Ipsilateral Synchronous Papillary and Clear Cell Renal Cell Carcinoma: a Case Report and Literature Review

Background: The rare disease of ipsilateral synchronous papillary and clear cell renal cell carcinoma was often misdiagnosed as a single tumor with intra-renal metastasis or some other diseases preoperatively. Both of the effective management and long overall survival might be affected as the different prognosis of the two kinds of tumors. Here, we report a case of ipsilateral synchronous papillary and clear cell renal cell carcinoma, and present the clinicopathological features as well as review the literature in China. Case presentation: A 70-year-old man presented with a single mass in the left renal revealed either by ultrasound or CT during a routine physical examination. The tumor was occurred as two isolated masses in the gross nding. Hematoxylin and eosin staining and immunohistochemistry were performed. Papillary cell carcinoma and clear cell renal cell carcinoma were the compositions of the tumors. Immunostainings were as follows: The papillary renal cell carcinoma showed positive for CK7, P504s, Pax8,Vimentin, and scatterly for CD10, the proliferation rates of Ki67 was just 3%; While the clear cell renal cell carcinoma was positive for Pax8,CAIX,Vimentin, and diffusely for CD10, but negative for CK7 and P504s, the Ki67 proliferation rates was 5%. The patient was diagnosed with ipsilateral synchronous papillary and clear cell renal cell carcinoma, and free from the disease 9 months after surgery. Conclusions: Ipsilateral synchronous papillary and clear cell renal cell carcinoma is a rare condition without specic clinical manifestations. The understanding of the computed tomography features and increasing the awareness or experience of the disease may be helpful to improve the preoperative diagnosis accuracy. Precise diagnosis should be based on histopathological morphology and immunostaining. As the different prognosis of the two tumors, optimal surgical treatment should be performed to prolong the survival time.


Background
The renal cell carcinoma (RCC) is the third most frequent malignancy of the urology system, which commonly originated from epithelial cells of the tubules [1]. The most common subtype of RCC is clear cell (80%), beside papillary(10%) and chromophobe type RCC(5%) [2]. As the two most common subtypes, papillary renal cell carcinoma (PRCC) and clear cell renal cell carcinoma (CCRCC) within the same renal was very rare at one time in the literature reviewed. Accurately diagnosis of RCC is necessary not only for prognosis but also for evaluation of therapeutic response. In the clinical practice, ipsilateral synchronous PRCC and CCRCC are often misdiagnosed as an isolated mass or a multiple lesion due to the intra-renal metastasis preoperatively. As a result, the patients may have a limited survival after the disease is nally con rmed postoperatively. Herein we reported a 72 years old male with a complex renal mass in our institution, and reviewed the clinicopathological features and therapeutic strategies of the literature, with a purpose to improve the accuracy of the pre-operative diagnosis.

Case Presentation
A 72 years old male was admitted to the inpatient because of left renal mass found by physical examination with no other complain. The patient had a long history of hypertension for 20 years. No family history associated was discovered. The initial impression on the ultrasound revealed a hypoechoic lobular mass with a volume of 7.8cm × 4.8cm × 2.8 cm in the middle to lower pole of the left renal. The subsequent computed tomography(CT) scan had shown a single endophytic mass of 7.5 cm in diameter, contrast enhancing (Fig. 1a). The physical examination found no vital signs. A diagnosis of angiomyolipoma (AML) was considered preoperative. The patient underwent laparoscopic left radical nephrectomy month later. Grossly, it revealed a two ipsilateral synchronous kidney mass (Fig. 1b). The rst lesion(Tumor I) was in the middle pole of the left renal with a brous pseudocapsule surrounded, measuring 5.0cm × 4.5 cm × 4.5 cm and protruding the kidney capsule with no invasion; the second lesion (Tumor II) was in the lower pole closed to the rst lesion, measuring 3.0cm × 3.0cm × 2.5 cm with an isolated capsule grossly (Fig. 2a). Both cutting surfaces of the tumors occurred solid and yellow-brown color, focal hemorrhage and no necrosis were shown. Histopathological examination of tumor I revealed tubular and papillary architectures containing a central brovascular core (Fig. 2b). The two growth patterns were both lined by cuboidal and columnar cells. The cells lining the papillary structures contained abundant eosinophlic and amphophilic cytoplasm. The nuclear features were moderate to large irregular nuclei containing coarse chromatin and prominent nucleoli. And neither geographic necrosis nor psammoma bodies were showed. Tumor II revealed a typical CCRCC features, tubular and nest patterns oating in a plexiform vascular pattem (Fig. 2c). The tumor cells were polygonal in shape with clear or eosinophilic cytoplasm. A pseudopapillary growth pattern without a true brovascular core was happened in some areas of the tumor II. Focal brosis and in ammatory in ltration was seen, but no necrosis was occurred. None of vessel invasion or peripheral fat in ltration was exhibited in both tumors. The PRCC showed positive for CK7,P504s,Pax8,Vimentin, and scatterly for CD10, the proliferation rates of Ki67 was just 3% (Fig. 2d,f,h); While the CCRCC was positive for Pax8,CAIX, Vimentin, and diffusely for CD10, but negative for CK7 and P504s, the Ki67 proliferation rates was 5% (Fig. 2e,g,i).The nal diagnosis was ipsilateral synchronous papillary cell carcinoma (WHO grade II-III) and clear cell renal cell carcinoma(WHO grade II-III) in the left kidney. The patient was discharged at the sixth day with no complication postoperatively. At the rst nine month follow-up, the patient was free from the disease with no recurrence or metastasis.

Discussion And Conclusion
The RCC is the most common solid mass of the kidney and comprises 2 to 3% of all cancers in adults [1]. Over the past years, RCC had been divided into clear cell and non-clear cell subtypes, while the most common subtype of nonclear cell RCC was the PRCC. Even rare, combination of different subtypes had been reported [3]. The histology mainly focused on the PRCC and CCRCC, which might present a challenge for the accurate diagnosis. The incidence of the ipsilateral synchronous PRCC and CCRCC was about 4.8% by Richstone et al [4]. The rare conditions were only about 12 cases that had been reported in the literature ranged from 1990 to 2020 in China. Therefore the rarity of the disease may contribute to the misdiagnosis in clinical practice. As in our case, an initial diagnosis of AML was impressed.
The underlying etiology and histogenesis of ipsilateral synchronous PRCC and CCRCC are still unclear, which partly affect the cognition of the clinician. The best known possible etiological factors for RCC are smoking, obesity, and hypertension [5]. Smoking is implicated to be the key for the etiology of RCC, with an increasing risk of dosedependent. Nonetheless, the relationship between obesity or hypertension and the disease are not yet rmly established. For our case, a history of hypertension for almost 20 years was mentioned. Interestingly, 7 cases of ipsilateral synchronous PRCC and CCRCC came from the same area were discovered by reviewing the literature in China. Further studies may be essential to consider whether the exposure to such a geogenic factor is a risk for the issue development.
Underwent ultrasound or abdominal CT could reveal the lesion preoperatively. Most CCRCC are hypervascular, the degree of enhancement performs a quickly decreasing in the phase of parenchyma, medullary and delayed, showing as "fast in and fast out". In contrast, there is no predominent difference of the enhancement shown in the three phases of the PRCC by the CT scan, as the vessels of the brovascular core are thin and sparse in the papilla [6].
Unfortunately, there is still a risk of 3.5% missing the coexisting tumors [4]. High to 70% of multifocal lesions were missed on preoperative imaging due to the small size or the adjacent location in Chinese cases reviewed. There were Diagnosis and subclassi cation of RCC must be based primarily on pathology. The most two common subtypes PRCC and CCRCC generally show the typical architectural and cytological characters prominently. But our case was diagnosed as the AML initially, because of the similar gross features. A cutting surface of yellow-brown color could make a confusion with the AML, as the latter is well circumscribed and has pushing the borders, also contains soft yellow regions admixed with rm tan regions. Elsewhere, the majority of PRCC is bilateral and multifocal, as well as areas of hemorrhage and necrosis are commonly seen in PRCC, a confusion with others is not hard to comprehend.
While, on microscopic, PRCC may be confused with CCRCC when a solid growth with clear cytoplasm exhibited, and CCRCC with papillary pattern or esophilia cytoplasm occurs as a confusion with PRCC. In this condition, the classic morphology features of the two tumors provide a great help to distinguish them, such as whether a pseudopapillary pattern was exhibited or not. And because of the different immunopro les shown in PRCC and CCRCC, immunohistochemical staining may also offer an important clue to the diagnosis. PRCC is strongly positive for CK8/18, CK7and P504s, while CCRCC is positive for CD10, CAIX and Vim strongly.CK7 may be expressed in both tumors, but PRCC often shows diffuse cytoplasm positive with CK7, while no positivity is observed in CCRCC. The result of our own case was the same as the literature, a strong positive of CK7 in PRCC and negative for CCRCC ( Fig. 2D, E).
Besides that, a differentiation might be necessary between PRCC and collecting duct carcinoma, when the latter had a papillary pattern. Nevertheless, the collecting duct carcinoma often exhibits as a high grade tumor with predominent desmoplastic stroma, and occur in the medulla. CK7 may be expressed in both tumors, but negativity for CEA, 34βE12 and some other biomarkers can help to exclude the PRCC. When thinking back to our initial gross diagnosis, if the epithelioid subtype of AML was exhibited, CCRCC might be misclassi ed as AML rstly. CCRCC is always positive for Vim, CD10 and CAIX, but negative for the biomarkers of AML, such as HMB45 and SMA. A careful attention to the morphology and immunohistochemistry may help to establish the correct diagnosis.
The aim of surgical management for patient with multifocal renal tumors is not only to prevent recurrence and metastasis, but also to minimize the number of surgical procedures and to prolong kidney function as long as possible. Both laparoscopic, robotic and partial nephrectomy for multiple lesions of the ipislateral renal tumors have been reported [7][8][9].Although laparoscopic radical nephrectomy has been the standard therapy for sporadic multifocal renal tumors, nephron sparing surgery (NSS) is now a good option for the mass with a diameter less than 3 cm. No matter which operation mode is selected, a right balance between oncologic control and renal functional preservation need to be considered. Even there had been a diagnosis of a single mass preoperatively, our patient still underwent the laparoscopic radical nephrectomy with a purpose to achieve a long survival time. And in the Chinese cases reviewed, 2 of the 3 cases diagnosed as a single mass underwent the NSS, and 3 cases diagnosed as a multiple-lesions mass with the considering of an intra-renal metastasis preoperatively, also underwent the NSS (Table 1). If a single mass or a multiple intra-renal metastasis lesion was con rmed, to preserve more renal function and improve the life quality of the patient, a NSS may performed. So in such condition, whether an adequate surgical range obtained, or whether a long life-time survival achieved, should be considered renew. Obviously, a precisely preoperative diagnosis is also the key to access a long survival time.
The prognosis of PRCC is more favorable than CCRCC, as the former behaves less aggressively than CCRCC. By now there was still not su cient data concerning survival to compare the subtypes of RCC with multifocality in the same kidney. Capaccio et al. reported three cases with ipsilateral synchronous PRCC and CCRCC [10]. All of the patients underwent laparoscopic radical nephrectomy, and one died from the cancer after a 5 years long survival. In the present case, the patient was free from the disease with no recurrence or metastasis for nine month.
As the incidence of ipsilateral synchronous PRCC and CCRCC was quite low. A lack of awareness or experience may exist among most clinicians. If there is a multifocality mass in a single kidney, intra-renal metastasis will be considered initially, the possibility of the existing of ipsilateral synchronous PRCC and CCRCC may be ignored. But as the prognosis of PRCC and CCRCC are quite different, the therapy strategies may be performed differently, such as operation mode or adjuvant chemotherapy. So even they represent a low incidence rate, different histological subtypes of multiple ipsilateral synchronous RCC need to be classi ed as a special entity postoperatively, because of the different therapy strategies performed latterly.
In conclusion, we presented a case of ipsilateral synchronous PRCC and CCRCC.

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Con ict-of-interest statement
The authors declare that there is no con ict of interest related to this report Ethics approval and consent to participate Written informed consent was obtained from all participants. Ethical approval was obtained from the Ethics Committee of Tianjin Fifth Central Hospital, China, in accordance with the ethical guidelines of the 1975 Declaration of Helsinki. Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor in-Chief of this journal.

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Written informed consent for publication was obtained from all participants.