Initial surgical management of sporadic medullary thyroid cancer: Guidelines based optimal care - A systematic review.

INTRODUCTION: Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor from parafollicular cells that produce calcitonin (Ct). Despite several existing guidelines for the surgical management of sporadic MTC (sMTC), optimal initial surgical management of the thyroid, the central and the lateral neck remains a matter of debate. METHODS: A systematic review in PubMed and Scopus for current guidelines addressing the surgical management of sMTC and its referenced citations was conducted as per the PRISMA guidelines. RESULTS: Two-hundred and one articles were identified, of which 7 met the inclusion criteria. Overall, guidelines vary significantly in their recommendations for the surgical management of sMTC. Only one guideline recommended partial thyroidectomy for limited disease, but the possibility to avoid completion thyroidectomy in selected cases is acknowledged in 42% (3/7) of the remaining guidelines. The majority of guidelines (71.4%; 5/7) recommended prophylactic central neck dissection (CND) for all patients while the remaining two guidelines recommended CND based on Ct level and tumor size. The role of prophylactic lateral neck dissection based on preoperative Ct levels was recommended by 42% (3/7) of guidelines. Overall, these guidelines are based on low-quality evidence, mostly single-center retrospective series, some of which are over 20 years old. CONCLUSION: Current surgical management guidelines of sMTC should be revised, and ought to be based on updated data challenging current recommendations, which are based on historic, low-quality evidence. Partial thyroidectomy may become a viable option for small, limited tumors. Prospective, multi-center studies may be useful to conclude whether prophylactic ND is necessary in all sMTC patients.

Psychosocial factors and patient and healthcare delays in large (class T3-T4) oral, oropharyngeal, and laryngeal carcinomas.

BACKGROUND: Psychosocial factors and socioeconomic status have been associated with incidence, survival, and quality of life among patients with head and neck cancer. We investigated the association between different psychosocial factors, socioeconomic status, and patient delays in T3-T4 oral, oropharyngeal, and laryngeal cancer. PATIENTS AND METHODS: We conducted a nationwide prospective questionnaire-based study (n = 203) over a 3-year period. RESULTS: We found no association between psychosocial factors (depression, social isolation, loneliness, and cynical hostility) and patient delay. Depression was three times more common among head and neck cancer patients compared with the general Finnish population. Head and neck cancer patients had lower educational levels and employment status, and were more often current smokers and heavy drinkers. CONCLUSIONS: Although we found no association between patient delay and psychosocial factors, patients diagnosed with a large head and neck cancer appeared to have a lower socioeconomic status and higher risk for developing depression, which should be considered in clinical practice.

The prognostic role of single cell invasion and nuclear diameter in early oral tongue squamous cell carcinoma.

BACKGROUND: The clinical significance of single cell invasion and large nuclear diameter is not well documented in early-stage oral tongue squamous cell carcinoma (OTSCC). METHODS: We used hematoxylin and eosin-stained sections to evaluate the presence of single cell invasion and large nuclei in a multicenter cohort of 311 cases treated for early-stage OTSCC. RESULTS: Single cell invasion was associated in multivariable analysis with poor disease-specific survival (DSS) with a hazard ratio (HR) of 2.089 (95% CI 1.224-3.566, P = 0.007), as well as with disease-free survival (DFS) with a HR of 1.666 (95% CI 1.080-2.571, P = 0.021). Furthermore, large nuclei were associated with worse DSS (HR 2.070, 95% CI 1.216-3.523, P = 0.007) and with DFS in multivariable analysis (HR 1.645, 95% CI 1.067-2.538, P = 0.024). CONCLUSION: Single cell invasion and large nuclei can be utilized for classifying early OTSCC into risk groups.

Laryngeal cancer relative survival trends from 1972 to 2021 in the Nordic countries.

BACKGROUND AND PURPOSE: Changes in treatment approaches, characterised by the shift from laryngectomy to a focus on organ-preserving methods may have potentially resulted in lower survival. We aim to identify differences in survival trends for laryngeal cancer (LC) in the Nordic countries over a period of 50 years, and discuss the potential impact of factors such as changes in treatment protocols. MATERIALS AND METHODS: Five-year relative survival (RS) data from 1972 to 2021 were obtained from the NORDCAN database 2.0 which included 33,692 LC cases, of which 85% were diagnosed among men. In the NORDCAN database, the age-standardised RS is calculated using the Pohar Perme estimator with individual International Cancer Survival Standards weights. Joinpoint regression models were used to assess potential shifts in trend over the years in RS. RESULTS: While Denmark and Norway demonstrated an increasing trend in 5-year RS from 1972 to 2021, in Finland and Sweden, the 5-year RS among men remained static, without any discernible significant trend. Over the 30-year period from 1992-1996 to 2017-2021, RS improved by 9, 4, 13, and 2 percentage points in Denmark, Finland, Norway, and Sweden, respectively. Among women in Sweden, a linear negative trend was observed, noticeable as a 16 percentage-point decline in 5-year RS from the earliest to the latest period. INTERPRETATION: The underlying causes for the differences in survival trends remain unclear. Besides differences in treatment protocols, several other factors can affect RS making the interpretation of RS trends challenging.

Presence of herpesviruses, parvoviruses, and polyomaviruses in sinonasal lymphoma.

PURPOSE: Sinonasal lymphoma (SL) is a rare lymphatic neoplasm of the nasal cavities, paranasal sinuses and nasopharynx. Whereas some risk factors for SL subtypes have been identified, their aetiology is unknown. Along with other predisposing factors, the viral association of lymphomas, such as Epstein-Barr virus (EBV) and Burkitt and Hodgkin lymphomas, is well-established. Modern molecular biology techniques have enabled the discovery of novel human viruses, exemplified by the protoparvovirus cutavirus (CuV), associated with cutaneous T-cell lymphoma. These findings, and the anatomical location of the sinonasal tract with its rich microbiome and infectious agents, justify in-depth studies among SL. METHODS: We analysed the presence of 20 viruses of Orthoherpesviridae, Parvoviridae, and Polyomaviridae by qPCR in 24 SL tumours. We performed RNAscope in situ hybridisation (RISH) to localize the viruses. Parvovirus-specific IgG was analysed by enzyme immunoassay and targeted next-generation sequencing (NGS) was applied to detect CuV in plasma. RESULTS: We detected viral DNA in 15/24 (63%) tumours; nine of EBV, six of human herpesvirus (HHV) -7, four each of HHV-6B and parvovirus B19, two of cytomegalovirus, and one each of CuV and Merkel-cell polyomavirus. We found tumours with up to four viruses per tumour, and localized CuV and EBV DNAs by RISH. Two of the ten plasma samples exhibited CuV IgG, and one plasma sample demonstrated CuV viremia by NGS. CONCLUSION: Viruses were frequent findings in SL. The EBV detection rate was high in diffuse large B-cell lymphoma, and co-detections with other viruses were prevalent.

Integration of 3D-printed middle ear models and middle ear prostheses in otosurgical training.

BACKGROUND: In otosurgical training, cadaveric temporal bones are primarily used to provide a realistic tactile experience. However, using cadaveric temporal bones is challenging due to their limited availability, high cost, and potential for infection. Utilizing current three-dimensional (3D) technologies could overcome the limitations associated with cadaveric bones. This study focused on how a 3D-printed middle ear model can be used in otosurgical training. METHODS: A cadaveric temporal bone was imaged using microcomputed tomography (micro-CT) to generate a 3D model of the middle ear. The final model was printed from transparent photopolymers using a laser-based 3D printer (vat photopolymerization), yielding a 3D-printed phantom of the external ear canal and middle ear. The feasibility of this phantom for otosurgical training was evaluated through an ossiculoplasty simulation involving ten otosurgeons and ten otolaryngology-head and neck surgery (ORL-HNS) residents. The participants were tasked with drilling, scooping, and placing a 3D-printed partial ossicular replacement prosthesis (PORP). Following the simulation, a questionnaire was used to collect the participants' opinions and feedback. RESULTS: A transparent photopolymer was deemed suitable for both the middle ear phantom and PORP. The printing procedure was precise, and the anatomical landmarks were recognizable. Based on the evaluations, the phantom had realistic maneuverability, although the haptic feedback during drilling and scooping received some criticism from ORL-HNS residents. Both otosurgeons and ORL-HNS residents were optimistic about the application of these 3D-printed models as training tools. CONCLUSIONS: The 3D-printed middle ear phantom and PORP used in this study can be used for low-threshold training in the future. The integration of 3D-printed models in conventional otosurgical training holds significant promise.

Occupation and tongue cancer in Nordic countries.

PURPOSE: Almost 200,000 tongue cancers were diagnosed worldwide in 2020. The aim of this study was to describe occupational risk variation in this malignancy. METHODS: The data are based on the Nordic Occupational Cancer (NOCCA) study containing 14.9 million people from the Nordic countries with 9020 tongue cancers diagnosed during 1961-2005. The standardized incidence ratio (SIR) of tongue cancer in each occupational category was calculated using national incidence rates as the reference. RESULTS: Among men, the incidence was statistically significantly elevated in waiters (SIR 4.36, 95% confidence interval (CI) 3.13--5.92), beverage workers (SIR 3.42, 95% CI 2.02-5.40), cooks and stewards (SIR 2.55, 95% CI 1.82-3.48), seamen (SIR 1.66, 95% CI 1.36-2.00), journalists (SIR 1.85, 95% CI 1.18-2.75), artistic workers (SIR 2.05, 95% CI 1.54-2.66), hairdressers (SIR 2.17, 95% CI 1.39-3.22), and economically inactive persons (SIR 1.57, 95% CI 1.42-1.73). Among women, the SIR was statistically significantly elevated only in waitresses (SIR 1.39, 95% CI 1.05-1.81). Statistically significant SIRs ≤ 0.63 were observed in male farmers, gardeners, forestry workers and teachers, and in female launderers. CONCLUSIONS: These findings may be related to consumption of alcohol and tobacco, but the effect of carcinogenic exposure from work cannot be excluded.

Six-month mortality has decreased for patients with curative treatment intent for head and neck cancer in Sweden.

BACKGROUND: In general, survival outcomes for patients with Head and Neck Cancer (HNC) has improved over recent decades. However, mortality within six months after diagnosis for curative patients remains at approximately 5%. The aim of this study was to identify risk factors for early death among patients with curative treatment, and furthermore, to analyze whether the risk of early death changed over recent years. MATERIAL AND METHOD: This real-world, population-based, nationwide study from the Swedish Head and Neck Cancer Register (SweHNCR) included all patients ≥18 years diagnosed with HNC with a curative treatment intent at the multidisciplinary tumor board from 2008 to 2020. A total of 16,786 patients were included. RESULTS: During the study period a total of 618 (3.7%) patients with curative-intended treatment died within six months of diagnosis. Patients diagnosed between 2008 and 2012 had a six-month mortality rate of 4.7% compared to 2.5% for patients diagnosed between 2017 and 2020, indicating a risk reduction of 53% (p <0.001) for death within six months. The mean time to radiation therapy from diagnosis in the 2008-2012 cohort was 38 days, compared to 22 days for the 2017-2020 cohort, (p <0.001). The mean time to surgery from diagnosis was 22 days in 2008-2012, compared to 15 days for the 2017-2020 cohort, (p <0.001). Females had a 20% lower risk of dying within six months compared to males (p = 0.013). For every year older the patient was at diagnosis, a 4.8% (p <0.001) higher risk of dying within six months was observed. Patients with a WHO score of 1 had approximately 2.4-times greater risk of early death compared to WHO 0 patients (p <0.001). The risk of early death among WHO 4 patients was almost 28 times higher than for WHO 0 patients (p <0.001). Patients with a hypopharyngeal tumor site had a 2.5-fold higher risk of dying within six months from diagnosis compared to oropharyngeal tumor patients (p <0.001). CONCLUSIONS: We found that the risk of early death decreased significantly from 2008 to 2020. During this period, the mean time to the start of treatment was significantly reduced both for surgery and oncological treatment regimes. Among patients with a curative treatment intention, increased risk of early death was associated with male sex, older age, advanced disease, increased WHO score, and a hypopharyngeal tumor site.

Artificial Intelligence-Driven Radiomics in Head and Neck Cancer: Current Status and Future Prospects.

BACKGROUND: Radiomics is a rapidly growing field used to leverage medical radiological images by extracting quantitative features. These are supposed to characterize a patient's phenotype, and when combined with artificial intelligence techniques, to improve the accuracy of diagnostic models and clinical outcome prediction. OBJECTIVES: This review aims at examining the application areas of artificial intelligence-based radiomics (AI-based radiomics) for the management of head and neck cancer (HNC). It further explores the workflow of AI-based radiomics for personalized and precision oncology in HNC. Finally, it examines the current challenges of AI-based radiomics in daily clinical oncology and offers possible solutions to these challenges. METHODS: Comprehensive electronic databases (PubMed, Medline via Ovid, Scopus, Web of Science, CINAHL, and Cochrane Library) were searched following the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. The quality of included studies and their risk of biases were evaluated using the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD)and Prediction Model Risk of Bias Assessment Tool (PROBAST). RESULTS: Out of the 659 search hits retrieved, 45 fulfilled the inclusion criteria. Our review revealed that the application of AI-based radiomics model as an ancillary tool for improved decision-making in HNC management includes radiomics-based cancer diagnosis and radiomics-based cancer prognosis. The radiomics-based cancer diagnosis includes tumor staging, tumor grading, and classification of malignant and benign tumors. Similarly, radiomics-based cancer prognosis includes prediction for treatment response, recurrence, metastasis, and survival. In addition, the challenges in the implementation of these models for clinical evaluations include data imbalance, feature engineering (extraction and selection), model generalizability, multi-modal fusion, and model interpretability. CONCLUSION: Considering the highly subjective and interobserver variability that is peculiar to the interpretation of medical images by expert clinicians, AI-based radiomics seeks to offer potentially useful quantitative information, which is not visible to the human eye or unintentionally often remain ignored during clinical imaging practice. By enabling the extraction of this type of information, AI-based radiomics has the potential to revolutionize HNC oncology, providing a platform for more personalized, higher quality, and cost-effective care for HNC patients.

Interpretable machine learning model for prediction of overall survival in laryngeal cancer.

Background: The mortality rates of laryngeal squamous cell carcinoma cancer (LSCC) have not significantly decreased in the last decades.Objectives: We primarily aimed to compare the predictive performance of DeepTables with the state-of-the-art machine learning (ML) algorithms (Voting ensemble, Stack ensemble, and XGBoost) to stratify patients with LSCC into chance of overall survival (OS). In addition, we complemented the developed model by providing interpretability using both global and local model-agnostic techniques.Methods: A total of 2792 patients in the Surveillance, Epidemiology, and End Results (SEER) database diagnosed with LSCC were reviewed. The global model-agnostic interpretability was examined using SHapley Additive exPlanations (SHAP) technique. Likewise, individual interpretation of the prediction was made using Local Interpretable Model Agnostic Explanations (LIME).Results: The state-of-the-art ML ensemble algorithms outperformed DeepTables. Specifically, the examined ensemble algorithms showed comparable weighted area under receiving curve of 76.9, 76.8, and 76.1 with an accuracy of 71.2%, 70.2%, and 71.8%, respectively. The global methods of interpretability (SHAP) demonstrated that the age of the patient at diagnosis, N-stage, T-stage, tumor grade, and marital status are among the prominent parameters.Conclusions: A ML model for OS prediction may serve as an ancillary tool for treatment planning of LSCC patients.

Toll-like receptors 2 and 4, and bacterial proteins in IgG4-related sialadenitis, other types of chronic sialadenitis and sialolithiasis.

Background: The association of chronic sclerosing sialadenitis and IgG4-related disease (IgG4-RD) has resulted in the more frequent identification of IgG4-positivity in submandibular gland inflammations, also uncovering IgG4 overexpression in nonspecific inflammations. These findings lead us to hypothesise that IgG4-positive sialadenitis represents a continuous inflammatory process overlapping histologically with IgG4-RD, possibly differing in aetiology. However, the antigen underlying IgG4 overexpression in IgG4-positive sialadenitis and IgG4-RD remains unknown. Materials and methods: Here, we investigated toll-like receptor (TLR) - mediated bacterial inflammation in submandibular gland tissues of patients with IgG4-positive and IgG4-negative chronic inflammatory lesions of the submandibular gland (n = 61), with noninflamed submandibular glands serving as controls (n = 4). Utilising immunohistochemistry, we assessed the expression of TLR2 and TLR4, lipopolysaccharide (LPS) and the P. gingivalis-specific antigen gingipain R1. Results: We observed TLR2- and TLR4-immunopositivity in 64 (98%) samples. However, TLR2 and TLR4 staining intensity was significantly stronger in the IgG4-positive group. LPS- and gingipain R1 immunopositivity were observed in 56 (86%) and 58 (89%) samples, respectively. LPS-positivity localised exclusively in mast cell-like cells, while gingipain R1-positivity remained scarce. Conclusions: A stronger TLR2 or TLR4 expression in IgG4-positive sialadenitis may indicate a tissue-related factor underlying this form of chronic sialadenitis. LPS- and P. gingivalis immunopositivity remained weak throughout this series. Thus, gram-negative bacteria may not represent pathogens underlying these forms of chronic sialadenitis.

Pretreatment fat-free mass index correlates with early death in patients with head and neck squamous cell carcinoma.

BACKGROUND: A significant proportion of patients with head and neck squamous cell carcinoma (HNSCC) are malnourished at diagnosis. In this study, we investigated how pretreatment body mass index (BMI) and fat-free mass index (FFMI) correlate with early death, and whether these measurements are useful markers of prognosis for risk stratification of head and neck cancer patients. METHODS: Patients (n = 404) with newly diagnosed, curable HNSCC and WHO performance status 0-2 were prospectively included and met with a study representative before treatment initiation, as well as up to four follow-up visits. All patients provided an estimate of body weight at 6 months prior to diagnosis. Bioelectrical impedance analysis (BIA) was performed for all patients before treatment initiation. RESULTS: Most patients had oropharyngeal (46%), oral cavity (28%), or laryngeal cancer (12%). Forty-five (11%) patients met the standardized criteria for malnutrition according to the Global Leadership Initiative on Malnutrition (GLIM) at diagnosis. FFMI at diagnosis was lower in patients who died within 6 and 12 months after the start of treatment than in patients who survived these time points (p = 0.035 and p = 0.005, respectively). CONCLUSIONS: In this study, pretreatment FFMI was an independent prognostic factor for death within 6 and 12 months after the start of treatment in patients with HNSCC. Pretreatment BMI was not an independent risk factor for death within 6 and 12 months after treatment termination. Thus, FFMI may be useful for risk stratification of patients with head and neck cancer.

Clinical decision making when cytology indicates a Warthin tumor.

Warthin tumor (WT) is a benign tumor usually affecting the parotid gland. The main diagnostic tool remains ultrasound combined with fine-needle aspiration cytology (FNAC). This study aims to examine how reliably FNAC indicates WT for clinical decision making regarding surgical versus conservative management. We included all patients who underwent FNAC from a parotid gland lesion between 2016 and 2018 at our institution, and whose FNAC revealed WT suspicion. The FNACs were divided into three groups based on the cytology report: certain, likely, and possible WT. The patients were divided into two groups based on having had either surgery or follow-up. We sent a questionnaire to patients who had not undergone surgery in order to obtain follow-up for a minimum of four years. Altogether, 135 FNAC samples, from 133 tumors and 125 patients, showed signs of WT. Of the 125 patients, 44 (35%) underwent surgery, and 81 (65%) were managed conservatively. Preoperative misdiagnosis in FNAC occurred in three (7%) surgically treated tumors. Their FNACs were reported as possible WTs, but histopathology revealed another benign lesion. In the conservatively treated group, two patients underwent surgery later during the follow-up. Cytological statements of WT were seldom false, and none were malignant. The majority of the patients were only followed-up and rarely required further treatment. A certain or likely diagnosis of WT in the FNAC report by an experienced head and neck pathologist is highly reliable in selecting patients for conservative surveillance.

Immunoexpression pattern of TLR3 and TLR7 in minor salivary gland adenoid cystic carcinoma and its role in prognosis.

OBJECTIVES: Adenoid cystic carcinoma (ACC) of the salivary glands has poor long-term prognosis and a high metastatic rate. Toll-like receptors (TLRs), first-line immune activators, have been associated with both tumor progression and suppression. We aimed to study TLR3 and TLR7 behavior in ACC. MATERIALS AND METHODS: We studied TLR3 and TLR7 immunoexpression of 46 minor salivary gland ACCs diagnosed at the Department of Otorhinolaryngology - Head and Neck Surgery, Helsinki University Hospital, Helsinki, Finland over the period 1974-2012. The associations of TLR3 and TLR7 immunoexpression with clinicopathological factors were evaluated by χ2-test and Fisher's exact test. RESULTS: In the majority of samples, both TLR3 and TLR7 were immunoexpressed in cytoplasm. The immunoexpression was heterogeneous between individual tumors. Stronger TLR7 immunoexpression associated with recurrence rate and poorer disease-specific survival (DSS). TLR3 did not associate significantly with survival although we found an inverse correlation between TLR3 and TLR7 immunopositivity. Hence, when TLR3 immunoexpression was negative or mild, TLR7 immunoexpression was moderate to strong, and vice versa. CONCLUSIONS: TLR3 and TLR7 are immunoexpressed in minor salivary gland ACC. TLR7 is potentially an independent prognostic marker for recurrence rate and DSS.

Altered microheterogeneity at several N-glycosylation sites in OPSCC in constant protein expression conditions.

Protein glycosylation responds sensitively to disease states. It is implicated in every hallmark of cancer and has recently started to be considered as a hallmark itself. Changes in N-glycosylation microheterogeneity are more dramatic than those of protein expression due to the non-template nature of protein glycosylation. This enables their potential use in serum-based diagnostics. Here, we perform glycopeptidomics on serum from patients with oropharyngeal squamous cell carcinoma (OPSCC), compared to controls and comparing between cancers based on etiology (human papilloma virus- positive or negative). Using MS2, we then targeted glycoforms, significantly different between the groups, to identify their glycopeptide compositions. Simultaneously we investigate the same serum proteins, comparing whether N-glycosylation changes reflect protein-level changes. Significant glycoforms were identified from proteins such as alpha-1-antitrypsin (SERPINA1), haptoglobin, and different immunoglobulins. SERPINA1 had glycovariance at 2 N-glycosylation sites, that were up to 35 times more abundant in even early-stage OPSCCs, despite minimal differences between SERPINA1 protein levels between groups. Some identified glycoforms' fold changes (FCs) were in line with serum protein level FCs, others were less abundant in early-stage cancers but with great variance in higher-stage cancers, such as on immunoglobulin heavy constant gamma 2, despite no change in protein levels. Such findings indicate that glycovariant analysis might be more beneficial than proteomic analysis, which is yet to be fruitful in the search for biomarkers. Highly sensitive glycopeptide changes could potentially be used in the future for cancer screening. Additionally, characterizing the glycopeptide changes in OPSCC is valuable in the search for potential therapeutic targets.

Risk of Second Primary Cancer Among Patients with Cardio-Esophageal Cancer in Finland: A Nationwide Population-Based Study.

Purpose: The occurrence of a second primary cancer (SPC) after primary esophageal carcinoma (EC) or gastric cardia carcinoma(GCC) is well acknowledged. However, previous research on the risk of SPC among these patients has been predominantly conducted in Asian countries. Yet, notable population-dependent variation in histological types and risk profiles exists. This register-based study assesses the histology-specific risk of SPC among individuals initially diagnosed with a first primary EC or GCC. Patients and Methods: We obtained data on 7197 patients diagnosed with EC/GCC in Finland between 1980 and 2022 from the Finnish Cancer Registry. Standardized incidence ratios (SIR) of SPC were subsequently calculated relatively to the cancer risk of the general population. Results: The average and median follow-up times were 2.8 years and 10.5 months. Adenocarcinomas and squamous cell carcinomas comprised 57.8% (n = 4165) and 36.6% (n = 2631) of all cases, respectively. An increased SIR was noted among EC/GCC patients after 15-20 years of follow-up (SIR 1.49, 95% CI: 1.01-2.11). Among adenocarcinoma patients, an increased SIR for SPCs of the digestive organs was seen in the 40-54-year-old group (SIR 9.86, 95% CI: 3.62-21.45). Squamous cell carcinoma patients displayed increased SIRs for cancer of the mouth/pharynx (SIR 3.20, 95% CI: 1.17-6.95) and respiratory organs (1.77, 1.07-2.76). Conclusion: Healthcare professionals should be aware of the increased risk of SPCs occurring in the mouth/pharynx, respiratory and digestive organs in survivors of EC/GCC. Patients should be advised about this risk and remain alert for symptoms, even beyond the standard 5-year follow-up period.