Clear cell and papillary renal cell carcinomas in hereditary papillary renal cell carcinoma (HPRCC) syndrome: a case report.

BACKGROUND: Hereditary papillary renal cell carcinoma (HPRCC) is a rare autosomal dominant disease characterized by the development of multiple and bilateral papillary type I renal cell carcinomas (RCC) and papillary adenomas caused by activating mutations in the MET proto-oncogene. Classically, distinctive histological features of RCC are described according to the familial renal cell carcinoma syndrome. To date, no clear cell RCC has been reported in HPRCC syndrome. CASE PRESENTATION: We describe the case of a 51-year-old man with a germline MET mutation detected on peripheral blood testing, and no germline VHL mutation, who developed numerous papillary tumors but also unexpectedly clear cell renal cell carcinomas. During the follow-up, an adrenal metastasis was observed 7 years after the initial diagnosis corresponding to a clear cell RCC metastasis. By immunohistochemistry, clear cell tumors showed focal cytokeratin 7, moderate racemase, and diffuse and membranous CAIX expression, while papillary tumors expressed strong diffuse cytokeratin 7 and racemase without CAIX positivity. Using FISH, VHL deletion was observed in one of the clear cell tumors, and the metastatic clear cell tumor presented a trisomy of chromosomes 7 and 17. These last genomic alterations are usually detected in papillary RCC, highlighting the potential link between both histological subtypes of tumors and the HPRCC syndrome. CONCLUSIONS: The pathologist must be aware that the presence of a non-papillary RCC associated with numerous papillary tumors should not exclude the diagnostic suspicion of HPRCC and thus to perform a thorough genomic study.

Value of Molecular Classification for Prognostic Assessment of Adrenocortical Carcinoma.

IMPORTANCE: The risk stratification of adrenocortical carcinoma (ACC) based on tumor proliferation index and stage is limited. Adjuvant therapy after surgery is recommended for most patients. Pan-genomic studies have identified distinct molecular groups closely associated with outcome. OBJECTIVE: To compare the molecular classification for prognostic assessment of ACC with other known prognostic factors. DESIGN, SETTING, AND PARTICIPANTS: In this retrospective biomarker analysis, ACC tumor samples from 368 patients who had undergone surgical tumor removal were collected from March 1, 2005, to September 30, 2015 (144 in the training cohort and 224 in the validation cohort) at 21 referral centers with a median follow-up of 35 months (interquartile range, 18-74 months). Data were analyzed from March 2016 to March 2018. EXPOSURES: Meta-analysis of pan-genomic studies (transcriptome, methylome, chromosome alteration, and mutational profiles) was performed on the training cohort. Targeted biomarker analysis, including targeted gene expression (BUB1B and PINK1), targeted methylation (PAX5, GSTP1, PYCARD, and PAX6), and targeted next-generation sequencing, was performed on the training and validation cohorts. MAIN OUTCOMES AND MEASURES: Disease-free survival. Cox proportional hazards regression and C indexes were used to assess the prognostic value of each model. RESULTS: Of the 368 patients (mean [SD] age, 49 [16] years), 144 were in the training cohort (100 [69.4%] female) and 224 were in the validation cohort (142 [63.4%] female). In the training cohort, pan-genomic measures classified ACC into 3 molecular groups (A1, A2, and A3-B), with 5-year survival of 9% for group A1, 45% for group A2, and 82% for group A3-B (log-rank P < .001). Molecular class was an independent prognostic factor of recurrence in stage I to III ACC after complete surgery (hazard ratio, 55.91; 95% CI, 8.55-365.40; P < .001). The combination of European Network for the Study of Adrenal Tumors (ENSAT) stage, tumor proliferation index, and molecular class provided the most discriminant prognostic model (C index, 0.88). In the validation cohort, the molecular classification, determined by targeted biomarker measures, was confirmed as an independent prognostic factor of recurrence (hazard ratio, 5.96 [95% CI, 1.81-19.58], P = .003 for the targeted classifier combining expression, methylation, and chromosome alterations; and 2.61 [95% CI, 1.31-5.19], P = .006 for the targeted classifier combining methylation, chromosome alterations, and mutational profile). The prognostic value of the molecular markers was limited for patients with stage IV ACC. CONCLUSIONS AND RELEVANCE: The findings suggest that in localized ACC, targeted classifiers may be used as independent markers of recurrence. The determination of molecular class may improve individual prognostic assessment and thus may spare unnecessary adjuvant treatment.

NIFT-P: Are they indolent tumors? Results of a multi-institutional study.

BACKGROUND: Encapsulated follicular variant of papillary thyroid carcinoma has recently been reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features on the basis of its highly indolent behavior, as proposed by an international group of experienced thyroid pathologists. METHODS: All patients from 9 high-volume endocrine surgery departments who underwent surgery between 2005 and 2015 and whose final surgical pathology revealed noninvasive follicular thyroid neoplasm with papillary-like nuclear features (>10 mm) were included in this study. The primary outcome was to determine the potential for recurrent disease in these patients. RESULTS: Among the 363 patients with noninvasive follicular thyroid neoplasm with papillary-like nuclear features, 76% were female with a median age of 50 years (5-86 years); 345 patients (95%) underwent total thyroidectomy. A total of 65 patients had an associated micropapillary thyroid carcinoma. In the group of 133 patients who underwent prophylactic lymph node dissection (37%), 1 patient had a micrometastasis but with an associated micropapillary thyroid carcinoma. Over a median follow-up period of 5 years, 1 patient with an associated micropapillary thyroid carcinoma had recurrent disease at 6 years. All patients with noninvasive follicular thyroid neoplasm with papillary-like nuclear features without micropapillary thyroid carcinoma had no lymph node metastasis or recurrent disease. CONCLUSION: We found that noninvasive follicular thyroid neoplasm with papillary-like nuclear features presents with indolent behavior. However, the identification of an associated micropapillary thyroid carcinoma should be carefully evaluated because it could be a factor for lymph node metastasis and/or of recurrence.

Clinicopathological description of 43 oncocytic adrenocortical tumors: importance of Ki-67 in histoprognostic evaluation.

Oncocytic adrenocortical tumors are a rare subtype of adrenal tumors with challenging diagnosis and histoprognostic assessment. It is usually believed that oncocytic adrenocortical tumors have a more indolent clinical behavior than conventional adrenocortical tumors. As the Weiss score overestimates the malignancy of oncocytic adrenocortical tumors owing to intrinsic parameters, alternative scores have been proposed. The Lin-Weiss-Bisceglia score is currently recommended. We performed a large nationwide multicenter retrospective clinicopathologic study of oncocytic adrenocortical tumors. Among the 43 patients in our cohort, 40 patients were alive without disease, 2 patients died of their disease and 1 patient was alive with relapse after a median follow-up of 38 months (20-59). Our data revealed that over 50% of the oncocytic adrenocortical tumor cases were diagnosed as carcinoma whatever the classification systems used, including the Lin-Weiss-Bisceglia score. The exception is the Helsinki score, which incorporates the Ki-67 proliferation index and was the most specific prognostic score for oncocytic adrenocortical tumor malignancy without showing a loss in sensitivity. A comparison of malignant oncocytic adrenocortical tumors with conventional adrenocortical carcinomas matched for age, sex, ENS@T stage and surgical resection status showed significant better overall survival of malignant oncocytic adrenocortical tumors.

Thyroid follicular adenomas and carcinomas: molecular profiling provides evidence for a continuous evolution.

Non-autonomous thyroid nodules are common in the general population with a proportion found to be cancerous. A current challenge in the field is to be able to distinguish benign adenoma (FA) from preoperatively malignant thyroid follicular carcinoma (FTC), which are very similar both histologically and genetically. One controversial issue, which is currently not understood, is whether both tumor types represent different molecular entities or rather a biological continuum. To gain a better insight into FA and FTC tumorigenesis, we defined their molecular profiles by mRNA and miRNA microarray. Expression data were analyzed, validated by qRT-PCR and compared with previously published data sets. The majority of deregulated mRNAs were common between FA and FTC and were downregulated, however FTC showed additional deregulated mRNA. Both types of tumors share deregulated pathways, molecular functions and biological processes. The additional deregulations in FTC include the lipid transport process that may be involved in tumor progression. The strongest candidate genes which may be able to discriminate follicular adenomas and carcinomas, CRABP1, FABP4 and HMGA2, were validated in independent samples by qRT-PCR and immunohistochemistry. However, they were not able to adequately classify FA or FTC, supporting the notion of continuous evolving tumors, whereby FA and FTC appear to show quantitative rather than qualitative changes. Conversely, miRNA expression profiles showed few dysregulations in FTC, and even fewer in FA, suggesting that miRNA play a minor, if any, role in tumor progression.

Infracentimetric parathyroid cysts in hyperparathyroidemia.

Parathyroid cysts are rare, more frequently functional. Here we report 2 cases of infracentimetric parathyroid cysts identified in parathyroid adenomas resected for hyperparathyroidemia and hypercalcemia. Chronic parathyroiditis was associated. Chromogranin and E-cadherin/uvomorulin were expressed heterogeneously in the cyst lining and in parathyroid cells. In one of the cases, CD10 and CD56 were expressed by the luminal membrane of parathyroid cells. CD31 was expressed in interparathyroid cell monocyte/macrophage membrane as well as CD68, several cells showing also CD10 and/or CD56 expression. Ki67 was expressed in sparse parathyroid cells, some of binucleated cells or with nuclear clumps. In conclusion, heterogeneous E-cadherin expression in parathyroid cells may only indirectly related to cyst formation while CD56 and CD10 seem not to relate at all. The relevance of nuclear clumps and Azzopardi phenomenon as well as of the presence of disperse monocyte/macrophage-type cells for the parathyroiditis lesions remains to be further investigated.

Shear Wave Elastography in Thyroid Nodules with Indeterminate Cytology: Results of a Prospective Bicentric Study.

BACKGROUND: The clinical management of thyroid nodules with indeterminate cytology (IC) remains challenging. The role of shear wave elastography (SWE) in this setting is controversial. The aim of the study was to assess the performances of SWE in terms of prediction of malignancy, reproducibility, and combined analysis with ultrasound (US) examination in thyroid nodules with IC. METHODS: This prospective study was conducted in two referral centers. Eligible patients had a thyroid nodule ≥15 mm with IC (Bethesda class III-V) for which surgery had been recommended. Patients underwent a standardized US evaluation combined with a SWE exam followed by surgery. SWE parameters included mean (meanEI; kPa) and max (maxEI) elasticity values, and ratio (meanEI nodule/parenchyma). RESULTS: One hundred and thirty-one nodules (median size 30 mm) in 131 patients were studied. IC was class III in 28%, class IV in 64%, and class V in 8% of cases. After surgery, 21 (16%) nodules were malignant, including nine papillary thyroid cancers (PTC), six follicular thyroid cancers, five poorly differentiated carcinomas, and one large B-cell lymphoma. SWE parameters were similar in benign and malignant nodules, including meanEI (20.2 vs. 19.6 kPa), maxEI (34.3 vs. 32.5 kPa), and ratio (1.57 vs. 1.38). In malignant nodules, meanEI, maxEI, and ratio were higher in the classic PTC variants (n = 4) than in the other PTC variants (n = 5; p < 0.02) and in non-PTC tumors (n = 12; p < 0.005). Intra- and inter-observer coefficients of variations for meanEI in nodules were 23% and 26%, respectively. The French Thyroid Imaging Reporting and Data System score, the American Thyroid Association US classification, and the EU-Thyroid Imaging Reporting and Data System were not associated with malignancy. CONCLUSIONS: Despite high elasticity values in classic PTC variants, conventional SWE indexes failed to discriminate between benign and malignant tumors in thyroid nodules with IC.

DUSP5 and DUSP6, two ERK specific phosphatases, are markers of a higher MAPK signaling activation in BRAF mutated thyroid cancers.

BACKGROUND: Molecular alterations of the MAPK pathway are frequently observed in papillary thyroid carcinomas (PTCs). It leads to a constitutive activation of the signalling pathway through an increase in MEK and ERK phosphorylation. ERK is negatively feedback-regulated by Dual Specificity Phosphatases (DUSPs), especially two ERK-specific DUSPs, DUSP5 (nuclear) and DUSP6 (cytosolic). These negative MAPK regulators may play a role in thyroid carcinogenesis. METHODS: MAPK pathway activation was analyzed in 11 human thyroid cancer cell lines. Both phosphatases were studied in three PCCL3 rat thyroid cell lines that express doxycycline inducible PTC oncogenes (RET/PTC3, H-RASV12 or BRAFV600E). Expression levels of DUSP5 and DUSP6 were quantified in 39 human PTCs. The functional role of DUSP5 and DUSP6 was investigated through their silencing in two human BRAFV600E carcinoma cell lines. RESULTS: BRAFV600E human thyroid cancer cell lines expressed higher phospho-MEK levels but not higher phospho-ERK levels. DUSP5 and DUSP6 are specifically induced by the MEK-ERK pathway in the three PTC oncogenes inducible thyroid cell lines. This negative feedback loop explains the tight regulation of p-ERK levels. DUSP5 and DUSP6 mRNA are overexpressed in human PTCs, especially in BRAFV600E mutated PTCs. DUSP5 and/or DUSP6 siRNA inactivation did not affect proliferation in two BRAFV600E mutated cell lines, which may be explained by a compensatory increase in other phosphatases. In the light of this, we observed a marked DUSP6 upregulation upon DUSP5 inactivation. Despite this, DUSP5 and DUSP6 positively control cell migration and invasion. CONCLUSIONS: Our results are in favor of a stronger activation of the MAPK pathway in BRAFV600E PTCs. DUSP5 and DUSP6 have pro-tumorigenic properties in two BRAFV600E PTC cell line models.

Clusterin expression in medullary thyroid carcinoma is inversely correlated with the presence of lymph node metastases.

Clusterin (CLU) is a sulfated glycoprotein implicated in many physiological and pathological processes, including tumorigenesis. Several studies have reported the overexpression of CLU in human neoplasm, examined by immunohistochemistry. However, there are no extensive data on its role in the thyroid. Here we investigate CLU expression in thyroid tumors, and the potential correlation between this expression and clinicopathological parameters. Immunohistochemistry with anti-CLU was performed on paraffin sections from 39 thyroid tumors. Only medullary thyroid carcinomas (MTCs) were positive (n = 5). To confirm these results, 130 further cases (including 4 C-cell hyperplasia), their matched lymph node metastases (46 cases), and lymph node recurrences (10 cases) were analyzed. All MTCs were subdivided according to World Health Organization classification. Cytoplasmic positivity was scored qualitatively (weak, moderate, strong) and quantitatively on a 5-tier scale from 0, 1+ (<10% of cells positive) to 5+ (>75%). Statistical analysis was performed. CLU was expressed in normal C cells, C-cell hyperplasia, all MTCs, their lymph node metastases, and recurrences. There was a strong association between CLU score and the cellular type (P < .004). CLU score was inversely correlated with the presence of lymph node metastases (P < .0001). There were no differences between primary and metastatic or recurrent tumors. CLU expression is related to the cellular type and inversely correlated with the presence of lymph node metastases, which could represent a new positive prognostic factor.

[Composite pheochromocytoma: A rare adrenal tumor]. / Le phéochromocytome composite : une tumeur rare de la surrénale.

INTRODUCTION: Composite pheochromocytoma is a rare tumor of the adrenal medulla composed of pheochromocytoma and neuroblastic tumor. We report the case of a composite pheochromocytoma detected in a patient with neurofibromatosis type 1. CASE REPORT: A 61-year-old male patient presented occasional sweats with palpitation and moderate high blood pressure. Urinary catecholamine level was increased. CT scan showed a heterogeneous tumor limited to the adrenal gland. Histologically, the tumor showed two components: pheochromocytoma and ganglioneuroma and was diagnosed as a composite pheochromocytoma. This tumor is particularly associated with neurofibromatosis type 1, the NF1 germline gene mutation may be involved in its physiopathology. CONCLUSION: Composite pheochromocytoma is a rare tumor whose pheochromocytoma component is suspected clinically but the final diagnosis is assessed by pathological examination. Prognosis is still difficult to establish due to the rarity of these tumors.

Heterogeneous Prognoses for pT3 Papillary Thyroid Carcinomas and Impact of Delayed Risk Stratification.

BACKGROUND: Papillary thyroid carcinomas (PTC) in the pT3 category constitute a heterogeneous group of tumors with a variable risk of recurrence. The objectives of this study were (i) to estimate disease-free survival (DFS) and identify prognostic factors associated with recurrence in a cohort of pT3 PTC, and (ii) to evaluate the concept of delayed risk stratification in a cohort of pT3 tumors. METHODS: A total of 560 patients with pT3 PTC, treated and followed at the authors' institution, were studied. They were divided into three groups: group 1, pT3 ≤10 mm; group 2, pT3 >10 mm with extrathyroidal invasion (ETI); and group 3, pT3 due to a tumor size >4 cm. DFS was estimated using the Kaplan-Meier method, and associated prognostic features were studied in univariate and multivariate Cox model-based analyses in each group. Then, DFS was studied for each group according to the six- to eight-month status (remission or not). RESULTS: DFS at 10 years was 75% for the entire cohort and was 89%, 67%, and 82% in groups 1, 2, and 3, respectively (p < 0.0001). Multivariate analysis identified three factors significantly associated with reduced DFS: lymph node (LN) involvement, male sex, and group 2 (>1 cm with ETI). A trend toward a worse prognosis in patients with pT3 N0/Nx PTC >10 mm with ETI was found in comparison with the other pT3 N0/Nx patients. When the six- to eight-month checkup was normal, the DFS at 10 years increased to 98%, 96%, and 91% in groups 1-3, respectively. Furthermore, in this case, initial LN involvement no longer seemed to affect the prognosis in those groups. CONCLUSION: PTC ≤10 mm with ETI and large tumors >4 cm without ETI both have a low-recurrence risk when there are no adverse associated prognostic features such as LN involvement. LN involvement, especially in the lateral compartment (N1b), is a strong prognostic factor of recurrence in pT3 PTC. Delayed risk stratification can be applied in pT3 PTC patients. Those cured at the first checkup, including those with limited LN involvement, have excellent outcomes, which should prompt clinicians to adapt subsequent management accordingly.

Molecular Pathology of Anaplastic Thyroid Carcinomas: A Retrospective Study of 144 Cases.

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is a rare tumor, with poorly defined oncogenic molecular mechanisms and limited therapeutic options contributing to its poor prognosis. The aims of this retrospective study were to determine the frequency of anaplastic lymphoma kinase (ALK) translocations and to identify the mutational profile of ATC including TERT promoter mutations. METHODS AND MATERIALS: One hundred and forty-four ATC cases were collected from 10 centers that are a part of the national French network for management of refractory thyroid tumors. Fluorescence in situ hybridization analysis for ALK rearrangement was performed on tissue microarrays. A panel of 50 genes using next-generation sequencing and TERT promoter mutations using Sanger sequencing were also screened. RESULTS: Fluorescence in situ hybridization was interpretable for 90 (62.5%) cases. One (1.1%) case was positive for an ALK rearrangement with a borderline threshold (15% positive cells). Next-generation sequencing results were interpretable for 94 (65.3%) cases, and Sanger sequencing (TERT) for 98 (68.1%) cases. A total of 210 mutations (intronic and exonic) were identified. TP53 alterations were the most frequent (54.4%). Forty-three percent harbored a mutation in the (H-K-N)RAS genes, 13.8% a mutation in the BRAF gene (essentially p.V600E), 17% a PI3K-AKT pathway mutation, 6.4% both RAS and PI3K pathway mutations, and 4.3% both TP53 and PTEN mutations. Nearly 10% of the cases showed no mutations of the RAS, PI3K-AKT pathways, or TP53, with mutations of ALK, ATM, APC, CDKN2A, ERBB2, RET, or SMAD4, including mutations not yet described in thyroid tumors. Genes encoding potentially druggable targets included: mutations in the ATM gene in four (4.3%) cases, in ERBB2 in one (1.1%) case, in MET in one (1.1%) case, and in ALK in one (1.1%) case. A TERT promoter alteration was found in 53 (54.0%) cases, including 43 C228T and 10 C250T mutations. Three out of our cases did not harbor mutations in the panel of genes with therapeutic interest. CONCLUSION: This study confirms that ALK rearrangements in ATC are rare and that the mutational landscape of ATC is heterogeneous, with many genes implicated in the follicular epithelial cell dedifferentiation process. This may explain the limited effectiveness of targeted therapeutic options tested so far.

DNA Methylation Is an Independent Prognostic Marker of Survival in Adrenocortical Cancer.

CONTEXT: Adrenocortical cancer (ACC) is an aggressive tumor with a heterogeneous outcome. Prognostic stratification is difficult even based on tumor stage and Ki67. Recently integrated genomics studies have demonstrated that CpG islands hypermethylation is correlated with poor survival. OBJECTIVE: The goal of this study was to confirm the prognostic value of CpG islands methylation on an independent cohort. DESIGN: Methylation was measured by methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA). SETTING: MS-MLPA was performed in a training cohort of 50 patients with ACC to identify the best set of probes correlating with disease-free survival (DFS) and overall survival (OS). These outcomes were validated in an independent cohort from 21 ENSAT centers. PATIENTS: The validation cohort included 203 patients (64% women, median age 50 years, 80% localized tumors). MAIN OUTCOME MEASURES: DFS and OS. RESULTS: In the training cohort, mean methylation of 4 genes (PAX5, GSTP1, PYCARD, PAX6) was the strongest methylation marker. In the validation cohort, methylation was a significant prognostic factor of DFS (P < 0.0001) and OS (P < 0.0001). Methylation, Ki67, and ENSAT stage were combined in multivariate models. For DFS, methylation (P = 0.0005) and stage (P < 0.0001) but not Ki67 (P = 0.19) remained highly significant. For OS, methylation (P = 0.0006), stage (P < 0.0001), and Ki67 (P = 0.024) were independent prognostic factors. CONCLUSIONS: Tumor DNA methylation emerges as an independent prognostic factor in ACC. MS-MLPA is readily compatible with clinical routine and should enhance our ability for prognostication and precision medicine.

Prognosis of papillary thyroid carcinoma in elderly patients after thyroid resection: A retrospective cohort analysis.

The size of the elderly population and the incidence of papillary thyroid carcinoma (PTC) in this group appear to be rapidly increasing, although published information based on more detailed older age groupings are lacking.This study aimed to determine the clinical features and outcomes of elderly patients in PTC.All consecutive patients who received surgery for PTC in our Department from 1978 to 2014 were included. We compared 3 patient groups: young (<65 years), older (65-75 years), and very old patients (>75 years). Total thyroidectomy was performed with lymph node (LN) dissection in most cases, and radioiodine therapy was administered as needed.A total of 3835 patients (3257 young patients, 450 older patients, and 128 very old patients) were identified. Very old patients were more likely to have advanced (III/IV) tumor, nodes, metastases (TNM) stage, greater tumor size, number of tumors, and extracapsular invasion compared with young and older patients. For the 2289 patients with LN dissection (60%), metastatic LNs were more frequent in the very old group (44%) than in the other groups (34% young and 33% older patients) (P = 0.01). Very old patients had more frequent distant metastases (5%) than the older (2%) and young groups (1%) (P < 0.001). The overall postoperative morbidity was not significantly different between the 3 age groups. Recurrence was documented in 202 (6.2%) young, 29 (6.4%) older, and 15 (11.7%) very old PTC patients (P = 0.04). The 5-year disease-free survival was 81.3% for very old, 92.9% for older, and 94.7% for young group (P < 0.001).Very old patients should be considered high-risk PTC patients and their therapeutic strategy may benefit from aggressive treatment.

Diffuse Sclerosing Variant of Papillary Thyroid Carcinoma Is Associated With Aggressive Histopathological Features and a Poor Outcome: Results of a Large Multicentric Study.

CONTEXT: Diffuse sclerosing variant (DSV) is a rare and aggressive subtype of papillary thyroid carcinoma (PTC). OBJECTIVE: The objective of the study was to investigate the clinicopathological features and prognosis of DSV patients and compare these findings with all other PTCs and high-risk PTCs. DESIGN AND SETTING: The data of patients who underwent surgery for DSV and PTC between 2003 and 2014 in seven surgical departments specialized in endocrine surgery were reviewed. PATIENTS: Fifty-six DSV patients were included (mean age 32.6 ± 12.5 y; 46 [82%] female) and were compared with 2945 non-DSV PTCs and 48 high-risk PTCs. RESULTS: Forty-six DSV patients (82%) were pT3, 43 (77%) had an extrathyroidal extension, and 54 (96%) had lymph node metastasis, including 48 patients with involvement in the lateral compartment (86%). During the follow-up period of 4.3 ±2.3 years, 19 patients (34%) had a recurrence, including 18 patients with an ipsilateral lateral compartment recurrence. The only prognostic factor for recurrence in the multivariate analysis was extranodal extension (odds ratio 3.4 [1.1; 10.8]). The 7-year recurrence-free survival (RFS) was 63%. The RFS was significantly worse in patients with DSV than in other PTC patients (hazard risk 8.5 [5.2; 13.9], P < .0001) and were similar to the RFS of high-risk PTCs (hazard risk 1.1 [0.6; 2.2], P = .5). CONCLUSION: DSV patients share the same recurrence rate as high-risk PTC patients. Despite aggressive surgical approaches, the recurrence rate within the first 5 years requires a careful ongoing surveillance, similar to the follow-up of high-risk PTC patients.

Can We Predict the Lateral Compartment Lymph Node Involvement in RET-Negative Patients with Medullary Thyroid Carcinoma?

BACKGROUND: Lateral lymph node dissection (LND) in the absence of macroscopic nodal metastasis remains controversial in sporadic medullary thyroid carcinoma (MTC). OBJECTIVES: The aims of our study were to determine the risk of lateral lymph node (LN) metastases with a focus on lateral contralateral N1, and to define a risk-adapted surgical treatment for these patients. METHODS: All patients who underwent surgery from 1980 to 2012 for previously untreated RET-negative MTC were reviewed. We focused on the lateral compartments of LN metastases and identified three groups: no lateral LN metastases, ipsilateral lateral (ILL)-LN metastases with no contralateral LN involvement, and contralateral lateral (CLL)-LN metastases. RESULTS: Overall, 131 patients underwent surgery for RET-negative MTC. A total thyroidectomy with LND was performed in 112 patients (85 %), including 97 patients who had an ILL-LND and 92 patients who had a CLL-LND. Lateral LN metastases (N1) occurred in 40 patients (37 %): 31 patients (32 %) had ILL-LN metastases with no contralateral LN involvement, and 9 patients (10 %) had CLL-LN metastases. The preoperative cut-offs for LN metastases in the ILL compartment were very low, with a smallest tumor size of 5 mm, and lowest serum calcitonin level of 38 pg/ml. Disease-free survival rates decreased from 92 % for patients with no lateral LN metastases to 41 % for patients with ILL-LN metastases and 0 % for patients with CLL-LN metastases. CONCLUSIONS: ILL-LND should be performed in every patient and only a minority of MTC patients with small micro-MTC, and low serum calcitonin levels should not have a CLL-LND.

MicroRNA-375/SEC23A as biomarkers of the in vitro efficacy of vandetanib.

In this study, we performed microRNA (miRNA) expression profiling on a large series of sporadic and hereditary forms of medullary thyroid carcinomas (MTC). More than 60 miRNAs were significantly deregulated in tumor vs adjacent non-tumor tissues, partially overlapping with results of previous studies. We focused our attention on the strongest up-regulated miRNA in MTC samples, miR-375, the deregulation of which has been previously observed in a variety of human malignancies including MTC. We identified miR-375 targets by combining gene expression signatures from human MTC (TT) and normal follicular (Nthy-ori 3-1) cell lines transfected with an antagomiR-375 inhibitor or a miR-375 mimic, respectively, and from an in silico analysis of thyroid cell lines of Cancer Cell Line Encyclopedia datasets. This approach identified SEC23A as a bona fide miR-375 target, which we validated by immunoblotting and immunohistochemistry of non-tumor and pathological thyroid tissue. Furthermore, we observed that miR-375 overexpression was associated with decreased cell proliferation and synergistically increased sensitivity to vandetanib, the clinically relevant treatment of metastatic MTC. We found that miR-375 increased PARP cleavage and decreased AKT phosphorylation, affecting both cell proliferation and viability. We confirmed these results through SEC23A direct silencing in combination with vandetanib, highlighting the importance of SEC23A in the miR-375-associated increased sensitivity to vandetanib.Since the combination of increased expression of miR-375 and decreased expression of SEC23A point to sensitivity to vandetanib, we question if the expression levels of miR-375 and SEC23A should be evaluated as an indicator of eligibility for treatment of MTC patients with vandetanib.

Does the T1 subdivision correlate with the risk of recurrence of papillary thyroid cancer?

BACKGROUND: Based on the AJCC seventh TNM classification, T1 intraglandular tumors are subdivided into T1a (≤10 mm) and T1b (11-20 mm), but the differences in prognosis remain controversial. The present study aimed to determine the clinicopathological features and outcomes of T1a and T1b patients. METHODS: A retrospective study of 2518 T1 patients, including 1840 T1a (73 %) and 678 (27 %) T1b patients who underwent surgery for PTC from 1978 to 2014, was conducted. In patients with a preoperative or operative diagnosis of PTC, a total thyroidectomy (TT) with prophylactic (macroscopically N0) or therapeutic (evident N1) lymph node dissection (LND) was performed. Other patients had a TT or partial thyroidectomy without LND. The mean follow-up time was 8.9 ± 8.8 years (median, 6.5 years; range, 1-36.4 years). RESULTS: A TT was performed in 2273 patients (90 %), including 1184 (52 %) with LND. Other patients (n = 245) had a single lobectomy with isthmectomy. Multifocality, bilaterality, number of tumors, sum of the largest size of all foci, vascular invasion, and (in patients with LND) LN metastases were significantly more frequent in T1b than in T1a patients. Of the 1184 patients with LND, 278 had LN metastases (N1, 23 %), including 136/680 T1a (20 %) and 142/504 (28 %) T1b patients (p = 0.002). These LN metastases were diagnosed after a prophylactic LND in 86/609 T1a (14 %) and 93/440 T1b (21 %) patients (p = 0.001). Recurrences were more frequent in T1b (n = 26, 3.8 %) than in T1a patients (n = 35, 1.9 %, p = 0.005). In the multivariate analysis, independent prognostic factors for recurrence in both groups were the number of tumors, the sum of the largest size of all foci and, in patients who had LND, LN metastases and extranodal extension. For N0-x patients, the recurrence rate was significantly higher in the T1b than in the T1a group (2.4 vs. 0.9 %, respectively, p = 0.005), although this rate was similar in N1 patients (16.2 % for T1a and 9.2 % for T1b patients, p = 0.1). The 5-year disease-free survival rates for T1a and T1b patients were 98.3 and 96.6 %, respectively (p = 0.01). CONCLUSION: For PTC patients, T1b had poorer clinicopathological features and increased risk of recurrence than T1a.

An International Ki67 Reproducibility Study in Adrenal Cortical Carcinoma.

Despite the established role of Ki67 labeling index in prognostic stratification of adrenocortical carcinomas and its recent integration into treatment flow charts, the reproducibility of the assessment method has not been determined. The aim of this study was to investigate interobserver variability among endocrine pathologists using a web-based virtual microscopy approach. Ki67-stained slides of 76 adrenocortical carcinomas were analyzed independently by 14 observers, each according to their method of preference including eyeballing, formal manual counting, and digital image analysis. The interobserver variation was statistically significant (P<0.001) in the absence of any correlation between the various methods. Subsequently, 61 static images were distributed among 15 observers who were instructed to follow a category-based scoring approach. Low levels of interobserver (F=6.99; Fcrit=1.70; P<0.001) as well as intraobserver concordance (n=11; Cohen κ ranging from -0.057 to 0.361) were detected. To improve harmonization of Ki67 analysis, we tested the utility of an open-source Galaxy virtual machine application, namely Automated Selection of Hotspots, in 61 virtual slides. The software-provided Ki67 values were validated by digital image analysis in identical images, displaying a strong correlation of 0.96 (P<0.0001) and dividing the cases into 3 classes (cutoffs of 0%-15%-30% and/or 0%-10%-20%) with significantly different overall survivals (P<0.05). We conclude that current practices in Ki67 scoring assessment vary greatly, and interobserver variation sets particular limitations to its clinical utility, especially around clinically relevant cutoff values. Novel digital microscopy-enabled methods could provide critical aid in reducing variation, increasing reproducibility, and improving reliability in the clinical setting.