Jason D. Prescott

The relationship between chronic lymphocytic thyroiditis and central neck lymph node metastasis in North American patients with papillary thyroid carcinoma

BACKGROUND Several studies have reported that concurrent chronic lymphocytic thyroiditis (CLT) with papillary thyroid carcinoma (PTC) is associated with improved prognosis of the PTC, including decreased lymph node metastasis. We sought to assess the incidence of central nodal metastasis (CNM) in patients with PTC and concurrent CLT. METHODS We studied 495 consecutive patients who underwent thyroidectomy with nodal excision for PTC. Pathology reports identified the presence of CLT and the extent of CNM. RESULTS There were 226 patients (46%) with CLT and 220 (44%) with CNM. Patients with CLT were more often female (88% vs. 71%; P < .001) and had a younger median age (43 vs. 47 years; P = .03), a lesser incidence of CNM (35% vs. 52.4%; P < .001), and a greater incidence of pT1a (40% vs. 25%; P < .001) and pT1b (38% vs. 29%; P < .001) tumors. Multivariate analysis showed that the presence of CLT was associated with a 39% decreased odds of CNM after adjusting for age, gender, tumor size, PTC histopathologic subtype, and presence of lymphovascular invasion (odds ratio, 0.61; 95% confidence interval, 0.38-0.99; P = .046). Predicted probability modeling showed that all females with CLT and no suspicious nodal findings on ultrasonography had a 9-11% risk of CNM with pT1a tumors. CONCLUSION Female patients of all ages with CLT and small PTCs have the least incidence of CNM.

Effect of Gene Expression Classifier Molecular Testing on the Surgical Decision-Making Process for Patients With Thyroid Nodules.

IMPORTANCE Commercial molecular testing, such as the gene expression classifier (GEC), is now being used in the work up of cytologically indeterminate thyroid nodules. While this test may be helpful in ruling out malignancy in a thyroid nodule, its effect on surgical decision making has yet to be fully defined. OBJECTIVE We aimed to determine the effect and outcome of GEC test results on the decision-making process for patients with thyroid nodules presenting for surgical consultation. DESIGN, SETTING, AND PARTICIPANTS A surgical management algorithm was developed that incorporated individual Bethesda System for Reporting Thyroid Cytopathology classifications, in addition to clinical, laboratory, and radiological findings. We then retrospectively applied this algorithm to 273 consecutive patients with thyroid nodules and GEC test results who had presented for surgical consultation between February 1, 2012, and December 31, 2014. INTERVENTIONS GEC testing. MAIN OUTCOMES AND MEASURES Changes in management were recorded to identify the effect of GEC testing on the surgical decision-making process. An alteration in management of 20% of cases was considered significant. RESULTS Of the 273 consecutive patients assessed by the GEC, mean (SD) age was 50.8 (14.7) years, 204 (74.7%) were female, and the mean (SD) nodule size was 2.4 (1.3) cm. Test results were suspicious for 233 (85.3%); benign for 31 (11.4%); and indeterminate for 8 (2.9%). The GEC test was also positive for medullary thyroid cancer for 1 patient (0.4%). The GEC test was correctly used as a rule-out test in only 127 patients (46.5%) with indeterminate nodules who lacked a clinical indication for surgery. The clinical management plan of only 23 (8.4%) patients was altered as a result of GEC test results, and of these 23 patients who proceeded to surgery, 16 patients (72.7%) were found to be inappropriately overtreated relative to postoperative histopathology analysis. We found that GEC testing did not affect the surgical decision-making process in 250 (91.6%) of our patients. In 146 cases, the use of GEC testing was not clinically indicated, and the test was being overused in patients for whom the results would not change surgical management. The positive predictive value of the GEC test for cytologically indeterminate nodules was 42.1%, and the negative predictive value was 83.3%. CONCLUSIONS AND RELEVANCE The GEC testing did not significantly affect the surgical decision-making process. Gene expression classifier testing is often used incorrectly and is overused in patients for whom the results would not change management. The GEC test demonstrated a lower than expected negative predictive value, and there was evidence of overtreatment among patients whose treatment was altered based on this test.

Differential in vivo tumorigenicity of diverse KRAS mutations in vertebrate pancreas: A comprehensive survey

Somatic activation of the KRAS proto-oncogene is evident in almost all pancreatic cancers, and appears to represent an initiating event. These mutations occur primarily at codon 12 and less frequently at codons 13 and 61. Although some studies have suggested that different KRAS mutations may have variable oncogenic properties, to date there has been no comprehensive functional comparison of multiple KRAS mutations in an in vivo vertebrate tumorigenesis system. We generated a Gal4/UAS-based zebrafish model of pancreatic tumorigenesis in which the pancreatic expression of UAS-regulated oncogenes is driven by a ptf1a:Gal4-VP16 driver line. This system allowed us to rapidly compare the ability of 12 different KRAS mutations (G12A, G12C, G12D, G12F, G12R, G12S, G12V, G13C, G13D, Q61L, Q61R and A146T) to drive pancreatic tumorigenesis in vivo. Among fish injected with one of five KRAS mutations reported in other tumor types but not in human pancreatic cancer, 2/79 (2.5%) developed pancreatic tumors, with both tumors arising in fish injected with A146T. In contrast, among fish injected with one of seven KRAS mutations known to occur in human pancreatic cancer, 22/106 (20.8%) developed pancreatic cancer. All eight tumorigenic KRAS mutations were associated with downstream MAPK/ERK pathway activation in preneoplastic pancreatic epithelium, whereas nontumorigenic mutations were not. These results suggest that the spectrum of KRAS mutations observed in human pancreatic cancer reflects selection based on variable tumorigenic capacities, including the ability to activate MAPK/ERK signaling.

The RET oncogene in papillary thyroid carcinoma

Papillary thyroid carcinoma (PTC) is the most common form of thyroid cancer, accounting for greater than 80% of cases. Surgical resection, with or without postoperative radioiodine therapy, remains the standard of care for patients with PTC, and the prognosis is generally excellent with appropriate treatment. Despite this, significant numbers of patients will not respond to maximal surgical and medical therapy and ultimately will die from the disease. This mortality reflects an incomplete understanding of the oncogenic mechanisms that initiate, drive, and promote PTC. Nonetheless, significant insights into the pathologic subcellular events underlying PTC have been discovered over the last 2 decades, and this remains an area of significant research interest. Chromosomal rearrangements resulting in the expression of fusion proteins that involve the rearranged during transfection (RET) proto‐oncogene were the first oncogenic events to be identified in PTC. Members of this fusion protein family (the RET/PTC family) appear to play an oncogenic role in approximately 20% of PTCs. Herein, the authors review the current understanding of the clinicopathologic role of RET/PTC fusion proteins in PTC development and progression and the molecular mechanisms by which RET/PTCs exert their oncogenic effects on the thyroid epithelium. Cancer 2015;121:2137–2146.

Evaluation of the Effect of Diagnostic Molecular Testing on the Surgical Decision-Making Process for Patients With Thyroid Nodules

IMPORTANCE Diagnostic molecular testing is used in the workup of thyroid nodules. While these tests appear to be promising in more definitively assigning a risk of malignancy, their effect on surgical decision making has yet to be demonstrated. OBJECTIVE To investigate the effect of diagnostic molecular profiling of thyroid nodules on the surgical decision-making process. DESIGN, SETTING, AND PARTICIPANTS A surgical management algorithm was developed and published after peer review that incorporated individual Bethesda System for Reporting Thyroid Cytopathology classifications with clinical, laboratory, and radiological results. This algorithm was created to formalize the decision-making process selected herein in managing patients with thyroid nodules. Between April 1, 2014, and March 31, 2015, a prospective study of patients who had undergone diagnostic molecular testing of a thyroid nodule before being seen for surgical consultation was performed. The recommended management undertaken by the surgeon was then prospectively compared with the corresponding one in the algorithm. Patients with thyroid nodules who did not undergo molecular testing and were seen for surgical consultation during the same period served as a control group. MAIN OUTCOMES AND MEASURES All pertinent treatment options were presented to each patient, and any deviation from the algorithm was recorded prospectively. To evaluate the appropriateness of any change (deviation) in management, the surgical histopathology diagnosis was correlated with the surgery performed. RESULTS The study cohort comprised 140 patients who underwent molecular testing. Their mean (SD) age was 50.3 (14.6) years, and 75.0% (105 of 140) were female. Over a 1-year period, 20.3% (140 of 688) had undergone diagnostic molecular testing before surgical consultation, and 79.7% (548 of 688) had not undergone molecular testing. The surgical management deviated from the treatment algorithm in 12.9% (18 of 140) with molecular testing and in 10.2% (56 of 548) without molecular testing (P = .37). In the group with molecular testing, the surgical management plan of only 7.9% (11 of 140) was altered as a result of the molecular test. All but 1 of those patients were found to be overtreated relative to the surgical histopathology analysis. CONCLUSIONS AND RELEVANCE Molecular testing did not significantly affect the surgical decision-making process in this study. Among patients whose treatment was altered based on these markers, there was evidence of overtreatment.

Curative surgical resection of adrenocortical carcinoma: Determining long-term outcome based on conditional disease-free probability

Objective: To evaluate conditional disease-free survival (CDFS) for patients who underwent curative intent surgery for adrenocortical carcinoma (ACC). Background: ACC is a rare but aggressive tumor. Survival estimates are usually reported as survival from the time of surgery. CDFS estimates may be more clinically relevant by accounting for the changing likelihood of disease-free survival (DFS) according to time elapsed after surgery. Methods: CDFS was assessed using a multi-institutional cohort of patients. Cox proportional hazards models were used to evaluate factors associated with DFS. Three-year CDFS (CDFS3) estimates at “x” year after surgery were calculated as follows: CDFS3 = DFS(x+3)/DFS(x). Results: One hundred ninety-two patients were included in the study cohort; median patient age was 52 years. On presentation, 36% of patients had a functional tumor and median size was 11.5 cm. Most patients underwent R0 resection (75%) and 9% had N1 disease. Overall 1-, 3-, and 5-year DFS was 59%, 34%, and 22%, respectively. Using CDFS estimates, the probability of remaining disease free for an additional 3 years given that the patient had survived without disease at 1, 3, and 5 years, was 43%, 53%, and 70%, respectively. Patients with less favorable prognosis at baseline demonstrated the greatest increase in CDFS3 over time (eg, capsular invasion: 28%–88%, &Dgr;60% vs no capsular invasion: 51%–87%, &Dgr;36%). Conclusions: DFS estimates for patients with ACC improved dramatically over time, in particular among patients with initial worse prognoses. CDFS estimates may provide more clinically relevant information about the changing likelihood of DFS over time.

Bilaterality in papillary thyroid carcinoma: does it influence prognosis?

Papillary carcinoma is the most prevalent thyroid tumor subtype, and the incidence of this variant is rising in developed countries.1 The majority of papillary thyroid cancers (PTC) are indolent, and 5-year survival among those patients receiving appropriate surgical and medical therapy is greater than 95%. Nonetheless, a subgroup of PTCs will behave aggressively, and these tumors are associated with poorer overall and disease-free survival. Identification of specific disease characteristics correlating with prognosis has therefore become an important goal, both in understanding PTC biology and in directing therapeutic intervention. Historically, prognostic variables have included age, histopathological subtype, larger tumor size, and presence of extrathyroidal extension/metastasis.1,2 Multifocality is also an important feature of PTC. Multi-focal disease is common, being identified in 38% of micropapillary carcinoma cases, and is associated with tumor recurrence. The American Thyroid Association recommends using “clinical judgment” when considering whether radioactive iodine ablation (RAI) should be used to treat multifocal PTC, especially in light of recent studies showing that, for microscopic multifocal PTC, RAI does not improve recurrence rates.2,3 In addition, significant interest has recently developed in ascertaining the relationship between PTC prognosis and the presence of mutations in BRAF, a tyrosine kinase-encoding protooncogene commonly mutated in PTC cells.4–6 In this edition of The Annals of Surgical Oncology, Wang and colleagues consider whether bilaterality should be considered a new, potentially important prognostic feature of PTC. Interestingly, though both multifocality and bilaterality in PTC are traditionally considered indications for total or near-total thyroidectomy, few data specifically examining the prognostic implications of bilateral disease have been reported.7,8 In their manuscript “Poorer prognosis and higher prevalence of BRAFV600E mutation in synchronous bilateral papillary thyroid cancer,” Wang and colleagues detail the first formal evaluation of the relationship between bilaterality and prognosis in 891 PTC patients treated with total or near-total thyroidectomy over a 9-year period who were retrospectively identified. Bilateral synchronous PTC was defined as cancer diagnosed in both thyroid lobes at the same time or within a period of 3 months following removal of the first tumor. The authors found that bilateral PTC is common, occurring in 19.9% of their cohort, and that bilaterality is associated with poorer prognosis. Increased rates of extrathyroidal extension, nodal metastasis, as well as an overall higher stage at presentation were associated with bilateral disease. Further, these findings correlated with disease-free and overall survival, both of which decreased in the context of bilateral disease. Taken together, Wang and colleagues’ findings suggest that bilaterality is an important feature of PTC biology that may improve the clinician’s ability to predict the behavior of these tumors. Because mutation of the BRAF protooncogene is now recognized as a common genetic aberrancy contributing to the pathophysiology of PTC, evaluation for BRAF mutation may also be important in assessing the prognostic relevance of disease bilaterality. As such, the authors were able to assay BRAF gene sequences obtained from 208 consecutive patients, identifying a statistically significant increase in the prevalence of BRAF protooncogene mutations in bilateral versus unilateral cases (65.7 vs. 50.4%, P = 0.038). Nonetheless, these data must be interpreted carefully, as mutation of the BRAF protooncogene in the bilateral disease cohort did not correlate with other known prognostic features of PTC, including tumor size and extrathyroidal extension. The identification of tumor features associated with poor prognosis plays an important role in defining the pathophysiology of cancer and provides insight into the clinical management of malignancy. Here, Wang and colleagues provide initial data suggesting that disease bilaterality confers poor prognosis among patients diagnosed with PTC. Although data describing the prognostic relevance of multifocal PTC have been previously reported, this study represents the first published report to examine the prognostic relevance of bilateral disease. Potentially important correlations between disease bilaterality and tumor size, BRAF protooncogene mutation, extrathyroidal extension, and metastasis are supported by the authors’ findings. Future studies should be done prospectively, should detail tumor sizes in each lobe, and should normalize the performance and extent of neck dissection, as well as the use of postoperative 131I therapy. Analysis of histopathological subtypes among PTC patients having bilateral disease, relative to unilateral cases, may also provide insight into the prognostic value of bilaterality. Although Wang and colleagues provide an interesting initial study of the significance of bilateral disease in cases of papillary thyroid carcinoma, additional data will be required to validate bilaterality as an independent predictor of disease prognosis.

Actual 10-year survivors following resection of adrenocortical carcinoma

Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with limited therapeutic options beyond surgical resection. The characteristics of actual long‐term survivors following surgical resection for ACC have not been previously reported.

Nomograms to Predict Recurrence-Free and Overall Survival After Curative Resection of Adrenocortical Carcinoma

IMPORTANCE Adrenocortical carcinoma (ACC) is a rare but aggressive endocrine tumor, and the prognostic factors associated with long-term outcomes after surgical resection remain poorly defined. OBJECTIVES To define clinicopathological variables associated with recurrence-free survival (RFS) and overall survival (OS) after curative surgical resection of ACC and to propose nomograms for individual risk prediction. DESIGN, SETTING, AND PARTICIPANTS Nomograms to predict RFS and OS after surgical resection of ACC were proposed using a multi-institutional cohort of patients who underwent curative-intent surgery for ACC at 13 major institutions in the United States between March 17, 1994, and December 22, 2014. The dates of our study analysis were April 15, 2015, to May 12, 2015. MAIN OUTCOMES AND MEASURES The discriminative ability and calibration of the nomograms to predict RFS and OS were tested using C statistics, calibration plots, and Kaplan-Meier curves. RESULTS In total, 148 patients who underwent surgery for ACC were included in the study. The median patient age was 53 years, and 65.5% (97 of 148) of the patients were female. One-third of the patients (35.1% [52 of 148]) had a functional tumor, and the median tumor size was 11.2 cm. Most patients (77.7% [115 of 148]) underwent R0 resection, and 8.8% (13 of 148) of the patients had N1 disease. Using backward stepwise selection of clinically important variables with the Akaike information criterion, the following variables were incorporated in the prediction of RFS: tumor size of at least 12 cm (hazard ratio [HR], 3.00; 95% CI, 1.63-5.70; P < .001), positive nodal status (HR, 4.78; 95% CI, 1.47-15.50; P = .01), stage III/IV (HR, 1.80; 95% CI, 0.95-3.39; P = .07), cortisol-secreting tumor (HR, 2.38; 95% CI, 1.27-4.48; P = .01), and capsular invasion (HR, 1.96; 95% CI, 1.02-3.74; P = .04). Factors selected as predicting OS were tumor size of at least 12 cm (HR, 1.78; 95% CI, 1.00-3.17; P = .05), positive nodal status (HR, 5.89; 95% CI, 2.05-16.87; P = .001), and R1 margin (HR, 2.83; 95% CI, 1.51-5.30; P = .001). The discriminative ability and calibration of the nomograms revealed good predictive ability as indicated by the C statistics (0.74 for RFS and 0.70 for OS). CONCLUSIONS AND RELEVANCE Independent predictors of survival and recurrence risk after curative-intent surgery for ACC were selected to create nomograms predicting RFS and OS. The nomograms were able to stratify patients into prognostic groups and performed well on internal validation.

Diagnostic performance of multidetector computed tomography in distinguishing unilateral from bilateral abnormalities in primary hyperaldosteronism: comparison of multidetector computed tomography with adrenal vein sampling.

Objective The management of patients with primary hyperaldosteronism (PH) varies depending on whether the unregulated aldosterone secretion localizes to a single unilateral adrenal gland, traditionally determined using adrenal vein sampling (AVS). This study seeks to determine if the performance of multidetector computed tomography (MDCT) examinations performed using the latest scanner technology can reasonably match the results of AVS, and potentially avoid AVS in some patients. Materials and Methods Computed tomographic scans in 56 patients with PH were independently reviewed by 2 radiologists for the presence of adrenal nodules and qualitative adrenal thickening. Results were correlated with AVS results. Results Of 35 patients with MDCT evidence of unilateral nodules, the imaging findings correctly predicted AVS localization in only 23 (65.7%) cases. When stratified by size, MDCT was accurate in only 71.4% of cases for nodules measuring 10 mm or less, and only 55.0% of cases for nodules measuring 11 to 20 mm. Of the 12 cases where MDCT did not correctly localize, AVS localized to the contralateral adrenal gland in 4 cases, whereas AVS suggested no lateralization in 8 cases. In patients with normal bilateral adrenal glands on MDCT, 2/7 (28.6%) of cases demonstrated unilateral localization on AVS, and in patients with bilateral adrenal nodules, only 3/14 (21.4%) did not demonstrate lateralization on AVS. Conclusions Multidetector computed tomography, even when performed with the latest generation of MDCT scanners, does not offer sufficient diagnostic accuracy to replace AVS in patients with PH.