Introduction

Simple renal cysts are the most common renal lesions incidentally diagnosed during abdominal imaging evaluations; on the contrary, the occurrence of parapelvic cysts, a subset of simple renal cysts, is a rare event. While urological management of parapelvic cysts has been widely investigated in recent years, only poor and outdated data are available about their clinical significance. The presence of renal cysts needs to be related to other signs and symptoms in order to identify treatable conditions (e.g. autosomal dominant polycystic kidney disease, ADPKD; tuberous sclerosis complex, TSC; polycystic liver disease, PLD). Furthermore, recent findings showed that parapelvic cysts could represent an imaging marker of Fabry disease which is a rare condition with a specific treatment. A simple renal cyst is defined as an anechoic mass with fluid content characterized by a thin and well-defined wall, in absence of septa or soft-tissue nodules at conventional ultrasound examination. It is known that the incidence of simple renal cysts increases with age, ranging from 0.22 to 0.55% in children up to 36% in the eighth decade. The aetiology of these lesions is unclear; they are assumed to derive from the diverticula of the convoluted tubules or collecting ducts [1].

Simple renal cysts are commonly found in patients with advanced chronic kidney disease (CKD), whereas their association with early forms of kidney disease is uncertain and the available data are controversial [2,3,4]. Parapelvic cysts arise within the renal parenchyma adjacent to the renal sinus [5]. These lesions are rarely identified in children and they account for 2.8–6% of all renal cysts in adults; in 21% of cases, they are bilateral and their presence does not correlate with renal function or kidney injury [6,7,8]. According to Rule et al., the incidence of parapelvic cysts directly correlates with age and male sex in a general population of potential kidney donors; on the contrary, in Fabry disease we recently found a lack of statistical association between parapelvic cysts and patients’ age and sex [9, 10].

On the basis of the most recent data concerning the role of parapelvic cysts as imaging markers of renal disease and the latest therapeutic advances in urological management, we reviewed the literature to provide a comprehensive overview of this rare condition, usually misdiagnosed and underestimated [11,12,13].

Bosniak Classification

In 1986, Bosniak proposed the first computed tomography (CT)-based classification of renal cysts, in order to assess the risk of malignancy and determine the management of cystic renal masses; it is characterized by four categories (I, II, III, and IV) according to the morphology and the enhancement features of renal cysts, after excluding infectious, inflammatory, and vascular aetiologies. Cysts included in the first two categories were considered benign whereas the last two categories represented potentially malignant lesions requiring surgical treatment. Due to the benign characteristics of many Bosniak III cysts detected by histological analysis, the category IIF (F for follow-up) was added in 2012 to indicate “probably benign” masses needing close follow-up, whereas Bosniak III cysts were defined as “indeterminate” with an approximate risk of malignancy of 50% and treated as Bosniak IV lesions (Table 1) [14,15,16,17]. The Bosniak classification has some limitations: it is based on the imaging characteristics alone and does not consider the other factors that might affect management, like the patients’ age, comorbidities, cyst location, cyst pathology, or clinical history [18]; it is operator-dependent [19]; only 50% of type III are malignant, thus leading to the surgical removal of many benign lesions. For this reason, an updated Bosniak Classification (version 2019) was proposed to formally introduce magnetic resonance imaging (MRI) to better and more objectively define the characteristics of renal lesions, to incorporate a larger proportion of renal masses commonly encountered in clinical practice, and place a larger proportion of cysts in the lower classes in order to avoid unnecessary surgery [5].

Table 1 Bosniak classification of cystic renal masses
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Parapelvic or Peripelvic Cysts?

The term sinus cysts includes two different patterns of cyst presentation: peripelvic cysts and parapelvic cysts. Even if these two terms are generally used as synonyms, peripelvic and parapelvic cysts are completely different not only with regard to localization, but also to number, size, and origin [20, 21]. The former are small, multiple, confluent, and present an irregular shape; they are likely to represent a congenital embryologic remnant or the sequelae of acquired lymphatic obstruction. On the other hand, parapelvic cysts are single and larger, localized in the sinus and most likely originating from adjacent parenchyma; their aetiology is still controversial and divergent theories regarding their pathogenesis have been proposed. Moreover, although parapelvic cysts may not be completely surrounded by renal parenchyma like simple cortical cysts, their aetiology is probably similar. Ultrasound examination is able to differentiate parapelvic cysts from peripelvic cysts, which are characterized by the presence of multiple and thin linear septa that extend radially from the renal hilum; furthermore, peripelvic cysts rarely cause symptoms that require treatment [20] (Figs. 1, 2).

Fig. 1
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Parapelvic cyst. Single and large cyst, presenting in the sinus and most likely originating from adjacent parenchyma

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Fig. 2
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Peripelvic cyst. Small, multiple, confluent and irregularly shaped cysts, raised in the renal sinus itself

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Diagnosis and Differential Diagnosis

Parapelvic cysts are an accidental finding during nephro-urological ultrasound examination and, although they are commonly asymptomatic, in a small, but non-negligible percentage of patients, they could result in lumbar discomfort, urinary tract infection, haematuria, renin-mediated arterial hypertension, obstruction with secondary hydronephrosis, urinary calculi (facilitated by obstruction and infection), pyelonephritis, spontaneous haemorrhage, renal function decline, and may even hide malignant lesions [22, 23]. At ultrasound evaluation, parapelvic cysts appear as hypoechoic lesions of spherical shape located in the renal pelvis, in close proximity to the collecting system, though without any communication; they appear as hypodense and non-enhancing lesions on CT scan whereas at MRI they are hypointense on T1-weighted images, and hyperintense on T2-weighted images without abnormal contrast enhancement.

Parapelvic cysts are more likely to be symptomatic compared to other types of simple renal cysts because of their close localization to vessels and urinary system [24, 25]. A careful history and physical examination, as well as other clinical findings such as hypertension, liver cysts or renal failure, facilitate the differential diagnosis. The mechanism of cyst-associated hypertension seems to be related to renal hypoperfusion and ischaemia, caused by cyst expansion and parenchymal compression which activates the renin–angiotensin–aldosterone system (the ‘Page kidney’ phenomenon) [26, 27]. In atypical clinical presentations, the differential diagnosis is fundamental because of the availability of specific treatments for some of the underlying conditions (Table 2) [28], such as TSC, PLD and ADPKD. TSC is a rare disease, predominantly affecting the brain, kidneys, heart, skin, and lungs, caused by the mutations of the TSC1 and TSC2 genes, encoding for hamartin and tuberin. These proteins form a complex which inhibits the mammalian target of rapamycin (mTOR) pathway and their mutation leads to the loss of cell division control resulting in renal angiomyolipoma and cysts [29]. Early diagnosis can dramatically impact the progression of the disease as specific treatments with mTOR inhibitors recently showed the ability to effectively slow the growth of cysts, reduce the need for surgery, and delay the beginning of renal replacement therapy [30,31,32]. PLD is another treatable rare disease, which can occur in two genetically distinct forms with similar clinical course: as a common extrarenal manifestation in ADPKD, caused by the mutation of the PKD1 and PKD2 genes, and more rarely by GANAB and DNAJB11, or as an isolated entity with limited or absent renal cysts (ADPLD), caused by the mutations in the PRKCSH and SEC63 genes that encode for sec-63 and hepatocystin proteins, which are expressed on hepatocytes and cholangiocytes, and are responsible for fluid transportation and epithelial cell growth. The use of somatostatin analogues recently showed the ability to decrease fluid production and cholangiocyte proliferation, thus reducing liver volume and improving patient symptoms [33]. ADPKD is another rare treatable condition characterized by the presence of multiple renal cysts; tolvaptan, a selective vasopressin V2 receptor antagonist, has recently been approved for the treatment of the disease as it showed that it was able to effectively slow down both kidney growth and the decline of renal function [34].

Table 2 Differential diagnosis of all kinds of renal cysts
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It is therefore crucial to make a differential diagnosis with hydronephrosis, which presents, instead, as interconnected areas of decreased echogenicity and has a cauliflower appearance [11]. In patients with hydronephrosis assessed at ultrasound, parapelvic cysts should be excluded, especially when renal function is normal and there are no underlying obstructive causes. The ultrasound “convexity sign” is very useful for the differential diagnosis: it consists in identifying wall convexity of the parapelvic cysts by ultrasonographic assessment, while hydronephrosis is characterized by dilated calyces with linear walls [35]. A CT examination after intravenous injection of contrast medium is necessary in order to distinguish a dilated renal pelvis from a parapelvic cyst; in fact, a mass within the renal sinus is considered a parapelvic cyst at CT scan if it is homogeneous, with an attenuation coefficient similar to water, no enhancement after intravenous infusion of contrast medium and no visible wall of the portion projecting outside the renal margin. Koratala et al. recently described the case of a parapelvic cyst mimicking hydronephrosis, casually identified in a potential kidney donor during ultrasound assessment; it was further investigated by contrast-enhanced CT, in which parapelvic cysts demonstrated to be distinct from the normal contrast-filled collecting system thus demonstrating the absence of hydronephrosis [13, 36]; this case clearly showed that, even if ultrasound suffices in most cases to identify parapelvic cysts, some lesions have to be investigated by CT to determine their nature. Moreover, excretory urogram could be used to identify the mass and exclude hydronephrosis when CT is not performed. Noteworthy, ultrasound is operator-dependent compared to CT and other techniques, which could be required to differentiate parapelvic cysts from other lesions such as renal sinus lipomatosis, easily diagnosed by CT due to the characteristic attenuation of fat. On the other hand, radiation and contrast medium used for CT urography, could outweigh the clinical benefits, especially in asymptomatic patients who do not require intervention (Figs. 3, 4 and 5). Interestingly, in a recent retrospective study, Dong et al. demonstrated that pre-contrast dual-energy spectral CT imaging, a new CT imaging mode that produces virtual monochromatic images, may be used to differentiate parapelvic cysts from hydronephrosis with no calculi in asymptomatic patients, thereby avoiding contrast-enhanced CT or CT urography examination [37].

Fig. 3
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Flow chart for diagnosis and treatment of parapelvic cysts

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Fig. 4
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Evaluation of parapelvic cysts with ultrasound imaging

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Fig. 5
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Evaluation of parapelvic cysts with computed tomography imaging

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In the near future, renal cysts will be analysed by an artificial intelligence algorithm leading to an automatic estimate of the risk of malignancy, and many studies have already been performed to investigate the application of machine-learning to the diagnosis of these lesions [38].

Parapelvic Cysts in Fabry Disease

Fabry disease is a rare X-linked genetic disorder of glycosphingolipid catabolism caused by mutations in the α-galactosidase A gene [39]. It is characterized by a heterogeneous presentation and paucity of specific early markers, often leading to a delayed or missed diagnosis [40, 41]. The recognition of Fabry disease is important because effective treatments are available, including enzyme replacement therapy (agalsidase alfa and agalsidase beta) and the chaperone migalastat. Several new compounds are being studied, including new forms of enzyme replacement therapy, substrate reduction therapy, mRNA, and gene therapies [42]. Noteworthy, in order to achieve a significant clinical benefit, it is fundamental to start the treatment in an early phase, before the development of organ damage. In this perspective, the identification of parapelvic cysts should warn both nephrologists and radiologists to consider the diagnosis of Fabry disease and many literature data strongly support a correlation between this type of renal lesions and Fabry disease [43, 44]. Recently, we conducted a multicentre retrospective study in a nationwide cohort of Fabry disease patients to evaluate the real prevalence of parapelvic cysts which have already been associated with Fabry disease: parapelvic cysts were detected in 28.9% of patients with Fabry disease vs 1.1% of control subjects by ultrasonography. Therefore, a more accurate ultrasound evaluation led to a 43.3% higher detection rate of parapelvic cysts in the same subjects. These data confirmed the previous results which reported a prevalence of 50% of parapelvic cysts in Fabry disease patients detected by CT or MRI [45]. More recently, Neves et al. also highlighted the more frequent occurrence of parapelvic cysts in Fabry disease patients compared to different glomerulopathies, regardless of the age, gender, and stage of CKD [46]. It is not clear if the parapelvic cysts in Fabry disease could be related to the defect of glycosphingolipid metabolism; we may hypothesize that cyst genesis is multifactorial and is the result of a variety of gene mutations, suggesting that different positions of cysts correspond to different molecular pathways underlying their development [47,48,49,50,51]. Finally, it would be useful to investigate the relationship between different genotypes of Fabry disease and the phenotype of parapelvic cysts, and to determine whether these characteristic lesions could be a risk factor for a more rapid worsening of renal function.

Treatment

Currently, there are no formal guidelines regarding the management and treatment of simple renal cysts. Moreover, parapelvic cysts represent a further concern due to their specific anatomical structure and deep location in the renal pelvis which could cause injury to renal blood vessels and collecting system [52, 53]. Renal cysts can be treated through minimally invasive procedures such as aspiration or sclerotherapy; both techniques are limited, respectively, by the high possibility of recurrence and the potential extravasation of the sclerosing agents, which could lead to potentially serious complications such as retroperitoneal inflammation (further associated with ureteropelvic junction obstruction, fever, and pain) [54, 55]. Laparoscopic renal-sparing cyst excision, de-roofing, decortication, and ablation are currently considered the gold standard in the treatment of symptomatic cysts, with success rates reaching up to 96% and a limited rate of intra- and post-operative complications (1–1.4%) [56]. However, due to the peculiar anatomical characteristics of parapelvic cysts, specialized surgical skills are required to properly treat large parapelvic cysts [57]. More recently, due to the close anatomical proximity between parapelvic cysts and renal pelvis, internal drainage via flexible ureteroscopy has been reported as another feasible, effective, and safe alternative to the laparoscopic approach. In a comparative analysis between ureteroscopy and laparoscopic surgery, both techniques obtained a comparable rate of success, with fewer complications, shorter operative time, and reduced length of stay in hospital in the group undergoing ureteroscopic treatment [58]. The technique is indeed particularly advantageous: it consists in a limited cut (< 1 cm) performed with a Holmium laser under direct vision, and in the subsequent drainage obtained with a double J tube. In a case-series by Zhao et al., 27/28 patients were successfully treated and only 1 case recurred (median follow up 39 months) [22]. The use of the flexible ureteroscope has further extended the applicability of the retrograde approach, even in parapelvic cysts positioned in disadvantageous locations for the rigid ureteroscope (as the lower calices) [22, 54, 55]. The retrograde approach has, moreover, another significant advantage, i.e. the possibility to simultaneously treat parapelvic cysts and renal stones [56,57,58,59]. Interestingly, as an alternative to ureteroscopy, Yang et al. performed percutaneous nephroscopy in a single obese patient in order to treat parapelvic cysts and ipsilateral stones [60].

Lastly, the retrograde approach overcomes the relative and absolute limitations of the laparoscopic approach, which are, respectively, the treatment of obese patients and of patients who previously underwent abdominal or retroperitoneal surgery (Fig. 3) [61,62,63,64].

Limitations

Our work aims to provide an overview on a very rare condition and to update readers on this specific topic, playing a significant role in continuing education; this work has some important limitations that should be taken into account for the appropriate interpretation of this review. First, the selection of the literature underwent convenience sampling, this review was neither protocol-driven nor systematic. Therefore, bias cannot be ruled out. Second, we provide a qualitative synthesis with no statistical analysis, so our conclusions cannot be considered objective and comprehensive of all the available data; consequently, the synthesized evidence may be incomplete, selected in a biased way and difficult to interpret because of the lack of quality assessment. Nevertheless, this narrative review provides a deep, reflective, and thoughtful understanding of the clinical importance of the diagnosis of parapelvic cysts.

Conclusions

Parapelvic cysts are rare lesions accidentally found on imaging tests, more often symptomatic compared to other renal cysts. Although parapelvic cysts were considered clinically unimportant and not associated with the decline of kidney function, more recent data suggest that their incidence in some rare renal pathological conditions such as Fabry disease can be higher than in the general population, raising the awareness that parapelvic cysts could lead to the diagnosis of rare and otherwise likely undiagnosed treatable conditions. Parapelvic cysts have to be differentiated from renal cysts with different localizations, which can be found in other treatable conditions such as ADPKD, PLD, TSC. In this perspective, parapelvic cysts could represent an important imaging marker of some renal diseases even before their clinical manifestation thus allowing nephrologists to early and properly start specific treatments.