704 Abstract. – OBJECTIVE: Patients with chronic disease whose treatments are limited may experience depression, anxiety, and stress-related symptoms, as well as an increase in the levels of these conditions. This study aims to determine the factors affecting the depression, stress, and anxiety levels of hepatocellular carcinoma (HCC) patients due to the fear of COVID-19 exposure. PATIENTS AND METHODS:118 patients with advanced HCC treated with non-transplant treatment options or on the waiting list due to the lack of a donor were enrolled. To evaluate the stress, depression, and anxiety levels during the COVID-19 process, Depression Anxiety Stress Scales (DASS-21) and the Coronavirus Anxiety Scale (CAS) were administered to 118 patients through a face-to-face interview. Sociodemographic and clinical characteristics were recorded, and the primary endpoint measure was the total score of DASS. In addition, the multilayer perceptron (MLP) model was constructed to predict the scores of the DASS-21 total. RESULTS: There were significant differences between DASS depression (p=0.010; p=0.030) DASS anxiety (p=0.010; p=0.010) and DASS total (p=0.046; p=0.023) scores in terms of gender and protective effect of the vaccine. Also, a significant difference between gender for the CAS scale was determined (p=0.044). The median score of the DASS total in the COVID-19 group was higher than in the nonCOVID-19 group; however, the increase was not significant. MLP model revealed that chronic disease, gender, age, place of residence, smoking, type of vaccine, and COVID-19 exposure were the most important predictors for the DASS total. CONCLUSIONS: Chronic disease, gender, and age were prominent factors in predicting the DASS-21 total score in HCC patients. Therefore, the crucial factors were clinically considered for managing depression, stress, and anxiety in HCC patients. Key Words: Hepatocellular carcinoma, COVID-19 pandemic, Depression, Anxiety, Stress. Introduction The most frequent primary cancer of the liver is hepatocellular carcinoma (HCC), the second greatest cause of cancer-related death worldwide. It is the fifth most frequent cancer in males and the seventh most prevalent cancer in women globally, with over half a million new cases identified yearly1,2. Treatment of the HCC varies across regions or countries according to the demographic characteristics, stage of the tumor, socioeconomic condition, and availability of treatment options3,4. However, effective treatment for HCC patients in the advanced stage is quite difficult because the disease can usually be diagnosed at an advanced stage3. If HCC is diagnosed at an early stage, it can be treated curatively by surgical resection or liver transplantation. However, most patients with HCC have a poor prognosis with a survival time of less than one year owing to the advanced disease and underlying liver dysfunction5. Cancer patients’ mental states and behavioral patterns may change due to heavy treatment exposure, and thence, anxiety, stress, and depression levels might increase6. With the COVID-19 pandemic, education, commerce, and social activities have been halted almost everywhere in the world. Transportation restrictions, social isolation, quarantine measures, and curfews have become commonplace, and the European Review for Medical and Pharmacological Sciences 2023; 27: 704-712 S. AKBULUT1,2, M. TAMER3, Z. KUCUKAKCALI2, M. AKYUZ3, H. SARITAS4, N. BAGCI3, F. CIFTCI1, M.S. AKBULUT5, E. KARABULUT1, S. YILMAZ1 1Department of Surgery and Liver Transplant Institute, Faculty of Medicine, Inonu University, Malatya, Turkey 2Department of Biostatistics and Medical Informatics, Faculty of Medicine, Inonu University, Malatya, Turkey 3Department of Surgical Nursing, Faculty of Nursing, Inonu University, Malatya, Turkey 4Department of Surgical Nursing, Faculty of Health Sciences, Siirt University, Siirt, Turkey 5Department of Social Work, Bingol State Hospital, Bingol, Turkey Corresponding Author: Sami Akbulut, MD, Ph.D; e-mail: akbulutsami@gmail.com Factors affecting anxiety, depression, and stress among patients with hepatocellular carcinoma during COVID-19 pandemicEffect of COVID-19 on HCC patients’ psychological perspective 705 concept of a “new normal” has emerged. Recent research on COVID-19 reported that this disease might cause fundamental changes in many societies’ psychological and social implications. Therefore, mental disorders such as anxiety, depression, and post-traumatic stress have evolved in the communities7,8. These developing psychological disorders may be more common in people with chronic diseases and cancer, and the restrictions related to COVID-19 can make them more anxious than others. This study aims to determine the factors affecting the depression, stress, and anxiety levels of non-transplant HCC patients due to the fear of contracting COVID-19. Patients and Methods Type, Place, and Time of Research This descriptive and survey-based cross-sectional study conducted at Inonu University (Liver Transplantation Institute), consisted of patients treated with non-transplant treatment options due to advanced HCC and those on the waiting list for an LT but had not had a chance to LT (DDLT or LDLT) until November 2021. Non- transplant treatment options consist of surgical resection, transarterial radioembolization (TARE), transarterial chemoembolization (TACE), microwave ablation (MWA), radiofrequency ablation (RFA), and systemic chemotherapy. Before starting the study, permission was obtained from the Directorate of Liver Transplantation Institute of Inonu University (2021/93882). Each participant gave consent before the questionnaire was distributed. Study Protocol and Ethics Committee Approval This study involving human participants followed the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Ethical approval was obtained from the Inonu University Institutional Review Board (IRB) for Non-Interventional Clinical Research (2021/2766). STROBE (Strengthening the reporting of observational studies in epidemiology) guideline was utilized for considering the checklist related to the current study9. Determination of the Research Population and Study Group Based on the patient information and management system (HBYS-ENLIL) data used in our tertiary referral hospital, 126 HCC patients – who were under the follow-up of our Liver Transplant Institute as of November 2021 and were found to be alive on the specified date – were evaluated as the target population of this study. These patients either had advanced HCC disease and had received one of the non-transplant treatment options (resection, TARE, TACE, MWA, RFA) or were on the waiting list due to the absence of a donor despite surgical indication. Before starting this study, the patients’ basic demographic data were examined and they were contacted by phone or WhatsApp. Eight patients who were not eligible to be included in the study for various reasons (communication disorder and inability to reach their phone) were excluded. The remaining 118 patients were included in this study. The current study evaluated the stress, depression, and anxiety levels of 118 HCC patients using standardized scales during the COVID-19 process. Whether there are any relationships between the scale scores, the demographic characteristics, and the status of COVID-19 exposure was determined. The minimum sample size required to detect a significant difference was calculated at 97, considering type I error (alpha) of 0.05, power (1- beta) of 0.8, an effect size of 0.29, and a two-sided alternative hypothesis. In the current study, 118 HCC patients were enrolled to increase the study’s power, and the primary endpoint measure was the DASS-21 total score. Inclusion and Exclusion Criteria Since this study was questionnaire-based research, HCC patients who were aged ≥ 18 years old, who had sufficient Turkish language to read or understand the questionnaire questions, and who were in the routine follow-up protocol of our center were included. Patients who did not want to respond to the survey or did not respond to some of the questions were excluded from this study. Variables and Scales Used in the Study Demographic and social characteristics form The questionnaire used in this study consisted of 26 questions and two scales. The sociodemographic and clinical characteristics in this study were briefly defined and recorded as follows: age, gender, height, weight, marital status, place of residence, education level, monthly income, cause of liver disease, presence of chronic disease [diabetes mellitus, hypertension, asthma, chronic obstructive pulmonary disease (COPD), cardiovascular disease], smoking, alcohol use, COVID-19 exS. Akbulut, M. Tamer, Z. Kucukakcali, M. Akyuz, H. Saritas, et al 706 posure, antiviral drug use, hospitalization due to COVID-19 (service, intensive care, and intubation), COVID-19 vaccination status (Sinovac, BioNTech, and both), vaccine dose (one, two, three, and four doses), post-vaccine COVID-19 status, the vaccine hesitancy, belief in the protection of the vaccine, and legal obligation for the vaccination. Coronavirus Anxiety Scale-Short Form (CAS-SF) CAS-SF, which aims to determine the severity of anxiety caused by the COVID-19 pandemic in society, was first defined by Lee10. The factor loads of the items ranged from 0.81 to 0.88, and the Cronbach’s alpha coefficient was calculated as 0.93. The validity and reliability tests of the Turkish version of this scale were performed by Biçer et al11. Biçer et al11 demonstrated that the factor loads of the items in the Turkish version of the CAS-SF scale, which consisted of one dimension and five items, varied between 0.625 and 0.784. Biçer et al11 calculated this scale’s Cronbach’s alpha coefficient as 0.832. The responses in the CAS-SF scale, which included five-point Likerttype questions, are listed as not at all (0 points), rare, less than one or two days (1 point), several days (2 points), more than seven days (3 points) and nearly every day over the last two weeks (4 points). The presence of anxiety related to COVID-19 was considered if the score was of 9 or above (min=0 and max=20). Lee10 calculated an optimal cut-off point for anxiety (≥ 9 points) using ROC curve analysis and calculated the sensitivity and specificity values of this cut-off point as 90% and 85% (AUC: 0.94; p<0.001), respectively. Depression, Stress and Anxiety Scale- Short Form (DASS-21) The long form of the DASS scale, developed by a study in 199512, encapsulates 42 items and three sub-dimensions. The Cronbach’s alpha internal consistency coefficients for the depression, anxiety, and stress sub-dimensions of the long version of the DASS scale were calculated as 0.91, 0.84, and 0.90, respectively. Henry and Crawford13 designed a short version of the DASS scale based on the hypothesis that the short form of the DASS scale is also valid for the same measurement. The Cronbach’s alpha reliability coefficient of the DASS-21 form was calculated as 0.93. Regarding sub-dimension analysis, Cronbach’s alpha coefficients of depression, anxiety, and stress sub-dimensions of the DASS-21 were estimated to be 0.88, 0.82, and 0.90, respectively. The Turkish adaptation of the DASS- 21 form was made by Yılmaz et al14. The DASS-21 scale, which consisted of four-Likert type questions, had choices as never (0 points; did not apply to me at all), sometimes (1 point; applied to me to some degree, or some of the time), often (2 point; applied to me to a considerable degree, or a good part of the time), almost always (3 point; applied to me very much, or most of the time). There are seven questions in each of the depression (3, 5, 10, 13, 16, 17, 21), anxiety (2, 4, 7, 9, 15, 19, 20) and stress (1, 6, 8, 11, 12, 14, 18) sub-dimensions. The Cronbach’s alpha reliability and internal consistency coefficient of the DASS-21 scale was 0.87 reported by Yılmaz et al14. In terms of sub-dimensions analysis, Cronbach’s alpha internal consistency coefficients of depression, anxiety, and stress were calculated as 0.819, 0.808, and 0.755, consecutively. There is no reverse-pointed item on the scale. Statistical Analysis Kolmogorov-Smirnov normality test was used to point out whether the variables had a normal distribution. Data were given as median (minimum-maximum) and number (percentage). Mann-Whitney U and Kruskal Wallis tests were used where appropriate for statistical analysis. Conover test was used for pairwise comparisons after the significant Kruskal Wallis test. Effect size is defined as the size of the difference between groups. For the Mann-Whitney U test, the effect size (Cohen d) is interpreted as a small effect between 0.20-0.50, a moderate effect between 0.50-0.80, and a large effect above 0.80. For the Kruskal Wallis test, the effect size (Cohen d) is commented as a small effect between 0.10 and 0.25, a moderate effect between 0.25 and 0.40, and a large effect with values above 0.4015. In the multilayer perceptron method (MLP), a feed-forward artificial neural network model from machine learning methods, COVID-19 exposure, gender, chronic illness, vaccination type, smoking, education level, and place of residence variables were taken as input variables, and DASS total variable was determined as output variable. Feature selection was not performed due to the potential clinical significance of the input variables included in the MLP model. Activation functions were hyperbolic tangent in the hidden layer(s) and identity in the output layer. The number of hidden layers and number of units in the hidden layer was 1, and the number of units and rescaling method for scale dependents was one and standardized, respectively. During the modeling phase, 70% of the data set was used as training and 30% as test data.Effect of COVID-19 on HCC patients’ psychological perspective 707 The sum of squares error and relative error were estimated to evaluate the model performance. A p <0.05 was considered statistically significant. SPSS Statistics 25.v0 program (IBM Corp., Armonk, NY, USA) was used in the analysis. Results Considering the inclusion and exclusion criteria, 118 HCC patients were included in the current study, with ages ranging from 20 to 80 years [median (IQR: 61.5)]. This study included 90 (76.27%) male and 28 (23.73%) female patients. The comparison results for the variables affecting the depression, stress, and anxiety levels caused by the fear of the COVID-19 exposure in patients treated with non-hepatic transplant options for HCC or who have not yet had the chance to be treated were given in Table I. Table I shows statistically significant differences in DASS-21 depression, DASS-21 anxiety, and DASS-21 total scores for gender. In the analyses for gender, the effect sizes are small, and the difference in terms of gender categories is clinically significant. No significant difference was found for the DASS- 21 stress score. There was a statistically significant difference in DASS-21 depression for education level. In the analyses for education level, the effect size (0.465) is large for DASS-21 depression, and the difference in terms of education level categories is clinically significant. There is a statistically significant difference in the DASS-21 depression and DASS-21 anxiety scores for chronic disease. However, no significant difference was found in DASS-21 stress and DASS-21 total scores. There was no statistically significant difference in the types of scores regarding COVID-19 exposure. In addition, no significant difference was found in the score types regarding the COVID-19 vaccine. While there was a statistically significant difference only for the DASS-21 anxiety score concerning vaccine hesitancy; no significant difference was identified in the other score types. There is a statistically significant difference in the DASS-21 depression, DASS-21 anxiety, and DASS-21 total scores according to the vaccine’s protectiveness. Pairwise comparisons showed a difference between the yes and no categories and the yes and no idea categories for the DASS-21 depression score. For the DASS-21 anxiety score, significant differences were observed between the yes and no idea categories and the no idea categories. The effect sizes concerning the vaccine protection for DASS-21 depression, DASS-21 anxiety, and DASS-21 total scores were 0.426 (large), 0.659 (large), and 0.451 (large), respectively. Finally, there was a difference between the yes and no categories for the DASS-21 total score. There was no statistically significant difference in the total score and sub-categories of the DASS-21 scale for the vaccine type. The comparison results of the CASSF scores of the variables are presented in Table II. While there were significant differences in the categories of gender and hospitalization variables in the analyses for the CAS-SF scores, no statistically significant difference was found in the categories of other variables. The graphical architecture for the MLP algorithm is depicted in Figure 1. According to the results from the MLP model’s importance values of the input variables affecting the DASS-21 total score are given in Table III. Among the importance values, chronic disease was the most prominent factor. As a result of modeling, the sum of squares error was 18,457, and the relative error was 0.79. Discussion The present study investigates what factors may influence depression, stress, and anxiety in patients with advanced HCC treated with non-liver transplant options or who have not yet received a liver transplant while on the waiting list for one. To achieve this goal, DASS-21 scales were implemented on the patients to assess depressive, anxiety, and stress-related emotional states. According to the World Health Organization (WHO), a healthy individual is free of sickness or impairment and has a good psychological and physical condition. In accordance with the WHO, technical and medical success with transplantation does not necessarily reflect individual health; at the same time, patients should also be in an appropriate range of psychological state16. Depression, an important mental health problem frequently encountered worldwide, reduces the quality of life and causes workforce losses by preventing human functionality, creativity, happiness, and satisfaction17. The presence of physical illness is both a direct and indirect cause of depressive disorder. Diagnosis of a new illness can often initiate a depressive episode. Chronic diseases, on the other hand, are factors of depression due to their features such as accompanying chronic pain, becoming dependent on others, causing limitations in daily life, and reducing the quality of life. Furthermore, there is concern that the sickness would spread among patients, leading to addiction18.708 Effect of COVID-19 on HCC patients’ psychological perspective Table I. Comparison of DASS-21 scores according to total and sub-dimensions for the variables. There is a statistically significant difference in group categories that do not contain the same letter (Conover test; p<0.05); *: Mann Whitney U test; **: Kruskal Wallis test; ES: Effect size. DASS-21 Depression DASS-21 Stress DASS-21 Anxiety DASS-21 Total Median Median Median Median (Min-Max) ES p (Min-Max) ES p (Min-Max) ES p (Min-Max) ES p Gender Female 2.5 (0-21) 0.466 0.010* 5 (0-17) 0.28 0.128* 1.5 (0-13) 0.41 0.010* 9 (0-43) 0.373 0.046* Male 1 (0-26) 2 (0-13) 0 (0-10) 4 (0-33) Educational level Illiterate 1 (0-26) 0.465 0.044** 3 (0-13) 0.055 0.395 0 (0-13) 0.039 0.412** 5.5 (0-33) 0.313 0.153 Primary school 2 (0-21) 3 (0-17) 0 (0-6) 6 (0-43) Middle School 0 (0-6) 2 (0-8) 0 (0-9) 3 (0-19) High school 0 (0-4) 1 (0-10) 0 (0-6) 1 (0-17) ≥ University 0 (0-14) 2 (0-11) 0 (0-10) 5 (0-32) Chronic disease? Yes 1 (0-26) 0.375 0.036* 4 (0-17) 0.284 0.124* 0 (0-13) 0.321 0.043* 6 (0-43) 0.359 0.054* No 1 (0-14) 2 (0-15) 0 (0-7) 4 (0-32) Exposed to COVID-19? Yes 1 (0-26) 0.041 0.817* 3 (0-11) 0.128 0.484* 0 (0-7) 0.002 0.991 6 (0-33) 0.009 0.962* No 1 (0-21) 3 (0-17) 0 (0-13) 5 (0-43) COVID-19 vaccine? Yes 1 (0-0) 0.243 0.595* 3 (0-0) 0.248 0.583 0 (0-0) 0.323 0.223* 5 (0-0) 0.276 0.465 No 1 (0-14) 3 (0-11) 0 (0-10) 7 (0-32) COVID-19 vaccine Yes 2 (0-26) 0.254 0.153* 3 (0-17) 0.21 0.239* 1 (0-10) 0.32 0.043* 7 (1-43) 0.347 0.062* hesitancy No 1 (0-16) 2 (0-15) 0 (0-13) 5 (0-32) Do you think the Yes 1a (0-14) 0.426 0.030** 2a (0-15) 0.084 0.333* 0 (0-13)a 0.659 0.001** 4 (0-32)a 0.451 0.023** COVID-19 vaccine No 4b (0-21) 5a (1-17) 5 (0-10)b 22 (1-43)b is protective? No idea 2.5b (0-26) 3.5a (0-13) 0 (0-11)a 7.5 (0-33)ab Type of COVID-19 Sinovac 1 (0-16) 0.25 0.173** 3 (0-15) 0.259 0.164* 0 (0-6) 0.213 0.212** 6 (0-27) 0.283 0.141** vaccine Biontech 1 (0-26) 2 (0-17) 0 (0-13) 5 (0-43) Both 0 (0-14) 2 (0-14) 0 (0-11) 2 (0-31)Effect of COVID-19 on HCC patients’ psychological perspective 709 Anxiety is a fear and worry that is difficult to define and can be in different intensities, ranging from a very mild feeling of uneasiness and tension to the degree of panic. Anxiety, fear, and panic are the most obvious reactions of individuals to the disease in general. These responses have been shown to impact patient recovery and behavior. The individual’s reactions to the disease, such as anxiety and depression, directly affect the way and power of coping with the disease19,20. Patients with HCC who are treated with options other than liver transplantation or who have not yet had the chance to transplant have a mood disorder caused by the disease due to the difficulties of intensive treatments. In addition, the idea of the emergence of any other diseases in these patients may increase their mood disorder. In this case, individuals who are already sick may be exposed to new diseases and extreme situations. In the analyses for the DASS-21 scale and its sub-dimensions in the study, significant differences were observed for gender and vaccine protection for the other scales except for the DASS- 21 stress scale. More anxiety and depression were observed in women than in men. Similarly, more anxiety and depression levels were observed in those who did not find the vaccine protective. In the CAS-SF scale score results, significant differences were found for the categories of gender and hospitalization variables. According to the modeling results from the MLP model, chronic disease, gender, age, place of residence, smoking, and educational status are the most effective factors on the DASS-21 total score, respectively. Implementing the MLP is of clinical importance for predicting the DASS-21 total score associated with HCC during COVID-19. The current study enlights by applying the MLP model to explore the potential factors related to the score of DASS-21 total and presents the medical estimations from the clinical point of view. Table II. Comparison of CAS-SF total score for the variables. *: Mann Whitney U test; **: Kruskal Wallis test; ES: Effect size. Variable Category CAS Total ES p Gender Female 0 (0-4) 0.179 0.044* Male 0 (0-6) Have you chronic disease? Yes 0 (0-3) 0.017 0.845* No 0 (0-6) Have you been exposed to COVID-19? Yes 0 (0-6) 0.115 0.196* No 0 (0-3) Have you had the COVID-19 vaccine? Yes 0 (0-6) 0.12 0.177* No 0 (0-0) Hospitalization due to COVID-19 Yes 0 (0-6) 0.571 0.014* No 0 (0-4) Type of vaccine Sinovac 0 (0-6) 0.260 0.820** BioNTech 0 (0-4) Both 0 (0-1) Vaccine dose One 0 (0-0) 0.185 0.537** Two 0 (0-4) Three 0 (0-6) Four 0 (0-0) Post-vaccine COVID-19 status Yes 0 (0-6) 0.116 0.192* No 0 (0-4) Have you hesitancy against the COVID-19 vaccine? Yes 0 (0-6) 0.054 0.545** No 0 (0-4) Do you think the COVID-19 vaccine is protective? Yes 0 (0-4) 0.365 0.058** No 0 (0-6) No idea 0 (0-0) Should COVID-19 vaccine applications Yes 0 (0-4) 0.302 0.102** be made compulsory by law?S. Akbulut, M. Tamer, Z. Kucukakcali, M. Akyuz, H. Saritas, et al 710 The psychological health of society is arguably a primary issue during such a crisis, and implementing mental health examination and support are important aims for coping with COVID-19’s mental health effects21. Within the framework of this study, several clinical scales were considered to measure the anxiety, depression, and stress levels of HCC patients during COVID-19. Clinical research reports22 increased anxiety and depression levels in people with chronic diseases, and the two conditions trigger each other. Similarly, in the current study, the Figure 1. The graphical architecture for the multilayer perceptron algorithm. Table III. Variable importance values for MLP model. Variables Importance Have you been exposed to COVID-19? 0.021 Gender 0.202 Do you have chronic disease? 0.227 Type of vaccine 0.070 Smoking 0.111 Education level 0.100 Place of residence 0.120 Age 0.149Effect of COVID-19 on HCC patients’ psychological perspective 711 MLP model revealed that the patients with chronic diseases were the most emotionally affected. In a study, women observed an increase in anxiety levels compared to men in the case of chronic obstructive pulmonary disease. According to the study results, it can be inferred that women are more anxious and stressed than men in case of an illness23. Similar to the findings of the mentioned study, it was determined that women were affected more emotionally and increased their anxiety in the present study. Possible effects of the COVID-19 pandemic on anxiety, depression, and stress among patients who have advanced-stage HCC were evaluated with basic and sophisticated approaches (i.e., machine learning algorithm). Additionally, Considering the outcomes of the DASS-21 scale, an important public health strategy can be developed collectively to evaluate and address the possible factors on the depression, anxiety, and stress states of HCC patients in the last stages of the COVID-19 pandemic. A medical study5 declares that education level reduces anxiety and depression, enhances the quality of life, and extends longevity in individuals with HCC who have had their tumor removed surgically. In the current study, education level was associated with the DASS-21 total score based on the outcome of the proposed MLP model. Based on the findings, it can be concluded that educational activities have positive effects on anxiety, stress, and depression. Psychological aspects were found to be linked to cancer patient survival24. Depression, hopelessness, and emotional repression are all risk factors for cancer patients having a lower survival time and quality of life25,26. Studies22-29 conducted during the COVID-19 process have shown that cancer patients have a greater fear of exposure to infection and that they experience anxiety and stress due to the risk of progression of their disease due to delays in their treatment. Exposure to COVID-19 was another key predictor in the proposed MLP model. In this context, it can be concluded that clinical improvement of depression, anxiety, and stress states is significant to increase the survival of advanced HCC patients. Limitations The present study may have some limitations. First, comprehensive inferences can be obtained by designing multicenter studies and with larger sample sizes. Second, precise estimates of the DASS-21 total score can be achieved by considering other demographic and clinical variables associated with HCC, and other machine learning models may be constructed. Conclusions To sum up, the MLP model revealed that chronic disease, gender, age, place of residence, smoking, type of vaccine, and the COVID-19 exposure were the most important predictors for the DASS-21 total score. Therefore, the crucial factors were clinically considered for managing depression, stress, and anxiety in HCC patients. Authors’ Contributions All authors contributed to the study’s conception and design. Material preparation, data collection, and analysis were performed by Tamer M., Akyuz M., Saritas H., Bagci N., Ciftci F. and Akbulut M.S. Akbulut S., Yilmaz S., Kucukakcali Z. and Karabulut E. wrote the first draft of the manuscript, and all authors commented on previous versions. All authors read and approved the final manuscript. Funding No financial support was received for this retrospective study. Conflict of Interest The authors declare no conflicts of interest regarding this manuscript. Informed Consent Each participant gave consent before the questionnaire was distributed. Data Availability The datasets analyzed during the current study are available from the corresponding author on reasonable request. Ethics Approval Ethics Committee Approval was approved by the Inonu University Institutional Review Board (IRB) for non-interventional studies (Approval No: 2021/ 2766). Acknowledgements None. References 1) Goodarzi E, Ghorat F, Mosavi Jarrahi A, Adineh H. A, Sohrabivafa M, Khazaei Z. Global incidence and mortality of Liver Cancers and Its relationship with the Human Development Index (HDI): An Ecology Study in 2018. WCRJ 2019; 6: e1255. 2) Mittal S, El-Serag HB. Epidemiology of hepatocellular carcinoma: consider the population. J Clin Gastroenterol 2013; 47: S2-6.S. Akbulut, M. Tamer, Z. Kucukakcali, M. Akyuz, H. Saritas, et al 712 3) Gomaa A, Waked I. Management of advanced hepatocellular carcinoma: review of current and potential therapies. 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Citation: Yönder, H.; Çelik, M.; Berhuni, M.S.; Genç, A.C.; Elkan, H.; Tatlı, F.; Özgönül, A.; Çiftçi, F.; Erkmen, F.; Karabay, O.; et al. Fournier’s Gangrene Mortality Index (FGMI): A New Scoring System for Predicting Fournier’s Gangrene Mortality. Diagnostics 2024, 14, 2732. https://doi.org/10.3390/ diagnostics14232732 Academic Editors: Laurent Bélec and Giulia Ciccarese Received: 13 October 2024 Revised: 29 November 2024 Accepted: 3 December 2024 Published: 5 December 2024 Copyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Article Fournier’s Gangrene Mortality Index (FGMI): A New Scoring System for Predicting Fournier’s Gangrene Mortality Hüseyin Yönder 1,* , Mehmet Çelik 2, Mehmet Sait Berhuni 1, Ahmed Cihad Genç 3 , Hasan Elkan 1, Faik Tatlı 1, Abdullah Özgönül 1, Felat Çiftçi 4 , Fırat Erkmen 5 , O˘guz Karabay 6 and Ali Uzunköy 1 1 Department of General Surgery, Faculty of Medicine, Harran University, ¸Sanlıurfa 63300, Turkey; drmsaitberhuni@hotmail.com (M.S.B.); dr_elkan@hotmail.com (H.E.); faiktatli-@hotmail.com (F.T.); drozgonul@yahoo.com (A.Ö.); aliuzunkoy@yahoo.com (A.U.) 2 Department of Infectious Diseases and Clinical Microbiology, Faculty of Medicine, Harran University, ¸Sanlıurfa 63300, Turkey; dr.mcelik12@gmail.com 3 Department of Internal Medicine, Sakarya Training and Research Hospital, Sakarya 54290, Turkey; genccihad@gmail.com 4 Clinic of General Surgery, ¸Sanlıurfa Training and Research Hospital, ¸Sanlıurfa 63250, Turkey; felatciftci@gmail.com 5 Clinic of General Surgery, ¸Sanlıurfa Balıklıgöl State Hospital, ¸Sanlıurfa 63050, Turkey; firaterkmen@gmail.com 6 Department of Infectious Diseases and Clinical Microbiology, Faculty of Medicine, Sakarya University, Sakarya 54290, Turkey; drkarabay@yahoo.com * Correspondence: hyonder@hotmail.com; Tel.: +90-5326620084 Abstract: Objectives: Fournier’s gangrene is an aggressive, rapidly progressing, and life-threatening necrotizing fasciitis of the perineal and genital regions. Various scoring systems have been developed for predicting survival and prognosis in Fournier’s gangrene. This retrospective study aimed to evaluate the effectiveness of the newly developed Fournier’s gangrene mortality index (FGMI) in predicting mortality associated with Fournier’s gangrene. Methods: The study included patients over the age of 18 years who were followed-up with a diagnosis of Fournier’s gangrene in the general surgery clinics of three different hospitals in ¸Sanlıurfa province between 2014 and 2024. The patients included in this study were divided into two groups: deceased (n = 20) and surviving (n = 149). In FGMI, the parameters used were age, creatinine level, albumin level, lymphocyte percentage, and neutrophil-to-lymphocyte ratio. Based on the total score and risk assessment, <5 points were categorized as low-to-moderate mortality risk and ≥5 points as high mortality risk. Results: A total of 169 patients with a diagnosis of Fournier’s gangrene were included in the study; 87 were men (51.48%). The median age of all patients was 53 (40–63) years; 20 patients (11.8%) died. The Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) score did not show a statistically significant difference between the deceased and surviving groups (p = 0.5). Compared to the survivors, the deceased had higher neutrophil counts, neutrophil percentages, neutrophil-to-lymphocyte ratios, platelet-to-lymphocyte ratios, and C-reactive protein-to-albumin ratios, whereas lymphocyte counts, lymphocyte percentages, eosinophil counts, eosinophil percentages, monocyte counts, and monocyte percentages were lower, and these differences were statistically significant. According to receiver operating characteristic (ROC) analysis, the ROC-area under the curve for predicting mortality based on an FGMI score of ≥5 was 0.88 (95% CI: 0.80–0.95) with a sensitivity of 90% and a specificity of 70% (p < 0.001). Univariate risk analysis was performed, and the odds ratio revealed that mortality risk in patients followed-up for Fournier’s gangrene with a FGMI score of ≥5 was 20 times higher (4.48–90.91) (p < 0.001). Conclusions: The results reveal that the FGMI score is a scoring system that can predict mortality at the initial clinical presentation of patients with Fournier’s gangrene. Another important finding of the present study is that the LRINEC score was not sufficiently effective in predicting mortality. Keywords: Fournier’s gangrene; LRINEC; Fournier’s gangrene mortality index; predictive Diagnostics 2024, 14, 2732. https://doi.org/10.3390/diagnostics14232732 https://www.mdpi.com/journal/diagnosticsDiagnostics 2024, 14, 2732 2 of 10 1. Introduction Fournier’s gangrene (FG), first described by Alfred Fournier in 1883, is an aggressive, rapidly progressing, and life-threatening necrotizing fasciitis of the perineal and genital regions [1,2]. FG causes obliterative endarteritis, leading to inflammation and edema. Necrosis occurs due to impaired blood circulation in the skin and subcutaneous tissues, leading to purplish-black discoloration of the skin. The hypoxic tissue provides a conducive environment for the growth of anaerobic bacteria, which produce nitrogen and hydrogen gases. Infection can spread along the fascia, leading to necrosis of the perineum, scrotum, lower abdominal wall, and upper thighs [3]. Predisposing factors for FG include diabetes mellitus (DM), urinary incontinence, local trauma, perineal or perirectal surgery, spread of periurethral/anal infections, genitourinary infections, anorectal abscess, immunosuppression, alcoholism, and kidney or liver diseases [4]. Studies show that men, especially in the older age group, are more affected by FG [5–7]. Furthermore, FG is typically polymicrobial, and multiple microorganisms are often isolated from wound cultures. Commonly isolated microorganisms include Staphylococcus spp., Streptococcus spp., Escherichia coli, Pseudomonas spp., and Bacteroides spp., and nonbacterial pathogens such as Candida spp. [3–8]. The most common clinical symptoms in patients diagnosed with FG are swelling of the external genital organs, pain, and high fever. The average time from the onset of symptoms to hospital admission is 5.1 ± 3.1 days. Moreover, delays in diagnosis after the onset of symptoms can lead to skin necrosis. Erythema can rapidly progress along anatomical fascial planes, with the potential to spread from the perineum to the clavicles along the anterior abdominal wall. Although the involvement of deeper tissues and the testes is rare, it can be a major indicator of a retroperitoneal or intra-abdominal infection source [9]. Due to the high mortality associated with FG, an aggressive treatment approach is required at the initial presentation, including the administration of broad-spectrum antibiotics [3]. Various scoring systems have been developed to predict survival and prognosis in FG. Wong et al. developed the Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) scoring system, which is a new, simple, and objective scoring system that can help distinguish necrotizing fasciitis from other soft tissue infections using routine laboratory tests that are easily performed in many centers [10]. In addition to this scoring system, the FG severity index (FGSI), the Uludag FG severity index, the simplified FG severity index (sFGSI), and the NUMUNE Fournier Score are used to estimate disease severity and mortality [11–14]. Although no single scoring system provides a definitive prognosis, different predictive scoring systems for mortality at the time of initial presentation are needed and can be beneficial in guiding clinicians’ decision-making processes. This retrospective cohort study aimed to evaluate the effectiveness of the newly developed Fournier’s gangrene mortality index (FGMI) for predicting disease-related mortality and compare its effectiveness with the LRINEC score and various other inflammatory indices. 2. Materials and Methods The study included patients over 18 years of age who were diagnosed with FG and underwent debridement after necrosis was detected in the genital or perianal region during clinical examination at the general surgery clinics of three tertiary hospitals in ¸Sanlıurfa province between 2014 and 2024. All patient data were obtained from the hospital information management system. Primary follow-up of the patients was conducted by the general surgery clinics, and consultations from urology and other relevant departments were requested, as needed. FG diagnosis was made based on anamnesis, physical examination, and abdominal computed tomography. Demographic information, systemic diseases, laboratory findings, number of debridements performed, length of hospital stay, and mortality status of all patients were evaluated. The patients included in the study were divided into two groups: deceased (n = 20) and surviving (n = 149). The blood parameters used to calculate the LRINEC score, including C-reactive protein (CRP); white blood cell count; hemoglobin; and sodium, creatinine, andDiagnostics 2024, 14, 2732 3 of 10 glucose levels, were recorded. Additionally, preoperative values for platelet count, albumin, neutrophil count, neutrophil percentage, lymphocyte count, lymphocyte percentage, monocyte count, monocyte percentage, eosinophil count, eosinophil percentage, neutrophilto-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), and CRP-to-albumin ratio (CRP/Alb) were evaluated. Furthermore, according to the LRINEC score, patients were categorized into three risk groups: low (LRINEC score ≤ 5), moderate (LRINEC score 6–7), and high (LRINEC score ≥ 8) [10]. Preoperative parameters and scores used in the FGMI are presented in Table 1. Based on the total score and risk assessment, <5 points were categorized as low-to-moderate mortality risk and ≥5 points as high mortality risk. Table 1. Scoring of the Fournier’s gangrene mortality index. Parameters Units Score Age ≥60 2 40–59 1 ≤39 0 Creatinine (mg/dL) ≥1.5 2 1.0–1.49 1 ≤0.99 0 Albumin (g/dL) ≤2.5 2 2.6–3.0 1 ≥3.1 0 Lymphocyte % ≤5% 2 6–9% 1 ≥10% 0 NLR ≥15 2 10–14 1 ≤9 0 NLR: Neutrophil-to-lymphocyte ratio. 2.1. Ethical Approval Ethical approval for the study was obtained from the Harran University Clinical Research Ethics Committee with the decision number HRÜ/24.09.34, dated 1 July 2024. 2.2. Statistical Analysis Descriptive analyses were conducted to describe the general characteristics of the study population. Visual (probability plots, histograms) and analytical tests (Kolmogorov– Smirnov and Shapiro–Wilk tests) were used to determine whether the data were normally distributed. Variables that did not show normal distribution were expressed as median (25th–75th percentiles). Mann–Whitney U test was used to compare two independent nonparametric variables, Kruskal–Wallis test was used for comparisons of three independent nonparametric groups, and Chi-square tests were used to compare categorical variables between the two groups. Categorical variables were reported as numbers and percentages. Furthermore, a new scoring system was created using parameters that showed a clinically significant difference between the deceased and surviving groups. To determine the mortality-predictive cutoff value of the new scoring system developed for Fournier’s gangrene patients, receiver operating characteristic (ROC) analysis was performed, and the area under the curve (AUC) was calculated. Based on this cutoff value, sensitivity and specificity of the scoring system in predicting mortality were calculated. An odds ratio risk analysis for mortality was performed according to the calculated cutoff valueDiagnostics 2024, 14, 2732 4 of 10 and expressed with a 95% confidence interval. For the multivariate analysis, the possible factors identified with univariate analyses were further entered into the logistic regression analysis to determine independent predictors of patient outcome. Hosmer–Lemeshow goodness-of-fit statistics were used to assess model fit. Post hoc power analysis was used for a 2 × 2 contingency table where the total score was categorized as 4 and below and 5 and above, α = 0.05, N = 169, and the effect size (w) was 0.395. A p-value of <0.05 was considered statistically significant in all analyses. All analyses were conducted using SPSS statistical software (IBM SPSS Statistics, Version 22.0. Armonk, NY, USA: IBM Corp.). 3. Results A total of 169 patients diagnosed with FG, 87 of whom were men (51.48%), were included in the study. The median age of all patients was 53 (range: 40–63 years) years; 20 patients (11.8%) died. The median age was 64.50 years (range: 56–80 years) in the deceased group and 51 years (range: 39–60 years) in the surviving group. A significant difference was observed between the groups in terms of age (p < 0.001). The median length of hospital stay for the patients was 14 days (range: 9–22 days). Although the number of debridements in the deceased group was lower compared to the surviving group, no significant difference was observed between the groups (p = 0.4). The presence of comorbidities was higher in the deceased group (75%) compared to the surviving group (57.05%), but this difference was not statistically significant (p = 0.1) (Table 2). Table 2. Demographic characteristics, comorbidity status, and general microbiological features of the patients. Variable Deceased (n = 20) Surviving (n = 149) Total (n = 169) p Age, year 64.50 (56–80) 51 (39–60) 53 (40–63) <0.001 Gender Male 9 (45%) 78 (52.35%) 87 (51.48%) =0.4 Female 11 (55%) 71 (47.65%) 82 (48.52%) Length of hospital stay, days 10.50 (3–22.5) 14 (9–22) 14 (9–22) =0.3 Number of debridements 1 (1–3) 2 (1–3) 2 (1–3) =0.4 Comorbidity Yes 15 (75%) 85 (57.05%) 100 (59.17%) =0.1 No 5 (25%) 64 (42.95%) 69 (40.83%) Polymicrobial infection Yes 5 (25%) 46 (30.87%) 51 (30.18%) =0.4 No 15 (75%) 103 (69.13%) 118 (69.82%) In the cultures taken from the 95 patients (56.21%), at least one bacterium was isolated. The most frequently isolated bacteria were E. coli (n = 53, 43.09%), S. anginosus (n = 11, 8.94%), and K. pneumoniae (n = 11, 8.94%) (Table 3). Table 3. Distribution of microorganisms isolated from patient cultures. Microorganisms n % Microorganisms n % E. coli 53 43.09 S. agalactiae 4 3.25 S. anginosus 11 8.94 A. baumannii complex 4 3.25 K. pneumoniae 11 8.94 Other streptococci 2 1.63 P. mirabilis 10 8.13 M. morganii 2 1.63 E. faecalis 8 6.50 Other bacteria 5 4.07 S. aureus 7 5.69 Total 123 100 Other staphylococci 6 4.88Diagnostics 2024, 14, 2732 5 of 10 There was no statistically significant difference in the LRINEC score between the deceased and surviving groups (p = 0.5). CRP levels were higher in the deceased group (29.47 mg/L) compared to the surviving group (20.76 mg/L), but this difference was barely within the significance limit (p = 0.05). In the deceased group, neutrophil count, neutrophil percentage, NLR, PLR, and CRP-to-Alb ratio were higher, whereas lymphocyte count, lymphocyte percentage, eosinophil count, eosinophil percentage, monocyte count, and monocyte percentage were lower compared to the surviving group. These differences were statistically significant (Table 4). Table 4. Comparison of preoperative laboratory parameters between the deceased and surviving groups. Variables Deceased (n = 20) Surviving (n = 149) Total (n = 169) p LRINEC Low 5 (25%) 57 (38.26%) 62 (36.69%) Moderate 3 (15%) 21 (14.09%) 24 (14.20%) =0.5 High 12 (60%) 71 (47.65%) 83 (49.11%) CRP (mg/dL) 29.47 (14.91–37.55) 20.76 (9.90–30.50) 21.98 (12.20–31.22) =0.05 White sphere (10 × 103/µL) 19.49 (14.80–24.27) 16 (11.60–20.40) 16 (11.69–20.80) =0.1 Hemoglobin (g/dL) 11.25 (8.88–12.80) 11.80 (10.30–13.20) 11.70 (10.10–13.20) =0.3 Sodium (mmol/L) 131 (128–134.50) 134 (130–138) 134 (130–137) =0.2 Creatinine (mg/dL) 1.50 (1–2.01) 0.90 (0.70–1.17) 0.90 (0.71–1.31) 0.001 Glucose mg/dL 170.50 (106–263.50) 168 (106–338) 168 (106–336) =0.9 Platelets (10 × 103/µL) 271 (186–380.50) 301 (238–395) 299 (228–392) =0.4 Albumin (g/dL) 2.68 (2.35–3) 3.20 (2.75–3.68) 3.10 (2.65–3.60) 0.001 Neutrophils (10 × 103/µL) 15.75 (13.26–22.20) 13.53 (8.50–17.29) 13.69 (9.06–18.20) 0.042 Neutrophil % 89.85 (84.77–91.62) 82.50 (74.51–86.74) 83.50 (75.59–87.30) <0.001 Lymphocytes (10 × 103/µL) 0.83 (0.48–1.17) 1.60 (1.09–2.27) 1.49 (0.94–2.17) <0.001 Lymphocyte % 4.81 (3.80–6.28) 9.56 (6.99–15.32) 8.83 (6.11–14.74) <0.001 Monocytes (10 × 103/µL) 0.60 (0.44–1.07) 0.96 (0.69–1.35) 0.90 (0.61–1.33) 0.023 Monocyte % 3.91 (2.39–4.84) 6.30 (4.80–8.39) 6.03 (4.53–8.15) <0.001 Eosinophils (10 × 103/µL) 0.01 (0–0.03) 0.05 (0.01–0.12) 0.04 (0.01–0.10) <0.001 Eosinophil % 0.04 (0.02–0.21) 0.37 (0.10–1.14) 0.30 (0.06–1.00) <0.001 NLR 18.21 (14.24–24.56) 8.55 (4.73–12.47) 9.59 (5.27–14.29) <0.001 MLR 0.86 (0.45–1.29) 0.65 (0.37–0.97) 0.68 (0.38–0.97) =0.1 PLR 371.70 (227.27–532.79) 185.33 (132.98–297.59) 192.76 (139.52–316.16) <0.001 CRP/Alb 11.19 (6.28–13.75) 7.15 (2.77–9.28) 7.39 (3.72–10.64) 0.003 LRINEC: Laboratory risk indicator for necrotizing fasciitis, CRP: C-reactive protein, NLR: Neutrophilto-lymphocyte ratio, PLR: Platelet-to-lymphocyte ratio, MLR: Monocyte-to-lymphocyte ratio, CRP/Alb: CRP/albumin. The multivariate analysis identified albumin (RR: 0.182, 95% CI: 1.106–27.027, p = 0.037) and NLR (RR: 0.055, 95% CI: 1.199–250.0, p = 0.037) as significant independent predictors of patient outcome. Other variables, such as age, creatinine, and lymphocyte percentage, were not statistically significant. A ROC analysis was performed to determine the cutoff value for predicting mortality using the newly developed FGMI. According to the analysis, a score of 5 or higher had a ROC-AUC of 0.88 (95% CI: 0.80–0.95) with a sensitivity of 90% and specificity of 70% forDiagnostics 2024, 14, 2732 6 of 10 predicting mortality (p < 0.001), (Figure 1). When univariate risk analysis was performed, the odds ratio revealed that mortality risk was 20 (4.48–90.91) times higher in patients followed up for FG with an FGMI score of ≥5 (p < 0.001). The post hoc power analysis result was calculated as 0.99925 (λ = 26.37; critical χ2 = 3.84). Diagnostics 2024, 14, x FOR PEER REVIEW 6 of 10 Figure 1. ROC curve predicting mortality in FG with FGMI score ≥ 5. 4. Discussion This study aimed to develop a new scoring system for predicting mortality in patients diagnosed with FG as well as to investigate the relationship between mortality and various inflammatory indices, particularly the LRINEC score. Although no significant relationship was observed between the LRINEC score and increased mortality, higher neutrophil counts, neutrophil percentages, NLRs, PLRs, and CRP/Alb ratios, and lower lymphocyte counts, lymphocyte percentages, eosinophil counts, eosinophil percentages, monocyte counts, and monocyte percentages in deceased patients suggest that these parameters are more significant indicators for predicting mortality. The high sensitivity (90%) and a 20-fold increase in mortality risk for the newly developed FGMI score with a cutoff value of ≥5 underscores its usefulness and significance as a scoring system in predicting mortality. Data in the literature on which gender FG is more common indicate that the disease is much more common in the male gender [7,12,13,15]. In the present study, the rates of female patients were found to be close to the rates of male patients. The high birth rates in the region where we conducted our study, the fact that these patients mostly live in rural areas and have poor hygiene conditions pose a risk for FG. In addition, it was observed in our study that 56 (56%) of 100 patients with concomitant diseases such as DM were female and 44 (44%) were male. Our region is different from other regions in this respect. In addition, patients who applied to the general surgery clinic were included in our study, not patients who applied to the urology clinic. We attribute the higher number of female patients compared to other studies to these reasons. Similar to other necrotizing soft tissue infections, older patients are more frequently affected by FG today [16]. In the study by Yilmazlar et al. [12], the age of 60 years and above was identified as an independent risk factor for mortality in FG patients. Benjelloun et al. [15] conducted a study in Morocco and discovered that patients who succumbed to Figure 1. ROC curve predicting mortality in FG with FGMI score ≥ 5. 4. Discussion This study aimed to develop a new scoring system for predicting mortality in patients diagnosed with FG as well as to investigate the relationship between mortality and various inflammatory indices, particularly the LRINEC score. Although no significant relationship was observed between the LRINEC score and increased mortality, higher neutrophil counts, neutrophil percentages, NLRs, PLRs, and CRP/Alb ratios, and lower lymphocyte counts, lymphocyte percentages, eosinophil counts, eosinophil percentages, monocyte counts, and monocyte percentages in deceased patients suggest that these parameters are more significant indicators for predicting mortality. The high sensitivity (90%) and a 20-fold increase in mortality risk for the newly developed FGMI score with a cutoff value of ≥5 underscores its usefulness and significance as a scoring system in predicting mortality. Data in the literature on which gender FG is more common indicate that the disease is much more common in the male gender [7,12,13,15]. In the present study, the rates of female patients were found to be close to the rates of male patients. The high birth rates in the region where we conducted our study, the fact that these patients mostly live in rural areas and have poor hygiene conditions pose a risk for FG. In addition, it was observed in our study that 56 (56%) of 100 patients with concomitant diseases such as DM were female and 44 (44%) were male. Our region is different from other regions in this respect. In addition, patients who applied to the general surgery clinic were included in our study, not patients who applied to the urology clinic. We attribute the higher number of female patients compared to other studies to these reasons. Similar to other necrotizing soft tissue infections, older patients are more frequently affected by FG today [16]. In the study by Yilmazlar et al. [12], the age of 60 years andDiagnostics 2024, 14, 2732 7 of 10 above was identified as an independent risk factor for mortality in FG patients. Benjelloun et al. [15] conducted a study in Morocco and discovered that patients who succumbed to FG (57.5 ± 19.24 years) were older compared to survivors (44.36 ± 16.05 years), with a statistically significant difference between the two groups (p < 0.001). In the present study, the median age of the deceased (64.50 years) was higher than that of the survivors (51 years), and this difference was statistically significant (p < 0.001). This finding indicates that age has a significant impact on mortality in patients diagnosed with FG. Despite studies aimed at elucidating the etiology and pathophysiology of FG, mortality rates remain high [17]. Since the 19th century, epidemiological studies on necrotizing skin diseases have provided better predictions of the causes of FG and the associated mortality rates [9]. Various studies have shown that FG-related mortality is higher in the presence of comorbidities such as liver failure, chronic alcoholism, DM, and advanced age [7,18–20]. Mortality rates related to FG have been reported to range between 5% and 42% in various studies conducted in different geographical regions worldwide and in Turkey [1,12,16,21–27]. In the present study, the mortality rate was 11.8%, consistent with the literature. Although patients who died from FG had higher comorbidity rates compared to survivors, the difference between the groups was not statistically significant. This suggests that comorbidities may affect mortality, but this effect might be limited. Predicting the course of the disease can be challenging for clinicians, but prognostic indicators such as FGSI, LRINEC, and NLR have been used in various studies to determine the severity and prognosis of FG [10,11,28,29]. The LRINEC score, developed by Wong et al. [10], is considered a strong diagnostic tool for necrotizing fasciitis based on various laboratory parameters, with scores above 6 indicating high positive predictive value. However, a systematic review investigating the reliability of the LRINEC score found a wide sensitivity range (43.2–80%), and its positive predictive (57–64%) and negative predictive values (42–86%) were lower than the initial results obtained by Wong et al. [10]. The authors recommended that the LRINEC score should be used concurrently with clinical evaluation and radiological diagnostic modalities for more accurate results [30]. In the study by Atilla et al. [26], no statistical difference was found between an LRINEC score of >6 and mortality. Similarly, Hahn et al. [21] showed no significant relationship between LRINEC (p = 0.7) and FGSI (p = 0.1) scores and mortality. In another case series, no significant relationship was observed between mean FGSI, LRINEC and NLR scores and mortality [28]. In contrast, Kincius et al. [22] showed that a 1-point increase in LRINEC score increased the risk of death 7.7-fold, and that the LRINEC cutoff value of 9 at initial presentation had a high predictive value for mortality. Similarly, in the study by Özlülerden et al. [24], the LRINEC score was identified as one of the predictive parameters for FG-related mortality. In the present study, it was shown that the LRINEC score was insufficient in predicting mortality. Our analyses revealed that, although the LRINEC score is a useful tool for supporting the diagnosis of necrotizing fasciitis, it is inadequate in accurately predicting the risk of death. This finding highlights the limitations of the LRINEC score, suggesting that it should not be solely relied upon in the management of patients with necrotizing fasciitis. Laboratory findings of FG are nonspecific. Hematological and biochemical abnormalities such as anemia, thrombocytopenia, leukocytosis, hypokalemia, hyponatremia, hypocalcemia, hyperglycemia, elevated creatinine, azotemia, and hypoalbuminemia can be observed throughout the course of the disease [31]. Moreover, several studies have shown notable differences in laboratory parameters between patients who died from FG and those who survived. In the study by Kincius et al. [22], CRP levels were significantly higher in patients who died (p = 0.005) [22]. In the study by Atilla et al. [26], hemoglobin, platelet count, and serum sodium levels were lower, and creatinine levels were higher in deceased patients, although there was no significant difference in CRP levels between deceased and surviving patients. Kabay et al. [32] found that white blood cell count, blood urea nitrogen, and creatinine levels were higher in those who died from FG, and hematocrit, sodium, and albumin levels were lower. In the study by Özlülerden et al. [24], higher NLRDiagnostics 2024, 14, 2732 8 of 10 levels were observed in deceased patients, with a cutoff value of 8.70 predicting mortality with 72.2% sensitivity and 52.3% specificity. Yim et al. [33] demonstrated that elevated NLR and PLR were more effective predictors of mortality in FG patients compared to the FGSI score. In the study by Demir et al. [34], hemoglobin and platelet counts were lower at initial presentation in patients who died from FG, whereas no statistically significant difference in NLR and white blood cell count was found between survivors and deceased patients. In a case series conducted in Indonesia, it was reported that NLR and FGSI had no predictive significance for FG-related mortality [35]. However, another study conducted in Indonesia reported that NLR had predictive significance for FG prognosis, and PLR did not [36]. In the present study, CRP levels were higher in deceased patients compared to survivors, although this difference was borderline significant (p = 0.05). As CRP reflects the presence and severity of infection, elevated CRP levels may be associated with mortality. Neutrophil count, neutrophil percentage, NLR, PLR, and CRP/Alb ratios were statistically higher in deceased patients, while lymphocyte count, lymphocyte percentage, eosinophil count, eosinophil percentage, monocyte count, and monocyte percentage were statistically lower compared to survivors. The suboptimal sensitivity and specificity of existing scoring systems related to necrotizing fasciitis in predicting mortality prompted the development of a new scoring system, leading to the present study. By using hematological and biochemical parameters with predictive significance along with patient age at the time of initial presentation, a new scoring system—FGMI—was developed to distinguish between survivors and nonsurvivors. Age, creatinine, albumin, lymphocyte percentage, and NLR were identified as predictive parameters for mortality. Accordingly, for an FGMI cutoff value of ≥5, the sensitivity and specificity were 90% and 70%, respectively (p < 0.001). Another significant finding was that when the cutoff value was set at ≥5, it indicated a 20-fold increase in the risk of mortality. These results indicate the high predictive power of the FGMI score in terms of mortality and demonstrate its usefulness as a scoring tool. Limitations This study has several limitations. First, its retrospective design imposes limitations on data quality and completeness. The study was limited to data from three hospitals in a specific geographical region, making it difficult to generalize the results to different populations or geographical regions. All patients diagnosed with FG were included in the study. Therefore, there is no bias, especially in terms of gender. Although 169 patients were included in the study, the relatively low number of patients who died (n = 20) limits the power of the statistical analyses and affects the reliability of some results. Additionally, this study did not directly compare FGMI’s effectiveness with other scoring systems, making it difficult to completely assess FGMI’s advantages or weaknesses over existing systems. The collection of laboratory and clinical data from different hospitals may have led to measurement errors or inconsistencies. Lastly, the absence of prospective studies to validate FGMI’s effectiveness and reliability raises questions about its potential effectiveness in clinical practice. These limitations suggest that the findings should be interpreted with caution and highlight the need for larger, prospective studies in the future. 5. Conclusions The results obtained in the present study demonstrate that the FGMI score is a successful predictor of mortality that can be used at the initial clinical presentation of patients with FG. Another important finding is that the LRINEC score was not sufficiently effective in predicting mortality. These results underscore the importance of considering these parameters in clinical management. Furthermore, early intervention and close follow-up in high-risk patients are critical for reducing mortality rates.Diagnostics 2024, 14, 2732 9 of 10 Author Contributions: Conceptualization, M.Ç. and O.K.; Methodology, M.Ç., F.Ç. and O.K.; Software, H.Y. and A.U.; Validation, H.Y., F.Ç. and A.U.; Formal analysis, M.S.B. and A.C.G.; Investigation, M.S.B. and A.C.G.; Resources, M.S.B. and H.E.; Data curation, A.C.G. and H.E.; Writing—original draft, M.Ç. and F.T.; Writing—review & editing, F.E., O.K. and A.U.; Visualization, H.E. and F.T.; Supervision, F.T., A.Ö. and F.E.; Project administration, H.Y. and A.Ö. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Institutional Review Board Statement: Ethical approval for the study was obtained from the Harran University Clinical Research Ethics Committee with the decision number HRÜ/24.09.34, dated 1 July 2024. 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WJGS https://www.wjgnet.com 0 December 27, 2020 Volume 12 Issue 12 World Journal of W J G S Gastrointestinal Surgery Submit a Manuscript: https://www.f6publishing.com World J Gastrointest Surg 2020 December 27; 12(12): 0-0 DOI: 10.4240/wjgs.v12.i12.0000 ISSN 1948-9366 (online) SYSTEMATIC REVIEWS Ectopic liver tissue (choristoma) on the gallbladder: A comprehensive literature review Sami Akbulut, Khaled Demyati, Felat Ciftci, Cemalettin Koc, Adem Tuncer, Emrah Sahin, Nese Karadag, Sezai Yilmaz ORCID number: Sami Akbulut 0000- 0002-6864-7711; Khaled Demyati 0000-0002-9591-2664; Felat Ciftci 0000-0002-8958-7121; Cemalettin Koc 0000-0002-5676-6772; Adem Tuncer 0000-0001-5381-513X; Emrah Sahin 0000-0001-5267-9068; Nese Karadag 0000-0003-0886-8122; Sezai Yilmaz 0000-0002-8044-0297. Author contributions: Akbulut S, Koc C and Yilmaz S designed the report; Tuncer A, Ciftci F, Koc C, Sahin E and Akbulut S performed the literature review; Akbulut S and Demyati K organized the report and wrote the paper; Karadag N provided the histopathological information; all authors reviewed the final version. Conflict-of-interest statement: There is no conflict of interest associated with the senior author or other coauthors who contributed to this manuscript. PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist. Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in Sami Akbulut, Felat Ciftci, Cemalettin Koc, Adem Tuncer, Emrah Sahin, Sezai Yilmaz, Department of Liver Transplant Institute, Inonu University, Malatya 44280, Turkey Khaled Demyati, Department of Surgery, An-Najah National University, Nablus 11941, Palestine Nese Karadag, Department of Pathology, Inonu University Faculty of Medicine, Malatya 44280, Turkey Corresponding author: Sami Akbulut, MD, Professor, Department of Liver Transplant Institute, Inonu University, Elazig Yolu 10. Km, Malatya 44280, Turkey. akbulutsami@gmail.com Abstract BACKGROUND Liver tissue situated outside the liver with a hepatic connection is usually called an accessory liver, and that without a connection to the mother liver, is called ectopic liver tissue. AIM To identify studies in the literature on ectopic liver tissue located on the gallbladder surface or mesentery. METHODS We present two patients and review published articles on ectopic liver tissue located on the gallbladder surface accessed via PubMed, MEDLINE, Google Scholar, and Google databases. Keywords used included accessory liver lobe, aberrant liver tissue, ectopic liver tissue, ectopic liver nodule, heterotopic liver tissue, hepatic choristoma, heterotopic liver tissue on the gallbladder, and ectopic liver tissue on the gallbladder. The search included articles published before June 2020 with no language restriction. Letters to the editor, case reports, review articles, original articles, and meeting presentations were included in the search. Articles or abstracts containing adequate information on age, sex, history of liver disease, preliminary diagnosis, radiologic tools, lesion size, surgical indication, surgical procedure, and histopathological features of ectopic liver tissue were included in the study. RESULTS A total of 72 articles involving 91 cases of ectopic liver tissue located on theAkbulut S et al. ELT near the gallbladder WJGS https://www.wjgnet.com 1 December 27, 2020 Volume 12 Issue 12 accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: htt p://creativecommons.org/License s/by-nc/4.0/ Manuscript source: Invited manuscript Specialty type: Gastroenterology and hepatology Country/Territory of origin: Turkey Peer-review report’s scientific quality classification Grade A (Excellent): 0 Grade B (Very good): 0 Grade C (Good): C, C Grade D (Fair): D Grade E (Poor): 0 Received: September 26, 2020 Peer-review started: September 26, 2020 First decision: October 21, 2020 Revised: November 12, 2020 Accepted: December 2, 2020 Article in press: December 2, 2020 Published online: December 27, 2020 P-Reviewer: Mizuguchi T, Ooi L, Wang G S-Editor: Fan JR L-Editor: Webster JR P-Editor: Li JH gallbladder surface or mesentery were analyzed. Of these 91 patients, 62 were female and 25 were male (no gender available for 4 patients), and the age range was 5 d to 91 years. Forty-nine patients underwent surgery for chronic cholecystitis or cholelithiasis, and 14 patients underwent surgery for acute cholecystitis. The remaining 28 patients underwent laparotomy for other reasons. Cholecystectomy was laparoscopic in 69 patients and open in 11 patients. The remaining 19 patients underwent various other surgical procedures such as autopsy, liver transplantation, living donor hepatectomy, Whipple procedure, and liver segment V resection. Histopathologically, hepatocellular carcinoma was detected in the ectopic liver tissue of one patient. CONCLUSION Ectopic liver tissue is a rare developmental anomaly which is usually detected incidentally. Although most studies suggest that ectopic liver located outside the gallbladder has a high risk of hepatocellular carcinoma, this is not reflected in statistical analysis. Key Words: Liver; Gallbladder; Ectopic liver tissue; Hepatic choristoma; Histopathological features; Hepatocellular carcinoma ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved. Core Tip: Ectopic liver tissue is a rare developmental anomaly usually detected incidentally. While it is often asymptomatic, there is a risk of malignant transformation and other complications such as bleeding and torsion. In this review, we present two cases of ectopic liver tissue located on the gallbladder surface and review published studies on ectopic liver tissue located on the gallbladder surface accessed via the PubMed, MEDLINE, Google Scholar, and Google databases. Although most studies suggest that ectopic liver located outside the gallbladder has a higher risk of hepatocellular carcinoma, this is not reflected in the statistical analysis. Citation: Akbulut S, Demyati K, Ciftci F, Koc C, Tuncer A, Sahin E, Karadag N, Yilmaz S. Ectopic liver tissue (choristoma) on the gallbladder: A comprehensive literature review. World J Gastrointest Surg 2020; 12(12): 0-0 URL: https://www.wjgnet.com/1948-9366/full/v12/i12/0.htm DOI: https://dx.doi.org/10.4240/wjgs.v12.i12.0000 INTRODUCTION Ectopic liver tissue is a rare developmental anomaly in which the liver tissue is situated outside the liver. It is usually asymptomatic and is discovered incidentally during surgery or autopsy, but there are potential complications. Torsion, malignant transformation, compression of adjacent organs, and intra-peritoneal bleeding are among the possible complications[1-72]. Liver tissue situated outside the liver with a hepatic connection is usually called an accessory liver, and that without a connection to the main liver, is called ectopic liver tissue. Accessory liver and ectopic liver tissues were first described by Morgagni in 1767 and by Corsy in 1922, respectively[1,20,36,72]. Subsequent reports showed that the accessory liver lobe most commonly occurs in the gallbladder wall, under the surface of the liver, at the gastrohepatic ligament, umbilical cord, adrenal glands, pancreas, pylorus, diaphragm, and the splenic capsule if a portion of the pars hepatica is displaced[28,31,34,44,36]. The histological architecture of the ectopic tissue resembles normal liver, although it does not have a complete functional architecture, is metabolically handicapped, and is more prone to carcinogenesis[2,6,36,40,62,72]. In this article, we report two cases of ectopic liver tissue and review the literature for articles published on ectopic liver tissue on the gallbladder surface or gallbladder mesentery[1-72]. The clinical and pathological characteristics are described in addition to an analysis of the possible clinical implications including malignant transformation.Akbulut S et al. ELT near the gallbladder WJGS https://www.wjgnet.com 2 December 27, 2020 Volume 12 Issue 12 MATERIALS AND METHODS The primary aim of this study was to review the articles published in the literature on ectopic liver tissue on the gallbladder surface or gallbladder mesentery. To achieve this aim, a literature search was conducted on PubMed, MEDLINE, Google Scholar, and Google databases using the following keywords: Accessory liver lobe, aberrant liver tissue, ectopic liver tissue, ectopic liver nodule, heterotopic liver tissue, hepatic choristoma, liver, gallbladder, heterotopic liver tissue on the gallbladder, ectopic liver tissue on the gallbladder, accessory liver lobe on the gallbladder, accessory liver tissue on the gallbladder alone or in different combinations. Language restrictions were not applied in this literature review. All documents published on ectopic liver tissue related to the gallbladder before June 2020 were reviewed. Patients with ectopic liver tissue found in the gallbladder lumen incidentally were excluded from the study. As a result, articles without an accessible full-text version, those without adequate information in the abstract, and those that did not include comprehensive information compared to other studies were excluded. The following information was collected: Publication year, country, type of article available (full-text, abstract), age, sex, clinical presentation, diagnostic modalities, indication for surgery, surgical approach, postoperative complications, and histopathologic features of specimens. The details of the literature search are provided in Table 1. The secondary aim of this study was to present two cases of ectopic liver tissue attached to the gallbladder wall that was discovered during living donor hepatectomy and recipient hepatectomy. RESULTS Review of the literature Using the PubMed, MEDLINE, Google Scholar, and Google databases, 72 articles involving 91 patients published between January 1925 and August 2020 were compatible with the above-mentioned criteria. The four countries with the highest numbers of published articles were Turkey (n = 13), the United States (n = 12), India (n = 8), and Japan (n = 7). Sixty-two articles were written in English, three in Turkish, two in Japanese, one in French, one in German, one in Chinese, one in Russian, and one in Spanish. The full text was obtained for 69 of the 72 articles, whereas only abstracts were available for three articles. Of the 91 patients, 62 were female and 25 male; no gender data were available for the remaining four patients. The age of these 87 patients ranged from five days to 91 years; this information was unavailable for the remaining four patients. Eleven patients had a history of various liver diseases, while 12 patients had no liver disease. No data could be obtained on whether the remaining 68 patients had any liver disease. Forty-nine patients underwent surgery for chronic cholecystitis and/or cholelithiasis, while 14 patients underwent surgery for a presumed diagnosis of acute cholecystitis. The remaining 28 patients underwent laparotomy for unrelated reasons. Sixty-one patients underwent laparoscopic cholecystectomy and 11 underwent open cholecystectomy. The remaining 19 patients underwent cholecystectomy and various surgical procedures such as autopsy, liver transplantation, living donor hepatectomy, Whipple procedure, and liver segment V resection. Demographic, clinical, and histopathological characteristics of the 91 patients with ectopic liver tissue are summarized in Tables 1 and 2. Case presentations Case 1: A 25-year-old woman [body mass index (BMI): 27 kg/m2, A Rh (+), graft volume: 600 cc, remnant liver: 29%] was admitted to our liver transplant institute to donate a part of her liver to her 33-year-old sister with cryptogenic liver cirrhosis. Radiological and biochemical examinations were completed using the preoperative donor evaluation algorithm available in our liver transplant institute. The donor candidate underwent laparotomy using a modified Makuuchi incision (reversed Lshaped incision). The exploration showed ectopic liver tissue approximately 15 mm × 5 mm in size, located in the gallbladder corpus, and had no association with the liver (Figure 1). Cholecystectomy was performed to include the ectopic liver tissue, and cholangiography was carried out via the cystic duct, and the biliary tract anatomy was found to be normal (Choi Type I). Right lobe donor hepatectomy was performed as previously described in our transplant institute. The donor was discharged without any postoperative complications. Macroscopically, the gallbladder specimen was 70 mm in length, 50 mm in diameter, and 3 mm in wall thickness. Histopathologically,Akbulut S et al. ELT near the gallbladder WJGS https://www.wjgnet.com 3 December 27, 2020 Volume 12 Issue 12 Table 1 Summary of the demographic and clinicopathological characteristics of 91 patients published in the literature between 1925 and 2020 Ref. Year Country Lang. Age Sex History of liver disease Preliminary diagnosis Radiologic tools Kachi et al[1] 2020 Lebanon English 44 F No CC US 62 F No CC NA Avdaj et al[2] 2020 Kosovo English 47 F No CC US Baral et al[3] 2019 United States English 67 F No CC US Yuksel et al[4] 2019 Turkey English 34 F NA CC US Mannan et al[5] 2019 S. Arabia English 38 F NA AC US Isa et al[6] 2019 Bahrain English 42 F No CC US Pandit et al[7] 2019 Nepal English 30 F NA Biliary pancreatitis US + MRCP Granek et al[8] 2019 Australia English 36 M NA AC US Lodha et al[9] 2018 India English 50 M NA Kidney tumor CT Topcu et al[10] 2018 Turkey English 64 F NA AC US 70 F NA Icterus US + CT + MR Burke et al[11] 2018 Ireland English 30 F NA CC US Greenberg et al[12] 2018 United States English 52 F FLD AP US + CT Termos et al[13] 2017 Kuwait English 73 F NA GBC US + CT Weber-Alvarez et al [14] 2017 Mexico English 37 F NA AC US Galimov et al[15] 2017 Russia Russian 70 M NA AC US Handra-Luca et al[16] 2016 France English 68 F NA CC US 56 F NA CC US Mani et al[17] 2016 United States English 56 M FLD AC CT Ito et al[18] 2016 Japan English 59 F NA CC MR + CT Leena et al[19] 2016 India English 25 M NA Cadaver Autopsy Karaca et al[20] 2016 Turkey English 43 F NA CC US Jaboury et al[21] 2016 Australia English 22 F NA CC NA 35 F NA CC US 45 F NA CC US 45 F NA CC NA Yahya et al[22] 2016 Libya English 20 F NA Penetrating injury NA Aslan et al[23] 2016 Turkey English 49 F NA CC US Longjam et al[24] 2016 India English 42 F NA CC US Kostov et al[25] 2016 Bulgaria English 49 M RCLM RCLM NA Bal et al[26] 2015 Turkey English 51 F NA CC US Smyth et al[27] 2015 Australia English 77 F NA CC US Abhilash et al[28] 2015 India English 45 F NA AC US Hussein et al[29] 2015 Lebanon English 49 F NA AC CT Yankol et al[30] 2015 Turkey English 30 M No Living donor US + CT + MRCP Arslan et al[31] 2014 Turkey English 59 F NA CC US Pulle et al[32] 2014 India English 43 F NA CC US Terakawa et al[33] 2014 Japan Japanese 33 F NA CC US + MRCPAkbulut S et al. ELT near the gallbladder WJGS https://www.wjgnet.com 4 December 27, 2020 Volume 12 Issue 12 Sirasanagandla et al [34] 2013 India English 62 M NA Cadaver NA Hassan et al[35] 2013 India English 32 F NA CC US Martinez et al[36] 2013 Brazil English 37 F NA AC US Ozturk et al[37] 2013 Turkey Turkish 35 F No CC US Yajima et al[38] 2013 Japan Japanese 73 F NA CC US + CT Khan et al[39] 2013 India English 32 F NA CC NA Karaman et al[40] 2012 Turkey English 63 M NA CC US Patel et al[41] 2012 United Kingdom English 21 F NA CC US Sozen et al[42] 2012 Turkey Turkish 40 F NA CC US Catani et al[43] 2011 Italy English 72 F NA AC US 83 F No CC US Dettmer et al[44] 2011 Switzerland English 91 F NA AC CT Nagar et al[45] 2011 United States English 25 F NA AP + Cystic mass US + CT + MRCP Ates et al[46] 2010 Turkey Turkish 64 F NA AC NA 49 M NA CC US Triantafyllidis et al[47] 2009 Greece English 56 F NA CC US Guzman et al[48] 2009 Mexico Spanish 36 M NA CC US Kyeong et al[49] 2008 S. Korea English 66 F NA CC CT Koh et al[50] 2007 Australia English 60 F NA AC NA Malhas et al[51] 2007 United Kingdom English 42 M FLD CC US 39 F NA CC US Soto et al[52] 2007 United States English 32 F NA CC US 47 M NA CC US 33 F NA CC US 27 M NA Gastric cancer US + CT Beltran et al[53] 2007 Chile English 35 M NA Pancreatic pseudocyst US + CT Wang et al[54] 2006 China Chinese 38 M NA Gallbladder polyps US Ikeda et al[55] 2006 Japan English 70 M No HCC + Cirr US + CT Ngowe et al[56] 2006 Cameroon French 46 F NA CC US Lundy et al[57] 2005 United States English 38 F FLD Liver tumor US + CT Leone et al[58] 2004 Italy English 54 F NO GBC US + CT Griniatsos et al[59] 2002 United Kingdom English 39 F NA CC US 49 M NA CC US Acar et al[60] 2002 Turkey English 55 F NA CC US Sakarya et al[61] 2002 Turkey English NA NA NA NA NA Arakawa et al[62] 1999 Japan English 48 M ALD ALD Autopsy Hamdani et al[63] 1994 United States English 49 M Cirr PSC US + CT Boyle et al[64] 1992 United States English 44 F No AC US Tejada et al[65] 1989 United States English 43 M NA CC + HS US 37 M CLL CLL CT 54 M Cirr ALD Laparoscopy 64 F Cirr Cirr CT Watanabe et al[66] 1989 Japan EnglishAkbulut S et al. ELT near the gallbladder WJGS https://www.wjgnet.com 5 December 27, 2020 Volume 12 Issue 12 71 F Cirr Cirr Laparoscopy Fellbaum et al[67] 1987 Austria German 34 F NA CC NA Natori et al[68] 1986 Japan English 56 F NA CC CT Ashby et al[69] 1969 United Kingdom English 42 M NA Duodenal ulcer NA NA NA NA CC NA NA NA NA CC NA NA NA NA CC NA BASSIS et al[70] 1956 United States English 5d M NA Cadaver No Thorsness et al[71] 1941 United States English 63 F NA Cadaver No Cullen et al[72] 1925 United States English 33 F No Jaundice NA CC: Chronic cholecystitis ± cholelithiasis; US: Ultrasound; NA: Non-available; AC: Acute cholecystitis; MRCP: Magnetic resonance cholangiopancreatography; CT: Computed tomography; MR: Magnetic resonance; FLD: Fatty liver disease; GBC: Gallbladder cancer; RCLM: Rectum cancer liver metastasis; ALD: Alcoholic liver disease; PSC: Primary sclerosing cholangitis; Cirr: Cirrhosis; HS: Hereditary spherocytosis; CLL: Cystic liver lesion; AP: Abdominal pain. the tissue (15 mm × 3 mm × 2 mm) located in the gallbladder corpus was ectopic liver tissue (Figure 2A and B). Case 2: A 45-year-old female patient with cryptogenic liver cirrhosis [BMI: 37.2 kg/m2, A Rh (-), MELD-Na: 16, Child: 10/C] presented to our liver transplant institute for live-donor liver transplantation. Both the liver recipient and the 40-year-old male [BMI: 25.5 kg/m2, A Rh (+), graft volume: 940 cc, remnant liver: 31%] living liver donor candidate were evaluated according to an algorithm consisting of radiological and biochemical analyses. Laparotomy was performed using a reversed L-shaped incision. During exploration, it was revealed that the liver had a macronodular appearance and a relatively small size. Ectopic liver tissue associated with the gallbladder mesentery was seen on the corpus of the gallbladder without an association with the liver. The ectopic liver tissue showed a cirrhotic appearance similar to the main liver tissue (Figure 3A and B). The gallbladder was removed en-bloc with the liver without recipient cholecystectomy as described previously (recipient hepatectomy). The recipient was discharged on postoperative day 15 without complications. The ectopic liver tissue, located in the gallbladder was also seen in the retrospective examinations of computed tomography sections (Figure 4). DISCUSSION Ectopic liver tissue is a rare developmental anomaly in which the liver tissue is situated outside the liver[9,19,28,60]. Four main types are described in the literature: Ectopic liver, which is not connected to the mother liver, and is usually attached to the gallbladder or intra-abdominal ligaments; microscopic ectopic liver found in the gallbladder wall; a large accessory liver lobe attached to the mother liver by a stalk; and a small accessory liver lobe, 10-30 g, attached to the mother liver[73]. However, this classification may not apply to all cases[60]. The real incidence of ectopic liver tissue attached to the gallbladder wall is difficult to assess; most cases are asymptomatic and are diagnosed at laparotomy, laparoscopy, or during an autopsy[1,2,14]. However, the incidence of ectopic liver tissue has been reported to range from 0.24% to 0.47%[2,31]. A review of 5500 autopsies showed that only 0.05% had ectopic liver tissue in which only three cases were attached to the gallbladder wall[74]. A review of 1060 laparoscopic procedures found ectopic liver tissue attached to the gallbladder wall in three patients (0.28%)[10]. To date, we detected only two (0.04%) patients with ectopic liver tissue among 4500 patients who underwent living donor hepatectomy or recipient hepatectomy Different theories have been proposed to explain the development of an ectopic liver at various sites: Development of an accessory lobe of the liver with atrophy or regression of the original connection to the main liver; migration or displacement of a portion of the pars hepatica to other sites, entrapment of a nest of cells in the region of the foregut following closure of the diaphragm or umbilical ring and trapping ofAkbulut S et al. ELT near the gallbladder WJGS https://www.wjgnet.com 6 December 27, 2020 Volume 12 Issue 12 Table 2 Summary of the surgical and histopathological characteristics of 91 patients published in the literature between 1925 and 2020 Ref. Lesion sizes (mm) Surgical indication Surgical procedure Histopathological findings of ELT Histopathological findings of GB Kachi et al[1], 2020 10 CC LC ELT NA 5 CC LC ELT NA Avdaj et al[2], 2020 NA CC LC ELT NA Baral et al[3], 2019 30 CC LC ELT NA Yuksel et al[4], 2019 17 CC LC ELT CC Mannan et al[5], 2019 5 AC LC ELT NA Isa et al[6], 2019 NA CC LC ELT NA Pandit et al[7], 2019 35 CC LC ELT NA Granek et al[8], 2019 19 AC LC ELT NA Lodha et al[9], 2018 20 Kidney tumor Lap nephrectomy ELT (no excised) NA Topcu et al[10], 2018 15 CC OC ELT NA 80 Pancreatic tumor Whipple procedure ELT NA Burke et al[11], 2018 NA CC LC ELT NA Greenberg et al[12], 2018 30 CC LC ELT NA Termos et al[13], 2017 30 Diag lap LC ELT NA Weber-Alvarez et al[14], 2017 10 AC LC ELT AC + CC Galimov et al[15], 2017 6 AC LC ELT Phlegmonous cholecystitis Handra-Luca et al[16], 5 CC LC ELT CC 2016 11 CC LC ELT CC Mani et al[17], 2016 NA CC LC ELT NA Ito et al[18], 2016 15 CC LC ELT NA Leena et al[19], 2016 15 Autopsy Autopsy ELT NA Karaca et al[20], 2016 15 CC LC ELT NA Jaboury et al[21], 2016 NA CC LC ELT NA 60 CC LC ELT NA NA CC LC ELT NA NA CC LC ELT NA Yahya et al[22 ], 2016 NA Penetrating injury Diag lap ELT NA Aslan et al[23], 2016 8 CC LC ELT NA Longjam et al[24], 2016 15 CC LC ELT CC Kostov et al[25], 2016 35 RCLM OC ELT Hydatid cyst on gallbladder wall Bal et al[26], 2015 20 CC LC ELT NA Smyth et al[27], 2015 20 CC LC ELT CC Abhilash et al[28], 2015 10 AC LC ELT CC Hussein et al[29], 2015 NA AC LC ELT NA Yankol et al[30], 2015 15 Donor hepatectomy LDH ELT Accessory gallbladder tissue Arslan et al[31], 2014 20 CC LC ELT NA Pulle et al[32], 2014 20 CC LC ELT CC Terakawa et al[33], 2014 12 CC LC ELT NAAkbulut S et al. ELT near the gallbladder WJGS https://www.wjgnet.com 7 December 27, 2020 Volume 12 Issue 12 Sirasanagandla et al[34], 2013 20 Autopsy Autopsy ELT NA Hassan et al[35], 2013 10 CC LC ELT CC Martinez et al[36], 2013 30 CC LC ELT Chronic inflammation Ozturk et al[37], 2013 20 CC LC ELT NA Yajima et al[38], 2013 6 CC LC ELT NA Khan et al[39], 2013 NA CC LC ELT (Fatty change) CC Karaman et al[40], 2012 11 CC LC ELT NA Patel et al[41], 2012 26 CC LC ELT NA Sozen et al[42], 2012 7 CC LC ELT NA Catani et al[43], 2011 15 AC LC ELT NA 14 CC LC ELT NA Dettmer et al[44], 2011 15 AC LC ELT Acute cholecystitis Nagar et al[45], 2011 45 AP + Cystic mass LC ELT CC Ates et al[46], 2010 5 AC LC ELT NA 6 CC LC ELT NA Triantafyllidis et al[47], 2009 15 CC LC ELT CC Guzman et al[48], 2009 30 CC LC ELT NA Kyeong et al[49], 2008 10 CC LC ELT CC Koh et al[50], 2007 15 AC LC ELT NA Malhas et al[51], 2007 NA CC LC ELT NA NA CC LC ELT NA Soto et al[52], 2007 8 CC LC ELT NA 12 CC LC ELT CC 17 CC LC ELT NA 7 Gastric cancer OC + Gastrectomy ELT NA Beltran et al[53], 2007 18 Pancreatic pseudocyst OC + Gastrectomy ELT NA Wang et al[54], 2006 11 Gallbladder polyps LC ELT CC + Polyps Ikeda et al[55], 2006 NA HCC OC + Segment V Resection NASH NA Ngowe et al[56], 2006 30 CC LC ELT CC Lundy et al[57], 2005 30 Diag lap LC ELT NA Leone et al[58], 2004 90 GBC OC ELT + HCC NA Griniatsos et al[59], 2002 10 CC LC ELT NA 15 CC LC ELT NA Acar et al[60], 2002 14 CC OC ELT Papillary epithelial hyperplasia Sakarya et al[61], 2002 NA NA LC NA NA Arakawa et al[62], 1999 15 Autopsy Autopsy ELT NA Hamdani et al[63], 1994 30 PSC LT ELT NA Boyle et al[64], 1992 20 AC OC ELT CC Tejada et al[65], 1989 11 CC OC + Splenectomy ELT CC 5 Cystic lesion of the liver Watanabe et al[66], 1989 Diag lap Biliary hamartoma NAAkbulut S et al. ELT near the gallbladder WJGS https://www.wjgnet.com 8 December 27, 2020 Volume 12 Issue 12 8 Cirr Diag lap NA NA 10 Cirr Diag lap NA NA 6 Cirr Diag lap NA NA Fellbaum et al[67], 1987 NA NA NA NA NA Natori et al[68], 1986 12 CC OC + Excision ELT Chronic inflammation Ashby et al[69], 1969 10 Duodenal ulcer OC + Excision ELT NA 15 CC OC ELT CC 10 CC OC ELT CC 6 CC OC ELT CC BASSIS et al[70], 1956 8 Autopsy Autopsy ELT NA Thorsness et al[71], 1941 5 Autopsy Autopsy ELT NA Cullen et al[72], 1925 12 Jaundice Excision NA NA NA: Non-available; LC: Laparoscopic cholecystectomy; AC: Acute cholecystitis; CC: Chronic cholecystitis ± cholelithiasis; RCLM: Rectum cancer liver metastasis; PSC: Primary sclerosing cholangitis; GBC: Gallbladder cancer; LDH: Lactate dehydrogenase; OC: Open cholecystectomy; Diag lap: Diagnostic laparoscopy; ELT: Ectopic liver tissue; HCC: Hepatocellular cancer. Figure 1 Intraoperative view of the ectopic liver tissue located in the gallbladder. hepatocyte-destined mesenchyma in several areas thus budding hepatic tissue before the closure of the pleuroperitoneal canal[23,28]. Ectopic and accessory liver may occur at different sites, including sites close to the liver, such as the gallbladder and hepatic ligaments or sites far from the liver, for example, omentum, retroperitoneum, and thorax, with the most common location on the gallbladder[66,75,76]. Ectopic liver tissue varies considerably in size[60,62]. Based on 72 reports reviewed in this study, the average size of the ectopic liver tissue was found to be 17.8 mm. In the literature, the reported size of ectopic livers (without hepatocellular carcinoma) ranges from a few millimeters to several centimeters[24,44,58]. No detailed reports on the vascular supply of ectopic liver tissue were given in most of the papers reviewed. In general, three different vascular supply patterns have been described for gallbladder-associated ectopic liver tissue: An artery arising from the cystic artery[50], a vascular pedicle arising from the liver parenchyma substance[26], and vascular structures embedded in a mesentery lying from the hepatic site to ectopic liver tissue[43]. The identification of vascular supply requires surgery to avoid bleeding during the main surgery[3,4,26]. Extensive traction of the gallbladder should be avoided in cases with direct vascular supply from the liver substance. Biliary drainage was not described in detail or was not evident intraoperatively in most reports. In general, accessory liver lobes are classified into three types based on biliary drainage: In type I, the duct of the accessory liver lobe drains into an intrahepatic bile duct of the native liver; in Type II, it drains into an extrahepatic bile duct of the native liver, and if both the accessory lobe and the main liver have a common capsule and the bile duct of theAkbulut S et al. ELT near the gallbladder WJGS https://www.wjgnet.com 9 December 27, 2020 Volume 12 Issue 12 Figure 2 Encapsulated liver tissue with normal histological features. A: HE × 1; B: HE × 2.5. Figure 3 Intraoperative view of the ectopic liver tissue located in the gallbladder mesentery along with the main cirrhotic liver. accessory lobe drains into an extrahepatic duct, it is considered Type III[34,77]. Ectopic liver might be associated with other anomalies such as biliary atresia, agenesis of the caudate lobe, omphalocele, bile duct cyst, cardiac, and conotruncal anomalies; however, these abnormalities were not reported when the heterotopic tissue was attached to the surface of the gallbladder[28,59]. Ectopic liver tissue and accessory liver lobes are often asymptomatic, and detection of ectopic liver tissue before surgical intervention or autopsy imaging studies is rare[8,11,20,34]. However, ectopic livers on rare occasions have been reported to cause recurrent abdominal pain due to torsion[78-80], intraperitoneal bleeding[81,82], hemorrhagic necrosis[83], compression of adjacent organs[84], as well as obstruction of the esophagus[85], portal vein[86], and neonatal gastric outlet[87]. The histological architecture of the ectopic tissue resembles normal liver, with regular lobules, central veins, and normal portal areas in most cases[28,47,59]. Unusual architecture of hepatic tissue with absence of the classical hexagonal lobule pattern has been equally described[34]. Ectopic liver like the main liver tissue can undergo fatty changes, hemosiderosis, cholestasis, cirrhosis, hepatitis, or malignant degeneration to hepatocellular carcinoma[36]. Although ectopic liver tissue usually has normal histology of the liver, that is, normal portal structure, regular lobules, and central veins, ectopic liver tissue has an increased risk of hepatocellular carcinoma[27,43,53]. The reason for this increased risk of hepatocellular carcinoma in patients with ectopic liver tissue is unclear, it has been proposed that biliary drainage is insufficient and/or blood supply is reduced in the ectopic liver tissue[58]. Furthermore, many hepatocellular carcinoma cases are related to ectopic liver tissue, and are not associated with cirrhosis in the main liver. Arakawa and colleagues[62] reported that in 22 hepatocellular carcinomaAkbulut S et al. ELT near the gallbladder WJGS https://www.wjgnet.com 10 December 27, 2020 Volume 12 Issue 12 Figure 4 Axial contrast-enhanced multidetector computed tomography section shows an ectopic liver tissue-like nodular lesion associated with the gallbladder. cases related to ectopic liver tissue, only six cases (27%) had cirrhosis in the main liver. It has been revealed that many authors have misinterpreted the results of the article by Yamashita and colleagues[78]. One of the most important reasons for this misinterpretation is that the article is written in Japanese. Another reason is that the authors copy each other directly without carefully reading the authors’ results[2,3,5,12,17,23,26,28,29,35,36,59,62]. In the review by Yamashita and colleagues[78], 70 cases of ectopic liver were reported in the literature up to 1985. One (4.5%) of 22 cases with ectopic hepatic tissue attached to the gallbladder developed hepatocellular carcinoma while eight (16.7%) of 48 cases with ectopic hepatic tissue located outside the gallbladder developed hepatocellular carcinoma. As a result of the statistical analysis carried out using the Yamashita and colleagues data, no statistically significant difference was found between ectopic liver tissue located on the gallbladder surface and its location outside the gallbladder in terms of hepatocellular carcinoma risk (P = 0.25). Many studies have suggested that ectopic liver tissue on the gallbladder is less susceptible to hepatocellular carcinoma development than ectopic liver tissue outside the gallbladder. A possible explanation proposed for this difference is that ectopic hepatic tissue attached to the gallbladder is an anomaly occurring later during the development of the biliary bud and is; therefore, well-differentiated[12,26,59,62]. However, the results of our analysis using the Yamashita and colleagues data[78] revealed that there was no difference. In the 72 articles reviewed in this study, including 91 patients with ectopic liver tissue attached to the gallbladder, only one patient reported having hepatocellular carcinoma in the ectopic liver tissue (1.09%). CONCLUSION Ectopic liver tissue is a rare developmental anomaly usually detected incidentally during surgery or autopsy. While it is often asymptomatic, it has a risk of malignant transformation and carries the potential for other complications such as bleeding and torsion. Although most studies have suggested that ectopic liver located outside the gallbladder has a higher risk of hepatocellular carcinoma, this is not reflected in the statistical analysis results. ARTICLE HIGHLIGHTS Research background Liver tissue situated outside the liver with a hepatic connection is usually called an accessory liver, and that without a connection to the mother liver, is called ectopic liver tissue. Ectopic liver tissue is a rare developmental anomaly usually detected incidentally.Akbulut S et al. ELT near the gallbladder WJGS https://www.wjgnet.com 11 December 27, 2020 Volume 12 Issue 12 Research motivation Although a limited number of case reports on ectopic liver tissue on the gallbladder surface or gallbladder mesentery have been published to date, no systematic literature research has been conducted. Research objectives While the main objective of this study was to review the articles published in the medical literature on ectopic liver tissue on the gallbladder surface or gallbladder mesentery, the secondary objective of this study was to present the medical history of two patients diagnosed with ectopic liver tissue. Research methods A systematic literature search was conducted on PubMed, Medline, Google Scholar, and Google databases using the following keywords: Accessory liver lobe, aberrant liver tissue, ectopic liver tissue, ectopic liver nodule, heterotopic liver tissue, hepatic choristoma, heterotopic liver tissue on the gallbladder, and ectopic liver tissue on the gallbladder. The search included articles published before June 2020 with no language restriction. Research results A total of 72 articles were identified involving 91 patients, 62 females and 25 males; no gender data were available for the remaining four patients. The age of these 87 patients ranged from five days to 91 years; this information was unavailable for the remaining four patients. Eleven patients had a history of various liver diseases, while 12 patients had no liver disease. Forty-nine patients had surgery for chronic cholecystitis and/or cholelithiasis, while 14 patients had surgery for a presumed diagnosis of acute cholecystitis. The remaining 28 patients underwent laparotomy for unrelated reasons. Sixty-one patients underwent laparoscopic cholecystectomy and 11 underwent open cholecystectomy. The remaining 19 patients underwent cholecystectomy and various surgical procedures such as autopsy, liver transplantation, living donor hepatectomy, Whipple procedure, and liver segment V resection. Research conclusions Ectopic liver tissue is a rare developmental anomaly usually detected incidentally during surgery or autopsy. While it is often asymptomatic, it has a risk of malignant transformation and carries the potential of other complications such as bleeding and torsion. Research perspectives First, a review of the literature and our clinical experience suggest that ectopic liver tissue-like lesions around the liver should be considered in the differential diagnosis of ectopic hepatocellular carcinoma, especially in patients with chronic liver disease. Therefore, even when the macroscopic appearance is normal, all ectopic liver tissue specimens should be sent for routine histopathological examination. Second, although most studies have suggested that ectopic liver located outside the gallbladder has a higher risk of hepatocellular carcinoma, this is not reflected in the statistical analysis results. REFERENCES Kachi A, Bou Rached C, El-Helou E, Kanj M, Kansoun AH. Incidental Finding of Ectopic Liver during Laparoscopic Cholecystectomy. Am J Case Rep 2020; 21: e921410 [PMID: 32009130 DOI: 10.12659/AJCR.921410] 1 Avdaj A, Namani S, Cake A, Bytyqi A. Case report of ectopic hepatic tissue, a rare finding during a laparoscopic cholecystectomy. 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Araştırma Makalesi / Research Article Harran Üniversitesi Tıp Fakültesi Dergisi (Journal of Harran University Medical Faculty) 2024;21(1):36-41. DOI: 10.35440/hutfd.1411520 36 Akut Apandisit Nedeniyle Opere Edilen Gebe Hastaların Sonuçları: 37 Vaka Serisinin Tek Merkez Deneyimi Results of Pregnant Patients Operated Due to Acute Appendicitis: Single-Center Experience of 37 Case Series Felat ÇİFTÇİ 1 , Mazlum YAVAŞ 2 1Şanlıurfa Eğitim ve Araştırma Hastanesi Genel Cerrahi Kliniği, Şanlıurfa, TÜRKİYE 2Şanlıurfa Eğitim ve Araştırma Hastanesi Gastroenteroloji Cerrahi Kliniği, Şanlıurfa, TÜRKİYE Öz Amaç: Akut apandisit, gebelerde en sık görülen non-obstetrik akut batın sebebidir. Bu çalışmada geniş bir gebe volümüne sahip olan merkezimizde akut apandisit sebebiyle opere edilen gebe hastaları literatür eş- liğinde değerlendirmeyi amaçladık. Materyal ve metod: Kasım 2015-ağustos 2022 tarihleri arasında akut apandisit nedeniyle opere edilen hastaların verileri retrospektif olarak incelenerek elektronik ortamda kayıt altına alındı. Hastaların geliş şikayetleri, fizik muayene bulguları, radyolojik verileri, operasyon tipi, patolojik verileri kaydedilerek literatür eşliğinde incelendi. Bulgular: Apendektomi yapılan 37 hastanın yaş ortalaması 27,7 (20-42) idi. Bu hastalarda en sık 2. trimesterda (%48,6) akut apandisit tanısı konuldu. Hastaların en sık başvuru şikâyeti karın ağrısı olup en sık fizik muayene bulgusu karında hassasiyet idi. Hastaların başvuru süreleri dikkate alındığında 24 saatten fazla gecikme perforasyon riskini arttırdığı gözlemlendi. Histopatolojik en sık görülen bulgu akut apandisit olmasına rağmen bir hastada nöroendokrin tümör, bir hastada ise enterobius vermicularis tespit edildi. Sonuç: Gebelik döneminde yeni başlayan sağ alt kadran karın ağrısı hastalarda akut apandisit akılda tutulmalıdır. Zira tanının dolayısıyla ameliyatın gecikmesi hem fetal hem maternal ciddi morbidite ve mortaliteye sebep olmaktadır. Anahtar Kelimeler: Apandisit, Gebe, Laparoskopi, Appendektomi Abstract Background: Acute appendicitis is the most common nonobstetric cause of acute abdomen in pregnant women. In this study, we aimed to evaluate pregnant patients who were operated on for acute appendicitis in our center, which has a large pregnant population, in the light of the literature. Materials and Methods: The data of patients operated on for acute appendicitis between November 2015 and August 2022 were retrospectively examined and recorded electronically. The patients' complaints, physical examination findings, radiological data, operation type, and pathological data were recorded and examined in the light of the literature. Results: The average age of 37 patients who underwent appendectomy was 27.7 (20-42) years. In these patients, acute appendicitis was diagnosed most frequently in the 2nd trimester (48.6%). The most common presenting complaint of the patients was abdominal pain, and the most common physical examination finding was abdominal tenderness. Considering the admission time of the patients, it was observed that a delay of more than 24 hours increased the risk of perforation. Although the most common histopathological finding was acute appendicitis, malignancy was detected in one patient and enterobius vermicularis was detected in another. Conclusions: Acute appendicitis should be kept in mind in patients with new-onset right lower quadrant abdominal pain during pregnancy. Because delay in diagnosis and therefore surgery causes serious morbidity and mortality for both the fetus and the mother. Key Words: Appendicitis, Pregnant, Laparoscopy, Appendectomy Sorumlu Yazar / Corresponding Author Dr. Felat ÇİFTÇİ Şanlıurfa Eğitim ve Araştırma Hastanesi, Genel Cerrahi Kliniği, Yenice, Eyyubiye, 63200, Şanlıurfa, TÜRKİYE E-mail: felatciftci@gmail.com Geliş tarihi / Received: 28.12.2023 Kabul tarihi / Accepted: 05.03.2024 DOI: 10.35440/hutfd.1411520Çiftçi ve Yavaş Gebelikte Akut Apandisit Harran Üniversitesi Tıp Fakültesi Dergisi (Journal of Harran University Medical Faculty) 2024;21(1):36-41. DOI: 10.35440/hutfd.1411520 37 Giriş Akut apandisit en sık görülen nonobstetrik akut batın nedenidir (1). Retrospektif serilerde gebelikte akut apandisit ortalama 1/766 oranında ve en sık 2. trimesterda tespit edilmiştir (2,3). Gebelik döneminde uterusun anatomik değişimi ve yer değiştirmesi, gastrointestinal sistem ile ilgili şikâyetlerin artışı ve gebelik kaynaklı fizyolojik lökositoz gibi sebepler akut apandisit tanısı konulmasında güçlüklere yol açmaktadır (4). Hem bu değişim sebebiyle hem de radyolojik olarak tanı konulmasında zorluklar yaşanabileceğinden dolayı bu hastalarda alvarado skorlamasından faydalanabilir (5). Tanıda gecikme maternal ve fetal morbidite ve mortalitede artışa neden olmaktadır. Erken tanı ve cerrahi müdahale ile appendiks perforasyonu gelişmeden önce tedavi yapılabilinirse komplikasyonların önüne geçilebilir (6,7). Tüm tetkik ve fizik muayenelere rağmen akut apandisit ön tanısı ile opere edilen gebe hastalarda negatif appendektomi oranı gebe olmayan hastalardan daha yüksektir (%31 - %10) (8). Bu çalışmanın amacı; akut apandisit tanısı alan ve bu sebeple opere edilen 37 gebe hastanın takipleri, tedavileri ve komplikasyonlarını retrospektif olarak incelemek bu konuda deneyimlerimizi literatür eşliğinde aktarmaktır. Materyal ve Metod Kasım 2016 ile Ağustos 2022 tarihleri arasında Şanlıurfa Eğitim ve Araştırma Hastanesi’nde gebe iken akut apandisit şüphesi ile apendektomi yapılan gebe hastaların verileri retrospektif olarak toplandı. Çalışmanın onayı, 01.11.2021 tarihli ve HRÜ/22.19.24 numaralı karar ile Harran Üniversitesi Etik Kurulu’ndan alındı. Elektronik arşiv taraması ile başvuru şikâyetleri ve bulguları, şikâyetlerin başlama süresi, fizik muayene bulguları, yaş, gebelik haftası, ek hastalıklar, hemogram parametrelerinden; beyaz kan hücresi (WBC), nötrofil, lenfosit, trombositler, kırmızı kan hücresi dağılım genişliği (RDW), ortalama trombosit hacmi (MPV)’ne bakıldı. Biyokimyasal parametrelerden; total bilirubin, c-reaktif protein (CRP), görüntüleme tekniklerinden; abdominal ultrasound/manyetik rezonans (USG/MRI) bulguları, anestezi şekli, operasyon şekli (açık, laparoskopik), operasyon süresi, preop/postop fetal iyilik hali kontrolü, preop/postop tokolitik kullanımı, hastanede kalış süresi, komplikasyonlar ve histopatolojik sonuçlara bakıldı. Gebelik haftası birinci, ikinci ve üçüncü trimester olarak gruplara ayrıldı. Şikâyetler, bulgular ve fizik muayene değerlendirmeleri sonrası akut apandisit ön tanısını teyit etmek için hastalara öncellikle batın USG ile bakıldı. Fizik muayene bulguları ile uyumsuz USG bakıları gereklilik halinde batın MRI ile kontrol edildi. Ayrıca USG ve MRI çekilemeyen durumlarda veya USG ve MRI ile tanı konulamayan fakat klinik ve laboratuvar bulguları akut apandisit ile uyumlu hastalarda fizik muayene ve laboratuvar verileri ile ameliyat kararı verildi. Negatif apandisit değerlendirilmesi patolojik verilere göre yapıldı. Tüm hastalar, preop, erken postop ve taburculuk öncesi kadın do- ğum ve obstetrik kliniğine konsülte edilip bunların fetal iyilik hali kontrol edildi. Klinik ve/veya radyolojik olarak akut apandisit tanısı konulan hastalar acil ameliyata alındı. Açık cerrahi yapılan hastalara spinal anestezi tercih edilirken, laparoskopik cerrahi yapılan tüm hastalara genel anestezi uygulandı. Akut apandisit tanısı konulup operasyona hazırlanan hastalara profilaktik 2.kuşak sefalosporin 1x1gr iv verildi. Perfore apandisitlerde postop antibiyotik tedavisi olarak intaniye görüşü doğrultusunda meropenem 3x1gr ortalama 5 gün devam edildi. Hastalarda gebelik haftasına göre açık veya laparoskopik teknik tercih edildi. Birinci ve ikinci trimesterda laparoskopik teknik tercih edilirken üçüncü trimesterda açık teknik tercih edildi. Açık cerrahide McBurney kesi yapıldı. Özellikle üçüncü trimesterde olan hastalarda maksimum hassasiyetin olduğu yerde insizyon tercih edildi. Laparoskopik teknik tercih edilen hastalarda, uterus büyüme seviyesine göre ilk trokar umblikusun yukarısından ve açık teknik ile girildi. Elde edilen verilerin istatistiksel analizi SPSS (Statistical Package for the Social Sciences versiyon 22.0, Chicago, Illinois, USA) ile yapıldı. Kategorik veriler sayı ve yüzde olarak hesaplandı. Sürekli değişkenler normal ise ortalama±standart sapma olarak, normal değilse median ve minimum-maksimum olarak hesaplandı. Çalışmanın tüm analizinde p<0.05 değeri anlamlı olarak kabul edildi. Bulgular Hastanemizde Kasım 2016-Ağustos 2022 tarihleri arasında yaklaşık 180.000 doğum gerçekleştirildi. Bu tarihler arasında 37 tanesi gebe olmak üzere toplam 1702 yetişkin hastaya apendektomi yapıldı. Gebe hastalardaki akut apandisit sebebiyle yapılan apendektomi oranı 2/10.000; apendektomi yapılan tüm erişkin hastalar (erkek+kadın) içinde gebelerin oranı ise 21/1000 idi. Apendektomi yapılan gebe hastaların yaş ortalaması 27,7±5,8 (range, 20-42) olarak hesaplandı. Tanı konulduğunda hastalar en sık 2.trimesterda 18 (%48,6) olup bunu sırası ile 1. trimester 13 (%35,1) ve 3.trimester 6 (%16,2) takip etti. Acile başvuru sırasında tüm hastalarda karın ağrısı ve hassasiyet mevcuttu. Ağrı en sık karın sağ alt kadrana (%81,8) lokalizeydi (Tablo 1). Biyokimyasal ve hematolojik sonuçlara bakıldığında ise ortalama WBC 13,2±4,4 (7-26) 103 /uL, MPV 10±2,2 (6,2-18,6) fL, RDV 12,8±2,3 (9,3- 18,3) %, median CRP 14,3 mg/L (0,5-342) idi. Batın USG yapılan 30 hastanın 21 tanesine (%70) akut apandisit tanısı konulmuşken, 9 tanesi (%30) normal olarak raporlanmış. USG ile normal olarak değerlendirilen 9 hastanın 4 tanesine MR ile akut appandisit tanısı konuldu. Bu 9 hastadan 2 tanesi MR normal olarak raporlandı. Geriye kalan 3 hastaya fizik muayene ve laboratuvar sonuçlarına göre ameliyat kararı verilmişti. USG yapılmamış olan 7 hastanın 2 tanesine MRI ile akut apandisit tanısı konuldu. Ameliyat edilen 5 hastanın ise herhangi bir görüntülemesi yoktu. Negatif apandisit tespit edilen 3 hastanın 1 tanesi USG’ de akut apandisit, 1 tanesi MRI’ da akut apandisit olarak raporlandı. Geriye kalan 1 tanesi ise klinik ve laboratuvar bulguları dikkate alınarak opere edildi.Çiftçi ve Yavaş Gebelikte Akut Apandisit Harran Üniversitesi Tıp Fakültesi Dergisi (Journal of Harran University Medical Faculty) 2024;21(1):36-41. DOI: 10.35440/hutfd.1411520 38 Tablo 1. Appendektomi yapılan hastaların demografik ve klinik sonuçları Başvuru şikayetleri n (%) Karın ağrısı 37 (100) İştahsızlık 18 (50.3) Bulantı 17 (45.9) Kusma 16 (43.2) Muayene Bulguları n (%) Hassasiyet 37 (100) Defans 25 (67.6) Rebound 34 (91.9) Ağrı Lokalizasyonu n (%) Sağ Alt Kadran 25 (67.6) Yaygın 9 (24.3) Epigastrik 3 (8.1) Ameliyat Şekli n (%) Açık Appendektomi 25 (67.6) Laparoskopik Appendektomi 12 (32.4) Trimester n (%) 1.Trimster 13 (35.1) 2.Trimster 18 (48.6) 3.Trimster 6 (16.2) Gerçekte akut apandisit olan 2 hastada USG ve MRI normal diye raporlanmıştı. Ultrasonografi doğruluk oranı %70, MR için 6/8 %75 iken USG ve MR kombine kullanıldığında tanısal doğruluk oranı yaklaşık (27/32) %84 olarak hesaplandı. Bu sebepledir ki tanı amacıyla USG ve MRI’ın birlikte kullanılması pozitif prediktif değerinin daha yüksek olmasını sağlayacaktır. Opere edilen hastaların 25’ine (%67,5) açık cerrahi teknik ile, 12’sine (%32,4) laparoskopik teknik ile apendektomi yapıldı (Tablo 1). Maternal ve fetal komplikasyonlar açısından açık ve laparoskopik teknikler arasında anlamlı fark izlenmedi (p>0,05). Operasyon sırasında hastaların %21,6’sı (n=8) perfore apandisit, %8’i (n=3) negatif appandisit ile uyumlu idi. Perforasyonu olan hastalar %37,5 (n=3) oranında laparoskopik teknik ile opere edildi. Perfore apandisit olan hastaların sadece 4 tanesine perioperatif dren takılmış olup 1 hastanın postoperatif 1. gün kalanların ise 2. günde dreni çekilmiştir. Perforasyonu olan hastaların şikâyetlerinin başlaması ile operasyon arasındaki süre ortalama 72,8 saat iken, perforasyonu olmayanlarda 18,3 saat idi. Trimesterlar arasında negatif apendektomi ve perforasyon oranları açısından anlamlı farkı izlenmedi (p>0,05)(Tablo 2). Postoperatif ortalama 6.saatte oral alım başlandı. Açık apendektomi yapılan hastaların ortalama taburculuk süresi 1,96 gün, laparoskopik apendektomi yapılanlarda ise 1,75 gündü. Median taburculuk süresi 1 gün ( min=1, max=15) olarak hesaplandı. Postop ilk 30 günlük takipte, trokar yerinde cerrahi alan enfeksiyonu gelişen 1 hasta drenaj-yara bakımı ile, perfore apandisit sonrası operasyon lojunda apse gelişen 1 hasta uygun antibiyoterapi (7 gün) ile tedavi edildi. Operasyonların 20 (%54,1) tanesi spinal anestezi altında, 17 tanesi (%45,9) genel anestezi altında yapıldı. Laparoskopik ortalama operasyon süresi 26 dakika, açık yapılanlarda ortalama operasyon süresi 32 dakika idi. Ortalama operasyon süresi 32,14±15,3 (15-82) dk olarak hesaplandı. Tüm hastalar preop ve postop dönemde kadın doğum ve obstetrik bölümüne konsülte edilip fetal iyilik hali değerlendirildi. Hiçbir hastada cerrahi sonrası 30 gün içerisinde obstetrik patoloji gelişmedi. Tablo 2. Parametrelerin Akut Appendisit Perforasyon Durumlarına göre Dağılımı Perfore Akut Appendisit (n:7) Non-Perfore Akut Appendisit (n:30) p Median Minimum Maximum Median Minimum Maximum Yaş 26 20 41 26 20 42 0,876 Apendiks(mm) (Radyolojik) 8,2 5,0 17,6 8,0 5,0 11,5 0,891 Operasyon süresi(dk) 28 15 70 38 20 82 0,161 Appendiks Çapı (Patolojik) (mm) 10 5 20 10 6 11 0,839 Appendiks Boyu (Patolojik) (mm) 65 40 110 70 50 80 0,969 T.Bil. 0,40 0,13 0,94 0,35 0,16 0,56 0,587 D.Bil. 0,16 0,09 0,33 0,13 0,08 0,30 0,297 CRP 11,3 0,5 116,3 110,2 7,0 341,5 0,020 WBC 12,0 7,0 24,0 13,0 9,0 26,0 0,341 Hb 12,0 9,0 14,0 12,0 10,0 13,0 0,984 PLT 220 155 387 192 126 370 0,253 Nötrofil 9,5 4,5 19,0 9,0 8,0 24,1 0,362 Lenfosit 1,70 0,75 3,56 0,99 0,57 2,63 0,057 RDW 13,0 9,8 18,3 12,4 9,3 14,6 0,372 MPV 9,9 6,2 18,6 10,0 9,4 13,3 0,312 T.Bil: Total bilirubin, D.Bil: Direkt Bilirubin, CRP: C-Reaktif Protein,Wbc: White Blooc Count, Hb: Hemogobin, PLT: Platelet, RDW: Red Blood Cells, MPW: Mean Platelet Volume Hastaların histopatoloii raporlarında; 3 (%8,1) hastada negatif apendektomi, 1 hastada nöroendokrin Tm + Low Grade Müsinöz apendiks neoplazm, 1 hastada gebelikle ilişkilidesidual oluşum, 1 hasta ise enterobius vermikularis tespit edildi (Tablo 3). Veri analizi yapılırken trimesterlere göre 2. ve 3. trimesterda bir arada 1. trimester ile karşılaştırıldı. Parametreler 1. timesterlar göre 2. ve 3. trimesterda bir arada karşılaştırıldı- ğında direkt bilirubin, WBC ve MPV açısından istatistiksel olarak anlamlı fark izlendi (Tablo 3 ). Perfore -nonperfore hastalardaki parameterler karşılaştırıldığında sadece CRP yüksekliği istatistiksel olarak anlamlı idi (Tablo 4 ). Perfore akut apandisit hastalarında yapılan univariate logistik regresyon analizde CPR ve belirtilerin başlama zamanı istatistiksel olarak anlamlı izlendi (Tablo 4 ).Çiftçi ve Yavaş Gebelikte Akut Apandisit Harran Üniversitesi Tıp Fakültesi Dergisi (Journal of Harran University Medical Faculty) 2024;21(1):36-41. DOI: 10.35440/hutfd.1411520 39 Tablo 3. Histopatolojik Sonuçlar n (%) Akut Apandisit 25 (75,6) Non-Apandisit 3 (8,1) Akut Flagmentöz Apandisit 3 (8,1) Gangrenöz Apandisit 2 (5,4) Enterobius Vermicularis 1 (2,7) Fiböz Obliterasiyon 1 (2,7) Akut Apandisit + Gebelikle ilişkili desidual oluşum 1 (2,7) Nöroendokrin Tümör+ Düşük Dereceli Müsinöz Appendiks Neoplazm 1 (2,7) Tablo 4. Parametrelerin Gebelik Trimesterlerine göre Dağılımı 1.trimester (n:13) ≥ 2.trimester (n:24) p Median Minimum Maximum Median Minimum Maximum Yaş 26 20 41 26 20 42 0,810 Apendiks(mm) (Radyolojik) 9,0 5,0 12,0 8,0 5,0 17,6 0,200 Operasyon süresi(dk) 25 15 82 33 15 70 0,662 Appendiks Çapı (Patolojik) (mm) 10 5 15 10 5 20 0,653 Appendiks Boyu (Patolojik) (mm) 65 45 95 70 40 110 0,701 T.Bil. 0,44 0,19 0,70 0,35 0,13 0,94 0,186 D.Bil. 0,25 0,09 0,33 0,12 0,08 0,31 0,040 CRP 14,4 1,2 147,3 12,4 0,5 341,5 0,975 Wbc 16,0 7,0 24,0 12,0 7,0 26,0 0,030 Hb 13,0 10,0 14,0 12,0 9,0 14,0 0,174 Plt 221 155 387 201 126 357 0,390 Nötrofil 12,6 5,3 19,0 9,0 4,5 24,1 0,024 Lenfosit 1,52 0,57 3,14 1,69 0,75 3,56 0,611 RDW 12,2 9,7 16,8 13,2 9,3 18,3 0,545 MPV 10,0 8,9 18,6 9,7 6,2 13,3 0,031 Perfore Appendisit Var/Yok 3//10 4//20 0,678 Negatif Appendektomi Var/Yok 1//12 2//22 0,722 T.Bil: Total bilirubin, D.Bil: Direkt Bilirubin, CRP: C-Reaktif Protein,Wbc: White Blooc Count, Hb: Hemogobin, PLT: Platelet, RDW: Red Blood Cells, MPW: Mean Platelet Volume Tartışma Akut apandisit, gebelerde en sık görülen nonobstetrik akut batın nedenidir (1)(9). Retrospektif serilerde gebelikte apandisit 1/766 oranında ve en sık 2. trimesterda tespit edilmiştir (2,3). Bu çalışmada da literatüre paralel olarak en sık 2. trimesterda (%48,6) akut apandisit tespit edildi. Babaknia ve arkadaşları tarafından ise yaklaşık 500.000 gebenin taramasında elde ettikleri verilere göre gebelerde görülme sıklığını 1/1500 olarak tespit etmişlerdir (10). Gebelerde akut apandisit tanısı, gebelikteki anatomik ve fizyolojik değişiklikler nedeniyle gebe olmayanlara göre daha zordur. Anoreksiya, bulantı ve kusma gibi gebeliğin fizyolojik özellikleri akut apandisit semptomlarını maskelemektedir (11). Rahmin ekspanse olması ve abdominal kaslarının tonusunun azalması, uterusun epigastriyuma doğru büyümesine ve apendiksin de yukarı doğru yer değiştirmesine sebep olur (12). Özellikle üçüncü trimester’da uterusun kitle etkisine sekonder olarak apendiksin kraniale doğru itilmiş olması ağrının sağ üst kadranda hissedilmesine neden olabilmektedir (13). Bununla birlikte bu çalışmada üçüncü trimesterdaki hastaların hiçbirinde ağrının lokalizasyonu sağ üst kadranda değildi (Tablo- 2). Bu nedenle öykü ve fizik muayene ile akut apandisiti teş- his etmek zordur. Olası iyonize radyasyon sebebiyle gebe hastalarda radyolojik görüntüleme tekniklerinin kullanımı kısıtlıdır. Gebe hastalarda radyolojik olarak ilk tercih USG iken, USG ile net tanı konulamayan hastalarda kesin tanı için en sık MRI tercih edilir (13). USG ile kesin tanı konulamayan fakat klinik olarak akut apandisit düşünülen seçilmiş vakalarda kesin tanı için MRI olmadığı merkezlerde 3mGy altında BT çekilebilir. Çünkü bu değer, fetal etkilere neden olduğu bilinen değerin (30mGy) çok çok altındadır (14). Çalışmamızda da tanı için ilk ve en sık olarak USG’yi tercih ettik ve bu şekilde hastaların %70’sına(n=21) akut apandisit tanısı koyduk. Bunların 11 tanesi (%52,3) ilk trimesterda, 5 tanesi (%23,8) ikinci trimesterda, 5 tanesi (%23,8) de üçüncü trimesterda idi. Ayrıca USG ile tanı konulmayan hastaların 8 tanesi (%88,9) ikinci trimesterda iken geri kalan 1 tanesi (%11,1) de üçüncü trimesterdaydı. Gebe hastalardaki akut apandisit perforasyonuna sebep olan nedenlerin başında; gebelik sebebiyle olası anestezinin abortus etkileri sebebiyle konservatif tedaviye meyilli olunması, gebelik belirtileri ile akut apandisit bulgularının karış- ması sebebiyle tanının gecikmesi, ileri gebelik haftası sebebiyle muayene bulgularının klasik apandisit bulgularından farklı olması, hastanın şikâyetlerinin başlaması ile cerrahiÇiftçi ve Yavaş Gebelikte Akut Apandisit Harran Üniversitesi Tıp Fakültesi Dergisi (Journal of Harran University Medical Faculty) 2024;21(1):36-41. DOI: 10.35440/hutfd.1411520 40 arasındaki sürenin uzamasıdır (15). Semptomların başlamasından sonra cerrahi müdahalenin 24 saatten fazla ertelenmesi, perfore apandisit riskini %14-43 oranında arttırır (7,16). Mevcut çalışmada da apendiks perforasyonu gelişen gebelerin hepsinde başvuru süresi 24 saatten fazlaydı (30- 144 saat). Bu sebeple tanıdaki gecikme arttıkça perforasyon riski de bir o kadar artmaktadır. Perforasyon, generalize peritonit ve sepsise yol açarak anne ve bebekte mortalite ve morbidite oranlarının artmasına sebep olur (12,16,17). Bu sebeple operasyon için olabildiğince erken karar vermek gerekir (16). Babaknia ve arkadaşları yaptığı çalışmaya göre perfore olmayan akut apandisit hastalarında fetal kayıp oranı %1,5, perfore akut apandisit hastalarında ise %35,7 olduğunu bildirmişlerdir(10). Bu çalışmada akut apandisit sebebiyle opere edilen hastalarımızdan 7 tanesinde (%18,9) perfore akut apandisit tanısı konulmuştur. Tanının acilen doğrulanması perforasyonu azalttığı gibi negatif appendekomi riskini de azaltmaktadır. Tanının gecikmesi sebebiyle olası fetal kayıp riskleri göz önüne alındığında gebelerde %20-35’lik negatif apendektomi oranı normal kabul edilir (18,19). Bizim çalışmamızda ise negatif apendektomi oranı %8,1 (3 hasta) olarak tespit edidi. Gebe akut apandisit hastaların operasyonunu planlarken hastanın trimesteri önemlidir. Cerrahın deneyimine göre açık veya laparaskopik apendektomi tercih edilebilir (20). Gebe bir kadında açık apendektomi yapılırken, McBurney noktasında veya daha yaygın olarak maksimum hassasiyet noktasında enine bir kesi yapılır (21,22). Vaka serileri ve kü- çük kohort çalışmaları, laparoskopinin tüm trimesterlerde ve birkaç komplikasyonla başarılı bir şekilde yapılabileceğini göstermektedir (2,23). Operasyonun laparoskopik olarak devam etmek cerrahın deneyimine ve uterusun boyutu ve pozisyonuna bağlıdır. 20 çalışmayı ve apandisitli 6200'den fazla hamile kadını içeren bugüne kadarki en büyük meta-analizde, laparoskopik cerrahi artmış fetal kayıp riski ile ilişkilendirildi (23). Fakat 20 çalışmanın sadece birinin prospektif olması (19 tanesi retrospektif), içlerinde randomize çalışmanın olmaması, gestasyonel yaşın belirtilmemiş olması eksik yanlarından idi (19). Laparoskopik apendektomi planlarken hastanın hafif sola deviye yapılması, açık bakı ile ilk trokarın girilmesi ve umblikus üstünde giriş yapılması gerekir. Ayrıca insüfliasyon için görüntü sağlanabilecek en düşük basınçta çalışılması gerekir (ortalama 12 mmHg) (24). Bizim pratiğimizde de opere ettiğimiz 37 gebe apandisitin 12 tanesine laparoskopik apendektomi, 25 tanesine ise açık apendektomi uyguladık. LA yaptığımız 9 gebe 2.trimesterda, 3 tanesi de 1.trimesterdaydı. 3.trimesterdaki gebelere rutin açık apendektomi yaptık. Opere ettiğimiz hastalardan perfore apandisit olanlardan1 tanesinde intraabdominal abse, 1 tanesinde ise trokar yerinde enfeksiyon gelişti. Abse gelişen hastaya 10 gün meropenem 3x1 ile tedavi olurken diğer hasta ise pansumanla tamamen iyileşti. Sonuç olarak; gebe iken akut apandisit sebebiyle apendektomi yapılan hastalarda ağrı lokalizasyonu fizik muayenede ilk iki trimesterde sağ alt kadranda iken 3.trimesterde uterusun büyümesi ve yukarı doğru yer değiştirmesi sebebiyle yukarıya kayabilmektedir. Fetal ve maternal morbidite ve mortaliteyi azaltmak için cerrahi kararı geciktirilmemelidir. Şikayetlerin başlaması ile cerrahi arasındaki süre 24 saati geçince perforasyon riski artmaktadır. USG ilk tercih edilmesi gereken radyolojik görüntüleme olması gerekirken şüpheli durumlarda MRI tercih edilmelidir. Laparoskopik veya açık teknik cerrahın tecrübesine göre karar verilmeli, iki tekniğin olası riskleri dikkate alınarak seçilmelidir. İki tekniğin kıyaslaması için daha çok randomize çalışma gereklidir. Etik onam: Bu çalışma, Harran Üniversitesi Etik Kurulu HRÜ/22.19.24 nolu kararı ile yapılmıştır. Yazar Katkıları: Konsept: F.Ç. Literatür Tarama: F.Ç. Tasarım: F.Ç. Veri toplama: M.Y. Analiz ve yorum: M.Y. Makale yazımı: F.Ç. Eleştirel incelenmesi: F.Ç. Çıkar Çatışması: Bu çalışma yapılırken herhangi bir kurum ve kişi ile herhangi bir çıkar çalışması veya çıkar çatışması yoktur. Finansal Destek: Bu çalışma herhangi bir fon tarafından desteklenmemiştir. Kaynaklar 1. Arer İM, Alemdaroğlu S, Yeşilağaç H, Yabanoğlu H. Gebelikte akut apandisit: 20 hamile kadın olgu çalışması. Ulus Travma ve Acil Cerrahi Derg. 2016;22(6):545–8. 2. Andersen B, Nielsen TF. Appendicitis in pregnancy: Diagnosis, management and complications. Acta Obstet Gynecol Scand. 1999;78(9):758–62. 3. Andersson REB, Lambe M. Incidence of appendicitis during pregnancy. Int J Epidemiol. 2001;30(6):1281–5. 4. Lee SH, Lee JY, Choi YY, Lee JG. Laparoscopic appendectomy versus open appendectomy for suspected appendicitis during pregnancy: A systematic review and updated metaanalysis. BMC Surg. 2019;19(1):1–12. 5. Tatli F, Yucel Y, Gozeneli O, Dirican A, Uzunkoy A, Yalçın HC, et al. 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Appendicitis During Pregnancy. Obstetrics and Gynecology.Çiftçi ve Yavaş Gebelikte Akut Apandisit Harran Üniversitesi Tıp Fakültesi Dergisi (Journal of Harran University Medical Faculty) 2024;21(1):36-41. DOI: 10.35440/hutfd.1411520 41 1977;50(1): 40-44. 11. Çınar H, Aygün A, Derebey M, Tarım İA, Akalın, Büyükakıncak S, vd. Significance of hemogram on diagnosis of acute appendicitis during pregnancy. Ulusal Travma ve Acil Cerrahi Dergisi. 2018;24(5):423–8. 12. Jung SJ, Lee DK, Kim JH, Kong PS, Kim KH, Bae SW. Appendicitis during Pregnancy: The Clinical Experience of a Secondary Hospital. J Korean Soc Coloproctol. 2012 Jun;28(3):152- 9. doi: 10.3393/jksc.2012.28.3.152. 13. Haksal MC, Turgut HT. Gebelerde akut apandisit : klinik deneyimimiz Acute appendicitis during pregnancy : Clinical Experience. Medical Journal of Kocaeli 2014;1:1-5 14. Long SS, Long C, Lai H, Macura KJ. Imaging strategies for right lower quadrant pain in pregnancy. Am J Roentgenol. 2011;196(1):4–12. 15. Zheng M, Li T, Li Y, Zhang T, Zhang L, Ma W, et al. Survival Profile and Prognostic Factors for Appendiceal Mixed Neuroendocrine Non-neuroendocrine Neoplasms: A SEER Population-Based Study. Front Oncol. 2020;10(8):1–10. 16. Bickell NA, Aufses AH, Rojas M, Bodian C. How time affects the risk of rupture in appendicitis. J Am Coll Surg. 2006;202(3):401–6. 17. Al-Qudah MS, Amr M, Sroujieh A, Issa A. Appendectomy in pregnancy: The experience of a university hospital. J Obstet Gynaecol (Lahore). 1999;19(4):362–4. 18. Carmelita A. Wallace&Maxim S. Petrov&David I. Soybel&Stephen J. Ferzoco&Stanley W. Ashley&Ali Tavakkolizadeh. Influence of Imaging on the Negative Appendectomy Rate in Pregnancy. J Gastrointest Surg. 2008;12:16–50. 19. McGory ML, Zingmond DS, Tillou A, Hiatt JR, Ko CY, Cryer HM. Negative Appendectomy in Pregnant Women Is Associated with a Substantial Risk of Fetal Loss. J Am Coll Surg. 2007;205(4):534–40. 20. Tanga MR, De Maio F, Ewing JB. Acute Appendicitis in Pregnancy. 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Original Article Ann Med Res 2024;31(7):546–552 Ann Med Res Current issue list available at AnnMedRes Annals of Medical Research journal page: www.annalsmedres.org The causes of death-censored graft loss among kidney transplant recipients Felat Ciftcia, Arife Simseka,∗, Turgut Piskina, Bulent Unala, Sait Murat Dogana, Ozkan Ulutasb, Yilmaz Tabelc, Serkan Sevgid, Idris Sahinb, Hulya Taskapanb, Sezai Yilmaza aInonu University, Faculty of Medicine, Department of General Surgery, Malatya, Türkiye bInonu University, Faculty of Medicine, Department of Internal Medicine, Division of Nephrology, Malatya, Türkiye cInonu University, Faculty of Medicine, Department of Pediatrics, Division of Pediatric Nephrology, Malatya, Türkiye dInonu University, Faculty of Medicine, Department of Radiology, Malatya, Türkiye ARTICLE INFO Keywords: Chronic allograft nephropathy Death-censored graft loss Extended criteria donors Graft failure Kidney transplantation Received: Jun 04, 2024 Accepted: Jul 23, 2024 Available Online: 26.07.2024 DOI: 10.5455/annalsmedres.2024.06.108 Abstract Aim: This study presents the causes of death-censored graft loss among kidney transplant recipients. Materials and Methods: Medical records of the patients, who had undergone kidney transplantation at a tertiary center between November 2010 and December 2018, were retrospectively reviewed. Death-censored graft loss was described as an irreversible graft failure signified by return to long-term dialysis (or re-transplantation). Inclusion criteria were: patients who had undergone kidney transplantation, and subsequently lost their first graft, and a follow-up of more than one year after kidney transplantation. Results: Of 269 kidney transplant recipients, 33 recipients with a mean age of 33.54 ± 15.37 years (17 male and 16 female) were included in the study. The rate of death-censored graft loss was 12.26%. Of graft failures, 3.03% occurred in the hyperacute phase, 18.18% in the acute phase, and 78.78% in the chronic phase. Chronic allograft nephropathy was the leading cause of graft failure (48.48%). Other causes were medical problems (18.18), immunological problems (18.18%) and surgical complications (15.15%). Conclusion: Identification of the true causes of graft failure described under the heading chronic allograft nephropathy is noteworthy. Comprehensive biochemical, physiological, pathological, immunological, and genetic research should be implemented to remove the obstacles in kidney transplantations. Copyright © 2024 The author(s) - Available online at www.annalsmedres.org. This is an Open Access article distributed under the terms of Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. Introduction Although Russian surgeon, Yurii Voronoy, had reported human allogenic kidney transplantation (KT) from a deceased donor in 1933, the first temporarily successful KT was performed by Louis Michon and Jean Hamburger in 1952, using a kidney from a living related donor [1- 3]. Michon and Hamburger had noted that the kidney was rejected and the patient had died within three weeks of transplantation. The plastic surgeon, Joseph Edward Murray, knowing the immunological obstacles associated with transplantation, conducted the first long-term successful KT between monozygotic twins in 1954. As stated by Murray, that was just the first step in overcoming failure in KT [2,3]. Today, KT has become the standard of care for patients with end-stage kidney disease due to its health and economic benefits over maintenance dialysis [4]. ∗Corresponding author: Email address: draksimsek@yahoo.com.tr ( Arife Simsek) The evolution of KT is a long story that includes both disappointment and perseverance. Advances in immunosuppression and the medical care of recipients have resulted in an improvement in graft survival in the early posttransplant period, though long-term graft survival has not been achieved [4]. International studies show that the ratio of graft failure ranges between 2% to 5% [5]. According to the Joint Report of the Ministry of Health and the Turkish Society of Nephrology, as of the end of 2018, 17.220 patients were followed up with a functioning graft, and the graft failure rate was 1.84% in patients transplanted in 2018 [6]. Long-term graft survival may be influenced by several factors; among these, patients’ death with a functioning graft (DWFG) is a major cause, which accounting for nearly half of the late losses [7]. It is usually associated with coexisting conditions, which may have been present before transplantation [7]. It is clinically distinct from graft loss due to progressive dysfunction. Thus, separation of DWFG from graft loss due to progressive dysfunction 546Ciftci F. et al. Original Article 2024;31(7):546–552 is suggested [7,8]. Among factors leading progressive graft dysfunction, chronic allograft nephropathy (CAN) is the main cause of death censored graft loss (DCGL) [8]. Donor related (age, hypertension, non-heart beating donors, delayed graft function) and recipient related (hypertension, recurrence of glomerular diseases, de novo disease, medical or surgical complications, infections) characteristics, immunologic factors and immunosuppressive regimen (doserelated nephrotoxicity of calcineurin inhibitors) are other causes of late graft loss [9,10]. This study presents the causes of DCGL among kidney transplant recipients. Materials and Methods Medical records of the 269 patients, who had undergone KT for end-stage kidney disease at a tertiary center between November 2010 and December 2018, were retrospectively reviewed. DCGL was described as an irreversible graft failure signified by return to long-term dialysis (or re-transplantation). Inclusion criteria were: patients who had undergone KT, and subsequently lost their first graft, and a follow-up of more than one year after KT. Exclusion criteria included the recipients of multi-organ transplants, the recipients who had died with a functioning kidney, and recipients who had been followed-up for less than one year after KT. The failed re-transplants were also excluded. A total of 33 patients met these criteria and were included in the study. The data belonging to the donors of these recipients were also extracted. The study was conducted according to the principles set forth by the Helsinki Declaration of 1975. Approval from the Human Ethics Committee of the Institution was obtained (Inonu University Health Sciences Non-invasive Clinical Research Ethics Committee, approval number: 2018/7-11). The data included demographics, clinical findings, laboratory findings and therapeutic interventions for both recipients and their donors. The following characteristics were recorded: Demographics (age and gender), comorbid factors (cardiovascular diseases, diabetes mellitus, endocrine diseases, central nervous system diseases), etiology and origin of the kidney disease, the presence of preemptive transplant and/or pre-transplant dialysis (peritoneal dialysis and/or hemodialysis), duration of dialysis treatment, the type of KT (deceased donor and/or living-donor transplant), the type of donor relationship (relative and/or non-relative), the presence of extended criteria donor, the presence of delayed graft function, the presence of surgical complications, choice of immunosuppressive regimen, the time from transplantation to DCGL, and causes of the DCGL. Hyperacute graft failure was defined as graft loss, which had developed within the first 72 hours of the transplantation. Acute graft failure included graft losses, which had developed within the period from the 72nd hour to the 3rd month of the transplantation. Chronic graft failure included graft losses, which had developed after the 3rd month of the transplantation. Early-surgical complications were described as surgical complications, which had developed within the first 28 days of the KT. Latesurgical complications were described as surgical complications, which had developed after day 28 of the KT. Delayed graft function was defined as the need for dialysis during the first week after transplantation. Extended criteria donor was defined as shown in Table 1. Surgical technique Donor nephrectomy: It was performed via either an open surgical (before 2017) or a ‘pure’ transperitoneal laparoscopic (through 2017 and beyond) approach. The left kidney was preferred for living-donor nephrectomy, unless it contradicted the donors’ benefits, because the renal vein is longer on the left. When vascular, urological or other abnormalities were present, the right kidney was procured. Kidney transplantation: The right iliac fossa was preferred for extraperitoneal placement of the transplanted kidney because the iliac vessels were more superficial than on the left side. When vascular or other abnormalities were present, or the right iliac fossa had been used before for renal transplantation, the left side was used. The left iliac fossa was also preferred in cases where the right iliac fossa had been reserved for pancreas transplantation in diabetic patients. Statistical analysis Data were analyzed using SPSS 22.0 for Windows (Inc, Chicago, USA). Descriptive frequencies were obtained for the demographic characteristics of the donors and recipients. The data were reported as mean ± standard deviation for normally distributed variables. Results Two hundred and sixty-nine KTs were performed between November 2010 and December 2018. Of them, 33 recipients (17 male and 16 female) with a mean age of 33.54 ± 15.37 (range: 3-60) years were included in the study. The rate of DCGL was 12.26%. Mean duration of graft survival was 36.5 ± 31.98 (range: 0-102) months (Table 2). Mean length of hospitalization was 10.15 ± 7.87 (range: 4-42) days. In the majority of cases (n:16; 48.4%) the cause of the kidney disease was unknown (idiopathic). Nephrocalcinosis, membranoproliferative glomerulonephritis (MPGN), hypertensive nephropathy, polycystic renal disease, diabetic nephropathy, and distal renal tubular acidosis secondary to vesico-ureteric reflux (VUR), renal agenesis, neurogenic bladder, Familial Mediterranean Fever, and Alport Syndrome were the other causes of renal failure (Table 2). Seventeen of the patients (51.5%) had at least one additional disease; hypertension was the most common (45.4%), followed by diabetes mellitus (9.09%) and epilepsy (9.09%). Twenty-five patients (75.75%) were on dialysis (18 on hemodialysis, 3 on peritoneal dialysis, and 4 on both forms of dialysis) with a mean duration of 60.8 ± 76.38 (range: 2-276) months. Nineteen of 33 (57.57%) transplants were from a living donor. Seventeen (51.5%) grafts were recruited from nonrelatives. Delayed graft function developed in 8 (24.2%) recipients (Table 2). Of graft failures, 3.03% occurred in the hyperacute phase, 18.18% (n:6) in the acute phase, and 78.78% (n:26) in the chronic phase. CAN was the leading cause of graft failure (48.48%). Other causes were medical problems in six 547Ciftci F. et al. Original Article 2024;31(7):546–552 Table 1. The definition of the extended criteria donor. Deceased Donor Living Donor Age ≥ 60 and < 5 Age ≥ 60 Vascular or anatomic variations Vascular or anatomic variations Kidney with simple cysts and/or stones Simple kidney cysts and/or stones in one kidney, which is planned to be recovered. Donors with multiple cysts in one kidney or simple cysts and/or stones in both kidneys are not eligible for donation. Presence of infection (except sepsis) Ischemia time longer than 24 hours Grafts with ATN (especially when CPR applied) ABO incompatible donors ABO incompatible donors * It is not applicable in our country * It is not applicable in our country Donors aged (≥ 50 - < 60), who have at least two of the following criteria. Donors aged (≥ 50 - < 60), who have at least one but no more than two of the following criteria. - Cerebrovascular accident - Previous history of cerebrovascular accident without serious sequelae - Hypertension - Hypertension (uncomplicated) - Diabetes Mellitus - Diabetes Mellitus (uncomplicated) - Serum creatinine >1.5 mg/dL at time of donation - Connective tissue disease (uncomplicated) Donors aged (≥ 5 - < 50), who have at least one of the following criteria. Donors aged (≥ 30 - < 50), who have only one of the following criteria. Donation is not eligible if the potential donors have two or more of the criteria. - Cerebrovascular accident - Hypertension (uncomplicated) - Hypertension - Diabetes Mellitus (uncomplicated) - Diabetes Mellitus - Connective tissue disease (uncomplicated) - Serum creatinine >1.5 mg/dL at time of donation *** Our clinic recommends not to recover kidney from the potential living donors aged (≥ 18 - < 30) securing donor interests. If it is preferred, it would be appropriate for donors not to have additional diseases. ATN: Acute tubular necrosis, CPR: Cardiopulmonary resuscitation. (18.18%) patients, immunological problems in six (18.18%) patients and surgical complications in five (15.15%) patients (Table 3). Hyperacute rejection developed in one patient (3.03%) due to ABO incompatible renal transplantation. Acute and chronic rejections accounted for 6.06% and 9.09% of graft failures, respectively. Non-adherence to immunosuppressive medication resulted in allograft rejection in 2 patients. Surgical complications, which were the underlying causes of graft failure in five (15.15%) patients, developed in 21 (63.6%) recipients. None of the patients developed intraoperative complications. Nearly half of surgical complications (n:10) developed in the early postoperative period (within 28 days of renal transplantation). Seven of the 21 (33.3%) patients underwent reoperation within the same week. Table 4 shows surgical complications and their management. Vascular thrombosis, which developed in two patients, who had undergone en-bloc and dual KT, and renal artery pseudoaneurysm, which developed in two patients, who had received the graft from the same deceased donor, in whom pseudomonas species were isolated from the tracheal aspirate, were the surgical causes of early-graft loss. İliac artery dissection was the surgical cause of chronic graft loss. Immunosuppressive therapy consisted of induction with [antihuman T-lymphocyte immunoglobulin (n:29) or Basiliximab (n:4) and methylprednisolone (n:33)], and triple therapy with methylprednisolone (n:32), antiproliferative agents [mycophenolate mofetil (n:21) or enteric-coated mycophenolate sodium (n:11)], and calcineurin inhibitors [immediate-release tacrolimus (n:30) or cyclosporine-A (n:2)]. Triple therapy could not be used in one patient due to hyperacute rejection. Discussion International studies show that the ratio of graft failure ranges between 2% to 5% [5]. According to the Joint Report of the Ministry of Health and the Turkish Society of Nephrology, as of the end of 2018, the graft failure rate was 1.84% in patients transplanted in 2018 [6]. In this study, DCGL occurred in 12.26% of the KTs, which was greater than that of national and international values. It should be noted that our national registry report only shows the graft failure within the first year of transplantations, which were performed on 2018. It does not include the rate of graft failure over the years. In concordance with the literature, CAN was the main cause of DCGL (48.48%) [8]. Of graft failures, 78.78% developed after 3 months of transplantation and CAN constituted 61.53% of them. CAN is the histologic description of the fibrosis, vascular and glomerular damage occurring in kidney allografts, and is independent of underlying etiology [11,12]. Actually, it refers to a clinical situation that causes graft loss, which could not be fully elucidated, with these gathered together under the collective heading. Transplant programs are based on monitoring the change in serum creatinine for identification of the patients at risk for CAN, but this change occurs 548Ciftci F. et al. Original Article 2024;31(7):546–552 Table 2. The characteristics of the donors and recipients. Characteristics Mean ± SD or (n) Age (recipient, year) 33.54 ± 15.37 Gender (recipient) Female 16 Male 17 Co-morbid disease (recipient) Yes 17 No 16 Causes of ESRD Idiopathic 16 Hypertensive nephropathy 2 Diabetic nephropathy 1 MPGN 3 Nephrolithiasis 4 Polycystic kidney disease 2 dRTA secondary to VUR 1 Renal agenesis 1 Neurogenic bladder 1 Alport Syndrome 1 Familial Mediterranean fever 1 Pre-transplantation RRT Preemptive 8 HD 18 PD 4 HD-PD 3 Mean duration of dialysis (month) 60.8 ± 76.38 Sources of Donor Kidneys Living donors 19 Deceased donors 14 Age (donor, year) 46.57 ± 22.08 Gender (donor) Female 18 Male 15 Extended criteria donor Yes 19 No 14 Ischemia time Warm ischemia time (second) 180.5 ± 73.5 Cold ischemia time (minute) 1299 ± 378 Delayed graft function Yes 8 No 25 Mean duration of graft survival (month) 36.5 ± 31.98 MPGN: Membranoproliferative glomerulonephritis, dRTA: Distal renal tubular acidosis, VUR: Vesico-ureteric reflux, RRT: Renal replacement therapy, HD: Hemodialysis, PD: Peritoneal dialysis. usually late in the course of the disease, and overlooks the severity of the pathological change. Histological evaluation prior to transplantation and afterwards may not be possible in every transplant center as in our center. Early-graft loss is a catastrophic event that is assumed to occur as a result of vascular thrombosis, acute rejection, primary non-function, and urological complications [13]. In current practice, graft loss due to rejection in the first 3 months of KT is unusual [13]. However, in this study, early-graft loss constituted 21.21% of all cases, and immunological rejections accounted for 42.85% of early-graft loss. As a result of immunological advances, graft loss due to hyperacute rejection has been considered so unusual that some authors did not deem it worthwhile to comment on it [13]. Unfortunately, in our series hyperacute rejection developed in one patient (3.03%) due to an ABOincompatible KT. In fact, this case was one of medical malpractice rather than immunological rejection. Our clinic adopted current strategies, which were defined to prevent allograft rejection. However, ABO incompatible KTs are not performed in our center because they are not covered by the requisite medical insurance. The information regarding blood groups of the transplant pairs had been uploaded incorrectly to the laboratory information system. Since we assumed that we would perform ABO-compatible KT, the immunosuppressive protocol was not adjusted to that of an ABO-incompatible one. It was one of the preventable factors for graft loss, which transplant team has to resolve. From that point onwards, which was in the early stage of the KT program, the transplant team has adopted a comprehensive control mechanism, including final confirmation of the laboratory results just before transplantation, irrespective of the previous laboratory records. If ABO-incompatible KT is to be planned, optimization of desensitization and patient-tailored immunosuppressive regimens are required to achieve better outcomes [14]. The other two patients with early graft loss were treated as if the underlying factor was immunological rejection, after all other causes were excluded, though protocol biopsy could not be performed. In our center, immunological rejections accounted for 18.18% of graft loss, half of those developed in early period. According to the Joint Report of the Ministry of Health and the Turkish Society of Nephrology, the rate of acute rejection within the first 6 months of transplantation was 13.38% [6]. Lack of protocol biopsy was an important obstacle to obtain better outcome. We think that protocol biopsy should be applicable in all transplant centers. Non-adherence to the immunosuppressive regimen leads to rejection, graft loss and even death [15]. Its prevalence in KT recipients varies between 20% and 70% [16]. Non-adherent recipients to immunosuppressive medications have 7-fold increase in risk of graft failure [17]. It is a preventable cause of the graft loss, and accounted for 33% of graft rejection in the current study, all of them developed in late period. Early detection of risk factors, which were explained by Belaiche et al, [15], (age below 50, male gender, low social support, unemployment, poor education, more than 3 months after transplant, living donor, re-transplant, more than 6 co-morbidities, more than 5 drugs/day, more than 2 intakes/day, negative beliefs, negative behaviors and negative satisfaction, depression, and anxiety) is essential to overcome non-adherence. 549Ciftci F. et al. Original Article 2024;31(7):546–552 Table 3. The causes of death-censored graft loss among kidney transplant recipients. Hyperacute phase (n) Acute phase (n) Chronic phase (n) Total (n) CAUSES Pre-renal Medical problems 7 Congestive heart failure (-) (-) 2 Surgical complications Vascular thrombosis (-) 2 (-) Renal artery pseudoaneurysm (-) 2 (-) Iliac artery dissection (-) (-) 1 Renal Medical problems 25 Recurrence of the primary disease (-) (-) 1 BKVN (-) (-) 2 Immunological problems 1 2 3 CAN (-) (-) 16 Post-renal Medical problems VUR + BKVN (-) (-) 1 1 Total (n) 1 6 26 33 CAN: Chronic allograft nephropathy, BKVN: BK virus nephropathy, VUR: Vesico-ureteric reflux. Table 4. The surgical complications and their management. Surgical complications (n) Management (n) Lymphovascular Vascular thrombosis 2 Reoperation (explantation of the renal graft) 2 External iliac artery dissection 1 Reoperation (the internal iliac artery was used for reanastamosis) 1 Lymphocele 2 Percutaneous drainage & Sclerotherapy 2 Renal artery pseudoaneurysm 2 Reoperation (explantation of the renal graft & resection of pseudoaneurysm with vascular reconstruction) 2 Lymphocele with intra-abdominal abscess 1 Percutaneous drainage & Reoperation 1 Renal & Perirenal Hematoma 4 Conservative management 1 Perirenal abscess 1 Reoperation 3 Drainage 1 Urological Ureteral leakage 1 Percutaneous nephrostomy and double -J- catheter placement 1 Ureteral obstruction 5 Percutaneous nephrostomy and double –J- catheter placement 4 Ureteral obstruction with pyelitis 1 Percutaneous nephrostomy and double –J- catheter placement & Reoperation 1 Ureteral obstruction with VUR 1 Percutaneous nephrostomy 1 Percutaneous nephrostomy and double –J- catheter placement & Reoperation 1 VUR: Vesico-ureteric reflux. Vascular thrombosis, which developed in two patients, who had undergone en-bloc and dual KT, and renal artery pseudoaneurysm, which developed in two patients, who had received the graft from the same deceased donor, in whom pseudomonas species were isolated from the tracheal aspirate, were the surgical causes (57.15%) of early-graft loss. Early-graft loss after KT may be more likely after the use of kidneys from suboptimal donors [18]. There is 550Ciftci F. et al. Original Article 2024;31(7):546–552 an organ supply shortage in our country and living kidney donation is the main graft source. Thus, we have to procure the kidney grafts from extended criteria donors to increase the organ pool. Extended criteria donor kidneys constituted 57.6% of the graft pool in the current study. There are no universal criteria defining extended criteria donors. It refers higher risk compared with a standard donor. The risk could be a disadvantage in the future not only for recipients but also for living donors. According to our criteria, which were previously described, any deceased donor candidate with infection (except those with sepsis) is eligible for donation under antimicrobial coverage. As known, the culture results of deceased donors can mostly be obtained after transplantation, as in the current study, due to laboratory procedures. Pseudomonas species were isolated from the blood cultures of both recipients. Although a culture-specific antibiotic regimen was started as soon as the culture result of the donor was obtained, renal artery pseudoaneurysm was not inevitable in either of the recipients. Renal artery pseudoaneurysm after KT is a rare complication and usually secondary to infection or technical default [19]. Infectious anastomotic pseudoaneurysms described in the literature (usually an opportunistic microorganism in origin) are limited to case reports and/or case series and do not exceed 30 cases [20]. Early diagnosis is a challenge, especially in fungal infections, which may be indolent for months [20]. Serial radiologic investigations and routine blood cultures may be implemented, especially in recipients of infected donors. Graft nephrectomy and resection of pseudoaneurysm with vascular reconstruction is the gold standard therapy in patients with large vascular defects [20]. Medical problems accounted for 23.07% of late-graft loss, and BKVN was responsible for half of these cases. With the use of more potent immunosuppressive regimens, BKVN has increasingly been recognized as resulting in allograft damage [21]. Recurrence of the primary disease and congestive heart failure were the other medical problems. The incidence of de novo congestive heart failure in kidney transplant recipients is 2–5 times higher than the incidence in the general population [22]. Hypoperfusion led to late-graft loss in two patients with de novo congestive heart failure. This was a descriptive study without a comparator. Thus, predictors of the graft loss were not evaluated. The lack of protocol biopsy was another limitation of the study. Conclusion In conclusion, there are several preventable factors for graft loss, which transplant teams have to resolve, these include creation of an effective training program to prevent malpractice, ensuring that patients are fully informed before transplantation to improve their adherence to immunosuppressive therapy, close monitoring of the patients to resolve their medical problems, adoption of a protocol biopsy and immunological support, and improving the management of the potential organ donor. There are many unresolved variables in KT and many problems, which remain to be elucidated in order to achieve long-term graft survival. Identification of the true causes of graft failure described under the heading CAN is noteworthy. Comprehensive biochemical, physiological, pathological, immunological, and genetic research should be implemented to remove the obstacles in KTs. Ethical approval Ethical approval was received for this study from Inonu University Health Sciences Non-invasive Clinical Research Ethics Committee (approval number: 2018/7-11). References 1. Barker CF, Markmann JF. Historical overview of transplantation. Cold Spring Harb Perspect Med 2013;3(4):a014977. 2. Gaston RS, Diethelm AG. A brief history of living donor kidney transplantation. In: Gaston RS, Wadström J, editors. Living Donor Kidney Transplantation, Current Practices, Emerging Trends and Evolving Challenges. 1st ed. London & New York: Taylor & Francis Group; 2005.p.1-7. 3. 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448 Annals of Medical Research DOI: 10.5455/annalsmedres.2019.11.713 2020(27)2:448-53 Original Article Retrospective view and treatment of iatrogenic ureteral injuries Recep Eryilmaz1, Rahmi Aslan1, Murat Demir2, Arif Mehmet Duran1, Felat Ciftci3, Kerem Taken1 1Van Yuzuncu Yil University, Faculty of Medicine, Depatmant of Urology, Van, Turkey 2Van Training and Research Hospital, Clinic of Urology, Van, Turkey 3Inonu University, Faculty of Medicine, Depatmant General Surgery, Malatya, Turkey Copyright © 2020 by authors and Annals of Medical Research Publishing Inc. Abstract Aim: Ureteral injuries are rare. Iatrogenic ureteral injury is the most common cause of ureteral traumas. This letter aims, evaluation of iatrogenic ureteral traumas and treatments. Material and Methods: Thirty two patients with major iatrogenic ureteral trauma were enrolled. Sonography, intravenous pyelography, CT of abdomen (contrast-enhanced and non-contrast enhanced), antegrade X-rays or diagnostic ureterenoscopy are used for the diagnosis. All patients were undergone endoscopic ureterenoscopy before the ureter was surgically repaired. Next, the surgical technique was decided. Injuries that can be managed with endoscopic approach were treated by inserting a Double J stent. For patients who were not eligible for endoscopic treatment, treatment was decided according to the location of ureteral injury. Results: Of the patients, 25 were female and 7 were male and mean age was 46.31±16.485 years. Ureteral injury was secondary to gynecologic intervention in 16 patients, general surgery procedures in 6 patients and urologic surgery in 10 patients. According to AAST, Grade 4-5 injury was identified in 71.9% of 32 patients, while Grade 3 and Grade 2 injuries were noted in 15.6% and 12.5% of patients, respectively. Four patients were treated in late period, while intraoperative or early treatment was instituted for 28 patients. Conclusion: Iatrogenic ureteral injuries develop mostly after laparoscopic or endoscopic pelvic surgeries. We should prefer endoscopic insertion of Double J stent for the first-line treatment. Keywords: Latrogenic; ureter; traumas; treatment Received: 11.11.2019 Accepted: 11.12.2019 Available online: 06.03.2020 Corresponding Author: Recep Eryilmaz, Van Yuzuncu Yil University, Faculty of Medicine, Depatmant of Urology, Van, Turkey E-mail: recepuro@hotmail.com INTRODUCTION Ureteral traumas are rare and account for approximately 1 to 2.5% of all urogenital system injuries. Etiologies are iatrogenic injury in 75% of ureteral injuries, blunt trauma in 18% of cases and penetrating injury in 7% of patients(1). Gynecologic procedures, general surgery procedures and urologic surgery procedures account for 64 to 82%, 15 to 26% and 11 to 30% of major iatrogenic ureteral injuries, respectively (2-4). According to classification developed by American Association for the Surgery of Trauma (AAST), ureteral injuries are examined over 5 grades listed below. Grade 1: only hematoma in the ureter Grade 2: Laceration <50% transection (caliber of the ureter) Grade 2: Laceration >50% transection Grade 4: Complete contusion in ureter <2 cm Grade 5: Complete contusion in ureter >2 cm Iatrogenic ureteral injuries do not have specific sign or symptoms; the diagnosis is usually established and only one third of the cases is intraoperatively recognized (5). Ureteral anatomoy should be known well and operation should be carefully and meticulously performed in order to avoid ureteral injuries. Today, surgeons review human pelvic anatomical models along with classical textbooks in order to know the pelvic anatomy better (6). This letter aims discussing evaluation and treatment of iatrogenic ureteral injuries that have a significant place among all urological injuries in the light of up-to-date literature.449 MATERIAL and METHODS After the study was approved by tertiary institution ethics committee (Nr. 05 dated 28/09/2018), medical files of 177 patients, who were examined for iatrogenic ureteral injuries and undergone necessary procedures in the last 6 years, were retrospectively reviewed. Patients are examined according to ureter injury scale of the AAST. Accordingly, the patients with ≥Grade 2 injury were included. The patients with no sufficient medical or follow-up data and with Grade 1 injury were excluded. One hundred forty five patients with Grade 1 ureteral injury were excluded. Thirty two patients with major iatrogenic ureteral trauma were enrolled. Sonography, intravenous pyelography, CT of abdomen (contrast-enhanced and non-contrast enhanced), antegrade X-rays or diagnostic ureterenoscopy are used for the diagnosis. Three treatment modalities, namely intraoperative treatment, early treatment and late treatment, were instituted for the patients. Intraoperative therapy implies the treatment during primary operation, while early treatment is started within postoperative one week and late treatment implies a modality that is started three months after the primary operation. For the patients in the group of late treatment, nephrosotomy was temporarily inserted. Endoscopic ureterorenoscopy was performed for all patients before the ureteral injury was surgically repaired (excluding ureteral injuries identified during open surgery and in the intraoperative period). Next, the surgical technique was decided. For injuries that could be treated with endoscopic technique, Double J stent was inserted. For patients who were not eligible for endoscopic management, the treatment was decided according to the location of ureteral injury. Open surgery, primary repair, release of ligation, pyeloplasty or end-to-end anastomosis of ureter were the options for the injuries of proximal ureter. Again, open surgery, release of ligation or end-to-end anastomosis of ureter was performed for injuries in the mid segment of ureter. For patients with complete trauma in distal ureter or with avulsion very close to the urinary bladder that end-to-end anastomosis of ureter was not an option, ureteroneocystostomy (UNC) was done and on the other hand, primary repair, end-to-end anastomosis, release of ligation or Boari flap was considered for other distal ureteral injuries depending on grade and location of the injury. Statistical Analysis Resultant data is reviewed with SPSS v.22 software. Compliance of continuous data to normal distribution was analyzed with Kolmogorov-Smirnov test. Mean and standard deviation are expressed for the data with normal distribution, while median and maximum and minimum values are expressed for the data that do not comply with normal distribution. Categorical and nominal variables are reviewed over frequency and percentiles. The relation between the grade of ureteral injury and the departments was analyzed with Chi-Square test. Results with Type 1 error value below 0.05 are deemed statistically significant. RESULTS Thirty two patients were undergone a procedure for major iatrogenic ureteral injury in our clinic in the last 6 years. Of the patients, 25 were female and 7 were male Table 1. Patient demographics, location of ureteral injury, grade of ureteral injury, the surgical department that caused the ureteral injury, time of surgery and operations are tabulated Gender Age Traumatized ureter site According to the(AAST) degree of injury Surgical section Treatment time Operation performed Female(F) 37 distal ureter Grade4-5 gynecology Late treatment UNC F 48 distal ureter Grade2-3 gynecologi Early treatment Suture ligation opening + dj insertion F 59 distal Ureter Grade4-5 General surgery Early treatment UNC F 40 distal Ureter Grade2-3 Gynecology intraoperatif Suture ligation opening + dj insertion F 54 distal ureter Grade2 gynecology intraoperatif DJ stent insertion F 82 distal ureter Grade4-5 gynecology intraoperatif UNC F 34 proximal ureter Grade4-5 urology intraoperatif pyeloplasty Male(M) 36 distal ureter Grade4-5 General surgery intraoperatif Boari flep M 73 distal ureter Grade3 urology intraoperatif Ureter repair + DJ insertion F 34 distal ureter Grade4-5 gynecology intraoperatif UNC Ann Med Res 2020(27)2:448-53450 and mean age was 46.31±16.485 years. Ureteral injury was secondary to gynecologic intervention in 16 patients, general surgery procedures in 6 patients and urologic surgery in 10 patients. Four patients were treated in late period, while intraoperative or early treatment was instituted for 28 patients. Pyelonephritis developed secondary to nephrostomy in 3 patients in the group of late treatment. From the widest perspective, iatrogenic ureteral injury cases enrolled in our study included ligation in 3 cases, partial transection in 3 cases, stricture in 3 cases, complete transection in 8 cases and avulsion in proximal or distal end of ureter in 15 cases. Of iatrogenic ureteral injuries secondary to gynecologic procedures, etiology was laparoscopic tumor surgery in 9 cases and open surgery in 7 cases. Ureteral injury develop following hysterectomy in 9 patients, caesarean section in 5 patients and resection of ovarian tumor in 2 patients. For ureteral traumas caused by general surgery procedures, the injury developed following laparoscopic colorectal tumor surgery in 3 cases, laparoscopic appendectomy in one case and open colorectal tumor surgery in one case. Ureteral traumas secondary to urologic procedures were F 46 bilateral distal ureter One side Grade 4-5 One side grade 2-3 gynecology Early treatment One side Opening the ligation + DJ UNC to the other side F 47 mid ureter Grade4-5 gynecology intraoperatif Ureter end-to-end anastomosis F 21 mid ureter Grade4-5 General surgery Late treatment Ureter end-to-end anastomosis F 71 distal ureter Grade2 gynecology intraoperatif DJ insertion F 38 distal ureter Grade4-5 gynecology Late treatment UNC F 46 distal ureter Grade4-5 gynecology Late treatment UNC F 30 bilateral distal ureter Grade2 gynecology intraoperatif Bilateral DJ insertion M 18 mid ureter Grade4-5 urology intraoperatif Ureter end-to-end anastomosis F 47 distal ureter Grade4-5 urology intraoperatif UNC M 28 mid ureter Grade4-5 urology intraoperatif Ureter end-to-end anastomosis F 48 mid ureter Grade4-5 gynecology Early treatment Ureter end-to-end anastomosis F 68 mid ureter Grade4-5 General surgery Early treatment Ureter end-to-end anastomosis M 44 mid ureter Grade4-5 General surgery Early treatment Ureter end-to-end anastomosis F 59 distal ureter Grade4-5 General surgery Early treatment Ureter end-to-end anastomosis F 34 distal ureter Grade2-3 gynecology Early treatment Ligation opening + DJ stenting F 23 proximal+distal ureter Grade4-5 urology Early treatment Pyeloplasty+UNC F 25 distal ureter Grade4-5 gynecology intraoperatif UNC M 49 distal ureter Grade4-5 urology intraoperatif UNC F 54 distal ureter Grade4-5 urology intraoperatif UNC F 67 distal ureter Grade3-4 urology intraoperatif Ureter repair + DJ insertion M 72 distal ureter Grade4-5 urology intraoperatif UNC F 50 distal ureter Grade2 gynecology Early treatment DJ insertion 32 patient M:Male F:Female AST: American Association for the Surgery of Trauma UNC: ureteroneocystostomy DJ:Doule j stent Ann Med Res 2020(27)2:448-53451 caused by endoscopic stone surgeries in 8 patients and open urinary bladder surgery in 2 patients. The patients with major pelvic mass were preoperatively inserted Double J stent. Double J stents that were inserted to ureter were removed 6 weeks after UNC and end-to-end anastomosis, but they were removed 4 weeks later in patients with partial ureteral trauma. Postoperative urinary drainage that persisted longer than 3 weeks developed in 2 patients in the group of early or intraoperative treatment. Nephrostomy was inserted to one of these patients. Only drainage volume was supervised in the other patient, as there was not hydronephrosis. These two patients were discharged in healthy condition in postoperative Week 4. Patient demographics, location of ureteral injury, grade of ureteral injury, the surgical department that caused the ureteral injury, time of surgery and operations are tabulated in Table 1. DISCUSSION The iatrogenic ureteral injuries include ligation, kinking by suture, transection, avulsion, partial transection, crush and devascularization associated with delayed necrosis or stricture (7). As also reported in the literature, there is a very wide range of iatrogenic ureteral injuries. In our study, distal ureter avulsion was more frequent and also stricture, ligation and transection were seen .Risk factors for ureteral injuries include previous operations, major pelvic masses, inflammatory diseases, malignant tumors and radiotherapy, while the possibility of ureteral injury increases when the surgeon is not familiar with congenital anomalies (8-10). Ureters should be clearly seen and peristalsis should be inspected, while operation is performed close to the ureters. Although ureteral stents help determining the location of injured ureter, they do not help prevent the injury (11). Ureteral stents are beneficial, if pelvic anatomy impairs due to a reason whatsoever and/or ureter cannot be located with routine methods (especially in large pelvic masses, kyphoscoliotic patients and when ureter cannot be selected completely in preop radiological examinations ) , and it is not necessary to use them in all cases (12). Incidence of iatrogenic ureteral injuries secondary to laparoscopic procedures increased, as laparoscopic surgery is ever increasingly performed and retroperitoneal dissection is a complex procedure. Gynecologic pelvic surgery is the most common etiology of iatrogenic ureteral injury. The risk of ureteral injury is high in laparoscopic hysterectomy (13). In our study, tumor surgery was the most common etiology of ureteral injuries that developed following laparoscopic gynecologic and general surgery procedures. Endoscopic removal of ureteral stone was the most common urologic procedure. Although insertion of DJ stent before major pelvic mass surgeries do not prevent iatrogenic ureteral injuries, the stent helps prevention of postoperative complication by facilitating intraoperative detection of the trauma, as double J stent can be seen in the lumen of injured ureter. Of the patients who were intraoperatively diagnosed with ureteral injury, three were patients with major pelvic mass from gynecology clinic who were preoperatively inserted double J stent. Therefore, we believe that insertion of DJ stent before major pelvic mass surgeries is a beneficial and important procedure. In present study, 50% of all iatrogenic ureteral injuries developed following gynecologic surgery. These traumas are caused by laparoscopic hysterectomy in 56.25% of patients, caesarean section in 31.25% of patients and ovarian tumor surgery in 12.5% of patients. Comparing to other surgical departments (gynecology, urology), iatrogenic ureteral injuries secondary to colorectal surgery are rare. However, ureteral injuries are most commonly caused by colorectal surgeries among general surgery procedures. The incidence ranges from 0.3% to 1.5 percent (14). In these study, 18.75% of all iatrogenic ureteral injuries developed after general surgery procedures. Considering ureteral injuries following general surgery procedures, 83.3% of the cases are caused by colorectal tumor surgery and 16.7% developed after appendectomy. Moreover, ureteral injury developed after laparoscopic surgery in 66.6% of patients and after open surgery in 33.4% of patients.Urologic surgery, including but not limited to ureteroscopy, lymphadenectomy and urinary diversion, may lead to iatrogenic ureteral injuries. The incidence of ureteral injury and stenosis may increase up to 13 percent. Iatrogenic ureteral injury develops most commonly following ureterorenoscopic procedures (15). In our study, 31.25% of all iatrogenic ureteral injuries developed after urologic surgery procedures. Endoscopic procedures were responsible for 8 patients, while the injury developed in one patient following repair of vesicovaginal fistula and in one patient following open vesical diverticulectomy. Endoscopic treatment of ureteral stone accounts for 80% of iatrogenic ureteral injuries secondary to urologic surgery procedures, while the rest 20% of injuries developed following open surgery. There is a wide range of therapeutic options for ureteral injuries and strictures, ranging from endoscopic treatment and complex reconstruction to renal autotransplantation, and the final treatment decision is based on length, severity and location of the injury in proximal, mid or distal ureter (16,17). While the distal one third of ureter is a common site of injury (91%), mid and proximal ureters are rarely affected – 7% and 2%, respectively (18). Treatment of iatrogenic ureteral injuries constitutes the most important part of this study. If the patient is not managed with an appropriate treatment modality, after iatrogenic ureteral injury is detected, the risk is high for infection, renal dysfunction and renal failure (19). Therefore, ureteral injuries should be correctly managed. First, non-invasive methods should be instituted that are followed by invasive modalities (20). In our study,four patients (12.5%) were started on treatment late and twenty eight (87.5%) patients were Ann Med Res 2020(27)2:448-53452 intraoperatively treated or started on treatment early. From a broad perspective, UNC was performed for 40.6% of patients with iatrogenic ureteral injury, while end-toend anastomosis, endoscopic insertion of Double J stent, release of ligation and insertion of Double J stent, open repair of ureter and insertion of Double J stent, pyeloplasty and Boari flap were performed in 25%, 12.5%, 9.4%, 6.3%, 3.1% and 3.1% of the patients, respectively. Urinary drainage that exceeded 3 weeks was detected in 2 patients in early postoperative period. Nephrostomy was inserted to one of these patients. Since the other patient did not have hydronephrosis, only drain monitoring was done. There was no return from drains in two patients in postoperative week 4. Since antegrade imaging showed that the ureter was intact in these patients, nephrostomy and drains were removed. On the other hand, pyelonephritis developed secondary to nephrostomy in 3 patients in the group of late treatment. These patients were admitted to the inpatient ward at certain intervals and managed with parenteral antibiotherapy. No postoperative early complication is faced in two patients with Grade 4-5 trauma in both distal and proximal ends of ureter. Since ureteral injury occurred in these two patients in a third party healthcare facility, they presented to our hospital for removal of double J catheter 3 months later. Another patient presented to and followed up by a third party healthcare facility. For the patient who presented to our hospital, the ureter was fibrotic and narrow throughout the entire trace, while double J stent was removed under guidance of URS. Since the ureter was fibrotic and the patient was young, a new double J stent was inserted and immediately referred to an advanced care facility for autotransplantation. When the patient presented for follow-up visit, we learned that the patient was undergone autotransplantation in a third party healthcare facility. When the patient who was followed up in a third party healthcare facility visited our hospital 2 years later, the kidney was not functioning at the surgery side. The patient was placed on follow-up, as the patient was old and had no complaint. First preference should be insertion of Double J stent for iatrogenic ureteral injuries. If this option fails, percutaneous nephrostomy should be done followed by re-insertion of double J stent several days later. If this option also fails, reconstructive surgery should be done depending on the location of injury (21). In our study, minimally invasive treatment is our principle for the treatment of iatrogenic ureteral injuries. Endoscopic placement of double J stent is our first preference for Grade 2-3 injuries of the ureter. However, the treatment decision is based on the injured part of ureter in Grade 4-5 ureteral injuries. Referral of the patient to an advanced care facility for autotransplantation or construction of neoureter from ileum without wasting time is very important to protect the kidney in patients with Grade 4-5 injury in both distal and proximal ends of ureter, if the ureter is not vascularized. CONCLUSION In conclusion iatrogenic ureteral injuries develop mostly after laparoscopic or endoscopic pelvic surgeries. Although treatment of iatrogenic ureter traumas depends on the degree of injury and the location of the ureter. Yet, our first preference should be endoscopic treatment for iatrogenic ureteral injuries. Competing interests: The authors declare that they have no competing interest. Financial Disclosure: There are no financial supports. Ethical approval: 28/09/2018 ANDDECİSİON NO:05 , Van Yuzuncu yil university ethics committe. Recep Eryilmaz ORCID: 0000-0002-4506-8784 Rahmi Aslan ORCID: 0000-0002-4563-0386 Murat Demir ORCID: 0000-0001-5029-8800 Arif Mehmet Duran ORCID: 0000-0002-9990-1516 Felat Ciftci ORCID: 0000-0002-8958-7121 Kerem Taken ORCID: 0000-0002-4370-4222 REFERENCES 1. Cem Karaali, Salih Budak, Mustafa Emiroğlu, et al. Iatrogenic Ureter Injuries Current Diagnosis and Treatment Methods. Cystoscope J 2014 :179-84. 2. Delacroix SE, Jr Winters JC. Urinary tract injures: recognition and management. Clin Colon Rectal Surg 2010;23:104-11. 3. 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See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/346082638 Coexistence of Right Obturator, Lacunar, Direct Inguinal, Bilateral Indirect Inguinal, and Bilateral Femoral Hernias and Treatment with Totally Extraperitoneal Laparoscopy Article · November 2020 DOI: 10.1007/s12262-020-02660-7 CITATIONS 0 READS 4 4 authors, including: Felat Çiftçi Inonu University 7 PUBLICATIONS 3 CITATIONS SEE PROFILE Emrah Sahin Inonu University 2 PUBLICATIONS 0 CITATIONS SEE PROFILE All content following this page was uploaded by Felat Çiftçi on 23 November 2020. The user has requested enhancement of the downloaded file.IMAGES IN SURGERY Coexistence of Right Obturator, Lacunar, Direct Inguinal, Bilateral Indirect Inguinal, and Bilateral Femoral Hernias and Treatment with Totally Extraperitoneal Laparoscopy M. Ates1 & F. Ciftci1 & E. Sahin1 & K. B. Sarici1 Received: 23 June 2020 /Accepted: 29 October 2020 # Association of Surgeons of India 2020 Abstract The majority of groin hernias are treated according to the findings of the physical examination, but patients may also have occult hernias. With the use of laparoscopy, hernias that were not noticed during the initial examination or even in radiological images are increasingly being detected intraoperatively. Here, we present the case of a 62-year-old gentleman diagnosed with seven different types of occult and non-occult bilateral inguinal hernias that were treated with laparoscopic totally extraperitoneal herniorrhaphy. A major advantage of this method is that it allows the simultaneous diagnosis and treatment of occult and rare inguinal hernias. Keywords Multiple inguinal hernias . Contralateral occurrence . Laparoscopic surgery . TEP Case Report and Introduction A 62-year-old gentleman was admitted with testicular pain of 1-month duration. Ultrasound revealed a right indirect inguinal hernia. Laparoscopic TEP hernia repair was performed. Exploration of the right inguinal area revealed the indirect and direct inguinal, lacunar, classic femoral, and right obturator hernia (Fig. 1). The patient’s left inguinal area was also dissected based on the results of previous research performed in our clinic on the inguinal region vascular anatomy [1]. Left indirect inguinal hernia and left femoral hernia were detected (Fig. 1). Bilateral myopectineal orifices were covered using polypropylene mesh. A rare and occult hernia is defined as a hernia that is detected by imaging or during surgical dissection but not by physical examination [2]. During conventional inguinal hernia repair, an accompanying occult hernia may be difficult to be detected, due to the narrow surgical field [2]. However, the use of totally extraperitoneal (TEP) laparoscopy for inguinal hernia repair can reveal an otherwise occult hernia in the pelvic or inguinal region. Discussion In patients undergoing unilateral laparoscopic inguinal hernia repair, an occult inguinal hernia on the non-suspicious side is detected in 11–28% of cases, and an occult femoral hernia in 9.2% [3]. The prevalence of rare hernias is not fully known. However, Koch et al. reported that, in a series of patients requiring emergency inguinal hernia repair, additional hernias outside the inguinal or femoral canal were found in 9.7% of cases [4]. Another study reported occult hernias in 22–33% of patients who underwent laparoscopic femoral hernia repair [5]. A lacunar hernia (Laugier, Gimbernat) develops in the opening of the lacunar ligament, and a Cloquet hernia (Callisen-Cloquet) in the pectineal fascia. An obturator hernia emerges through the obturator canal, which is 2– 3 cm long and 1 cm wide. The reported incidence of obturator hernias is 0.07–1.1% [5]. Several different types of hernias and their anatomical localizations are shown in (Fig. 2). Rare and occult hernias are seldom detected during open anterior herniorrhaphy, and their surgical treatment is difficult due to the close relationship with neurovascular structures. In * E. Sahin emrahsahin02@yandex.com 1 Department of General Surgery, Turgut Ozal Medical Center, Inonu University Faculty of Medicine, Malatya, Turkey Indian Journal of Surgery https://doi.org/10.1007/s12262-020-02660-7patients undergoing laparoscopic intraperitoneal mesh repair, extraperitoneal occult hernias may be undetected and, thus, left untreated [6]. Cases in which patients presented with simultaneous occult hernias have been reported in the literature and include the case of one patient with three inguinal hernias and that of another patient with six inguinal hernias [6, 7]. Our patient had seven inguinal hernias simultaneously (of 6 occult), including two rare hernias (lacunar and obturator). In summary, occult inguinal hernias are not detectable via routine physical examination, but they often coexist with other inguinal hernias. Laparoscopic TEP herniorrhaphy allows both the diagnosis and treatment of occult and rare hernias in the inguinal region. Compliance with Ethical Standards Conflict of Interest The authors declare that they have no conflict of interest. References 1. Ates M, Kinaci E, Kose E, Soyer V, Sarici B, Cuglan S, Korkmaz F, Dirican A (2016) Corona mortis: in vivo anatomical knowledge and the risk of injury in totally extraperitoneal inguinal hernia repair. Hernia 20:659–665 2. Miller J, Cho J, Michael MJ, Saouaf R (2014) Role of imaging in the diagnosis of occult hernias. JAMA surg 149:1077–1802 Fig. 2 Different types of hernias Fig. 1 Left-side preperitoneal view; indirect inguinal and femoral hernia. *ih, indirect inguinal hernia; *fh, femoral hernia; *sc, spermatic cord structures; *iev, inferior epigastric vessels; *iv, iliac vessels; *op, pubic bone. Right-side preperitoneal view; coexistence of direct inguinal, indirect inguinal, femoral, lacunar, obturator hernia. *dh, direct inguinal hernia; *ih, indirect inguinal hernia; *Lh, Laugier’s hernia; *fh, femoral hernia; *oh, obturator hernia *sc, spermatic cord structures; *iev, inferior epigastric vessels; *op, pubic bone; *cm, right corona mortis Indian J Surg3. Henriksen NA, Thorup J (2012) Unsuspected femoral hernia in patients with a preoperative diagnosis of recurrent inguinal hernia. Hernia 16:381–385 4. Koch A, Edwards A, Haapaniemi S, Nordin P (2005) Prospective evaluation of 6895 groin hernia repairs in women. Br J Surg 92: 1553–1558 5. Powell BS, Lytle N, Stoikes N, Webb D (2015) Primary prevascular and retropsoas hernias: incidence of rare abdominal wall hernias. Hernia 19:513–516 6. Tran HM, Tran K, Zajkowska M, Lam V (2014) Single-incision laparoscopic intraperitoneal onlay mesh repair for the treatment of multiple recurrent inguinal hernias. JSLS p:18. 7. Alabraba E, Psarelli E, Meakin K, Quinn M, Leung M, Hartley M (2014) The role of ultrasound in the management of patients with occult groin hernias. Int J Surg 12:918–922 Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Indian J Surg View publication stats
Laparoscopic management of giant gastrointestinal stromal tumor masquerading as infected mesenteric cyst Ann. Ital. Chir., 89, 3, 2018 1 Ann. Ital. Chir., 2018 89: ???-??? pii: 0000000000000 Pervenuto in Redazione Maggio 2018. Accettato per la pubblicazione Giugno 2018 Correspondence to: Sami Akbulut, Ass. Prof. FICS, FACS, Department of Surgery and Liver Transplant Institute, Inonu University Faculty of Medicine, Elazig Yolu 10. Km Malatya 44280, Turkey (e-mail: akbulutsami@gmail.com) Sami Akbulut, Felat Ciftci, Abuzer Dirican Department of Surgery and Liver Transplant Institute, Inonu University Faculty of Medicine, Malatya, Turkey Laparoscopic management of giant gastrointestinal stromal tumor masquerading as infected mesenteric cyst Gastrointestinal stromal tumors (GISTs) are the most common non-epithelial (mesenchymal) tumors of the gastrointestinal tract. Although GISTs appear as solid and well-circumscribed lesions in most patients, they may also appear as solid-cystic (mixed) or pure cystic lesions due to reasons like intra-tumor hemorrhage and necrosis in a very small percentage of patients. Hence, cystic GISTs mostly lead to a diagnostic dilemma. In this paper we aimed to report a case of pure cystic giant GIST that was drained percutaneously twice after being misdiagnosed as a mesenteric cyst. An 84-yearold man was operated for a pre-diagnosis of a recurrent mesenteric cyst. The operation was started with the three-trocar laparoscopic technique. Six thousand milliliters of purulent fluid were drained from the cystic lesion. Then, a mini incision was performed above the umbilicus and the cyst and the distal ileal segment where it was originated were removed from the abdominal cavity. After the resection of a 15-cm ileal segment together with the cystic lesion, an intestinal anastomosis was performed. The histopathological and immunohistochemical findings showed that the mass was a GIST (size: 20 cm, mitosis: 3/50 HPF, Ki 67: %15, CD117: positive, DOG-1: positive). The patient was in the high-risk group according to the risk stratification systems and thus put on imatinib treatment. KEY WORDS: Abscess, Cystic Degeneration, GIST, Ileum, Mistreatment Lav. 2880 dence per million persons is calculated 6.8-6.9 in North America, 5.4-19 in Europe, and 7.7-22 in Asia 4. The large-scale epidemiological studies have shown that GISTs are more common among the elderly, men, blacks, and persons living in Asia/Pacific islands 4. The female-tomale ratio varies between 0.75 and 1.5 4. Although GISTs can be seen in every age group between 10 and 93 years, the median age at the time of diagnosis is between 56.3 and 69 years 4. One or more of the diagnostic techniques of endoscopy, endoscopic ultrasonography (EUS), contrast-enhanced computerized tomography (CT), magnetic resonance imaging (MRI), 18FDGPET CT, and histopathological staining can be used for diagnosis. Although GISTs appear mostly as a solid and well-circumscribed lesions in imaging studies, depending on lesion size, they may rarely be seen as pure cystic or solid-cystic (mixed) lesions. Cystic degeneration both causes a diagnostic dilemma and, by causing mistreatment of a lesion, and treatment delay 1. Herein, we aimed to report a case of a huge infected cystic GIST that previously underwent percutaneous drainage twice for a diagnosis of a mesenteric cyst. Introduction Gastrointestinal stromal tumors (GISTs) are the most common non-epithelial (mesenchymal) tumors of the gastrointestinal tract 1-4. They are considered to originate from the intestinal pacemaker cells called Cajal interstitial cells located in the Auerbach’s myenteric plexus found in the muscularis propria of the gastrointestinal tract. Genetic studies have shown that, except for a small proportion of patients, GISTs are related to mutations of the C kit (CD117) and platelet derived growth factor receptor alpha (PDGFR ) genes. The annual incidence of GISTs varies by geographical region. The annual inciCase Report An 84-year-old man presented to our outpatient clinic with abdominal pain and distention. It was learned that he had been treated at our hospital for acute renal failure, ileus, and distention three years ago, when he had been detected by radiological studies to have a lesion measuring 200*180*170 mm consistent with a mesenteric cyst. At that time, his symptoms had been possibly attributed to compression by the cyst, and therefore at least 10 liters of non-purulent fluid had been drained from the cystic lesion under ultrasonographic guidance. The patient had presented to our hospital again four months ago with the complaint of abdominal distention, when a percutaneous drainage catheter was put into the cystic lesion and approximately 6 liters non-purulent fluid had been drained. Fluid’s cytological examination had revealed no malignancy. The patient’s physical examination was notable for severe distention of abdominal wall, and the above-mentioned lesion filled almost entire abdominal cavity (Fig. 1). Preoperative routine biochemical and complete blood count parameters were within normal limits. A contrast-enhanced abdominal CT showed a lobulated cystic lesion with a size of S. Akbulut, et al. 2 Ann. Ital. Chir., 89, 3, 2018 Fig. 1: Preoperative view of the lesion completely filling the abdominal cavity. Fig. 2: The appearance of the lesion filling the abdominal cavity considerably in axial (A), coronal (B) and sagittal (C) sections. Fig. 3: The view of the resected giant cystic lesion on the back-table. Fig. 4: Postoperative view of patient’s incision scars.205*250*230 mm, which contained air densities and had a maximum wall thickness of 24 mm, compressing the abdominal wall posteriorly. (Fig. 2 A-C). Radiologically, a duplication cyst, a mesenteric cyst, and a cystic degeneration of a tumoral lesion were considered in the differential diagnosis. A decision was made to proceed with surgery on the basis of available clinical and radiological findings. During the operation the abdominal cavity was entered using a total of three trocars, one below the umbilicus and the two in the right upper quadrant. As the cystic lesion caused both huge and severe dense adhesions, abdominal cavity could not be clearly evaluated. Therefore, first a veress needle was placed percutaneously into the cyst and approximately 6000 cc purulent fluid was drained. As no clear dissection plane could be discerned between the posterior wall of the cyst and small bowel segments, the cystic lesion and the intestinal segment from which it originated were removed from the abdominal cavity through a supraumbilical mini-incision. The cystic lesion was noted to originate from an ileal segment, 40 cm proximal to the ileocecal valve. An approximately 15- intestinal loop was excised en bloc together with the cyst (Fig. 3). Intestinal integrity was achieved with an end-to-end ileo-ileal anastomosis (Fig. 4). The histopathological and immunohistochemical findings suggested that the cystic lesion was a high-risk GIST [size: 20 cm, mitosis: 3 /50 HPF, Ki 67: %15, necrosis: none, atypia: severe, CD117 (+), DOG-1(+), CD34(-), S100(-), SMA (-)]. Considering the overall performance of the patient, imatinib maleate therapy was commenced to reduce the risk of recurrence. Discussion GISTs were first defined by Mazur and Clark in 1983. Genetic studies have shown that a mutation develops in the C-kit (CD117) gene in 85-95% of GISTs and in platelet derived growth factor receptor alpha (PDGFRA) receptor genes in 5-7%. In a part of GISTs neither Ckit (CD117) nor PDGFRA receptor gene mutations can be detected, and this type of GISTs are designated as wild-type GIST. Histologically, 70% of GISTs feature spindle cells, 20% epithelioid cells, and the remainder 10% mixed cell types 3. GISTs constitutes 0.1-3% of all gastrointestinal system cancers and 80% of all mesenchymal tumors of the gastrointestinal system. The most commonly involved organs, in descending order, are the stomach (55.6%), small intestine (31.8%), colorectal (6%), other locations (5.5%) and esophagus (0.7%) 3,4. Symptoms produced by GISTs are related to tumor size and location. An 81.3 % Eighty-one-point three percent of GISTs may cause nonspecific symptoms such as pain, early satiety, and abdominal bloating 4. Tumor does not cause bleeding, obstruction, or severe pain unless it has been ulcerated. However, 18.7% of GISTs are incidentally detected by radiological and/or endoscopic studies performed for other indications 3,4. Endoscopic, radiological, and histopathological diagnostic modalities should be used in conjunction for both the diagnosis and differential diagnosis of GISTs. They classically appear as a submucosal mass in endoscopic studies. EUS has the advantage of better delineating the relationship of a submucosal mass with neighboring tissues and biopsy sampling whenever needed. Contrast-enhanced CT is the most commonly preferred radiological tool. It is highly effective for making the diagnosis of both primary and metastatic tumor. Oral and intravenous contrastenhanced CT is particularly helpful for GISTs arising from gastrointestinal tractus. MRI is typically helpful for showing GISTs of anorectal origin. PET is mostly useful for GISTs of unknown primary or with uncertainties in CT. 18FDG-PET CT is also quite sensitive for showing tumor response among patients receiving tyrosine kinase treatment. Radiologically, the majority of GISTs appear as smooth-bordered, shiny, and solid masses. However, large GISTs may have a radiologically complex appearance due to intratumoral bleeding, cystic degeneration, and necrotic changes. In other words, some GISTs may appear as pure cystic or solid-cystic (mixed) lesions. The majority of large GISTs have a tendency of growing exophytically and thus too difficult to discern for their origin at preoperative studies. Despite being quite rare, cystic GISTs may almost always cause a diagnostic dilemma. GISTs may show cystic changes in the conditions below: (i) in primary cystic GIST the tumor may directly appear as a cystic lesion; (ii) inability of blood flow perfusing tumor’s center to increase proportionately to tumor’s growth rate may cause liquefaction and necrosis resulting in cystic degeneration in the center of the tumor; (iii) hepatic and pancreatic metastases of GISTs mostly appear as cystic lesions. The majority of these lesions are diagnosed as cystic lesions of the liver or the pancreas and treated accordingly. A cystic degeneration may occur in the center of a tumor during the treatment with (iv) imatinib 1,2,5. The case we presented here is the best example of how much difficulty one could face in the differential diagnosis of cystic lesions. This is because he had presented to hospital numerous times and the lesion was percutaneously drained twice for causing compressive signs. We believe that many authors experience the dilemma we have faced 5,6. The most common cystic lesions of the abdominal cavity are mesenteric cysts, retroperitoneal cysts, duplication cysts, pseudocysts of the pancreas, cystic neoplasms of the pancreas, splenic cysts, and hepatic cysts 7. All of the above-mentioned radiological and endoscopic diagnostic tools can be used differential diagnosis. Apart from these, cystic degeneration of tumors like GIST may also radiologically appear as cystic lesions. Hence, tumors like GIST should be definitely included in the differential diagnosis of incidentally detected cystic lesions. To our Ann. Ital. Chir., 89, 3, 2018 3 Laparoscopic management of giant gastrointestinal stromal tumor masquerading as infected mesenteric cystopinion, diagnostic laparoscopy may be highly useful for these lesions. Some risk groups have been described to predict a tumor’s risk of aggressive behavior (metastasis, recurrence, GIST related mortality) on the basis of some parameters like tumor size, mitosis number, tumor localization, and tumor perforation 3. The most commonly used risk classification systems to assess malignancy potential of GISTs are NIH consensus criteria (Fletcher’s criteria), Modified NIH criteria (Joensuu criteria), Mittinen’s criteria (AFIP criteria) and AJCC/UICC criteria (TNM classification) (Table I-IV). These risk classification systems have been developed to predict a tumor’s aggressive behavior potential and to determine the duration of medical therapy. While Fletcher’s and AFIP criteria are used to assess non-metastatic tumors, TNM classification is used to assess both primary and metastatic tumors’ behaviors. In the case presented here, tumor size was >10 cm and thus it was a high-risk tumor, with a tumor progression risk of 52% according to the AFIP criteria. Therefore, imatinib was commenced. Conclusions The ideal therapy for localized/resectable GISTs is tumor resection with clear surgical borders 3. There is no difference at all between laparoscopic and open surgery provided that oncological surgical principles be complied with. After resection, a decision should be made as to how a tumor is to be followed, depending on risk criteria and genetic mutations. Clinical follow-up should be performed in the very low risk group; adjuvant imatinib therapy for about three years in the intermediate risk group; and adjuvant imatinib for at least three years in the high-risk group. As for metastatic/unresectable GISTs, imatinib therapy is started either as palliative or neoadjuvant therapy. Three months later, surgical therapy is performed if the tumor becomes resectable. If no change occurs in tumor size, or if it grows in size or develops drug resistance, sunitinib or regorafenib may be considered in their respective order 3. S. Akbulut, et al. 4 Ann. Ital. Chir., 89, 3, 2018 TABLE I - NIH Consensus Criteria (Fletcher’s Criteria) for GISTs risk assessment Risk Group Size (cm) Mitotic Count (/50HPF) Very Low <2 <5 Low 2-5 <5 Intermediate <5 6-10 Intermediate 5-10 <5 High >5 >5 High >10 Any Risk assessment: recurrence, distant metastasis, aggressive behaviour, mortality due to GIST TABLE II - Modified NIH Criteria (Joensuu Criteria) for GISTs risk assessment Risk Group Size Mitotic Primary (cm) Count(/50HPF) tumor site Very Low <2 ≤5 Any Low 2.1-5 ≤5 Any Intermediate 2.1-5 >5 Gastric Intermediate <5 6-10 Any Intermediate 5.1-10 ≤5 Gastric High Any Any Tumor rupture High >10 Any Any High Any >10 Any High >5 >5 Any High 2.1-5 >5 Non-gastric High 5.1-10 ≤5 Non-gastric Risk assessment: recurrence, distant metastasis, aggressive behaviour, mortality due to GIST TABLE III - AJCC/UICC TNM classification for GISTs Group T (cm) N M Mitotic Count (/50HPF) Stage I T1 (≤2) N0 M0 ≤5 T2 (>2 T ≤5) N0 M0 ≤5 Stage II T3 (>5 T ≤10) N0 M0 ≤5 Stage IIIA T1 (≤2) N0 M0 >5 Stage IIIA T4 (>10) N0 M0 ≤5 Stage IIIB T2 (>2 T ≤5) N0 M0 >5 Stage IIIB T3 (>5 T ≤10) N0 M0 >5 Stage IIIB T4 (>10) N0 M0 >5 Stage IV Any T N1 M0 Any Stage IV Any T Any N M1 Any M: distant metastasis, N: lymph node metastasis, T: primary tumor size. TABLE IV - Meittinen’s Criteria (AFIP) for risk of disease progression in GISTs Group Size Mtotic Count Jejenum/Ileum (cm) (/50HPF) (disease progression rate) I ≤ 2 ≤ 5 None II >2 to ≤5 ≤ 5 Low (4.3%) IIIa >5 to ≤10 ≤ 5 Moderate (24%) IIIb >10 ≤ 5 High (52%) IV ≤ 2 > 5 High (50%) V >2 to ≤5 > 5 High (73%) VIa >5 to ≤10 > 5 High (85%) VIb >10 > 5 High (90%)Riassunto I tumori stromali gastrointestinalei (GIST) sono I più frequenti tumori non epiteliali, mesenchimali, del tratto digerente. Sebbene si presentino in genere come lesioni solide e ben delimitate nella maggior parte dei casi, possono anche presentarsi come masse miste solido-cistiche o come lesioni puramente cistiche a seguito di emorragie intratumorali e necrosi in una piccola percentuale di pazienti. Per queste ragioni I GIST cistici pongono per lo più delle difficoltà di diagnosi. In questo articolo si riferisce il caso di un gigantesco GIST puramente cistico, che è stato drenato due volte per via percutanea sulla falsa diagnosi di cisti mesenterica. Si trattava di un anziano paziente di 84 anni sottoposto ad intervento per un’errata diagnosi di cisti mesenterica recidivante. L’intervento è stato iniziato con la tecnica laparoscopice dei tre trocar, e dalla formazione cistica sono stati drenati 6 litri di fluido purulento. Quindi è stata eseguita una mini incisione al di sopra dell’ombelica ed è stata asportata dalla cavità addominale la cisti ed il tratto ileale terminale di 15 cm sede di origine della lesione. Completando l’intervento con l’anastomosi intestinale. Il reperto istopatologico e immunoistochimico hanno dimostrato la natura GIST della massa, delle dimensioni di 20 cm (3/50 mitosi per campo di osservazione, Ki 67: %15, CD117: positive, DOG-1: positive). Si trattava di un paziente ad alto rischio secondo il sistema di stratificazione, e pertanto è stato destinato al trattamento con intimab. References 1. Tamhankar AS, Tamhankar TA: A large cystic gastrointestinal stromal tumor within lesser sac: A diagnostic dilemma. South Asian J Cancer, 2018; 7:4-10. 2. Okasha HH, Amin HM, Al-Shazli M, Nabil A, Hussein H, Ezzat R: A duodenal gastrointestinal stromal tumor with a large central area of fluid and gas due to fistulization into the duodenal lumen, mimicking a large duodenal diverticulum. Endosc Ultrasound, 2015; 4:253-56. 3. Lim KT, Tan KY: Current research and treatment for gastrointestinal stromal tumors. World J Gastroenterol 2017; 23(27): 4856- 866. doi:10.3748/wjg.v23.i27.4856 4. Soreide K, Sandvik OM, Soreide JA, Giljaca V, Jureckova A, Bulusu VR: Global epidemiology of gastrointestinal stromal tumours (GIST): A systematic review of population-based cohort studies. Cancer Epidemiol. 2016; 40:39-46. doi: 10.1016/j.canep.2015.10.031. 5. Hamza AM, Ayyash EH, Alzafiri R, Francis I, Asfar S: Gastrointestinal stromal tumour masquerading as a cyst in the lesser sac. BMJ Case Rep. 2016; 2016. pii: bcr2016215479. doi: 10.1136/bcr-2016-215479. 6. Hansen Cde A, José FF, Caluz NP: Gastrointestinal stromal tumor (GIST) mistaken for pancreatic pseudocyst - case report and literature review. Clin Case Rep. 2014; 2(5):197-200. doi: 10.1002/ccr3.92. 7. Sun KK, Xu S, Chen J, Liu G, Shen X, Wu X: Atypical presentation of a gastric stromal tumor masquerading as a giant intraabdominal cyst: A case report. Oncol Lett, 2016; 12(4):3018-20. Ann. Ital. Chir., 89, 3, 2018 5 Laparoscopic management of giant gastrointestinal stromal tumor masquerading as infected mesenteric cyst
CASE REPORT Should We Excise the Ectopic Liver Tissue Associated with the Gallbladder Encountered during Laparoscopic Cholecystectomy? Case Report Zeki Öğüt ̇ 1 , Adem Tunçer2 , Felat Çiftçi3 Received on: 06 October 2023; Accepted on: 27 October 2023; Published on: 19 December 2023 A b s t r ac t There is no consensus regarding the clinical management of hepatic choristoma, which is a rare condition during cholecystectomy surgeries. Data regarding the increased risk of malignancy are questioned. In our case, we added a new case to this discussion. Keywords: Case report, Ectopic liver tissue, Gallbladder, Hepatic choristoma. World Journal of Laparoscopic Surgery (2023): 10.5005/jp-journals-10033-1571 B ac kg r o u n d Choristoma means the presence of normal cells or tissues in abnormal localizations. The clinic of these tissues is usually insignificant, but depending on their appearance, they can be confused with malignant masses.1 Ectopic liver, diaphragm, hepatic ligaments, omentum, stomach, adrenal glands, pancreas, spleen, esophagus, and umbilical cord can be found in intra, extra, and retroperitoneal regions such as retroperitoneum and thorax, but the gallbladder is the most common site.2 In this paper, we will present a case of hepatic choristoma, which was discovered incidentally during elective laparoscopic cholecystectomy and did not require resection. C a s e D e s c r i p t i o n A 44-year-old female patient was admitted to our clinic 2 months after her acute cholecystitis attack and treatment. The patient’s physical examination was normal, and laboratory analyses were normal. There was no finding in favor of choristoma in the patient with cholelithiasis in his radiological imaging. Intraoperatively, incidentally, there was an ectopic liver tissue of approximately 15 × 5 mm in size, originating from the liver on the left side of the gallbladder and attached to the serosa of the gallbladder (Fig. 1). Standard laparoscopic cholecystectomy was completed without disconnecting the hepatic choristoma from the liver. Postoperative follow-up of the patient was uneventful. The histopathological findings were chronic cholecystitis and cholelithiasis. D i s c u s s i o n Hepatic choristomas are a rare condition that is usually encountered incidentally during abdominal surgery. Most hepatic choristomas are asymptomatic; rarely, they can be symptomatic.3 Ectopic tissue is usually attached to the serosa of the gallbladder or within its wall. If the ectopic liver receives its blood supply from the liver parenchyma, resection may prolong bleeding and operative time, as it may cause uncontrollable bleeding during resection. Previous studies have reported increased malignancy due to vascular nutrition and biliary drainage of the choristoma.4,5 In recent studies, it has been determined that these choristomas do not have any findings in favor of increased malignancy.6 Since the risk of malignancy is not high, we did not resect the © The Author(s). 2023 Open Access. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons. org/licenses/by-nc/4.0/), which permits unrestricted use, distribution, and non-commercial reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. 1–3Department of General Surgery, State Hospital General Surgery Clinic, Ceylanpınar, Şanlıurfa, Turkey Corresponding Author: Zeki Öğüt, Department of General Surgery, State Hospital General Surgery Clinic, Ceylanpınar, Şanlıurfa, Turkey, Phone: +90 5301085810, e-mail: drzeki44@gmail.com How to cite this article: Öğüt Z, Tunçer A, Çiftçi F. Should We Excise the Ectopic Liver Tissue Associated with the Gallbladder Encountered during Laparoscopic Cholecystectomy? Case Report. World J Lap Surg 2023;16(2):108–109. Source of support: Nil Conflict of interest: None Patient consent statement: The author(s) have obtained written informed consent from the patient’s parents/legal guardians for publication of the case report details and related images. Fig. 1: Hepatic choristomaShould We Excise the Ectopic Liver Tissue Associated with the Gallbladder? World Journal of Laparoscopic Surgery, Volume 16 Issue 2 (May–August 2023) 109 choristoma in order not to prolong the operation time and not cause complications. Clinical Significance The thought that the risk of malignancy is greatly increased in hepatic choristoma should not lead us to major resections and major surgical procedures. We think it is very valuable to give the surgeon the right to make choices on a case-by-case basis. O r c i d Zeki Öğüt https://orcid.org/0000-0002-7698-9586 Adem Tunçer https://orcid.org/0000-0001-5381-513X Felat Çiftçi https://orcid.org/0000-0002-8958-7121 R e f e r e n c e s 1. Avdaj A, Namani S, Cake A, et al. Case report of ectopic hepatic tissue, a rare finding during a laparoscopic cholecystectomy. Int J Surg Case Rep 2020;68:100–103. DOI: 10.1016/j.ijscr.2020.01.014. 2. Lodha M, Pande H, Puranik A. Ectopic liver on gall bladder serosa a case report and brief review of literature. Indian J Clin Anat Physiol 2018;5(2):289–290. DOI: 10.18231/2394-2126.2018.0067. 3. Weber P, Weber-Sánchez A, Carbó-Romano R, et al. Laparoscopic treatment of hepatic choristoma in the gallbladder wall: A clinical case presentation and literature review. Rev Gastroenterol Mexico 2017;82(2):189–190. DOI: 10.1016/j.rgmx.2016.02.00. 4. Arslan Y, Altintoprak F, Serin KR, et al. Rare entity: Ectopic liver tissue in the wall of the gallbladder – A case report. World J Clin Cases 2014; 2(12):924–926. DOI: 10.12998/wjcc.v2.i12.924. 5. Reports C. Propensity of Ectopic Liver to Hepatocarcinogenesis: Case Reports and a review of the literature. Hepatology 1999;29(1):57–61. DOI: 10.1002/hep.510290144. 6. Akbulut S, Demyati K, Ciftci F, et al. Ectopic liver tissue (choristoma) on the gallbladder: A comprehensive literature review. World J Gastrointest Surg 2020;12(12):534–548. DOI: 10.4240/wjgs.v12.i12.534.
CASE REPORT Should We Excise the Ectopic Liver Tissue Associated with the Gallbladder Encountered during Laparoscopic Cholecystectomy? Case Report Zeki Öğüt ̇ 1 , Adem Tunçer2 , Felat Çiftçi3 Received on: 06 October 2023; Accepted on: 27 October 2023; Published on: 19 December 2023 A b s t r ac t There is no consensus regarding the clinical management of hepatic choristoma, which is a rare condition during cholecystectomy surgeries. Data regarding the increased risk of malignancy are questioned. In our case, we added a new case to this discussion. Keywords: Case report, Ectopic liver tissue, Gallbladder, Hepatic choristoma. World Journal of Laparoscopic Surgery (2023): 10.5005/jp-journals-10033-1571 B ac kg r o u n d Choristoma means the presence of normal cells or tissues in abnormal localizations. The clinic of these tissues is usually insignificant, but depending on their appearance, they can be confused with malignant masses.1 Ectopic liver, diaphragm, hepatic ligaments, omentum, stomach, adrenal glands, pancreas, spleen, esophagus, and umbilical cord can be found in intra, extra, and retroperitoneal regions such as retroperitoneum and thorax, but the gallbladder is the most common site.2 In this paper, we will present a case of hepatic choristoma, which was discovered incidentally during elective laparoscopic cholecystectomy and did not require resection. C a s e D e s c r i p t i o n A 44-year-old female patient was admitted to our clinic 2 months after her acute cholecystitis attack and treatment. The patient’s physical examination was normal, and laboratory analyses were normal. There was no finding in favor of choristoma in the patient with cholelithiasis in his radiological imaging. Intraoperatively, incidentally, there was an ectopic liver tissue of approximately 15 × 5 mm in size, originating from the liver on the left side of the gallbladder and attached to the serosa of the gallbladder (Fig. 1). Standard laparoscopic cholecystectomy was completed without disconnecting the hepatic choristoma from the liver. Postoperative follow-up of the patient was uneventful. The histopathological findings were chronic cholecystitis and cholelithiasis. D i s c u s s i o n Hepatic choristomas are a rare condition that is usually encountered incidentally during abdominal surgery. Most hepatic choristomas are asymptomatic; rarely, they can be symptomatic.3 Ectopic tissue is usually attached to the serosa of the gallbladder or within its wall. If the ectopic liver receives its blood supply from the liver parenchyma, resection may prolong bleeding and operative time, as it may cause uncontrollable bleeding during resection. Previous studies have reported increased malignancy due to vascular nutrition and biliary drainage of the choristoma.4,5 In recent studies, it has been determined that these choristomas do not have any findings in favor of increased malignancy.6 Since the risk of malignancy is not high, we did not resect the © The Author(s). 2023 Open Access. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons. org/licenses/by-nc/4.0/), which permits unrestricted use, distribution, and non-commercial reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. 1–3Department of General Surgery, State Hospital General Surgery Clinic, Ceylanpınar, Şanlıurfa, Turkey Corresponding Author: Zeki Öğüt, Department of General Surgery, State Hospital General Surgery Clinic, Ceylanpınar, Şanlıurfa, Turkey, Phone: +90 5301085810, e-mail: drzeki44@gmail.com How to cite this article: Öğüt Z, Tunçer A, Çiftçi F. Should We Excise the Ectopic Liver Tissue Associated with the Gallbladder Encountered during Laparoscopic Cholecystectomy? Case Report. World J Lap Surg 2023;16(2):108–109. Source of support: Nil Conflict of interest: None Patient consent statement: The author(s) have obtained written informed consent from the patient’s parents/legal guardians for publication of the case report details and related images. Fig. 1: Hepatic choristomaShould We Excise the Ectopic Liver Tissue Associated with the Gallbladder? World Journal of Laparoscopic Surgery, Volume 16 Issue 2 (May–August 2023) 109 choristoma in order not to prolong the operation time and not cause complications. Clinical Significance The thought that the risk of malignancy is greatly increased in hepatic choristoma should not lead us to major resections and major surgical procedures. We think it is very valuable to give the surgeon the right to make choices on a case-by-case basis. O r c i d Zeki Öğüt https://orcid.org/0000-0002-7698-9586 Adem Tunçer https://orcid.org/0000-0001-5381-513X Felat Çiftçi https://orcid.org/0000-0002-8958-7121 R e f e r e n c e s 1. Avdaj A, Namani S, Cake A, et al. Case report of ectopic hepatic tissue, a rare finding during a laparoscopic cholecystectomy. Int J Surg Case Rep 2020;68:100–103. DOI: 10.1016/j.ijscr.2020.01.014. 2. Lodha M, Pande H, Puranik A. Ectopic liver on gall bladder serosa a case report and brief review of literature. Indian J Clin Anat Physiol 2018;5(2):289–290. DOI: 10.18231/2394-2126.2018.0067. 3. Weber P, Weber-Sánchez A, Carbó-Romano R, et al. Laparoscopic treatment of hepatic choristoma in the gallbladder wall: A clinical case presentation and literature review. Rev Gastroenterol Mexico 2017;82(2):189–190. DOI: 10.1016/j.rgmx.2016.02.00. 4. Arslan Y, Altintoprak F, Serin KR, et al. Rare entity: Ectopic liver tissue in the wall of the gallbladder – A case report. World J Clin Cases 2014; 2(12):924–926. DOI: 10.12998/wjcc.v2.i12.924. 5. Reports C. Propensity of Ectopic Liver to Hepatocarcinogenesis: Case Reports and a review of the literature. Hepatology 1999;29(1):57–61. DOI: 10.1002/hep.510290144. 6. Akbulut S, Demyati K, Ciftci F, et al. Ectopic liver tissue (choristoma) on the gallbladder: A comprehensive literature review. World J Gastrointest Surg 2020;12(12):534–548. DOI: 10.4240/wjgs.v12.i12.534.
