Pseudocapsule of Small Renal Cell Tumors: CT Imaging Spectrum and Correlated Histopathological Features Gang Li1#, Xianqi Lu2#, Yunshen Ding3, Qiang Luo4, Liang Xu5, Dongsheng Zhu6*, Changyi Quan1** Purpose: To systematically analyze histopathologic features of pseudocapsule in small renal cell tumor (diameter ≤ 4cm), assess the integrity of pseudocapsules by Computed Tomography (CT), and provide theoretical basis for the safety of nephron sparing surgery. Materials and Methods: The pathological data of 116 patients who underwent surgery with clear cell renal cell carcinoma admitted from May 2010 to October 2017 were retrospectively analyzed. All patients underwent a CT scan of the abdomen including an unenhanced and three-phase (arterial, nephrographic and excretory) post contrast series. Thorough gross examination and histological sections were used to determine the integrity of the pseudo- capsule by two uropathologists. The consistency between pathological findings and CT imaging were evaluated by Kappa consistency test. Results: The mean diameter of tumor was 3.0cm, range (2.6 ± 0.8) cm. On CT the pseudocapsule can present with one of the three following feathers:1) A regular and distinct halo; 2) lobulated clear margins;3) blurred margins. On histopathology, complete psuedocapsule was found in 85 tumors, incomplete psuedocapsule in 25 and no psuedo- capsule was found in 6 tumors; CT scan findings demonstrated a regular halo in 82 tumors, lobulated clear margins in 26 and blurred margins in 8 tumors(Kappa = 0.833, P = 0.000). Conclusion: Most small renal cell tumors have an obvious psuedocapsule. Preoperative determination of the psue- docapsule’s integrity is particularly important. CT scan can reliably evaluate the tumor margins and demonstrate the psuedocapsule when present. The imaging results are well correlated with the pathologic findings. Keywords: pseudocapsule; small renal carcinoma; pathology; CT; surgery INTRODUCTION Renal cell carcinoma is the most common malig-nant tumor of the kidney in adults.(1) It accounts for 3% of all adult malignancies and the incidence of the young is increasing.(2,3) In recent years, with the de- velopment and widespread use of imaging diagnostic technology, detection rate of early asymptomatic small renal masses (SRMs) is significantly improved, there- fore, the incidence of early-stage renal cell carcinoma increased steadily year by year.(4-6) Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype. Most renal cancer is low degree of malignancy 1Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin Institute of Urology, Tianjin City, 300211, China. 2Department of Urology, Tianjin Wuqing Hospital , Tianjin City, 300000,China 3Department of Urology, Tianjin Baodi Hospital,Baodi Clinical College of Tianjin Medical University, Tianjin City, 301800,China 4Department of Urology, The People’s Hospital of Jiangyin,Wuxi City,214000,China. 5Department of Urology, China Medical University Aviation General Hospital, Beijing City, 100012, China. 6Department of surgery, The First People’s Hospital of Lianyungang, Affiliated to Xuzhou Medical University, Lianyungang, China. #These authors contribute equally to the article *Correspondence: Department of surgery, The First People’s Hospital of Lianyungang, Affiliated to Xuzhou Medical University, 182 Tongguan North Road, Lianyungang 222000, P.R. China. Tel:+86 18961321672,email:zhudongsheng@tmu.edu.cn. **Tianjin Medical University, No. 22, Qixiangtai Road, Tianjin, 300211, P.R. China. Tel: +86 16600380083, E-mail: zhudongsheng@tum.edu.cn Received January 2020 & Accepted May 2020 and grows slowly,(7) and squeezes the renal parenchy- ma or surrounding tissue to form the pseudocapsule, which is the protective response of the body to limit the growth and proliferation of tumor. It was initially de- scribed in the early 1900s and was commonly identified in ccRCC. However, high degrees of malignant tumors are invasive with no obvious pseudocapsule. For patients with small renal cell carcinoma, under the premise of no distant metastasis, partial nephrectomy is the general choice.(8) Nephron sparing surgery(NSS) maximizes the preservation of renal function, it has shown oncological efficacy and favorable outcomes in UROLOGICAL ONCOLOGY Urology Journal/Vol 18 No. 3/ May-June 2021/ pp. 301-306. [DOI: 10.22037/uj.v16i7.5907] carefully selected patients with T1a tumors, also offers an equally effective form of local control as well as 5- year disease-specific survival rates.(9) The integrity of the pseudocapsule determines the safety and feasi- bility of partial nephrectomy. Additional, regardless of the presence or absence of pseudocapsule, there is no difference in surgical approach. Hence, preoperative determination of pseudocapsule integrity is particularly important. As far as we know, the literature on preop- erative judgments of pseudocapsule integrity is less re- ported in English to date. Therefore, we evaluate the in- tegrity of the pseudo-capsule by computer tomography (CT), and systematically analyze the histopathological characteristics of the pseudo-capsule of renal cell tumor (diameter ≤ 4cm) to provide a theoretical basis for the safety of NSS. MATERIALS AND METHODS Study Population A retrospective study was conducted to value the re- lationships between CT imaging spectrum and histo- pathological features of 116 patients who underwent NSS in our hospital with clear cell of renal cell carci- noma admitted from May 2000 to October 2016. All patients had received preoperative CT examination included unenhanced and three-phase (arterial, portal, and nephrographic-excretory) contrast-enhanced and signed informed consent. The study included 116 pa- tients (65 men, 51 women; mean age, 56 years; range, 33–78 years). Based on the tumor growth pattern, small renal cell carcinoma is divided into single nodular type, infiltration type (nodular boundary uncertainty) and multi-nodular fusion. All tumors were single nodular and less than 4 in diameter. 114 of the 116 patients had no symptoms and were referred because of a small re- nal mass found incidentally at physical examination. A renal tumor was detected at CT examination in 12 pa- tients. No patient had distant metastases. Only 2 cases were referred with clinical symptoms which is slight pain. Procedures Thorough gross examination of the pseudocapsule in- cluding pseudocapsular invasion and completeness of PC was performed by the uropathologist. If the pseudo- capsules existed, but some were infiltrated, it is defined as incomplete psuedocapsule. We striped the pseudo- capsule completely to do pathological sections. Entire sections including the tumor-PC-parenchyma interface and representative sections from the largest plane of the tumor were submitted. All specimens were step-sec- tioned at 5-mm intervals, entirely embedded in paraf- fin blocks, stained with hematoxylin and eosin. Tumor grade was according to the Fuhrman criteria. All CT examinations were performed using a 64- MDCT scanner. Unenhanced scans and contrast-en- hanced scans were reconstructed at 3-mm intervals. The margins of the tumor were recorded and classified on the CT. CT and pathological findings were compared by case analysis. Sample size Based on our pilot data, the sample size was estimated on a power of 80 % at the 5 % significance level. It has been suggested that at least 22 patients per group were required. These study protocols were approved by the medical ethics committee of the Second Hospital of Tianjin Medical University, Tianjin Institute of Urology. This work was supported by Tianjin Municipal Natural Science Foundation (Grant 17JCYBJC26000) Pseudocapsule of small renal cell tumors -Li et al. Table 1. Comparing CT scan and pathological results CT scan(n) Pathological results(n) Total Kappa coefficient P-value Positive Negative Positive 107 1 108 0.833 .000 Negative 3 5 8 Total 110 6 116 Figure 1. Microscopically, integrated psuedocapsule of ccRcc. The pathological components of pseudocapsule include compressed renal parenchyma, hyperplastic fibers, and inflammatory cells. (hematoxylin and eosin staining, ×40). Urological Oncology 302 Statistical analysis SPSS Statistics 20.0 was used for statistical analysis. The pathological results as gold standard, using Kappa test analysis to judge consistency with the CT detecting results. Kappa coefficient > 0.7 and < 0.4 indicates a high or low consistency between the two results respec- tively; P < .05 was considered statistically significant. RESULTS The mean diameter of tumor was 3.0 cm, range (2.6 ± 0.8) cm. Pathological results showed 7 cases were of FuhrmanⅠgrade, 39 cases were of grade Ⅰ-Ⅱ, 55 cases were of grade Ⅱ, 12 cases were of grade Ⅱ-Ⅲ, 3 cases were of grade Ⅲ and 0 cases were of grade Ⅳamong the 116 cases of clear cell carcinoma. Integrated psue- docapsule (Figure 1) were found in 85 (73.3%) tumors with the thickness ranged from 0.2 to 1 mm, 25 (21.6%) without integrated psuedocapsule (Figure 2) and 6 (5.2%) cases had no obvious psuedocapsule (Figure 3). Tumor infiltrated while not penetrated into the psuedo- capsule were found in 16 cases (13.8%), while tumors penetrated into the psuedocapsule were found in 7 cases (6.0%). The pathological components of pseudocapsule include compressed renal parenchyma, hyperplastic fibers, and inflammatory cells. In MDCT, the presence of pseudocapsule on CT had three kinds. 82(70.7%) cases of RCC were confirmed with a regular halo surrounding a renal neoplasm (Fig- ure 4). 26 (22.4%) had clear margin but not continuous or lobulated (Figure 5), 8 (6.70%) were found present- ing blurred margin (Figure 6) surrounding the tumor. The pathological results as gold standard, The sensitiv- ity, specificity, positive predictive value and negative predictive value of CT detecting psuedocapsule was 97.3% (107/110), 83.3% (5/6), 99.1% (107/108), 62.5% (5/8), respectively and the consistency between CT and pathological results were high by Kappa test analysis in which the Kappa value was 0.833 (Table1). The presence of a regular and distinct halo surrounding a renal neoplasm presented the completeness of pseudo- capsule. Clear margin but not continuous or lobulated was regards as incomplete capsule while blur margin presented no capsule. DISCUSSION At present, small renal cancer is well differentiated, the clinical stage is low, the natural growth rate is slow and the prognosis is better. Nephron sparing surgery (NSS) is safe and reliable in the treatment of small renal cell carcinoma, with a low rate of recurrence and mortali- Figure 2. Microscopically, incomplete psuedocapsule of ccRcc. Tumor infiltrated and penetrated into the psuedocapsule resulting in pseudocapsule discontinuity (hematoxylin and eosin staining, ×100). Figure 3. Microscopically, no psuedocapsule of ccRcc. The neoplastic cells directly interfaced with normal renal parenchyma without any fibrous band (hematoxylin and eosin staining, ×100). Pseudocapsule of small renal cell tumors -Li et al. Vol 18 No 3 May-June 2021 303 ty. (10,11) A meta-analysis confirms that NSS can reduce the incidence of postoperative chronic kidney disease relative to radical nephrectomy 61%, 19% reduction in mortality. RCCs usually have no true histologic capsule but are surrounded by pseudocapsule.(12)- Pseudocapsule is an important feature which is helpful to evaluate the dif- ferentiation of renal cell carcinoma.(13) Pseudocapsule formation is the result of tumor growth, which causes compression, ischemia, and necrosis of the adjacent renal parenchyma.(14) This is a protective response that the body limits the growth and spread of the tumor. In early stage of small and low-grade RCCs, the presence of pseudocapsule is often seen,(15) which is a good in- dicator of renal cancer prognosis.(6) Complete pseudo- capsule predicts higher degree of differentiation and the lesion is still early; the other hand, the incomplete pseu- docapsule herald higher diffusion and metastasis rate. (16) Joseph M et al. found clear cell RCC exhibits the most consistent PC, a complete PC was found in 77% of 60 cases with T1 stage clear cell tumors.(17) NSS can only be performed if the tumor is confined to the renal parenchyma and there is a significant pseudocapsule around it.(18) Wei Xi et al. findings suggest that pseu- docapsule status is of good prognostic implications in RCC and lack of pseudocapsule certainly had remarka- ble adverse impact on patient outcome.(19) Thus, we dis- cuss the judgment of its completeness preoperatively to ensure pathology margin postoperative. There are different reports about detecting pseudocap- sules in small kidneys, such as ultrasound and MRI and CT. Hricak et al.(20) reported that a pseudocapsule was observed on MRI firstly in 1985, both of which showed a low signal band between tumor and normal renal parenchyma in both T1WI and T2WI. Yamashita et al. showed that T2WI is the most sensitive through different sequences of MR pseudocapsules display study.(15) Moreover, MRI has been reported to be more reliable imaging modality, the accuracy ranging from 74% to 93%, the sensitivity was 87.5% and the specific- ity was 80.8% respectively. Preoperative MRI showed complete pseudocapsule around the tumor which sug- Figure 4. Abdominal CT shows a regular halo surrounding a renal neoplasm. Figure 5. Abdominal CT shows the renal mass had clear margin but not continuous or lobulated. Pseudocapsule of small renal cell tumors -Li et al. Urological Oncology 304 Vol 18 No 3 May-June 2021 305 gesting the feasibility of enucleation. Ultrasound has a higher veracity up to 89.29% in diagnosis of small re- nal cell cancer, it can detect more than 1cm mass. Con- ventional ultrasound in detecting RCC pseudocapsules can manifest as two types of echogenicity: hypoechoic halo or slightly hyperechoic bands around the tumor. Ultrasound contrast showed enhanced echo around the tumor and enhancing time is longer, the sensitivity was 85.7%, much higher than conventional ultrasound. (13) There are few studies on the performance of RCC pseu- docapsules by CT. Yamashita et al.(15) studied 52 cases of renal cell carcinoma and compared the ability of de- tecting pseudocapsules between enhanced CT and MRI, they concluded the MRI T2-weighted image showing the most accurate. Tsili et al.(21) retrospectively studied 29 histologically proven RCCs which examinations were performed with a 16-MDCT scanner preopera- tively. They finally concluded that multiphase MDCT with multiplanar reformations had satisfactory results in detecting renal pseudocapsule in RCC and imaging in the portal and nephrographic phases with coronal and sagittal reformations proved more accurate. In our studies, among 116 cases, integrated psuedocap- sule were found in 85 (73.3%) tumors with the thick- ness ranged from 0.2 to 0.8 mm, 25 (21.6%) without integrated psuedocapsule and 6 (5.2%) cases had no ob- vious psuedocapsule. Wang et al. concluded clear cell renal carcinomas showed the thickest pseudocapsule (average 0.23 mm) among 178 renal tumors.(22) This is similar to our findings. In MDCT, the presence of pseu- docapsule on CT had three kinds. 82 (70.7%) cases of RCC were confirmed with a regular halo surrounding a renal neoplasm. 26 (22.4%) had clear margin but not continuous or lobulated, 8 (6.70%) were found present- ing blurred margin surrounding the tumor. The consist- ency between CT and pathological results were high by Kappa test analysis. This provides a certain basis for determining the integrity of the pseudocapsule by CT preoperatively. 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