SFE-AFCE-SFMN 2022 Consensus on the management of thyroid nodules : Recommendations in thyroid cytology: from technique to interpretation.

The SFE-AFCE-SFMN 2022 consensus deals with the management of thyroid nodules, a condition that is a frequent reason for consultation in endocrinology. In more than 90% of cases, patients are euthyroid, with benign non-progressive nodules that do not warrant specific treatment. The clinician's objective is to detect malignant thyroid nodules at risk of recurrence and death, toxic nodules responsible for hyperthyroidism or compressive nodules warranting treatment. The diagnosis and treatment of thyroid nodules requires close collaboration between endocrinologists, nuclear medicine physicians and surgeons, but also involves other specialists. Therefore, this consensus statement was established jointly by 3 societies: the French Society of Endocrinology (SFE), French Association of Endocrine Surgery (AFCE) and French Society of Nuclear Medicine (SFMN); the various working groups included experts from other specialties (pathologists, radiologists, pediatricians, biologists, etc.). This section deals with the technique and interpretation of thyroid fine-needle aspiration biopsy (FNAB), a reference test for the analysis of thyroid nodules.

Is There an Optimal Definition for a Positive Circumferential Resection Margin in Locally Advanced Esophageal Cancer?

BACKGROUND: Two definitions of a positive circumferential resection margin (CRM) in esophageal cancer coexist: one by the College of American Pathologists (CAP) (CRM = 0 mm) and another by the Royal College of Pathologists (RCP) (CRM ≤ 1 mm). This study aimed to evaluate the prognostic value of both definitions in esophageal cancer and to identify a new cutoff value for the CRM to predict survival. METHODS: Patients who underwent curative esophageal resection for locally advanced (≥ pT3) adenocarcinoma or squamous cell carcinoma were selected from 2007 to 2016. The CRM was reassessed using an ocular micrometer. Overall survival (OS) and disease-free survival were estimated with uni- and multivariate analyses. RESULTS: The study enrolled 283 patients: 48 with a positive CRM according to the CAP definition and 171 with a positive CRM according to the RCP definition. In the multivariate analysis, a positive CRM according to both definitions was significantly associated with a poor OS (CAP: hazard ratio [HR], 2.26, p < 0.001; RCP: HR, 1.42, p = 0.035). A CRM of 0 mm was predictive of a worse OS and DFS than a CRM of 1 mm or less (p < 0.0001), whereas no significant difference was found between a CRM greater than 1 mm and a CRM of 1 mm or less, indicating that the CAP definition was more accurate for predicting prognosis and recurrence. New cutoff CRM values of 100 µm in squamous cell carcinoma and 200 µm in adenocarcinoma were optimal for predicting OS. CONCLUSION: The CAP definition was more accurate for predicting prognosis and recurrence. The study identified a new cutoff value of CRM according to histologic type.

miR-219-1-3p is a negative regulator of the mucin MUC4 expression and is a tumor suppressor in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers in the world with one of the worst outcome. The oncogenic mucin MUC4 has been identified as an actor of pancreatic carcinogenesis as it is involved in many processes regulating pancreatic cancer cell biology. MUC4 is not expressed in healthy pancreas whereas it is expressed very early in pancreatic carcinogenesis. Targeting MUC4 in these early steps may thus appear as a promising strategy to slow-down pancreatic tumorigenesis. miRNA negative regulation of MUC4 could be one mechanism to efficiently downregulate MUC4 gene expression in early pancreatic neoplastic lesions. Using in silico studies, we found two putative binding sites for miR-219-1-3p in the 3'-UTR of MUC4 and showed that miR-219-1-3p expression is downregulated both in PDAC-derived cell lines and human PDAC tissues compared with their normal counterparts. We then showed that miR-219-1-3p negatively regulates MUC4 mucin expression via its direct binding to MUC4 3'-UTR. MiR-219-1-3p overexpression (transient and stable) in pancreatic cancer cell lines induced a decrease of cell proliferation associated with a decrease of cyclin D1 and a decrease of Akt and Erk pathway activation. MiR-219-1-3p overexpression also decreased cell migration. Furthermore, miR-219-1-3p expression was found to be conversely correlated with Muc4 expression in early pancreatic intraepithelial neoplasia lesions of Pdx1-Cre;LSL-Kras(G12D) mice. Most interestingly, in vivo studies showed that miR-219-1-3p injection in xenografted pancreatic tumors in mice decreased both tumor growth and MUC4 mucin expression. Altogether, these results identify miR-219-1-3p as a new negative regulator of MUC4 oncomucin that possesses tumor-suppressor activity in PDAC.

The MUC4 mucin mediates gemcitabine resistance of human pancreatic cancer cells via the Concentrative Nucleoside Transporter family.

The fluorinated analog of deoxycytidine, Gemcitabine (Gemzar), is the main chemotherapeutic drug in pancreatic cancer, but survival remains weak mainly because of the high resistance of tumors to the drug. Recent works have shown that the mucin MUC4 may confer an advantage to pancreatic tumor cells by modifying their susceptibility to drugs. However, the cellular mechanism(s) responsible for this MUC4-mediated resistance is unknown. The aim of this work was to identify the cellular mechanisms responsible for gemcitabine resistance linked to MUC4 expression. CAPAN-2 and CAPAN-1 adenocarcinomatous pancreatic cancer (PC) cell lines were used to establish stable MUC4-deficient clones (MUC4-KD) by shRNA interference. Measurement of the IC50 index using tetrazolium salt test indicated that MUC4-deficient cells were more sensitive to gemcitabine. This was correlated with increased Bax/BclXL ratio and apoptotic cell number. Expression of Equilibrative/Concentrative Nucleoside Transporter (hENT1, hCNT1/3), deoxycytidine kinase (dCK), ribonucleotide reductase (RRM1/2) and Multidrug-Resistance Protein (MRP3/4/5) was evaluated by quantitative RT-PCR (qRT-PCR) and western blotting. Alteration of MRP3, MRP4, hCNT1 and hCNT3 expression was observed in MUC4-KD cells, but only hCNT1 alteration was correlated to MUC4 expression and sensitivity to gemcitabine. Decreased activation of MAPK, JNK and NF-κB pathways was observed in MUC4-deficient cells, in which the NF-κB pathway was found to have an important role in both sensitivity to gemcitabine and hCNT1 regulation. Finally, and in accordance with our in vitro data, we found that MUC4 expression was conversely correlated to that of hCNT1 in tissues from patients with pancreatic adenocarcinoma. This work describes a new mechanism of PC cell resistance to gemcitabine, in which the MUC4 mucin negatively regulates the hCNT1 transporter expression via the NF-κB pathway. Altogether, these data point out to MUC4 and hCNT1 as potential targets to ameliorate the response of pancreatic tumors to gemcitabine treatment.

Tumor size of hepatocellular carcinoma in noncirrhotic liver: a controversial predictive factor for outcome after resection.

BACKGROUND: Hepatocellular carcinoma in noncirrhotic liver (NC-HCC) presents usually with large size, which is seen as a contraindication to liver transplantation (LT) or even resection. The objective of our single-center study was to identify prognostic factors following resection of large NC-HCCs and to subsequently devise a treatment strategy (including LT) in selected patients. METHODS: From 2000 to 2010, 89 patients who had hepatic resection for NC-HCC (large ≥ 8 cm in 52) were analyzed with regard to pathological findings, postoperative and long-term outcome. RESULTS: Five patients died postoperatively. After a mean follow-up of 35 ± 30 months, NC-HCC recurred in 36 patients (26/47 survivors in group 8 cm+, 10/37 in group 8 cm-; p = 0.007). Five-year overall (OS) and disease-free survival (DFS) rates were significantly worse for group 8 cm+ (43.4% vs. 89.2% and 39.3% vs. 60.7% for group 8 cm-, p < 0.05). Seven patients underwent re-hepatectomy and/or LT for isolated intrahepatic recurrence, with 5-year DFS of 57.1%. In a multivariate analysis, the factors associated with poor OS and DFS were vascular invasion and tumor size ≥ 8 cm in the overall population and vascular invasion, fibrosis and satellite nodules in group 8 cm+. Adjuvant transarterial chemotherapy was a protective factor in group 8 cm+. In 22 isolated NC-HCC cases with no vascular invasion or fibrosis, tumor size had no impact on five-year DFS (85%). CONCLUSIONS: Although patients with NC-HCC ≥ 8 cm had a poorer prognosis, the absence of vascular invasion or fibrosis was associated with excellent survival, regardless of the tumor size. In recurrent patients, aggressive treatment (including LT) can be considered.

Guidelines of the French society of endocrinology for the management of thyroid nodules.

The present document is a follow-up of the clinical practice guidelines of the French Society of Endocrinology, which were established for the use of its members and made available to scientific communities and physicians. Based on a critical analysis of data from the literature, consensuses and guidelines that have already been published internationally, it constitutes an update of the report on the diagnostic management of thyroid nodules that was proposed in France, in 1995, under the auspices of the French National Agency for Medical Evaluation (l'Agence nationale d'évaluation médicale). The current guidelines were deliberated beforehand by a number of physicians that are recognised for their expertise on the subject, coming from the specialities of endocrinology (the French Thyroid Research Group) and surgery (the French Association for Endocrine Surgery), as well as representatives from the fields of biology, ultrasonography, cytology and nuclear medicine. The guidelines were presented and submitted for the opinion of the members of the Society at its annual conference, which was held in Nice from 7-10 October 2009. The amended document was posted on the website of the Society and benefited from additional remarks of its members. The final version that is presented here was not subjected to methodological validation. It does not claim to be universal in its scope and will need to be revised in concert with progress made in technical and developmental concepts. It constitutes a document that the Society deems useful for distribution concerning the management of thyroid nodules, which is current, efficient and cost effective.

Laparoscopic resection vs. open liver resection for peripheral hepatocellular carcinoma in patients with chronic liver disease: a case-matched study.

BACKGROUND: Studies that compare laparoscopic to open liver resection for hepatocellular carcinoma (HCC) in cirrhotic patients are rare and may have suffered from low patient numbers. This work was designed to determine the impact of laparoscopic resection on postoperative and long-term outcomes in a large series of cirrhotic patients with hepatocellular carcinoma (HCC) compared with open resection. METHODS: From 2002 to 2009, 36 patients with chronic liver disease with complicating HCC were selected for laparoscopic resection (laparoscopic group, LG). The outcomes were compared with those of 53 patients who underwent open hepatectomy (open group, OG) during the same period in a matched-pair analysis. The two groups were similar in terms of tumor number and size and number of resected segments. RESULTS: Morbidity and mortality rates were similar in the two groups (respectively 25 and 0% in LG vs. 35.8 and 7.5% in OG; p = 0.3). Severe complications were more frequent in OG (13.2%) than in LG (2.8%; p = 0.09). Despite similar portal hypertension levels, complications related to ascites (namely evisceration or variceal bleeding) were fatal in 4 of 12 affected patients in OG but 0 of 5 cases in LG (p = 0.2). The mean hospitalization durations were 6.5 ± 2.7 days and 9.5 ± 4.8 days in LG and OG, respectively (p = 0.003). The surgical margins were similar in the two groups. Although there was a trend toward better 5-year overall survival in LG (70 vs. 46% in OG; p = 0.073), 5-year disease-free survival was similar (35.5 vs. 33.6%). CONCLUSIONS: Laparoscopic resection of HCC in patients with chronic liver disease has similar results to open resection in terms of postoperative outcomes, surgical margins, and long-term survival.

Galectin-3 regulates MUC1 and EGFR cellular distribution and EGFR downstream pathways in pancreatic cancer cells.

MUC1 is a transmembrane glycoprotein which is typically expressed at the apical membrane of normal epithelial cells. In cancer cells, the over-expression of MUC1 and its aberrant localization around the cell membrane and in the cytoplasm favours its interaction with different protein partners such as epidermal growth factor receptor (EGFR) and can promote tumour proliferation through the activation of oncogenic signalling pathways. Our aims were to study the mechanisms inducing MUC1 cytoplasmic localization in pancreatic cancer cells, and to decipher their impact on EGFR cellular localization and activation. Our results showed that galectin-3, an endogenous lectin, is co-expressed with MUC1 in human pancreatic ductal adenocarcinoma, and that it favours the endocytosis of MUC1 and EGFR. Depletion of galectin-3 by RNA interference increased the interaction between MUC1 and EGFR, EGFR and ERK-1,2 phosphorylation, and translocation of EGFR to the nucleus. On the contrary, silencing of galectin-3 led to a decrease of cyclin-D1 levels and of cell proliferation. The galectin-3-dependent regulation of MUC1/EGFR functions may represent an interesting mechanism modulating the EGFR-stimulated cell growth of pancreatic cancer cells.

Ectopic hyperprolactinaemia in a woman with a mesocolic perivascular epithelioid cell tumor ("PEComa").

Ectopic prolactin secretion remains exceptional and originates mainly from malignant tumors. We report the case of a 47-year-old woman who presented amenorrhea leading to unravel important hyperprolactinaemia (269 ng/mL) with no hypothalamo-pituitary mass on magnetic resonance imaging (MRI). Pelvic imaging revealed the presence of a large pelvic mass that originated from the mesocolon. After complete surgical extraction, histological examination was in favour of a "perivascular epithelioid cell tumor" (PEComa). Prolactin levels normalized after surgical extraction and remained normal after a 3-year follow-up, totally free of tumour recurrence and/or metastasis. This suggests that hyperprolactinaemia was most likely related to the PEComa, despite negative reactions with antiprolactin antibodies at immunohistochemistry. Alternatively to a direct prolactin secretion by the tumor, one could hypothesize that the tumour secreted a prolactin stimulating factor or a dopamine antagonist that could not be identified. In conclusion, in face of an important hyperprolactinaemia without any hypothalamic-pituitary mass, it remains important to search for an ectopic prolactin production, such as a PEComa.

Autocrine induction of invasion and metastasis by tumor-associated trypsin inhibitor in human colon cancer cells.

From the conditioned medium of the human colon carcinoma cells, HT-29 5M21 (CM-5M21), expressing a spontaneous invasive phenotype, tumor-associated trypsin inhibitor (TATI) was identified and characterized by proteomics, cDNA microarray approaches and functional analyses. Both CM-5M21 and recombinant TATI, but not the K18Y-TATI mutant at the protease inhibitor site, trigger collagen type I invasion by several human adenoma and carcinoma cells of the colon and breast, through phosphoinositide-3-kinase, protein kinase C and Rho-GTPases/Rho kinase-dependent pathways. Conversely, the proinvasive action of TATI in parental HT29 cells was alleviated by the TATI antibody PSKAN2 and the K18Y-TATI mutant. Stable expression of K18Y-TATI in HT-29 5M21 cells downregulated tumor growth, angiogenesis and the expression of several metastasis-related genes, including CSPG4 (13.8-fold), BMP-7 (9.7-fold), the BMP antagonist CHORDIN (5.2-fold), IGFBP-2 and IGF2 (9.6- and 4.6-fold). Accordingly, ectopic expression of KY-TATI inhibited the development of lung metastases from HT-29 5M21 tumor xenografts in immunodeficient mice. These findings identify TATI as an autocrine transforming factor potentially involved in early and late events of colon cancer progression, including local invasion of the primary tumor and its metastatic spread. Targeting TATI, its molecular partners and effectors may bring novel therapeutic applications for high-grade human solid tumors in the digestive and urogenital systems.

Does the RET variant G691S influence the features of sporadic medullary thyroid carcinoma?

OBJECTIVE: The RET (rearranged during transfection) proto-oncogene G691S variant is over-represented in the germline of patients with sporadic medullary thyroid carcinoma (sMTC) vs. normal controls but so far is not associated with any medical or pathological features of the tumour. The aim of our study was to assess the influence of this variant on the age of onset, clinical, biological and pathological features of sMTC. DESIGN AND PATIENTS: One hundred patients with histologically proven MTC, for whom the germline genetic analysis of RET was negative and medical records were available, were included in the study. RESULTS: Patients with the heterozygous GS variant or the homozygous SS variant (n = 36) were on average 8.0 years younger than patients with the wild-type GG variant (n = 64, mean age 43.9 vs. 51.9 years, P < 0.01). The former group did not differ from the wild-type group in terms of MTC size, prevalence of C-cell hyperplasia (CCH) or papillary thyroid carcinoma (PTC). However, the prevalence of an increased preoperative basal calcitonin (bCT) level (> 1000 pg/ml) was 2.75-fold higher in the patients with the GS or SS variant than in those with the wild-type variant (P < 0.001). The proportion of patients with lymph node metastases was also higher in the former group (P < 0.05). Multivariate analysis confirmed that the presence of the RET variant is independently associated with higher preoperative bCT values (P = 0.011). CONCLUSIONS: Our data demonstrate that the RET G691S variant could modulate the age of onset of sMTC as demonstrated previously for familial tumours. Moreover, this variant is an independent predictor of a higher basal calcitonin synthesis rate in patients with sMTC.

Thyrotoxicosis revealing metastases of unrecognized thyroid cancer: a report on two cases.

We report two cases of thyrotoxicosis-revealing functional metastases of a follicular carcinoma that extended to the bones, liver and kidneys in one case and to the lungs in the other. Both patients had undergone surgical intervention for a thyroid nodule more than 15 years before the diagnosis of thyrotoxicosis and metastatic dissemination. In both the cases, the carcinoma was not recognized by the pathologist after the first surgical intervention, but was finally diagnosed several years later due to the occurrence of thyrotoxicosis. Iodine-131 therapy was effective at suppressing the thyrotoxicosis in both the patients. The effectiveness on the metastatic extension was very different for each patient: in the first case, the patient died a few years later without any control of the metastatic tissue. For the second patient, the metastases disappeared a few months after radioiodine treatment, with the patient still in remission more than 10 years later. The physiopathology and the evolution of these two cases are discussed with the data available in the literature.

Contribution of genetic analysis in screening for MEN1 among patients with sporadic disease and one or more typical manifestation.

Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal dominant hereditary syndrome (OMIM 131100) due to MEN1 gene mutations, predisposing to the development of hyperplasic and tumoral lesions of neuroendocrine tissues. Since the identification of the gene in 1997, more than 400 different mutations of MEN1 have been registered. Genotypic analysis of MEN1 remains fastidious and must be reserved to targeted situations. If the lesions appear in a familial assessed context, there is a strong argument to search for MEN1 mutation. This is not the case in a sporadic context. With experience acquired in our laboratory, we evaluated the frequency of MEN1 mutations in patients with sporadic presentations. Our aim was to better define criteria for MEN1 genotypic analysis. One hundred and twenty four blood samples from unrelated patients, who gave their written informed consent, were analyzed. These patients exhibited 1 to 4 manifestations of MEN1 without any familial context. After DNA extraction, the analysis was undertaken by PCR-sequencing of all the MEN1 coding exons and exon/intron boundaries or by PCR of the pre-screened fragments alone, a technique made possible by indirect screening mutation methods. Mutations were identified by comparing the sequences to the reference MEN1 sequence available from GENBANK (U93237.1). Mutations were identified in 19 patients, with variable prevalence according to clinical manifestations: 100% for patients with 4 manifestations, 45.5% for patients with 3 manifestations, 19% for patients with 2 manifestations and 2% for patients with only one manifestation. Mutations were: 11 point variations (58%), including 2 splicing sites and 8 frameshift mutations (42%) including 5 deletions, 2 insertions and 1 insertion/deletion; one mutation was identified twice. We showed a relationship between clinical presentation and MEN1 mutation identification, especially with the number of clinical manifestations but also with the type of manifestation. Pancreatic manifestations were significantly linked with probability of mutation. In a sporadic context with at least two established manifestations of MEN1, the overall probability of identifying a mutation was 26%, warranting MEN1 genotypic analysis.

[Fatal fulminant Epstein-Barr virus hepatitis]. / Hépatite fulminante fatale à Epstein-Barr virus.

Infectious mononucleosis is a common and benign disease. Although hepatic cytolysis is common during infectious mononucleosis, fulminant hepatitis is rare. We report an observation of a fatal fulminant hepatitis complicating a primary EBV infection in a 15 year-old male.

[Paragangliomas: clinical and secretory profile. Result of 39 cases]. / Paragangliomes: profil clinique et sécrétoire. A propos de 39 cas.

THIS RETROSPECTIVE STUDY AIMS: To define a clinical and secretory profile of paragangliomas extra-adrenal chromaffin tumors. METHODS: From 1971 throughout 2002, 39 paragangliomas have been observed in 38 patients (22 male, 16 female, average age 41,2 years). RESULTS: Four were located above the diaphragm, 35 were sub-phrenic (6 of the organ of Zuckerkandl), 32 secreted catecholamines, 23 were hypertensive (with only one without hypersecretion of catecholamines). Among 29 (131)I-metaiodobenzylguanidine scans (MIBG) reviewed, 20 tumors took up the radiopharmaceutical. The treatment was surgical in 35 cases with addition of external radiotherapy and MIBG in one case each; two patients died before any treatment. Two patients with persistent disease after surgery were successfully treated by surgery or MIBG. Histologically, 20 were malignant and 17 were seemingly benign. All exclusive dopamine secreting paragangliomas were malignant. Six patients relapsed two of which for a tumor initially classified as benign. The treatment of recurrences was surgical, by MIBG or by external radiotherapy. Nine patients had a family history of chromaffin tumor(s). The genetic survey made in five of these nine patients was positive in all cases.

Thyroid carcinomas involving follicular and parafollicular C cells: seventeen cases with characterization of RET oncogenic activation.

Recent studies have focused on the occurrence of concomitant medullary-papillary thyroid carcinomas (MTC-PTC). The aims of this report were to compare the frequency of occult PTC in a population with MTC versus a control population that had undergone thyroidectomies and to check whether differences could be related to particular phenotype or genotype. To achieve these goals, we determined the frequency of occult PTC among patients operated for MTC (n = 82) or undergoing total thyroidectomy mainly for goiter and/or nodules (n = 7313) between 1994-2001. We then examined the clinical, histologic, and genetic characteristics (using a bio-chemical family inquiry and screening for RET germline mutations) of patients with associated PTC-MTC. Results show a significantly higher frequency of occult PTC in MTC (14.7%) than in total thyroidectomy (6.8%; p < 0.01). Seventeen cases of MTC or bilateral C-cell hyperplasia (CCH) and separate occult PTC were identified from 16 different families. Although common RET mutations providing evidence of familial forms of MTC were identified in only 3 of 16 families, clinical and histologic features usually seen in inherited forms of MTC such as young age of occurrence, bilateral CCH or associated case in family were found in 11 of the remaining 14 patients. In conclusion, results suggest that the association of MTC-PTC is not only a coincidence. Surprisingly, 11 of 17 MTC-PTC patients exhibited clinical, histologic, and/or family features usually encountered in familial forms despite the fact that no RET defect were present. This suggests the possible involvement of another gene or uncommon abnormality of RET gene.