European' health care indicators and pancreatic cancer incidence and mortality: A mediation analysis of Eurostat data and Global Burden of Disease Study 2019.

AIM: To highlight correlations existing between incidence and mortality of pancreatic cancer, and health care indicators in 36 European countries. METHODS: The Global Burden of Disease (GBD) and Eurostat databases were queried between 2004 and 2019. Incidence and mortality were age-standardized. From Eurostat, indicators regarding expenditure, hospital beds, medical technology, health personnel, physicians by medical specialty and unmet needs for medical examination were extracted. Correlations between GBD and Eurostat data were analysed through mediation analysis applying clustering for countries. RESULTS: Incidence increased by +0.6% per year (p = 0.001) and mortality by +0.3% (p = 0.001), being increasing for most of the European countries considered. Incidence and mortality were strongly positively correlated (p = 0.001). Higher current health expenditure, expenditure in inpatient curative care, the number of available beds, the number of computed tomography scan, magnetic resonance units, practising medical doctors were all related to higher incidence (p < 0.05), whereas the unmet need for medical examinations was related to lower incidence. When the mediator' effect of incidence was handled, these indicators, together with expenditure on outpatient curative cares, the number of pet scanners and of radiation therapy equipment, were related to lower mortality (p < 0.05). CONCLUSIONS: Health care environment correlates with reported incidence and mortality of pancreatic cancer. This highlights both that ameliorated socio-economic societies suffer from higher incidence but lower mortality, as well as the epidemiological bias originating from countries' diagnostic ability.

Systemic Inflammatory Indices in Second-Line Soft Tissue Sarcoma Patients: Focus on Lymphocyte/Monocyte Ratio and Trabectedin.

A second-line standard of treatment has not yet been identified in patients with soft tissue sarcomas (STS), so identifying predictive markers could be a valuable tool. Recent studies have shown that the intratumoral and inflammatory systems significantly influence tumor aggressiveness. We aimed to investigate prognostic values of pre-therapy neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), systemic inflammatory index (SII), progression-free survival (PFS), and overall survival (OS) of STS patients receiving second-line treatment. In this single-center retrospective analysis, ninety-nine patients with STS were enrolled. All patients received second-line treatment after progressing to anthracycline. PFS and OS curves were calculated using the Kaplan-Meier method of RNA sequencing, and CIBERSORT analysis was performed on six surgical specimens of liposarcoma patients. A high NLR, PLR, and SII were significantly associated with worse PFS (p = 0.019; p = 0.004; p = 0.006). Low LMR was significantly associated with worse OS (p = 0.006). Patients treated with Trabectedin showed a better PFS when the LMR was low, while patients treated with other regimens showed a worse PFS when the LMR was low (p = 0.0154). The intratumoral immune infiltrates analysis seems to show a correlation between intratumoral macrophages and LMR. PS ECOG. The metastatic onset and tumor burden showed prognostic significance for PFS (p = 0.004; p = 0.041; p = 0.0086). According to the histologies, PFS was: 5.7 mo in liposarcoma patients vs. 3.8 mo in leiomyosarcoma patients vs. 3.1 months in patients with other histologies (p = 0.053). Our results confirm the prognostic role of systemic inflammatory markers in patients with STS. Moreover, we demonstrated that LMR is a specific predictor of Trabectedin efficacy and could be useful in daily clinical practice. We also highlighted a possible correlation between LMR levels and the percentage of intratumoral macrophages.

Inframesocolic Approach for Robotic Enucleation of Branch-Duct Intraductal Papillary Mucinous Neoplasm of the Pancreas.

BACKGROUND: The inframesocolic approach to the uncinate process of the pancreas has been rarely described in literature. To the best of our knowledge, no robotic cases have been reported. METHODS: The case of a 74-year-old woman, with a 43-mm branch-duct intraductal papillary mucinous neoplasm with worrisome features within the uncinate process of the pancreas, is described. RESULTS: After diagnostic work-up, due to the uncertain potential of malignancy and the strong motivation of the patient to undergo surgery, we performed a robotic enucleation through an inframesocolic approach. The neoplasm was more than 1 cm from the main pancreatic duct. Final pathological diagnosis revealed a low-grade dysplasia branch-duct intraductal papillary mucinous neoplasm. CONCLUSIONS: The inframesocolic approach could represent an easy way to access the uncinate process of the pancreas, allowing safe limited resection in selected cases such as small branch-duct IPMN or pancreatic neuroendocrine tumors.

Implementation of a patient blood management in an Italian City Hospital: is it effective in reducing the use of red blood cells?

To evaluate the effect of patient blood management (PBM) since its introduction, we analyzed the need for transfusion and the outcomes in patients undergoing abdominal surgery for different types of tumor pre- and post-PBM. Patients undergoing elective gastric, liver, pancreatic, and colorectal surgery between 2017 and 2020 were included. The implementation of the PBM program was completed on May 1, 2018. The patients were grouped as follows: those who underwent surgery before the implementation of the program (pre-PBM) versus after the implementation (post-PBM). A total of 1302 patients were included in the analysis (445 pre-PBM vs. 857 post-PBM). The number of transfused patients per year decreased significantly after the introduction of PBM. A strong tendency for a decreased incidence of transfusion was evident in gastric and pancreatic surgery and a similar decrease was statistically significant in liver surgery. With regard to gastric surgery, a single-unit transfusion scheme was used more frequently in the post-PBM group (7.7% vs. 55% after PBM; p = 0.049); this was similar in liver surgery (17.6% vs. 58.3% after PBM; p = 0.04). Within the subgroup of patients undergoing liver surgery, a significant reduction in the use of blood transfusion (20.5% vs. 6.7%; p = 0.002) and a decrease in the Hb trigger for transfusion (8.5, 8.2-9.5 vs. 8.2, 7.7-8.4 g/dl; p = 0.039) was reported after the PBM introduction. After the implementation of a PBM protocol, a significant reduction in the number of patients receiving blood transfusion was demonstrated, with a strong tendency to minimize the use of blood products for most types of oncologic surgery.

Robotic surgery for gastric cancer in the west: A systematic review and meta-analyses of short-and long-term outcomes.

BACKGROUND: This review aims to merge all the western studies dealing with robotic gastrectomies (RG) to provide pooled results and higher levels of evidence supporting the use of robotic gastrectomy for the treatment of gastric cancer also at western latitudes. METHODS: A systematic literature search was performed in PubMed, Embase, and Scopus for studies published between 2010 and 2020 concerning RG in western centers. Case series and comparative studies (robotic versus open and robotic versus laparoscopic) were included. RESULTS: After screening 1732 articles, 10 articles with a total of 988 patients undergoing RG in western centers were eligible for inclusion. Included studies showed a relatively low risk of bias. The pooled conversion rate was 3.9% (95% CI 1.2-7.9). The pooled overall complications rate was 15% (7.1-25.3) with a mortality rate of 2.5% (1.1-4.7). The pooled 5-year overall survival rate was 60.4% (46.0-74.1). The pooled analyses of the comparative studies (robotic versus open) included 132 robotic and 305 open gastrectomies and showed comparable safety parameters. The robotic group had a pooled 5-year overall survival of 55.2% (33.7-75.8) versus 50.8% (36.4-65.2) of the open group (RR 1.10, 0.78-1.55; p = 0.248 - I2 51.8, 0.0-86.1; p = 0.125). The meta analyses of the results from the studies comparing the robotic (n = 679) and the laparoscopic (n = 1355) approach (LG) showed similar morbidity (RG 19.9%, 10.2-32.0 versus LG 15.6%, 8.7-24.0; p = 0.706) and mortality rates (RG 5.5%, 3.9-7.3 versus LG 4.3%, 3.3-5.4; p = 0.272). RG had longer operative time (RG 327 min, 297-358 versus LG 248, 222-275; p = 0.001) and lower blood loss (RG 99 ml, 96-103 versus LG 133, 104-161; p < 0.001) than laparoscopic gastrectomy. CONCLUSION: Based on the available data from western centers, robotic gastrectomy is comparable with the open and the laparoscopic approaches with regards to short term outcomes. Survival data of RG were similar to open gastrectomies, but studies on long-term outcomes are required to confirm these results.

Comparison of Efficacy and Safety of 4 Combinations of Laparoscopic and Intraoperative Techniques for Management of Gallstone Disease With Biliary Duct Calculi: A Systematic Review and Network Meta-analysis.

Importance: Several techniques are used for surgical treatment of gallstone disease with biliary duct calculi, but the safety and efficacy of these approaches have not been compared. Objectives: To compare the efficacy and safety of 4 surgical approaches to gallstone disease with biliary duct calculi. Data Sources: MEDLINE, Scopus, and ISI-Web of Science databases, articles published between 1950 and 2017 and searched from August 12, 2017, to September 14, 2017. Search terms used were LCBDE, LC, preoperative, ERCP, postoperative, period, cholangiopancreatography, endoscopic, retrograde, rendezvous, intraoperative, one-stage, two-stage, single-stage, gallstone, gallstones, calculi, stone, therapy, treatment, therapeutics, surgery, surgical, procedures, clinical trials as topic, random, and allocation in several logical combinations. Study Selection: Randomized clinical trials comparing at least 2 of the following strategies: preoperative endoscopic retrograde cholangiopancreatography (PreERCP) plus laparoscopic cholecystectomy (LC); LC with laparoscopic common bile duct exploration (LCDBE); LC plus intraoperative endoscopic retrograde cholangiopancreatography (IntraERCP); and LC plus postoperative ERCP (PostERCP). Data Extraction and Synthesis: A frequentist random-effects network meta-analysis was performed. The surface under the cumulative ranking curve (SUCRA) was used to show the probability that each approach would be the best for each outcome. Main Outcomes and Measures: Primary outcomes were the safety to efficacy ratio using overall mortality and morbidity rates as the main indicators of safety and the success rate as an indicator of efficacy. Secondary outcomes were acute pancreatitis, biliary leak, overall bleeding, operative time, length of hospital stay, total cost, and readmission rate. Results: The 20 trials comprised 2489 patients (and 2489 procedures). Laparoscopic cholecystectomy plus IntraERCP had the highest probability of being the most successful (SUCRA, 87.2%) and safest (SUCRA, 69.7%) with respect to morbidity. All approaches had similar results regarding overall mortality. Laparoscopic cholecystectomy plus LCBDE was the most successful for avoiding overall bleeding (SUCRA, 83.3%) and for the shortest operative time (SUCRA, 90.2%) and least total cost (SUCRA, 98.9%). Laparoscopic cholecystectomy plus IntraERCP was the best approach for length of hospital stay (SUCRA, 92.7%). Inconsistency was found in operative time (indirect estimate, 19.05; 95% CI, 2.44-35.66; P = .02) and total cost (indirect estimate, 17.06; 95% CI, 3.56-107.21; P = .04). Heterogeneity was observed for success rate (τ, 0.8), operative time (τ, >1), length of stay (τ, >1), and total cost (τ, >1). Conclusions and Relevance: The combined LC and IntraERCP approach had the greatest odds to be the safest and appears to be the most successful. Laparoscopic cholecystectomy plus LBCDE appears to reduce the risk of acute pancreatitis but may be associated with a higher risk of biliary leak.

Is radical surgery always curative in pancreatic neuroendocrine tumors? A cure model survival analysis.

BACKGROUND: Adjuvant therapy after curative surgery for sporadic pancreatic neuroendocrine tumor (pNETs) is not currently recommended, assuming that all patients could be cured by a radical resection. The aim of our study is to establish how many and which kind of patients remained uncured after radical resection of pNET. METHODS: Retrospective study involving 143 resected sporadic pNETs. The survival analysis was carried out using the cure model, describing the cure fraction and the excess of risk recurrence. Multivariate analyses were made in order to evaluate the non negligible effect of demographics, clinical and pathological factors on survival parameters. The results were reported as percentages, fractions, ORs and HRs with 95% confidence interval (95 CI %). RESULTS: The cure fraction and the excess of hazard rate of the whole population were 57.1% (37.4-74.6, 95% CI) and 0.06 (0.03-0.07, 95% CI), respectively. Two independent factors were related to the cure fraction: TNM stage (OR 0.27 ±â€¯0.17; P = 0.002) and grading (OR 0.11 ±â€¯0.18; P = 0.004). Considering the excess of hazard rate, only two independent factors were related to an increased risk of recurrence: TNM stage (HR 3.49 ±â€¯1.12; P = 0.004) and grading (HR 4.93 ±â€¯1.82; P < 0.001). CONCLUSION: The radical surgery has a high probability of cure in stages I-II or in grading 1 while, in stages III-IV or in grading 3 tumors, surgery alone failed to achieve a "cure". A multimodal treatment should be employed in order to avoid a recurrence of the disease.

Laparoscopic distal pancreatectomy: which factors are related to open conversion? Lessons learned from 68 consecutive procedures in a high-volume pancreatic center.

BACKGROUND: Laparoscopic distal pancreatectomy represents a difficult surgical procedure with an high conversion rate to open procedure. The factors related to its difficulty and conversion to open distal pancreatectomy were rarely reported. The aim of the present study was to identify which factors are related to conversion from laparoscopic to open distal pancreatectomy. METHODS: A retrospective study of a prospective database of 68 patients who underwent laparoscopic distal pancreatectomy was conducted at a high-volume center by pancreatic surgeons experienced with laparoscopic surgery. Pre-intra and postoperative data were collected. Patients who completed a laparoscopic distal pancreatectomy were compared with those who needed a conversion to the open approach as regard demographic, clinical, radiological, and surgical data. Univariate and multivariate analyses were carried out. RESULTS: Univariate analysis suggested that the site of the lesion, the extension of pancreatic resection, and the requirement for an extended procedure to adjacent organs were significantly associated with the risk of conversion to the open approach. Multivariate analysis showed that only the extension of the pancreatic resection (subtotal pancreatectomy) was significantly related to the odds of conversion [odds ratio (OR) 19.5; 95% confidence interval (CI) 1.1-32.3; P = 0.038]. Preoperative suspicion of malignancy differed between the two groups; however, this difference did not reach statistical significance (P = 0.078). CONCLUSIONS: Despite the limitations of the study, only the extension of pancreatic resection seemed to be the main factor related to conversion during laparoscopic distal pancreatectomy.

Multicolour versus monocolour inking specimens after pancreaticoduodenectomy for periampullary cancer: A single centre prospective randomised clinical trial.

BACKGROUND: R status represents an important prognostic factors in periampullary cancers. Thus, it is useful to verify if it can be influenced by different techniques of margination. METHODS: Single-centre, randomised clinical trial of patients affected by periampullary cancer who underwent pancreaticoduodenectomies which included two different types of margination: arm A (multicolour inking) and arm B (monocolour inking). The primary endpoint was the overall R1 resection rate and its difference between the two arms. The secondary endpoints were the R1 resection rate in each margin and its difference between the two arms, and the impact of margin status on survival. RESULTS: Fifty patients were randomised, 41 analysed: 22 in arm A, 19 arm B. The overall R1 status was 61%, without significant differences between the two arms. The margin most commonly involved was the superior mesenteric artery (SMA) (36.6%). A trend in favour of arm B was shown for the superior mesenteric artery margin (arm A = 22.7% versus arm B = 52.6%; P = 0.060). The anterior surface (P = 0.015), SMA (P = 0.047) and pancreatic remnant (P = 0.018) margins significantly influenced disease-free survival. CONCLUSIONS: The R status was not influenced by different techniques of margination using a standardised pathological protocol. The SMA margin seemed to be the most important margin for evaluating both R status and disease-free survival.

Impact of surgery and surveillance in the management of branch duct intraductal papillary mucinous neoplasms of the pancreas according to Fukuoka guidelines: the Bologna experience.

The objective of the study was to evaluate the Fukuoka guidelines in indicating the proper management for recognising the risk factors of malignancy. Data of patients with branch duct intraductal papillary mucinous neoplasms who underwent pancreatic resection or surveillance according to the Fukuoka risk parameters were collected in a prospective database. The clinical outcome (development of pancreatic cancer, overall and disease-specific survival) and pathological results were evaluated in all patients and in resected cases, respectively. The data of 197 patients were collected: 23 primarily resected and 174 primarily followed. Of the latter, 16 were secondarily resected. Among the patients resected, 21 (53.9%) showed diagnosis of in situ or invasive carcinoma and only contrast-enhancing mural nodules were significantly related to malignancy (P = 0.002), with a DOR of 3.3 and an LH+ of 2.2. Development of pancreatic cancer was shown in ten (5.7%) of the patients primarily followed. The overall survival and disease-specific survival were similar between patients primarily followed and primarily resected. It seems reasonable to suggest that a branch duct intraductal papillary mucinous neoplasm should be treated as a benign and indolent disease that is rarely malignant. Enhancing mural nodules represent the best indicator for surgery.

Minimally Invasive Pancreaticoduodenectomy: What is the Best "Choice"? A Systematic Review and Network Meta-analysis of Non-randomized Comparative Studies.

BACKGROUND: Many mini-invasive pancreaticoduodenectomy (MIPD) techniques have been reported, but their advantages with respect to an open technique (OPD) and with respect to each other are unclear. METHOD: A systematic literature search of studies comparing different types of MIPD was carried out: laparoscopic-assisted (LAPD), totally robotic (TRPD), totally laparoscopic (TLPD) or totally laparoscopic-robotic assisted (TLPD-RA) to OPD. The primary endpoint was postoperative mortality. The secondary endpoints were intraoperative, postoperative and oncological outcomes. A network meta-analysis was designed to generate direct, indirect and mixed estimate effects, between different approaches, for each variable. The effects were reported as pairwise comparisons and hierarchical ranking as to each approach could be the best or the worst for each outcome, expressed by the surface under the cumulative ranking curve. RESULTS: Twenty studies were identified, involving 2759 patients: 1813 OPDs, 81 LAPDs, 505 TRPDs, 224 TLPDs and 136 TLPD-RAs. No differences regarding postoperative mortality were found in pairwise comparison. The LAPD technique had a high probability of being the worst approach, while TRPD had a high probability of being one of the best. Regarding the secondary endpoints, OPD was the best regarding operative time and postoperative bleeding, but the worst regarding blood loss and wound infection. The TRPD or TLPD-RA techniques seemed to be the best for delayed gastric emptying, length of hospital stay, harvested lymph nodes and postoperative morbidity. The TLPD technique was often the worst approach, especially for overall and major complications, postoperative bleeding and biliary leak. CONCLUSION: The safest MIPDs are those involving a robotic system which seems to have a promising role in ameliorating the outcomes of OPD, especially when compared to a laparoscopic approach.

Prospective validation of a preoperative risk score model based on pancreatic texture to predict postoperative pancreatic fistula after pancreaticoduodenectomy.

BACKGROUND: In 2015, basing on objective preoperative factors related to pancreas remnant texture (body mass index, Wirsung duct size and preoperative diagnosis), we proposed a score model to predict the risk of postoperative pancreatic fistula after partial pancreatectomies. The aim of the present study was to prospectively validate this preoperative predictive risk score for postoperative pancreatic fistula after pancreaticoduodenectomy. METHODS: Prospective study of consecutive patients who underwent pancreaticoduodenectomy in which a preoperative risk score, based on factors related to the pancreatic texture, was calculated. The risk score model was tested by comparison with subjective intraoperative assessment of the pancreas remnant texture and drain amylase value on postoperative day 1. Sensitivity, specificity, positive and negative likelihood ratio and area under the curve were calculated. RESULTS: Eighty-four patients who underwent pancreaticoduodnectomy were analyzed. Clinically relevant pancreatic fistulas rate was 40.6%. The risk score model with a cut-off of 6 increased the odds of pancreatic fistula approximately 3 fold but it was not independently related to it. On the contrary, considering a cut-off of 5, the risk score model increased the odds of pancreatic fistula 11-16 fold and it was independently related to it. The new risk score model and pancreatic texture had high sensitivity (97% and 88%, respectively) and low specificity (34% and 60%, respectively) while the amylase drain value had low sensitivity (44%) and high specificity (92%). CONCLUSIONS: The preoperative risk score model with a cut-off of 5 was a useful predictor of clinically relevant pancreatic fistula after pancreaticoduodenectomy. The drain amylase value represents a complementary factor to the risk score in predicting a pancreatic fistula.

Sporadic Small (≤20 mm) Nonfunctioning Pancreatic Neuroendocrine Neoplasm: is the Risk of Malignancy Negligible When Adopting a More Conservative Strategy? A Systematic Review and Meta-analysis.

BACKGROUND: The management of small (≤20 mm), nonfunctioning pancreatic neuroendocrine neoplasms (pNENs) remains under debate. The European Neuroendocrine Tumor Society guidelines advocate the possibility of a conservative approach. METHODS: A systematic literature search was conducted to identify all studies comparing the risk of malignancy in small pNENs with respect to large ones (>20 mm). Malignancy was defined based on the presence of nodal metastases. Distant metastases, tumor grading (G2-3), vascular microscopic invasion, stage III-IV, and overall and disease-free survival also were evaluated. The data were reported in two ways: using the risk difference (RD) and the likelihood of being helped or harmed (LHH). RESULTS: The search identified only 6 eligible studies with an overall population of 1697 resected pNENs: 382 (22.5%) small and 1315 (77.5%) large. The RD of lymph nodal metastases was -0.26 (95% confidence interval (CI): -0.31 to -0.22; P < 0.001). The LHH was 0.34, suggesting that the risk of leaving a malignancy during follow-up due to the adoption of a conservative strategy was three times higher than the benefits. The risk difference of distant metastases, G3 lesions, G2-G3 lesions, stage III/IV, microscopic vascular invasion, death, and recurrence of the disease were lower in small NF-PNETs than large ones. The related LHH values suggested that a watch-and-wait policy never provided a benefit. CONCLUSIONS: Even if the malignancy rate in sporadic, small pancreatic neuroendocrine neoplasms was lower than in large ones, this difference did not justify a watch-and-wait policy.

Is pancreaticogastrostomy safer than pancreaticojejunostomy after pancreaticoduodenectomy? A meta-regression analysis of randomized clinical trials.

OBJECTIVE: To evaluate the clinically relevant POPF rate between Pancreatogastrostomy (PG) and pancreaticojejunostomy (PJ) after pancreaticoduodenectomy (PD). To evaluate the confounding factors affecting meta-analytic results. METHODS: A systematic literature search of randomized clinical trials (RCTs) comparing PG to PJ with an International Study Group of Pancreatic Fistula (ISGPF) definition of postoperative pancreatic fistula (POPF). Risk difference (RD) and number needed to treat or harm (NNT and NNH) were used. Fixed and random-effect models were applied. Impact of confounding covariates on the meta-analytic results was evaluated using meta-regression analysis, reporting ß coefficient ± standard error (SE). RESULTS: Seven RCTs were identified involving 1184 patients: 603 PG and 581 PJ. RD in the fixed model of clinically relevant POPFs suggested that PG was superior to PJ (RD-0.07; 95% CI: -0.11 to -0.03) with an NNT of 14 (95% CI: 9 to 33). In random model, PG was not superior to PJ (RD-0.06; 95% CI: -0.13 to 0.01) with an NNT of 17 and a possibility of harm in some cases (NNH = 100). Meta-regression suggested that the increase in the proportion of "soft pancreas" in the PG arm corresponded to a more positive value of RD (ß = 0.47 ± 0.19; P value: 0.045 ± 0.003). CONCLUSION: A PG could be slightly superior to PJ in the prevention of clinically relevant POPF. The presence of high risk pancreatic remnant remains the main limitation of PG.

Is surgery the best treatment for sporadic small (≤2 cm) non-functioning pancreatic neuroendocrine tumours? A single centre experience.

BACKGOUND: There is currently there is substantial controversy regarding the best management of non-functioning pancreatic neuroendocrine tumours ≤2 cm. METHODS: Retrospective study involving 102 surgically treated patients affected by non-functioning pancreatic neuroendocrine tumours. Patients having small tumours (≤2 cm) (Group A) and those having large tumours (>2 cm) (Group B) were compared regarding demographics, clinical and pathological factors with the aim of evaluating the risk of malignancy and survival times. RESULTS: The small tumours were T3-4 in 11% and G2-3 in 36.6% of cases; lymph node and distant metastases were present in 31% and 8% of the cases, respectively. When small and large tumours were compared, significant differences were found in relation to the presence of symptoms (P = 0.012), tumour status (P > 0.001), grading (P > 0.001) and years lost due to disability (P = 0.002). Multivariate analysis of the factors predicting malignancy and survival times showed that tumour size was related only to grading (P < 0.001). The years of life lost and disability adjusted life years were influenced by age at of diagnosis, the presence of symptoms and years lost due to disability only by grading. CONCLUSIONS: Tumour size alone did not seem to be reliable in predicting malignancy because, first, small tumours (≤2 cm) could present lymph node or distant metastases, and could be G2-3 in a non-negligible percentage of cases and second, their risk of malignancy and survival time are similar to large tumours. Additional parameters have to be considered in order to establish the proper management of small tumours, such as age at diagnosis, presence of symptoms and grading.