Among patients referring to emergency room with abdominal pain, acute appendicitis is still one of the most common conditions requiring emergency surgery with an incidence between 4 and 8% [
15]. Diagnosis of acute appendicitis can be supposed considering physical symptoms and clinical history of the patient, experience of the surgeon, laboratory tests and radiological findings. There are many scoring systems that can help to increase the clinical diagnostic accuracy of acute appendicitis, such as Alvarado Score, modified Alvarado Score [
1], Ohmann Score [
2] and RIPASA [
3]. Score systems are useful for stratifying patients with acute abdominal pain and suspected acute appendicitis. Score results should be evaluated in order to guide the decision-making progress toward discharge, observation or surgery. Diagnosis of acute appendicitis is not always straightforward, and mortality and morbidity of this condition may increase when surgical treatment is delayed [
16]. Misdiagnosis is more likely to occur when patient present atypical symptoms, such as pain in unexpected location. This circumstance can happen since appendix may assume variable anatomical position: retrocecal, subcecal, preileal, postileal, pelvic, subhepatic, mesoceliac, left-sided, projection of right-sided long appendix into the left lower quadrant area [
17]. Differential diagnosis of left lower quadrant tenderness is challenging when left-sided acute appendicitis occurs, and it includes diverticular disease, primary epiploic appendagitis, acute pancreatitis, mesenteric ischemia, but also genitourinary tract disorders like pelvic inflammatory disease (PID), ovarian torsion, ectopic pregnancy, epididymitis, prostatitis, testicular torsion, cystitis [
18,
19]. Finally, non-specific abdominal pain (NSAP) is also an occurrence to be considered in differential diagnosis of acute abdominal pain [
20]. Left-sided acute appendicitis may occur in association with anatomical anomalies, such as situs viscerum inversus totalis (SIT) and midgut malrotation (MM) or in the context of a syndromic scenario such as Kartagener’s syndrome [
21], which can complicate diagnostic process and management of these patients [
22]. Situs viscerum inversus totalis (SIT) is a condition characterized by a mirror reversal of the normal asymmetrical arrangement of the viscera and the incidence of this anomaly is approximately of 1/8000–25,000 live births [
23‐
26]. SIT is a rare autosomal recessive or in some cases autosomal dominant congenital disease consisting in developmental defect during embryogenesis. Most of the patients affected by SIT are asymptomatic, with normal life expectancy. SIT can occur in combination with primary ciliary dyskinesia, also known as Kartagener’s syndrome, which involves mutations that disrupt motile cilia [
24]. Kartagener’s syndrome is characterized by the following trilogy: dextrocardia, recurrent sinusitis and bronchiectasis; male patients are almost infertile because of immobile spermatozoa. The incidence of this autosomal recessive syndrome is about 1/30,000 live births [
27]. Midgut malrotation (MM) consist in a rotation anomaly of the embryonic bowel [
28]. There are different types of MM: non-rotation, incomplete rotation, reverse rotation and anomalous fixation of the mesentery [
29]. MM is caused by genetic mutation in the gene BCL6 affecting the signaling pathway for intestinal rotation. Thus, it is characterized by a non-rotation of the primitive intestinal loop around superior mesenteric artery axis. Incidence of MM is about 1/6000 live births [
28]. The most common type of rotational anomalies is non-rotation. In most of the cases it is a silent anomaly; it can also be associated with other congenital anomalies such as congenital heart disease (like heterotaxy), congenital diaphragmatic hernia, omphalocele, intestinal atresia and complex anorectal malformation [
30]. Patients with MM usually have a good prognosis and life expectancy. The incidence of acute appendicitis associated with SIT or MM is rare, approximately between 0.016 and 0.024% [
31,
32]. In our review of literature, we could observe a prevalence of this condition in males (68.5% of the examined sample), with a median age for both sexes of 27 years. In the majority of cases the anatomical anomaly was unknown (83,6%) although today it has become more and more frequent to discover anatomical defects beforehand thanks to fetal morphology ultrasound [
5]. The primary endpoint of this review was to clarify the role of radiological examination for diagnosis of anatomical condition like SIT and MM in patients with acute appendicitis. We registered that the worldwide diffusion of abdominal US and CT scan dramatically improve the diagnosis and knowledge of these uncommon conditions. So, we can observe that if we considered the reports since 1995 (59 cases of 73, 81%) the diagnosis of anatomical anomalies was preoperatively in 55 cases, respectively, with the use of CT scan (n. 38, 64.4%), abdomen US (n. 17, 29%) and X-ray (n. 1; 1.7%). Only 4 patients had an intraoperative diagnosis of SIT or MM. One of the secondary endpoints was to identify the location of pain because, as above-mentioned, many score systems used for diagnosis of acute appendicitis considered this symptom, In our review the most of the patients referred to emergency department with left lower quadrant pain (69.9%). In the other cases pain was localized in other abdominal areas, causing diagnostic difficulties. Blegen et al. [
33] in 1949 reviewed 144 cases of patients with SIT who were submitted to surgical procedures; among these, 77 patients had acute appendicitis and the site of maximum pain was located in left lower quadrant only in 23 cases. This evidence stresses the fact that clinical presentation alone may be misleading and further investigations are mandatory. Besides clinical features, diagnosis of acute appendicitis in patients with SIT or MM may be based on electrocardiogram, which can be particularly useful when a dextrocardia is present, but mostly on abdominal ultrasound and CT scan. As we noted in our review, the X-ray investigation was useful in few cases and in the older decades, while the CT scan was the most accurate tool for correct diagnosis (59% of the cases). In the past X-rays were helpful to detect dextrocardia and right-sided gastric bubble. More recently, ultrasound is widely used when acute appendicitis is suspected, but it has several limitations, such as it is operator-dependent and can be ineffective in patients with high BMI or in case of meteorism. The sensitivity of CT scan in acute appendicitis is 94% [
34]. The pathognomonic CT scan signs of acute appendicitis are the following: distended appendix, fluid-filled, measuring more than 6 mm in diameter in right lower quadrant [
35]. Ben Ely et al. [
29] describe the most frequent findings of intestinal malrotation at CT abdominal scan such as abnormal right-sided position of duodeno-jejunal junction, right-sided location of small bowel and left-sided location of colon with ceacum on the left, abnormal superior mesenteric artery (SMA)/superior mesenteric vein (SVM) relationship with SMV positioned to the left of SMA instead of to the right of the artery, and hypoplasia of the uncinate process of the pancreas. In the case of SIT, a left-sided liver and a right-sided spleen and stomach are fundamental clues for the correct diagnosis. In 15.1% of the cases of this review the diagnosis was intraoperative either because there was not the opportunity to perform a CT abdominal scan or because the CT scan findings were not conclusive. We can retain that the risk of false diagnosis can be reduced with the effective use of CT scan, especially when atypical clinical features are present. The last endpoint of this review was the evaluation of surgical management of these patients. As known laparoscopic appendectomy is the standard therapeutic treatment of acute appendicitis. The advantages of this technique are rapid post-operative recovery, shorter hospital stay, less surgical stress and lower post-operative complications [
36]. Furthermore, laparoscopic appendectomy represents a valuable tool when clinical and radiological findings are unclear and the appendix is in a rare anatomical position avoiding large incisions needed for adequate access. Laparoscopy allows the inspection of all abdominal cavity, consenting to confirm the initial diagnostic suspect and to recognize other pathological findings [
37,
38]. Standard laparoscopic appendectomy can be modified and tailored for patient with SIT or MM [
39]. In our review 20 patients (27.4%) underwent laparoscopic appendectomy and only in one case conversion to open surgery was required. Palanivelu et al. [
16] in 2007 reviewed 18 cases of acute appendicitis in patients with appendix in an abnormal position, highlighting about the feasibility and the advantages of laparoscopic approach for these conditions, included SIT. Akbulut et al. [
4] in 2010 reviewed 95 cases of left-sided appendicitis, and 8 of them were treated with minimally invasive approach. In these cases the authors described the advantages of laparoscopy in differential diagnosis and surgical treatment, but with several difficulties related to different operating field with “mirror image” and reverse laparoscopic view that can be represent a technical challenge also for experienced surgeon. There is no standard position for trocars insertion in these peculiar cases and the surgeon should modify port placement following the main principles of laparoscopy such as triangulation and ergonomy [
40‐
42].