Atypical Renal Cyst (Clear Cell Type)


 Background: Atypical cysts do not diagnostic criteria form classification as any of the variants of renal tumors, which have led to diagnostic difficulties. When these cysts have been encountered in surgical pathology practice it can be easily misdiagnosed as renal carcinoma and results in overtreatment. Case presentation: A 55-year-old Chinese woman with a right renal cystic mass came to our hospital. The computed tomography revealed bilateral cysts in both kidneys. In histology, the right renal cystic mass was arranged by stratified epithelium with short papillary projections and tufting. The covered epithelial cells were characterized by clear cytoplasm and small nuclei. Immunohistochemistry, these epithelial cells were diffusely positive for CK7, CK8, CK18, Vimentin and EMA, weakly positive for RCC and PAX-8, while diffusely negative for AMACR, CD10 and TFE-3. And the Ki-67 positive rate was 3%. Based on the immunohistochemical profile and histological features, the final diagnosis is an atypical renal cyst (clear cell type). The patient underwent right nephrectomy. The patient is alive and without any sign of subsequent renal cancer during 11 months of follow-up. Conclusion: Atypical renal cyst is extremely rare among the routine renal pathological diagnosis, we report this case to enhance the understanding and differential diagnosis of the atypical renal cyst and remind the pathologist of this precancerous lesion, and therefore, to avoid unnecessary or excessive treatment.


Background
Atypical renal cyst is extremely rare, and one central review and several scattered cases have described this disease in English-language literature, to our knowledge [1][2][3][4][5][6][7][8][9] . These cystic lesions haven been called as renal cysts with papillary hyperplasia or renal cysts with atypical epithelial proliferation. However, there is a lack of standardized terminology of these cystic lesions. In the largest publication on atypical renal cysts, Matoso et al. [1] divide them into three groups: clear cell, eosinophilic strati ed; eosinophilic papillary. Atypical renal cysts usually occur in patients with complex syndromes (autosomal dominant polycystic kidney disease (APDK), von-Hipple-Lindau disease (VHLD), tuberous sclerosis complex (TSC)) or patients in chronic hemodialysis [1,[10][11][12] . Rarely, atypical renal cysts occur in patients who do not suffer from end-stage renal disease. Still, they are associated with another solid renal cancer or represent a similar nding on imaging studies for other reason [1] . There are no noticeable gender differences, and the age of onset varies from 17 to 80 years old. Multifocal is slightly more than unifocal, and the size of cyst varies from 0.8 cm to 10 cm. Per the de nition, the clear cell group of atypical cysts are lined by strati ed epithelium which is composed by cuboidal cells and characterized by clear cytoplasm and small nuclei (International Society of Urological Pathology (ISPU) nuclear grade 1 to 2). Occasionally, the cysts have an epithelial lining which was "piled up" or strati ed and/or with short papillary projections or tufting, but lacking nests/cords of epithelial cells in the stroma or septa and without a solid mural nodule. By immunohistochemistry, the cuboidal lining cells are positive for CK7 and CAIX, and variably express AMACR and CD10. Cytogenetic abnormalities have been found till now include trisomy 7 and 17. These Cytogenetic features are similar to those of clear papillary renal cell carcinoma (CPRCC), which suggest that clear cell type of atypical cysts may be the precursor of CPRCC [1] . In contrast to clear cell type, strati ed eosinophilic and eosinophilic papillary type of atypical renal cysts are lined by cuboidal cells with scant eosinophilic cytoplasm. The immunophenotype and cytogenetic abnormalities are similar to that of the clear cell type. Besides, there is one case which found 3p deletion in the eosinophilic papillary type case. Although the clinical follow-up is limited in many cases, the great majority has no recurrence or metastasis, which suggests a relative inert prognosis. In the current case, we report a case of the atypical renal cyst (clear cell type).

Case Presentation
Clinical history A 55-year-old Chinese woman was admitted to our hospital because a lump can be touched on the right waist along with pain. Physical examination found a round mass in the right area. The mass was soft and could not be pushed. No hematuria, no urinary frequency and urgency were found. The patient's past medical history is normal. Computed tomography (CT) scanning showed a cystic mass and exhibited with low-density shadow (8 x 9.2 ) in the inferior pole of the right kidney. The left kidney was normal in size, and two low-density shadows (1.1 x 0.7 and 0.7 x 0.5 ) were visible in the left renal parenchyma, which protruded from the outline of the kidney. Neither bilateral renal pelvis compression, kidney stone, nor enlargement of abdominal or retroperitoneal lymph nodes was found in CT scanning. Besides, there were no signs of ascites and no signi cant abnormalities in the bilateral adrenal glands (Fig. 1). The patient underwent right nephrectomy. The patients recovered well after the operation. CT recheck found no apparent abnormalities.

Immunohistochemical staining
Complete sampling of the double right renal cyst was performed according to conventional guidelines. All specimens were xed in 10% formalin and embedded in para n. A series of thick sections were cut from each para n-embedded block. Immunohistochemistry studies were performed using the streptavidin-peroxidase system (Ultrasensitive; Mai Xin Inc., Fuzhou, China) according to the manufacturer's instructions. The primary antibodies used were the rabbit monoclonal anti-α-methylacyl-CoA racemase (AMACR),mouse monoclonal anti-cytokeratin (CK), mouse monoclonal anti-cytokeratin (CK)7, mouse monoclonal anti-CK8, mouse monoclonal anti-CK18, and mouse monoclonal anti-CD10 and directed against epithelial membrane antigen (EMA), Ki-67, Paired box 8 (PAX8), Vimentin, RCC and TFE-3. All antibodies were purchased from Mai Xin Inc., Fuzhou, China. The primary antibody was replaced with phosphatebuffered saline for negative controls.

Morphological ndings
All the right renal cystic mass was sampled to exclude the renal cancer accompanied with cystic change. No mural nodule was found under general or microscopy examination ( Fig. 2A). The cyst is lined by cuboidal cells with clear cytoplasm and small nuclei ( Fig. 2B-C). The lining epithelium was "piled up" or strati ed and/or with short papillary projections or tufting, but lacking nests/cords of epithelial cells in the stroma or septa and without a solid mural nodule ( Fig. 2D-E). The lining epithelial cells showed minimal atypia with small nuclei (ISUP grade 1) (Fig. 2F).

Immunohistochemical ndings
The lining cells were positive for CK ( Final diagnosis is atypical renal cyst based on above ndings.

Discussion
The renal cystic lesion is frequently encountered in clinical practice; it may include benign cysts, precancerous lesions, or malignant lesions [13] . Among these lesions, the most common is simple renal cortical cysts, followed by renal cell carcinoma with the cystic change, and atypical renal cyst, which is much less encountered. By de nition, atypical renal cysts are those cystic masses of the kidney that bear an epithelial lining "piled up" or strati ed and/or have short papillary projections or tufting. The epithelial cells are cytologically bland with small nuclei and a variable amount of clear or eosinophilic cytoplasm. The stroma or septa should be free of nests/cords of epithelial cells and often coexist with other diseases [1] . A review of the English literature at PubMed (www.ncbi.nlm.nih.gov) shows that 14 papers with a total of 42 cases had relevant information and clinical records. Due to the rarity of this renal cyst, we discuss the case and make a literature review of previous cases (all cases were summarized in Table 1) to enhance the understanding and differential diagnosis of the atypical renal cyst to alert pathologists to the precancerous lesion and to avoid unnecessary or excessive treatment. The age of the patients was between 17 and 80 years old. There was no signi cant gender difference. Atypical renal cysts often occur in unilateral kidneys, and multilocular cysts are slightly more than Renal cystic lesions are relatively common, and the CT manifestations of the atypical renal cyst are complex and lack of signs of typical renal cyst, which may easily lead to misdiagnosis. Therefore, it is necessary to differentiate from other renal cystic diseases. The ultrasonography of simple renal cysts was smooth and without separation. They are common and require no clinical follow-up or treatment because they do not pose any risk for malignant transformation [14] . Unless the cyst is large, it compresses other kidney tissue or surrounding organs. At this time, surgical treatment needs to be considered. We must admit the coexistence of renal cell carcinoma and atypical renal cysts do exist in clinical practice [15,16] . Ibrahim et al. [6] found that atypical renal cysts exist in renal parenchyma close to the renal carcinomas. The characteristics of atypical cells lining the cysts are similar to those found in the close well-differentiated renal cell carcinomas [17] . DNA quantitative studies show that both the renal cell carcinomas and the atypical cyst lining cells have the same DNA indices and are essentially DNA euploid [6] . And it was reported that atypical renal cysts associated with end-stage renal disease had been considered to be precursors of malignant renal tumours [9] . These descriptions suggest that atypical renal cysts may be associated with renal carcinoma. CT and ultrasound have a high diagnostic value for cystic renal carcinoma [19,20] . The Bosniak classi cation system, created in 1986 [21] , established morphological CT criteria to differentiate between benign cysts and maliganat cysts. Studies have shown that Bosniak criteria combined with ultrasound can greatly improve the diagnostic of benign and malignant renal cystic lesions [22] . If the shape of the renal cyst found by ultrasound examination does not have the characteristics of a simple renal cyst and the boundary with the surrounding renal tissue is unclear, the inner wall is not smooth, or there are nodules and separation, which most likely cystic kidney cancer or a complex renal cyst. At this time, CT or enhanced CT examination is needed to eliminate the possibility of renal malignancy further. But exact diagnosis is di cult at times because the imaging features between CRCC and benign renal cystic diseases are similar [23] . Therefore, if necessary, an ultrasound-guided  [24] . But in the case, the morphological nding shows that the lining epithelium is "piled up" or strati ed and/or with short papillary projections or tufting, and computed tomography (CT) scanning shows that there is lacking nests/cords of epithelial cells in the stroma or septa and without a solid mural nodule.
Therefore, we excluded renal cancer accompanied by cystic change and diagnosed it as an atypical renal cyst. Also, to reduce the misdiagnosis of cystic renal carcinoma and improve the understanding of cystic renal carcinoma and atypical renal cyst, we should comprehensively analyze the patient's medical history, symptoms, signs and imaging examinations to make the diagnosis correct and provide reliable clinical support. For patients with atypical renal cysts, the possibility of cystic renal cancer should be considered before surgeries to avoid misdiagnosis.
Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent inherited nephropathy, which due to mutations in the PKD1 or PKD2 gene [25,26] . Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive enlargement of kidney cysts leading to chronic kidney disease (CKD) and end-stage renal disease (ESRD) [27][28][29] . Characteristic pathological changes and imaging tests are the primary diagnostic basis of ADPKD. Commonly used imaging examinations mainly include ultrasound and magnetic resonance imaging (MRI) [30] . In this case, the patient had no typical pathological features and family genetic history. Therefore, the genetic polycystic kidney is not considered rst.
Here, we reported a rare case of atypical renal cyst (clear cell type). Atypical renal cyst is extremely rare among the routine renal pathological biopsies. Based on its histopathologic features, it might be over diagnosed as renal cell carcinoma with cystic change and caused unnecessary treatment and excessive psychological burden. This study followed the principles of the Declaration of Helsinki.

Consent for publication
Written consent for publication was obtained from the patient discussed in this report.

Availability of data and materials
Not applicable.

Competing interests
The authors declare that they have no competing interest. All authors have read and approved the manuscript.  CT results. CT scanning showed multiple renal cyst, the biggest one was in the inferior pole of right kidney (8 cm x 9.2 cm). Two smaller cysts were in the left renal parenchyma. The arrows indicated the renal cysts.

Supplementary Files
This is a list of supplementary les associated with this preprint. Click to download.