Pleuropericardial Cyst: A Review of the Literature

Background: Pleuropericardial cysts (PPCs), account for 5 - 10% of all mediastinal tumours, are rare lesions occurring in approximately 1 in 100000 persons and are usually congenital and rarely acquired. They are detected post-mortem or incidentally on routine chest X-ray (CXR) and in most cases multi detector Computer Tomography is used to confirm the diagnosis. As benign course and clinical latency are characteristic features of such cysts and the occurrence of complications is rare, the majority of them can be left untreated. Methods: The aim of the study is to review the literature regarding PPCs and create a table which summarises all the published cases in order to draw a conclusion about the epidemiology, as well as the diagnostic and therapeutic approach to PPCs exclusively. We reviewed retrospectively the clinical manifestation, diagnostic and therapeutic approach in 101 cases of PPCs since the 19 th century Results: Our statistical analysis led to the following results: mean age of initial detection: 48.7 ± 17.2 years, female:male ratio: about 3:2, presence of symptomatology: 37/101 cases, most common location: right cardiophrenic angle (RCPA), most common method of initial detection: CXR in 49/101 cases, mean maximal diameter: 8,3 ± 3 cm. Conclusion: The management of a pleuropericardial cyst should be based on an algorithm in which the cyst’s size, shape and compressibility along with clinical presentation and patient’s fitness and preferences are be taken into consideration. When interventional is required, surgical resection by means of traditional open surgery or minimally invasive methods are considered to be the gold standard and along with percutaneous aspiration are the methods that have mostly been used.


Introduction
Pleuropericardial cysts, account for 5 -10% of all mediastinal tumours, are rare lesions occurring in approximately 1 in 100000 persons and are usually congenital but exceptionally acquired. They are detected post-mortem or incidentally on routine chest X-ray and in most cases multi detector Computer Tomography is used to confirm the diagnosis. As benign course and clinical latency are characteristic features of such cysts and the occurrence of complications is rare, the majority of them can be left untreated.
53-year-old woman 5 . Symptoms coexisting with such cysts were first described by Freedman and Simon, D' Abreu and Churchill and Mallory. Reviewing the literature, it was Adrian Lambert who was the first to propose a pathogenesis, noting the similar embryological origin of PPCs and diverticula from disconnected mesenchymal lacunae which normally fuse to develop the pericardial coelom. He also attempted for the first time to differentiate the thin-walled cysts of the mediastinum, all of which had previously been reported as "probably of lymphatic origin" 6 . Greenfield et al. introduced the term "Spring water cyst" 7 . By 1958, at least 120 cases of mesothelial cysts had been reported 8,9 . PPCs are cyst walls made up of a single layer of mesothelial cells and a loose stroma of fibrous tissue with collagen and elastic fibres. They usually contain clear, serous fluid and that is why they are also called 'spring water' cysts 10 . Finally, both the expression of epithelial membrane antigen and calretinin and the absence of an actin-positive subepithelial smooth muscle layer may be helpful in the diagnosis of a PPC 11 .
The aim of this study was to review the literature and present a review article about PPCs including a table with all the data of: a) all the published cases reported as "pleuropericardial cysts" in the title and b) some of the published cases described as "pericardial cysts" in the title which are also called "pleuropericardial cysts" either in other review articles or even in the same article. According to our knowledge, this is the first organized attempt to review whole literature with focus in PPCs.
Finally, we analysed statistically the data associated with the age of initial detection, gender and cyst size and location, in order to draw a conclusion regarding the epidemiology of PPCs exclusively.

Methods
We aimed to review the literature regarding PPCs and create a table which summarises all the published cases in order to draw a conclusion about the epidemiology, as well as the diagnostic and therapeutic approach of PPCs exclusively.
We first searched the PubMed and Medline databases for any publications concerning PPCs. After this we searched for a systematic review reporting PPCs. No systematic reviews were found. We found only a review of treatment of four cases with video-thoracoscopy. We also found a review for benign cysts of the mediastinum. We then independently searched PubMed (until February 2018) using the following free text terms: "pleuropericardial cyst", "pleuropericardial cyst" AND "treatment" OR "symptoms" OR "location" OR "intervention" OR "surgery" OR "case". Then we searched for pericardial cysts also. We included case reports, abstracts, editorials and articles in all languages describing the location or symptoms or treatment or intervention or surgery in patients with PPC. The database created from the electronic searches compiled in a reference manager program (Endnote X8) and all duplicated citations was eliminated. The following data were collected: (1) publication details such as title, authors, and other citation details, (2) patient data such as age, sex, symptoms (3) details of PPC (location, size, and approval), (4) data of intervention or surgery, (5) followup data. All in all, we reviewed 139 publications and found 101 cases of PPCs.
As described in "Discussion", plenty of terms have been used to describe a PPC. So, review references are mostly based on the terms "pericardial" and "pleuropericardial" and we decided to include the following in table 1: 1) All the published cases referred as "pleuropericardial cysts" in the title.
2) All the published cases referred as "pericardial cysts" in the title which are called "pleuropericardial cysts" either in other review articles or even in the same article but later on, in the text.
After having collected the data from all the cysts referred as PPCs (101 cases from 47 publications), we carried out an univariate statistical analysis regarding the following parameters: age of initial detection, gender, cyst size and location, method of initial detection as well as presence of symptomatology. Cases with non-mentioned data were excluded from the analysis.

Results
As far as the mean age of initial detection is concerned, our statistical analysis showed that this was approximately 48.7 ± 17.2 years, ranging from 3 to 76 years in 50 cases out of 101. Regarding gender, the female:male ratio was calculated to be about 3:2 (29:21) among 50 cases, while the most frequent location was the right cardiophrenic angle (RCPA) accounting for 39,6% followed by the left (LCPA) at 18,9% among 53 patients. CXR was the method used for initial detection in 49/101 cases. The percentage was probably higher, as the method for initial detection was not mentioned in 41 cases. Symptomatology was present in 37 cases out of 101. Finally, the mean maximal diameter was 8.3 ± 3 cm, varying between 1.5 and 17 cm in 42 out of 101 patients.

Discussion
Plenty of terms have been employed in the literature to characterise PPCs. Most have been used to define the localisation, the contents, the histology or the pathogenesis of such cysts. These terms are: pericardial coelomic cysts 6 , pericardial cysts, hydrocele of the mediastinum, simple cyst of the mediastinum, serosal cyst, spring-or clear-water cyst 7 , para-pericardial cyst, pleuropericardial cyst, pleural cyst and mesothelial mediastinal cyst. the complete closure of the proximal recess gives rise to a PPC 1 . As far as inflammatory cysts are concerned, they develop as a result of loculated pericardial effusion 12 .
PPCs account for 5-10% of mediastinal tumours and 11% 2 or 30% 4,5 of mediastinal cysts. Prevalence is approximately 1 in 100000 persons 8 and they constitute the second most common type of primary mediastinal cysts after bronchial ones 19,20 . All ages may be affected, but PPCs are most frequently identified between the third and fifth decade of life, while they are rarely detected in childhood [21][22][23][24] . More specifically, less than 20 cases in children have been reported in the literature 25 . As far as gender is concerned, the female: male ratio varies among many studies and it has been described to be 1:1 22  PPCs are usually congenital in origin but other causes such as inflammation (rheumatic pericarditis, bacterial infection particularly tuberculosis, echinococcosis), trauma, post cardiac surgery and chronic haemodialysis [12][13][14][15][16][17] have been reported. Congenital PPCs usually originate from failure of fusion of one of the mesenchymal lacunae that form the pericardial sac, during embryogenesis after the third week of gestation 6,18 . Another theory of the pathophysiology of such cysts explains the origin of PPCs by means of differential perseverance and graded constriction of ventral recess of the pericardial coelom. The ventral parietal recess is a diverticular structure where most of PPCs are located. Perseverance of this structure forms the diverticulum, constriction of the proximal part of which results in either a diverticulum with a narrow neck or a PPC in communication with the pericardial cavity, while Pleuropericardial cysts, account for 5 -10% of all mediastinal tumors, are rare lesions occurring in approximately 1 in 100000 persons and are usually congenital but exceptionally acquired.
No systematic review for pleuropericardial cysts was found.
We reviewed all literature and found 100 cases since 19 th century.
PPCs can occur in any compartment of the mediastinum 29 , but are usually detected in the visceral mediastinum 30,31 attached to the parietal pericardium. The most frequent site is the right cardiophrenic angle (51-75%), followed by the left (28-38%) [19][20][21]32,33 . Those PPCs occurring elsewhere other than the cardiophrenic angles (8% -16%) are usually superior to the heart and right-sided 34 . A frequent site is the right latero-tracheal region 35 . In this case, the cyst originating from the upper recess of the pericardium extends posteriorly from the pericardial cavity around the ascending aorta 36,37 . Other unusual sites that have also been reported include the other two mediastinal compartments, the vascular hila, the subcarinal area and the left heart border 33,[38][39][40][41][42] . Moreover, the PPCs that are detected in locations remote from the pericardium are believed to be pedunculated with a stalk that connects them with the pericardium 43,44 . Almost 5% of PPCs are in communication with the pericardium through determinable tube-like structures 45 . However, others studies indicate that they are always attached to the pericardium directly or by a pedicle 10,19,20 , although a visible connection between the cyst and the pericardium is rarely detected 46,47 . Finally, a PPC may occasionaly present as a mobile chest lesion, described by the term "wandering PPC" 48 and in this case, it should be differentiated from solitary fibrous tumours of the pleura, which are the most common mobile chest masses 49 .
PPCs usually have a diameter of 2-15cm 44,50-52 and weigh 100-200gr 25 . However, there have been reported cases up to 28cm 53 or even larger containing 1300ml of fluid 34 or measuring 25x37x5cm 54 , while other were as large as a grapefruit 55 .
The majority of PPCs are asymptomatic (50-75%) in adults and are found post-mortem or incidentally on routine CXR 38,56 . However, two thirds of children diagnosed with a PPC develop symptomatology 8 .When they are symptomatic, in general due to increasing size and consequent compression or invasion on nearby organs, the symptoms are generally dominated by respiratory signs, such as dyspnoea, stridor, wheezing, chest discomfort including vague chest pain, heaviness, retrosternal pressure or substernal pain, persistent cough, sputum, haemoptysis, dysphagia and epigastric pain. Circulatory signs such as tachycardia, palpitations, fatigue, cyanosis and weakness may also be found 8,19,31,44,47,50,[57][58][59][60][61]62 . There can also appear signs of nervous compression presented as hoarseness due to unilateral vocal cord paralysis as a result of left recurrent laryngeal nerve compression 63

Complications
The mediastinum is a narrow non-extendable space. Consequently, every mediastinal mass, including PPCs, can compress adjacent organs and this can even occasionally lead to complications as well as life-threatening emergencies 9,14,37,58,64,70,71 .

Diagnostic approach-Differential diagnosis
The diagnostic approach to PPCs is based on the clinical presentation and the results of imaging studies. However, the fact that PPCs may be clinically and radiologically similar to other mediastinal lesions makes the diagnosis challenging. The location and nature of mediastinal lesions are very important for the differential diagnosis. Differential diagnosis of PPCs is quite wide and includes not only lesions found in the middle mediastinum where PPCs are most commonly identified, but also lesions occurring in the other two mediastinal compartments 9,11,29,[72][73][74][75][76] .
A CXR can localise as well as identify PPCs by means of posterior-anterior and lateral views. However, a disadvantage of this method is the fact that it cannot provide much information about the morphology and the expanse of the lesion. Further imaging studies such as MDCT, MRI, ultrasonography, angiography and positron emission tomography (PET) scan are used in order to complement and corroborate the initial diagnosis or suspicion 40,58,77 .
With CXR, PPCs are demonstrated as teardrop formations on the lateral views as the cysts tend to adjust to the medial aspect of the pulmonary fissure. Furthermore, this projection can depict the alteration in shape and the movable nature of fluid-filled PPCs, during respiration or postural changes 41,51,64,78,79,80 . In postero-anterior projection, PPCs usually appear as rounded or oval opaque shadows with uniform density and well-defined borders and without calcification 77 . PPCs can also take on different and unusual radiologic appearances, such as a dumbbell shape 20,28,81 .
MDCT with or without contrast remains the gold standard for further investigation of a mediastinal mass 14 .
It estimates the size and nature of the mass, defines its position within the mediastinum and how it is related to the adjacent structures, providing valuable information about its morphology as well as its extent 82,83 . On a CT scan, the PPC is a thin-walled, well-marginated, oval homogeneous mass, usually unilocular, while multilocular cysts have also been reported 8 . Their attenuation is low (0-20HU), although sometimes it may be a little higher than water density (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40). This is probably because of a high protein and cells content due to bleeding or infection 84 . As they are commonly avascular 25 , they are not enhanced with contrast agents 46,85 . Other atypical CT findings include the presence of calcification, a sharp upper border 25,44,86 and the presence of associated pericardial effusion. Moreover, MDCT can show stalks connecting PPCs to the pericardium, thus a certain diagnosis can be established even for PPCs in unusual locations 48,[87][88][89][90][91][92][93] . PPC torsion can also get depicted via a CT scan as a mass of soft tissue in which there is an internal intertwine with fat and soft tissue attenuation, called the ''whirl sign'' which was first described in intestinal volvulus 28,94,95 .
Two-dimensional echocardiography was first used in order to detect a pericardial cyst 96 . Transthoracic and in some cases transoesophageal echocardiography is a superior noninvasive method, which can accurately depict the PPC's position and distinguish it from other possible diagnoses (solid tumours, fat pads, coronary, ventricular or aortic aneurysms) 14,20,96 . Ultrasonographically PPCs appear typically as homogeneous anechoic thin-walled masses 29,67 . Transoesophageal echocardiography can be helpful especially for PPCs in unusual locations and in case of haemodynamic compromise in order to confirm a 1. Congenital cysts of primitive foregut origin (bronchogenic cyst, enterogenic cyst and esophageal duplication cysts) 17. Lymphomas 2. Broncial cysts 18. Mesenchymal tumors (sarcomas 44 , hemangiomas and lymphangiomas 133 ) 3. Localised pericardial or pleural effusion 9 19. Right middle lobe pathology 4. Ventricular aneurysms or aneurysms of the ascending aorta 20. Morgagni hernia 5. Fluid-filled superior aortic recess 134   suspected compression of the large vessels or the cardiac cavities 97,98 . Finally, ultrasonography can set the diagnosis of PPCs prenatally beyond the 14th week of gestation 99 .
MRI is similar to CT as far as the efficacy in detecting a tumour is concerned 100 . MRI is a useful tool for both the initial diagnosis of a mediastinal mass and the posttherapeutic follow-up. It gives a better anatomical depiction of PPCs, including those in atypical locations and their relationships to adjacent structures, including blood vessels, without the use of contrast material 20 . Thus, it is helpful in differentiating PPCs from vascular anomalies such as aortic aneurysms 37,101,102 . MRI findings are diagnostic, showing a smooth-walled and well-defined structure with high signal intensity on T2-weighted images, low-to-intermediate signal intensity on T1weighted images and no enhancement after intravenous contrast administration 85,93,103,104 . High signal intensity is rarely seen on T1-weighted images in the case of high protein content 20 . Furthermore, MRI should be the method of choice with children and infants 104 .
Arteriography provides help in defining whether the lesion in question is a part of a vascular structure 105 . In cases where diagnosis remains challenging, cyst puncture and sequent injection of a contrast material for diagnostic and therapeutic reasons has been used 106 . Finally, two incidentally detections of PPCs by means of I 131 total body scan due to the uptake of I 131 through the pericardial serosa have been reported 107,108 .

Therapeutic approach
The management of all mediastinal cysts can vary from conservative follow-up, percutaneous aspiration with or without ethanol, minocyclin or doxycyclin injection to surgical treatment by means of interventional thoracoscopy or thoracotomy 43,109,110,146 . PPCs are commonly asymptomatic and most of them can be left without treatment. So, in the case of an asymptomatic patient and undoubted radiological diagnosis of a PPC, conservative management with cautious follow-up by means of non-contrast-lowdose CT or ultrasound or MRI is advised 38,70,98,111 . Although there are no specific guidelines concerning either the duration or the frequency of the follow-up and the information about safety is poor, it is widely suggested to take into consideration the patient's (new symptoms, complications) as well as the cyst's (size) stability in order to decide how to continue the management. The longest described follow-up lasted 25 years and eventually a 2.5L cyst was resected 52 . Treatment is indicated in the case of symptomatic, large-sized asymptomatic cysts, uncertain diagnosis and possibility of malignant potential, atypical location such as close to large vessels, high density on CT, or the presence of complications. Such treatment is required in order to prevent life-threatening emergencies such as airway and/or haemodynamic impairment, or patient's concern 23,32,40,41,[112][113][114] . Thus, any anterior mediastinal lesion should be considered potentially malignant and should be surgically excised as soon as possible 115 .
Surgical excision of the cyst has been considered the gold standard of management especially in complicated cases with excellent outcomes 98,116 . It is worthy noting that although cardiopulmonary bypass is not usually required for PPCs removal, it should be on standby, mainly in case of possible cardiac compression, erosion of the right ventricular free wall or if extensive cardiac manipulation is required 41 . Partial cyst resection is also recommended in the case of tight adhesions to the nearby structures 116 .
Apart from traditional open surgery, resection of mediastinal masses including PPCs has been carried out successfully by VATS or VATS with mini-thoracotomy since 1992 26,32,111,[117][118][119][120][121][122] . These minimally invasive procedures reduce surgical trauma and postoperative pain compared to open surgery leading to a shorter period of recovery and hospitalisation 123,124 . Furthermore, the Harmonic Scalpel which is an ultrasonically activated scissor, is recommended for performing VATS more quickly 125 . However, VATS also has limitations especially for removing anterior and upper mediastinal lesions 4,122,[126][127][128] giving only a limited view of the area of interest. In addition, thoracoscopy should be an option for treatment only in the case of well-encapsulated and <6cm sized masses, although successful resections via VATS on larger ones have been reported 52,111,126 . Robotic surgery using the da Vinci TM Robotic System is another minimally invasive therapeutic modality which has proved to be safe and useful, but its cost remains a strong limitation 129 . Taking into consideration the above, smallto-moderate sized and typically located PPCs could be safely and successfully removed by these modern surgical procedures.
Percutaneous aspiration of the PPC contents by a thin needle puncture under ultrasound or CT guidance has been used for both diagnosis and therapy 12,84,106,110 . However, complications such as vascular injury, pneumothorax, anaphylaxis, and infection have been referred and recurrence in about one third of patients has been recorded 57,110,[130][131][132] . Thus, percutaneous aspiration of such cysts must be performed only in case of comorbidities that contraindicate surgery, when there is a need for temporary decompression before the removal of a large symptomatic cyst 9,12,133 , when there is a suspicion of a tubercular PPC in order to confirm the diagnosis preoperatively 13 or when a patient refuses surgery.
To sum up, the management of PPCs is based on an algorithm. The cyst's size, shape and compressibility along with clinical presentation and the patient's fitness and preference should be taken into consideration so that the appropriate management can be chosen 9 .

Prognosis
The absence of symptomatology is an indicative sign of good prognosis 14 , while post-resection prognosis is excellent with low rates of morbidity and mortality 87,98 . Only one case of recurrence after excision has been documented 78 .

Limitations
After reviewing the literature and attempting to statistically analyse the data from table 1 we identified the following limitations: 1. Regarding the nomenclature and the classification of mesothelial cysts, plenty of terms have been used to describe a PPC. Thus, review references are mostly based on the terms "pericardial" and "pleuropericardial" and the inclusion criteria are mentioned in "Methods". That may have affected our results as some cysts which are referred to with a different term have been excluded.
2. We had to exclude many cases from the pool of PPCs as there were not specific data with regard to the examined parameters.
3. We chose to calculate the mean maximal diameter as an objective measurable feature of size. However, our result concerning this parameter may be biased and overestimated, given that our pool of cases of cysts with known size consisted mainly of symptomatic cysts (30 out of 42 patients) which are generally supposed to be larger.

Conclusion -Recommendations
PPCs are rare and usually clinically silent, but can occasionally cause life threatening complications. The majority of them are congenital due to developmental deficits and are most commonly found incidentally via routine radiography between the third and fifth decade of life. In this study, we found out that the mean age of initial detection is roughly 48.7 years, the mean maximal diameter is 8.3 cm and the female:male ratio is approximately 3:2, which is in line with the literature. The RCPA constitutes the most common location, according to our statistical analysis.
MDCT is recommended as the method of choice in all cases, while cardiac MRI can be useful when diagnosis is more challenging.
The management algorithm of PPCs can be divided into two main categories, based on whether there is symptomatology or not. The presence of symptoms depends on the cyst's size and eventual compression of the mass.
1. In the case of a small asymptomatic PPC that does not cause compression, follow-up with serial transthoracic echocardiography is recommended.
2. Apart from the symptomatic and/or complicated and/or large PPCs, surgery is also recommended in the case of an initially asymptomatic PPC which grows in size. This is in order to prevent complications and life-threatening emergencies. The patient's concern constitutes a relative indication for surgical management 9 .
Surgical resection by means of traditional open surgery or minimally invasive methods is considered to be the gold standard, and this along with percutaneous aspiration are the methods that have mostly been used. Percutaneous aspiration and ethanol sclerosis is recommended for large symptomatic PPCs while the patient is waiting for surgery.