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Supplementary Tables S1-S2.

Purpose: Activation of the Wnt/β-catenin signaling pathway is frequent in adrenocortical carcinoma (ACC) and might be associated with a more aggressive phenotype. The objective of this study was to assess the prognostic value of β-catenin immunohistochemistry and CTNNB1 (β-catenin gene)/APC (adenomatous polyposis coli gene) mutations in patients with resected primary ACC.Experimental design: In 79 patients with resected primary ACC from a French cohort (Cochin-COMETE), β-catenin expression was assessed on tumor specimens by immunohistochemistry. For patients with available DNA (n = 49), CTNNB1, and APC hotspot (mutation cluster region), were sequenced. Association between these results and the clinicopathologic characteristics of the ACC and overall and disease-free survival were studied. Results were confirmed on a tissue microarray from an independent multicentric cohort of 92 ACC from Germany (German-ENSAT cohort).Results: In the Cochin-COMETE cohort, the presence of a β-catenin nuclear staining was significantly associated with a higher ENSAT tumor stage (i.e., stages III and IV), higher Weiss score, more frequent necrosis, mitoses, and CTNNB1/APC mutations. β-Catenin nuclear staining and the presence of CTNNB1/APC mutations were both associated with decreased overall and disease-free survival, and were independent predictive factors of survival in multivariate analysis. The same results were observed in the German-ENSAT cohort.Conclusions: Wnt/β-catenin activation, confirmed by the presence of β-catenin nuclear staining, is an independent prognostic factor of overall and disease-free survival in patients with resected primary ACC. Clin Cancer Res; 17(2); 206–11. ©2010 AACR. Clin Cancer Res; 17(2); 328–36. ©2010 AACR.

Supplementary Table 3 from Transcriptome Analysis Reveals that p53 and β-Catenin Alterations Occur in a Group of Aggressive Adrenocortical Cancers

Supplementary Table 2 from Transcriptome Analysis Reveals that p53 and β-Catenin Alterations Occur in a Group of Aggressive Adrenocortical Cancers

Supplementary Table 1 from Transcriptome Analysis Reveals that p53 and β-Catenin Alterations Occur in a Group of Aggressive Adrenocortical Cancers

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, who developed numerous papillary tumors but also unexpectedly clear cell renal cell carcinomas. During the follow-up, an adrenal metastasis was observed seven years after the initial diagnosis corresponding to a clear cell RCC metastasis. Using FISH, the metastatic tumor presented a trisomy of chromosomes 7 and 17. These 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.

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.

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.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, pT310 mm with extrathyroidal invasion (ETI); and group 3, pT3 due to a tumor size4 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).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 PTC10 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.PTC ≤10 mm with ETI and large tumors4 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.

Resume Introduction Le pheochromocytome composite est une tumeur medullosurrenalienne rare associant un pheochromocytome et une tumeur neuroblastique. Nous presentons le cas d’un pheochromocytome composite decouvert chez un patient atteint d’une neurofibromatose de type 1. Observation Il s’agissait d’un patient de 61 ans presentant des episodes de sueurs associes a des palpitations et une hypertension arterielle moderee. Biologiquement, le dosage des derives methoxyles urinaires etait eleve. L’imagerie montrait une tumeur intra-surrenalienne heterogene. A l’examen histologique, la tumeur etait composee d’un pheochromocytome et d’un ganglioneurome, faisant porter le diagnostic de pheochromocytome composite. Il s’agit d’une tumeur frequemment associee a la neurofibromatose de type 1, la mutation germinale du gene NF1 pouvant etre impliquee dans sa physiopathologie. Conclusion Le pheochromocytome composite est une tumeur rare dont la composante pheochromocytome est suspectee cliniquement mais dont le diagnostic est anatomopathologique. Le pronostic reste mal connu du fait de la rarete de ces tumeurs.

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

Lateral lymph node dissection (LND) in the absence of macroscopic nodal metastasis remains controversial in sporadic medullary thyroid carcinoma (MTC). 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. 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. 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. 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.

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.

The current pathological diagnosis of Aldosterone Producing Adenoma (APA) is limited to the description of nodules and/or hyperplasia in the resected adrenal gland, independent of their functional characteristics. The aim of our study was to characterize histopathological markers to confirm the presence and identify the sites of aldosterone production and to discriminate KCNJ5-related APA. We investigated 18 adrenals with APA and 15 with non-functioning adrenal incidentaloma (NFAI) for expression of Disabled-2 and GIRK4, two markers of zona glomerulosa (ZG), and 77 adrenals with APA with known mutational status for GIRK4 expression. Two-thirds of APA and only one NFAI exhibited both GIRK4 and Disabled-2 membrane staining, allowing to correctly classify 79% of adenomas. Remarkably, 28/32 APA with KCNJ5 mutations exhibited lower GIRK4 expression in APA relative to peritumoral ZG. This was highly specific for KCNJ5 mutations, indicating that GIRK4 immunohistochemistry might be used for initial screening of the somatic mutation status.

International audience; Hirsutism induced by hyperandrogenism can be associated with polycystic ovary syndrome, 21-hydroxylase (OH) deficiency or androgen-secreting tumors, including ovarian and adrenal tumors. Adrenal androgen-secreting tumors are frequently malignant. Adrenal oncocytomas represent rare causes of hyperandrogenism. The aim of the study was to investigate steroidogenic enzyme expression and steroid secretion in an androgen-secreting adrenal oncocytoma in a young woman presenting with hirsutism. Hyperandrogenism was diagnosed on the basis of elevated plasma Δ4-androstenedione and testosterone levels. Pelvic ultrasound was normal, CT scanning revealed a right adrenal mass. Androgens were assessed in adrenal and ovarian vein samples and proved a right adrenal origin. Adrenalectomy normalized androgen levels and the adrenal tumor was diagnosed as an oncocytoma. Real time-PCR, immunohistochemistry and cell culture studies were performed on tumor explants to investigate the steroid secretion profile. Among enzymes required for cortisol synthesis, 17α-OH and 3β-hydroxysteroid dehydrogenase 2 (3β-HSD2) were highly expressed whereas 21-OH and 11β-OH were weakly produced at the mRNA and/or protein levels. Enzymes involved in testosterone production, 17β-HSD5 and 17β-HSD3, were also detected. ACTH receptor was present in the tissue. Cortisol, Δ4-androstenedione and testosterone secretions by cultured cells were increased by ACTH. These results provide the first demonstration, to our knowledge, of abnormal expression profile of steroidogenic enzymes in an adrenocortical oncocytoma. Our results also indicate that Δ4-androstenedione hypersecretion resulted from high 17α-OH and 3β-HSD2 expression in combination with low expression of 21-OH and 11β-OH. Testosterone production was ascribed to occurrence of 17β-HSD5 and 17β-HSD3. Finally, our results indicate that androgen secretion was stimulated by ACTH.

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.

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., SCOPUS: ar.j, info:eu-repo/semantics/published

International audience; 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.

International audience; 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

Objectif Le role de l’elastographie par ondes de cisaillement (EOC) dans le bilan des nodules thyroidiens a cytologie indeterminee (CI) reste controverse. L’objectif de cette etude prospective bicentrique etait d’evaluer les performances de l’EOC dans des nodules a CI en termes de prediction de malignite, reproductibilite, et analyse combinee avec l’echographie standard. Patients et methodes Les patients eligibles presentaient un nodule thyroidien ≥ 15 mm avec CI (Bethesda III a V) pour lequel la chirurgie etait conseillee. Une echographie et une EOC standardisee ont ete realisees avant chirurgie ( Resultats Sur 131 nodules a CI, 21 (16 %) etaient malins dont 9 cancers papillaires (CPT), 6 vesiculaires, 5 peu differencies et 1 lymphome. Les parametres EOC etaient similaires dans les nodules benins et malins, notamment EImoy (20,2 contre 19,6 kPa), EImax (34,3 contre 32,5 kPa) ou ratio (1,57 contre 1,38). Dans les cancers, les EImoy, EImax et ratio etaient plus eleves dans le variant classique (n = 4) que dans les autres variants CPT (n = 5) (p Discussion Malgre des valeurs d’elasticite elevees dans le variant classique du CPT, les parametres conventionnels EOC ne permettent pas de predire la malignite dans les nodules thyroidiens a CI.

Adrenocortical carcinoma (ACC) is a rare cancer with poor prognosis. Pan-genomic analyses identified p53/Rb and WNT/β-catenin signaling pathways as main contributors to the disease. However, isolated β-catenin constitutive activation failed to induce malignant progression in mouse adrenocortical tumors. Therefore, there still was a need for a relevant animal model to study ACC pathogenesis and to test new therapeutic approaches. Here, we have developed a transgenic mice model with adrenocortical specific expression of SV40 large T-antigen (AdTAg mice), to test the oncogenic potential of p53/Rb inhibition in the adrenal gland. All AdTAg mice develop large adrenal carcinomas that eventually metastasize to the liver and lungs, resulting in decreased overall survival. Consistent with ACC in patients, adrenal tumors in AdTAg mice autonomously produce large amounts of glucocorticoids and spontaneously activate WNT/β-catenin signaling pathway during malignant progression. We show that this activation is associated with downregulation of secreted frizzled related proteins (Sfrp) and Znrf3 that act as inhibitors of the WNT signaling. We also show that mTORC1 pathway activation is an early event during neoplasia expansion and further demonstrate that mTORC1 pathway is activated in ACC patients. Preclinical inhibition of mTORC1 activity induces a marked reduction in tumor size, associated with induction of apoptosis and inhibition of proliferation that results in normalization of corticosterone plasma levels in AdTAg mice. Altogether, these data establish AdTAg mice as the first preclinical model for metastatic ACC.

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.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.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.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.

International audience; 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.

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.

Diffuse sclerosing variant (DSV) is a rare and aggressive subtype of papillary thyroid carcinoma (PTC).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.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.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.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).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.

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.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.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.

Les lesions corticosurrenaliennes benignes regroupent un large eventail de maladies avec des morphologies ainsi que des secretions de steroides distinctes. Contrairement au corticosurrenalome, aucune vision globale moleculaire des alterations moleculaires n’est disponible pour ces tumeurs. Objectifs Fournir une classification moleculaire des tumeurs corticosurrenaliennes benignes, en utilisant une serie de mesures non biaisees pan-genomiques dans une cohorte incluant tous les types de tumeurs corticosurrenaliennes benignes. Methodes L’etude effectuee rapporte l’analyse pan-genomique incluant transcriptome, miRNome, methylome, mutations et alterations chromosomiques de 146 lesions adrenocorticales benignes. Resultats Le transcriptome, le methylome, le miRNome et le statut mutationnel convergent en une seule classification avec quatre groupes principaux : (i) les tumeurs productrices de cortisol, regroupant differents types partageant une activation commune de la voie AMPc/PKA par des mecanismes distincts. Le transcriptome a permis d’identifier une signature steroidogene ; (ii) des adenomes corticosurrenaliens (ACA) sans ou avec une secretion legere de cortisol, associes a des mutations de la beta-catenine ; (iii) des hyperplasies macronodulaires primaires avec des mutations ARMC5, montrant une signature d’expression ovarienne ; (iv) des ACA produisant de l’aldosterone, en dehors d’autres tumeurs benignes. Les alterations epigenetiques et la steroidogenese semblent associees, incluant l’hypomethylation des ilots CpG dans les tumeurs sans ou avec une secretion legere de cortisol, les profils des miARN definissant des groupes moleculaires specifiques, et la regulation directe de l’expression des enzymes steroidogenes par la methylation. Conclusion Cette premiere caracterisation pan-genomique a grande echelle des lesions corticosurrenaliennes benignes represente une nouvelle ressource importante pour l’etude de la tumorigenese corticosurrenalienne et de la steroidogenese.

International audience; BackgroundBased 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.MethodsA 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).ResultsA 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).ConclusionFor PTC patients, T1b had poorer clinicopathological features and increased risk of recurrence than T1a.

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

International audience; Expression des enzymes de la stéroïdogenèse dans une tumeur surrénalienne oncocytaire sécrétant des androgènes Milène Tetsi Nomigni, Sophie Ouzounian, Alice Benoit, Jacqueline Vadrot, Frédérique Tissier, Sylvie Renouf, Hervé Lefebvre, Sophie Christin-Maitre, et Estelle LouisetL’hirsutisme est induit par un hyperandrogénisme associé à un syndrome des ovaires polykystiques, un déficit en 21-hydroxylase ou une tumeur ovarienne ou surrénalienne sécrétant des androgènes. Les tumeurs surrénaliennes productrices d’androgènes sont le plus souvent malignes et très rarement des oncocytomes. Nous avons caractérisé in vitro les profils sécrétoire et d’expression des enzymes de la stéroïdogenèse d’une tumeur surrénalienne oncocytaire bénigne, ôtée chez une jeune femme présentant un hirsutisme associé à des taux plasmatiques élevés de Δ4-androstènedione et testostérone. Les expériences de Q-PCR et d’immunohistochimie montrent que parmi les enzymes requises pour la synthèse du cortisol, la 17α-hydroxylase (OH) et la 3β-hydroxystéroïde deshydrogénase (HSD) 2 étaient fortement exprimées, alors que la 21-OH et la 11β-OH n’étaient que faiblement produites dans la tumeur. Les enzymes indispensables à la synthèse de testostérone, les 17β-HSD5 et 17β-HSD3, ont également été détectées. Le récepteur de l’ACTH était présent dans l’oncocytome mais pas celui de la LH. Les cellules tumorales en culture sécrétaient du cortisol et des androgènes, majoritairement de la Δ4-androstènedione et plus faiblement de la testostérone. Les sécrétions hormonales étaient stimulées in vitro par l’ACTH. Les résultats montrent que l’hypersécretion de Δ4-androstènedione résultait d’une forte expression de 17α-OH et 3β-HSD2 combinée à une faible expression de 21-OH et 11β-OH. La synthèse de testostérone était due aux activités des 17β-HSD5 et 17β-HSD3. Finalement, nos données indiquent que cette tumeur très rare présentait à la fois un phénotype de cellules des zones fasciculée et réticulée mais n’avait pas les caractéristiques de cellules stéroïdogènes gonadiques.

ContextComputed tomography (CT) unenhanced attenuation value of ObjectiveTo determine from a routine clinical perspective if unenhanced attenuation value is influenced by cortisol secretion in ACAs.DesignThis was a retrospective study of cases collected between 2009 and 2012.SettingThis study was conducted in a tertiary-care university hospital.PatientsSeventy-two patients operated on for an ACA (Weiss score ≤2) were analysed. Thirty-four patients had an ACA oversecreting cortisol (Cush-ACA). Thirty-eight patients had an ACA without cortisol oversecretion (Non Hyper-ACA).Main outcome measureCT unenhanced attenuation value was correlated with the functional status. The Weiss score items were analysed.ResultsAmong the 34 patients with a Cush-ACA a minority (n=7) had an unenhanced attenuation value under 10 HU. Among the high precontrast density (>10 HU) Cush-ACAs, washout analysis after contrast administration was consistent with the benign nature of the tumor in ∼60% of the cases. Less than 25% clear cells (lipid-rich cells), a Weiss score item, was present in 50% of the Cush-ACAs in favour of a lipid-poor content.ConclusionsUnenhanced attenuation value has a poor sensitivity to diagnose an ACA in case of cortisol oversecretion due to poor lipid content. Nevertheless, the accuracy of washout analysis was preserved in the group of Cush-ACAs.

Objectif Evaluer les performances de l’examen extemporane (EE) des nodules thyroidiens « indetermines » a la cytoponction (classification Bethesda) et son impact sur l’etendue de la chirurgie thyroidienne. Patients et methodes Analyse retrospective de 244 cytologies indeterminees, dont 75 nodules thyroidiens operes (atypies de signification indeterminee/lesion folliculaire de signification indeterminee, ASI/LFSI, n = 9 ; neoplasme folliculaire/suspicion de neoplasme folliculaire, NF/SNF, n = 31 ; suspicions de malignite, SM, n = 35). Les resultats possibles de l’EE sont « benin », « malin » ou « attendre l’examen definitif » c’est-a-dire non contributif. Resultats Dans la categorie ASI/LFSI, l’EE etait non contributif dans 4 cas/9 (44 %). Dans la categorie NF/SNF, 5 nodules/31 etaient des cancers a l’histologie definitive. L’EE etait non contributif dans 25 cas/31 (80 %) parmi lesquels 3 nodules etaient malins (dont une reprise chirurgicale). Dans la categorie SM (n = 35), l’histologie definitive retrouvait 24 cancers. L’EE etait contributif dans 10 cas/35 (29 %) et a permis de diagnostiquer 9 cancers/24 avec elargissement adequat du geste en peroperatoire (thyroidectomie totale + curage). L’EE etait non contributif dans 25cas/35, dont 15 cancers non diagnostiques. Discussion L’EE etait non contributif pour 53 des 75 nodules classes indetermines (71 % - IC 95 % = 0,59–0,79). Sur les 29 cancers thyroidiens, 12 ont ete diagnostiques a l’EE, dont 9 appartenaient a la categorie SM. Conclusion Il semble que l’EE soit plus performante dans la categorie SM et influence l’etendu du geste operatoire de facon adequat dans cette categorie. Son interet est a discuter dans les categories 4 et 5 de Bethesda.

We have read with great interest the article by Na et al. [1]. Dystrophic macrocalcifications, although more frequent in benign nodules, may also occur in malignant thyroid tumors, along with the wellknown psammoma-type calcifications [1-4]. We recently had an opportunity to study a thyroid microcarcinoma with extensive calcification.

Dans un contexte de contraintes budgetaires fortes pesant sur le financement des systemes de sante dans les pays de l’OCDE, les financeurs de l’offre de soins cherchent a conjuguer efficience economique et qualite du service rendu a la population couverte. Les annees 2000 ont vu l’emergence de programmes locaux ou nationaux d’incitation financieres a la qualite, a destination des professionnels de premiere ligne mais egalement les structures hospitalieres.Nous avons identifie et analyse la bibliographie consacree a l’etude de ces programmes en Europe mais egalement aux Etats-Unis, et avons confronte les resultats recueillis a la vision d’acteurs de plusieurs systemes de sante.Les resultats des programmes de paiement a la performance en Europe et dans le monde montrent une amelioration le plus souvent modeste et transitoire des indicateurs evalues. Neanmoins, notre analyse fait apparaitre un interet fort des acteurs pour la perennisation des modes de financement complementaires a la seule tarification a l’activite. Nous ouvrons a la discussion, plusieurs propositions d’axes strategiques visant a renforcer de facon durable le dispositif francais existant.

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 ( 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

Les hyperplasies micronodulaires de la surrenale (PPNAD) sont des tumeurs endocrines associees a des mutations inactivatrices de PRKAR1A, le gene codant la sous-unite regulatrice 1a de la PKA. Ces mutations conduisent a l’activation de cette signalisation et a un syndrome de Cushing ACTH-independant. Les souris invalidees pour Prkar1a specifiquement dans le cortex surrenalien (AdKO) developpent des hyperplasies composees de cellules a caracteristiques fœtales. Pour expliquer la presence inappropriee de ces cellules nous avons emis l’hypothese qu’un defaut de SUMOylation pouvait participer a l’etiologie des PPNAD. En effet, le maintien de cellules fœtales au sein de la surrenale adulte est aussi une caracteristique des souris Sf-12KR/+ exprimant une forme non-SUMOylable du facteur trans Sf-1, indispensable a l’organogenese de la glande. En cultures cellulaires et in vivo, nous montrons que l’activation de la signalisation PKA altere l’expression des genes impliques dans le processus de SUMOylation ce qui concourt a une deSUMOylation rapide des proteines surrenaliennes. En accord avec un role inhibiteur de la PKA, nous montrons que la SUMOylation est sensible aux modifications de l’axe HPA. De maniere interessante, la SUMOylation globale est diminuee a la fois dans les surrenales des souris AdKO et au niveau des nodules des patients atteints de PPNAD. Enfin dans la corticosurrenale saine, il existe un gradient de SUMOylation inversement correle a la sensibilite cellulaire a la PKA. L’ensemble de ces resultats suggerent une implication de la SUMOylation dans la physiopathologie du PPNAD mais aussi dans la zonation fonctionnelle et/ou la reponse au stress de la corticosurrenale.

Les tumeurs corticosurrenaliennes oncocytaires (CSO) rares sont des pronostics incertain. La classification Lin-Weiss-Bisceglia (LWB) est la reference [1] . Etude retrospective multicentrique avec recueil des donnees cliniques de patients avec CSO confirme par double relecture anatomopathologique, par les experts du reseau COMETE. Trente-trois patients (18 femmes et 15 hommes) ont ete inclus avec un suivi median de 36 mois, 52 % des tumeurs etaient des incidentalomes, 52 % etaient secretantes (androgeniques : 11/17). Les tumeurs ont ete classees selon LWB : benignes (n = 7), borderline (n = 5) et malignes (n = 21). Les caracteristiques medianes de la population etaient : âge 48 ans (respectivement 37, 51, 48 ans dans les 3 groupes), taille tumorale 7 cm (respectivement 4,5, 9,5, 9,5 cm), poids 156 grammes (respectivement 17, 380 et 103 g). Densite spontanee et SUVmax etaient comparables dans les 3 groupes. Tous ont eu une chirurgie (26 surrenalectomies, 7 chirurgies elargies) permettant une resection tumorale R0. Toutes les tumeurs benignes et borderline avaient un Ki67 5 % et 30 % > 10 %. Douze ont eu un traitement adjuvant par mitotane, 2 une radiotherapie. Un patient a recidive apres 3 mois et est decede de sa maladie (23 mois de suivi), un patient etait M1 synchrone (os) et en vie apres 24 mois de suivi. Ils avaient eu les 3 traitements. Ces 2 cas etaient classes malins, avec Ki67 les plus eleves (respectivement 20 et 15 %). Cette large etude retrospective montre que l’evolution des CSO malins semble indolente. Le Ki67 apparait discriminant dans le pronostic.

Introduction Notre objectif etait d’evaluer la faisabilite et la valeur ajoutee des mesures de densites tumorales scannographiques (criteres de CHOI) pour evaluer la reponse chez les patients traites par ITK pour un cancer differencie de la thyroide refractaire au radioiode (CDT RR). Materiels et methodes Vingt-neuf patients traites par ITK pour un CDT RR de 2006 a 2015 dans notre centre ont ete evalues par scanners. Une relecture radiologique selon les criteres RECIST et les criteres de CHOI a ete effectuee en aveugle des donnees clinique par un radiologue experimente. Resultats Les scanners injectes etaient disponibles pour relecture chez 13 patients (age median : 67 ans, sexe masculin : 5/13). Tous ces patients etaient evaluables selon les criteres RECIST et de CHOI. Les lesions cibles evaluables selon RECIST et CHOI etaient principalement pulmonaires (51 %), pleurales (20 %) et mediastinales (17 %). A la premiere evaluation tumorale, une reponse partielle etait observee chez deux (15,4 %) et neuf (69,2 %) patients selon les criteres RECIST et de CHOI respectivement. La variation mediane de densite tumorale etait de–42 % (–79 %– + 90 %). Apres une mediane de suivi de 25,3 mois, la mediane de survie globale etait de 31,1 et 57,3 mois pour les patients non-repondeurs et repondeurs selon CHOI respectivement. Conclusion l’evaluation de la reponse tumorale utilisant la densite scannographique est faisable pour les CDT RR, y comprise en cas de lesions pulmonaires. Les criteres de CHOI semblent identifier plus de patients repondeurs parmi les patients atteints de CDT RR beneficiant des ITK.

Objectifs Estimer la survie sans recidive de patients ayant un carcinome papillaire thyroidien (CPT) pT3 et apres re-stratification du risque a 6 mois, identifier les facteurs pronostiques associes au risque de recidive. Patients et methodes Analyse retrospective entre 1975 et 2014 de 580 patients suivis pour un CPT pT3 et divises en 3 groupes : groupe 1 : micropT3 ≤ 10 mm avec extension extrathyroidienne (EET) ( n = 160), groupe 2 : les pT3 > 10 mm avec EET ( n = 335) et groupe 3 : macropT3 de plus de 4 cm sans EET ( n = 85). La survie sans recidive (Kaplan–Meier) et les facteurs pronostics (modele de Cox) uni et multivariees sont analyses. Resultats Cent quinze evenements (19,8 %) (recidive ou persistance) ont ete rapportes pendant un suivi median de 5,4 ans (1,94–9,38). La survie sans recidive a 10 ans etait significativement differente entre les 3 groupes et respectivement de 89 %, 67 %et 82 % ( p p p = 0,008) et le sexe masculin ( p = 0,007). Un bilan (thyroglobuline sous stimulation et echographie cervicale) normal a 6 mois augmente significativement la survie sans recidive respectivement a 98 %, 96 % et 91 % dans les 3 groupes. Discussion La survie sans recidive des CPT du groupe 3 est meilleure que celle des CPT du groupe 2 et encore amelioree en cas de bilan normal a 6 mois. L’EET est un facteur plus pejoratif que la taille dans les CPT pT3.

Objectif Malgre les progres recents le cancer anaplasique thyroidien reste de pronostic sombre sans reelle possibilite therapeutique. De facon parallele, les techniques recentes de biologie moleculaire pourraient permettre une meilleure comprehension des differentes voix d’activation et ainsi deboucher sur des traitements plus adaptes au profil moleculaire de ces tumeurs. Methode Cent quarante-quatre cas ont ete collectes. Un panel de 50 genes (Ion AmpliSeq™ Cancer Hotspot Panel v2 de Life technologies) a ete sequence avec le ion PGM system™ NGS. La recherche de la translocation de ALK a ete effectuee par IHC et par FISH. Resultats On retrouve essentiellement des alterations de la voie BRAFV600E/ERK 1/2-MEK 1/2 et de la voie PI3K-AKT dans 53 % et 20 %, respectivement. Elles sont associees dans 67 % des cas (mutations non mutuellement exclusives). Les mutations de BRAF sont presentes dans 13 % des cas et dans 6 % des cas de facon isolee. 18 % des alterations de la voie PI3K-AKT sont isolees. P 53 est mute dans 56 % des cas. Les autres mutations retrouvees de facon plus marginales sont des mutations activatrices des genes ALK, ATM, RET, SMARCB1, ABL, ERRBB2, FGFR1. Une translocation de ALK a ete identifiee. Conclusion Il s’agit de la plus grosse serie publiee qui confirment les alterations predominantes des voies BRAFV600E/ERK 1/2-MEK 1/2 et de la voie PI3K-AKT. Cependant, celle-ci ne sont que tres rarement isolees, associees dans la plupart du temps a une activation de p53 ou une activation des 2 voies expliquant ainsi les tres faibles reponses therapeutiques observees.

Background: Recurrence of adrenocortical carcinoma (ACC) even after complete (R0) resection occurs frequently. Objective: The aim of this study was to identify markers with prognostic value for patients in this clinical setting. Design, Setting, and Participants: From the German ACC registry, 319 patients with the European Network for the Study of Adrenal Tumors stage I-III were identified. As an independent validation cohort, 250 patients from three European countries were included. Outcome Measurements and Statistical Analysis: Clinical, histological, and immunohistochemical markers were correlated with recurrence-free (RFS) and overall survival (OS). Results: Although univariable analysis within the German cohort suggested several factors with potential prognostic power, upon multivariable adjustment only a few including age, tumor size, venous tumor thrombus (VTT), and the proliferation marker Ki67 retained significance. Among these, Ki67 provided the single best prognostic value for RFS (hazard ratio [HR] for recurrence, 1.042 per 1% increase; P < .0001) and OS (HR for death, 1.051; P < .0001) which was confirmed in the validation cohort. Accordingly, clinical outcome differed significantly between patients with Ki67 = 20%(for the German cohort: median RFS, 53.2 vs 31.6 vs 9.4 mo; median OS, 180.5 vs 113.5 vs 42.0 mo). Using the combined cohort prognostic scores including tumor size, VTT, and Ki67 were established. Although these scores discriminated slightly better between subgroups, there was no clinically meaningful advantage in comparison with Ki67 alone. Conclusion: This largest study on prognostic markers in localized ACC identified Ki67 as the single most important factor predicting recurrence in patients following R0 resection. Thus, evaluation of Ki67 indices should be introduced as standard grading in all pathology reports of patients with ACC.