjuvant RAI should be monitored for myeloid malignancies as part of cancer surveillance.

CIRCULATING THYROID-STIMULATING HORMONE RECEPTOR MESSENGER RNA AS A MARKER OF TUMOR AGGRESSIVENESS IN PATIENTS WITH PAPILLARY THYROID MICROCARCINOMA

BACKGROUND We have previously shown that thyroid-stimulating hormone receptor messenger RNA (TSHR mRNA) is detectable in the peripheral blood of patients with papillary thyroid microcarcinoma (PTmC). The aim of this study was to analyze the utility of TSHR mRNA status as a marker of tumor aggressiveness in patients with PTmC. METHODS Preoperative TSHR mRNA values were obtained in 152 patients who underwent thyroidectomy and were found to have PTmC on final pathology. Clinical parameters were analyzed from an institutional review board-approved database using χ(2) and t tests. RESULTS Preoperatively, TSHR mRNA was detected in the peripheral blood in 46% of patients, which was less than that for macroscopic papillary thyroid carcinoma (PTC) (80%) but higher than for benign thyroid disease (18%) (P<.001). The focus of cancer was larger in the TSHR mRNA-positive group compared to the negative group (0.41 vs. 0.30 cm, respectively, P = .015). The prevalence of tall-cell variant was higher in the TSHR mRNA positive group. The rates of lymph node (LN) metastasis (16% vs. 10%), multifocality (46% vs. 49%), and extra-thyroidal extension (10% vs. 5%) were similar between the TSHR mRNA-positive and-negative groups, respectively. In patients 45 years or older, rate of LN metastasis was higher in those who were TSHR mRNA positive (10%) versus negative (2%) (P = .039). TSHR mRNA positivity predicted a higher likelihood of radioactive iodine treatment (36% vs. 17%, P = .009) postoperatively. CONCLUSION This study shows that TSHR mRNA, which is a marker of circulating thyroid cancer cells, is detectable in about half of patients with PTmC. The positivity of this marker predicts a higher likelihood of LN involvement in patients with PTmC who are 45 years or older.

Anaplastic thyroid cancer in young patients: A contemporary review

PURPOSE Little is known about prognostic factors and treatment outcomes in young patients with anaplastic thyroid cancer (ATC). The goal of this study is to define the clinical features of this subgroup. MATERIAL AND METHODS Patients age 55 or younger with either ATC or well-differentiated thyroid cancer (WDTC) with anaplastic changes were identified using electronic medical record at the Cleveland Clinic. The same number of patients older than 55 was randomly selected to serve as control. Progression-free survival (PFS), overall survival time (OST) and cause-specific mortality (CSM) were measured against age, tumor histology, extent of disease, and treatment modalities. RESULTS Twelve patients age 55 or younger were identified. The median age was 51 years. Four patients had WDTC with anaplastic components--mixed tumor group (MTG). Their median PFS, OST, and CSM at 24 months were 21.5 months, 51 months, and 25%, respectively. For the other 8 patients who had pure ATC, their median PFS, OST, and CSM were 3.5 months, 6 months, and 100%, respectively. Patients in the MTG had better survival compared to the pure ATC and control group in terms of PFS (p = 0.0047 and p = 0.0053), OST (p = 0.0028 and p = 0.0029) and the CSM at 24 months (p = 0.0339 and p = 0.0096). In the pure ATC group, patients with positive cervical lymph node and distant metastases had similar overall survival outcomes (6 vs. 8 months, p = 0.4995). CONCLUSION Prognostic factors favoring survival in young patients with ATC include ATC arising within WDTC. Once full anaplastic transformation occurs, age was not a significant factor in survival.

Risk of developing chronic myeloid neoplasms in well-differentiated thyroid cancer patients treated with radioactive iodine

Exposure to ionizing radiation increases the risk of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN), but such risks are not known in well-differentiated thyroid cancer (WDTC) patients treated with radioactive iodine (RAI). A total of 148 215 WDTC patients were identified from Surveillance, Epidemiology and End Results registries between 1973 and 2014, of whom 54% underwent definitive thyroidectomy and 46% received adjuvant RAI. With a median follow-up of 6.6 years, 77 and 66 WDTC patients developed MDS and MPN, respectively. Excess absolute risks for MDS and MPN from RAI treatment when compared to background rates in the US population were 6.6 and 8.1 cases per 100 000 person-years, respectively. Compared to background population rates, relative risks of developing MDS (3.85 (95% confidence interval, 1.7–7.6); P=0.0005) and MPN (3.13 (1.1–6.8); P=0.012) were significantly elevated in the second and third year following adjuvant RAI therapy, but not after thyroidectomy alone. The increased risk was significantly associated with WDTC size ⩾2 cm or regional disease. Development of MDS was associated with shorter median overall survival in WDTC survivors (10.3 vs 22.5 years; P<0.001). These data suggest that RAI treatment for WDTC is associated with increased risk of MDS with short latency and poor survival.

Diagnostic accuracy of circulating thyrotropin receptor messenger RNA combined with neck ultrasonography in patients with Bethesda III-V thyroid cytology

BACKGROUND The aim of this study was to analyze the usefulness of thyrotropin receptor messenger RNA (TSHR-mRNA) combined with neck ultrasonography (US) in the management of thyroid nodules with Bethesda III-V cytology. METHODS Cytology slides of patients with a preoperative fine needle aspiration (FNA) and TSHR-mRNA who underwent thyroidectomy between 2002 and 2011 were recategorized based on the Bethesda classification. Results of thyroid FNA, TSHR-mRNA, and US were compared with the final pathology. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. RESULTS There were 12 patients with Bethesda III, 112 with Bethesda IV, and 58 with Bethesda V cytology. The sensitivity of TSHR-mRNA in predicting cancer was 33%, 65%, and 79 %, and specificity was 67%, 66%, and 71%, for Bethesda III, IV, and V categories, respectively. For the same categories, the PPV of TSHR-mRNA was 25%, 33%, and 79%, respectively; whereas the NPV was 75%, 88%, and 71%, respectively. The addition of neck US to TSHR-mRNA increased the NPV to 100% for Bethesda III, and 86%, for Bethesda IV, and 82% for Bethesda V disease. CONCLUSION This study documents the potential usefulness of TSHR-mRNA for thyroid nodules with Bethesda III-V FNA categories. TSHR-mRNA may be used to exclude Bethesda IV disease. A large sample analysis is needed to determine its accuracy for Bethesda category III nodules.

The utility of peripheral thyrotropin receptor mRNA in the management of differentiated thyroid cancer

BACKGROUND Our aim was to analyze the utility of peripheral thyrotropin receptor (TSHR) messenger RNA (mRNA) in predicting and detecting the recurrence of differentiated thyroid cancer. METHODS Peripheral blood TSHR-mRNA was obtained in 103 patients before and after total thyroidectomy. An analysis was performed to correlate peripheral blood TSHR-mRNA concentration with oncologic outcomes. RESULTS Tumor types were papillary (n = 92), follicular (n = 9) and Hürthle cell (n = 2) cancer. Preoperative TSHR-mRNA was ≥1.02 ng/μg in 85% (88/103). On follow-up (median 48 months), 10 patients (10 %) developed recurrence. Recurrence rate in patients with a preoperative TSHR-mRNA ≥ 1.02 ng/μg was 11% versus 0% in those with a lesser concentration. TSHR-mRNA correctly diagnosed 7 (70%) of 10 recurrences. Of 19 patients with positive thyroglobulin (Tg) antibodies, TSHR-mRNA confirmed disease-free status in 12 (63%) and recurrence in 1 (5%). For Tg, TSHR-mRNA and whole-body radioactive iodine scan, sensitivity was 70%, 70%, and 75%; specificity 94%, 76%, 97%; PPV 54%, 24%, and 67%; and NPV 97%, 96%, and 98%, respectively, in detecting recurrent disease. CONCLUSION This study shows that patients with preoperative TSHR-mRNA ≥1.02 ng/μg may be at a greater risk for recurrence compared with those with a lesser concentration. In the presence of Tg antibodies, TSHR-mRNA accurately predicted disease status in 68% of patients. Its overall performance in detecting recurrence was similar to Tg and whole-body radioactive iodine scan, albeit with lower specificity and PPV.

Diabetes therapy and cancer risk: where do we stand when treating patients?

The pathophysiology of type 2 diabetes mellitus conveys increased cancer risk, and any antidiabetic drug may alter that risk in a favorable or unfavorable way. This article discusses the links between diabetes and cancer, the different agents available for treating diabetes, and the cancer risk associated with these therapies. Several classes of diabetes drugs are under scrutiny for potentially promoting cancer in a population already at risk.