Differences in clinical and computed tomography imaging features between two types of mixed epithelial and stromal tumor of the kidney: Suggestions for patient management

Background To analyze the differences in clinical features and computed tomography characteristics in the two types of mixed epithelial and stromal tumor of the kidney (MESTK) and to establish a treatment plan for the MESTK types. Methods 17 patients underwent multidetector computed tomography (MDCT) before surgery and had a pathological diagnosis of MESTK were enrolled. Their clinical information (R.E.N.A.L.Nephrometry Score (R.E.N.A.L. (cid:0) NS), radical nephrectomy (RN), partial nephrectomy (PN), etc.) were collected. The radiological features included renal sinus fat invagination (SFI), maximal diameter (MD), capsule and septa of the tumor, etc. were also analyzed. They were divided into two types according to the MD solid /MD tumor ratio (type A with > 63%; type B with ≤ 63%). An independent-sample t-test and Fisher exact test were used to assess the differences between the two groups. Results MESTKs demonstrated a variable multi-septate cystic and solid components with a delayed enhancement. There were 9 patients for type A and 8 subjects for type B. Compared with type A, the lesions in type B have larger MD (79.13±39.06 vs. 41.22±24.19, p = 0.028), higher R.E.N.A.L. (cid:0) NS (10.03±0.50 vs. 8.95±1.26, P (cid:0) 0.001), higher RN (75.00% vs.22.22%, p =0.015), larger SFI (87.5% vs.33.3%, p=0.05), more septa (100% vs. 0%, p <0.001) and more capsule (100% vs. 11.1%, p < 0.001). type 17 (low: n 0; moderate: n (41.18%); high: n 10 (58.82%)).

In clinical work, the preoperative radiologic diagnosis of MEST is challenging and is easy to be misdiagnosed as other renal neoplasms -renal cell carcinoma (RCC) -leading to inappropriate treatment. Furthermore, it is still unclear whether the imaging features and clinical data can help make a suitable treatment plan for the patients with MESTK.
In our study, the patients with MESTK were divided into two types based on the proportion of MD solid / MD tumor in the maximal slice (type A: the ratio > 63%; type B: the percentage ≤63%). Our purpose is to analyze the clinical and radiologic features of MESTK, with emphasis on evaluating the differences in clinical and computed tomography characteristics and proposing a patient management plan for the two types.

Patients
Ethical approval was obtained from Institutional Review Board of the Xiangya Hospital, Central South University. This retrospective study was performed in accordance with the provisions of the Declaration of Helsinki. The requirement for informed consent was exempted by the Institutional Review Board of the Xiangya Hospital, Central South University as all data was analyzed anonymously (number 2018111101). From June 2011 to November 2020, 17 patients pathologically diagnosed with MESTK (13 women and 4 men the median age was 45.12 ± 10.77 years (range from 21 to 61y), who underwent preoperative multidetector CT (MDCT) within 15 days before the surgical procedure were recruited. The clinical information (the follow-up time, gender, age, clinical symptoms, menstrual status, surgery methods (PN and RN), and and R.E.N.A.L. Nephrometry Score (R.E.N.A.L. NS)) were collected (R= Radius (tumor size as maximal diameter); E = Exophytic/endophytic properties of the tumor; N = Nearness of tumor deepest portion to the collecting system or sinus; A = Anterior (a)/posterior(p) descriptor; and L= Location relative to the polar line (13)). For R.E.N.A.L NS, the range of 4 to 6, 7 to 9 and 10 to 12 were deemed low, moderate and high complexity lesions, respectively. The beginning and end of the follow-up period was the time the patient had surgery and the latest MDCT or ultrasound examination in our hospital.

Imaging analysis
All MDCT images were transferred into the imaging workstation (Advantage Workstation 4.4, GE Healthcare, Buc, France) and image post-processing (sagittal and coronal images) was performed. Two experienced radiologists (J.C. and G.P, reviewers 1 and 2 with 5 and 7 years of clinical experience in kidney MDCT, respectively) assessed the imaging characteristics without knowing the clinical and pathological information including the maximal diameter (MD), shape, location, calci cation, septa state, mural nodule, capsule of the tumor, renal sinus fat invagination (SFI), and the enhancement degree and pattern. SFI is de ned as the direct contact of the tumor with the renal sinus stroma or fat cell (14), which appears as an invasion of the fat tissue of the renal sinus on MDCT. But it is not considered invasive if the tumor impinges on (but is separated from the fat by a connective tissue layer) the perinephric or renal sinus fat (15). Enhancement patterns were evaluated and analyzed with the CT attenuation for each phase for all MESTK. A region of interest (ROI) was drawn on the solid component of the tumor (size: 40-60 mm 2 ) on EP images, avoiding the cystic and calci ed parts in the tumor. Then, it was copied to plain, CMP, and NP images of the same slice. For each subject, the above measurements were carried out two more times on different occasions within a week, and the average CT attenuation was calculated for each phase to obtain the enhancement pattern (wash out or delayed enhancement). Gradual enhancement pattern was considered present when the tumor attenuation in the nephrographic phase was at least 20 HU greater than that in the corticomedullary phase (16), while gradual washout pattern was de ned when the CT value of the subsequent phase was reduced to less than 20 Houns eld units (HU) (17). The degree of enhancement was de ned as the difference between the attenuation value of the unenhanced scan and the CMP. A difference higher than 50 HU was classi ed as marked, between 20 and 50 HU as moderate, and less than 20HU as weak enhancement (6).
A threshold value of 25% (proportion of solid components in a cyst-solid tumor) is used in the Bosniak classi cation (version 2019) of renal cystic masses with solid components (18,19). The Bosniak classi cation can be used for patients with cyst-solid mass when the proportion of solid part ≤ 25%. But, the Bosniak classi cation cannot be applied when the percentage of the solid element > 25%. However, it is di cult for radiologists to estimate -qualitatively -the volume percentage of the solid part on MDCT. The volume of mass and solid components are relative to their respective diameter (D) (V = (4/3)πR 3 and R = D/2), So, the maximal diameters (MD) were used to replace the corresponding volume in our study, and the equation is as follow: where MD tumor is the maximal diameter of tumor in the slice in which the mass has the greatest size and MD solid is the maximal diameter of the solid part in the same slice. When the ratio of the MD of the solid part in mass ≤ 63%, it was classi ed into type B (can be classi ed with Bosniak classi cation), and into type A when the ratio > 63% (cannot be classi ed with Bosniak classi cation). The detailed illustration is shown in Fig.1.
For lesions classi ed into type B, the number of septa, septal thickness, septal enhancement, wall thickness, wall enhancement, and mural nodularity on MDCT were assessed, and Table 1 gives the reference standard during image analysis. Lesions were classi ed into I-IV category with Bosniak Classi cation (18).

Statistical analysis
An independent-sample t-test was used to assess differences in the MD, age, and R.E.N.A.L. NS between type A and type B. The Fisher exact test was used to analyze gender, clinical symptoms, surgery methods, shape, RSI, calci cation, septa, mural nodules, capsules, and enhancement patterns in the two groups. Statistical analyses were performed with SPSS 18.0 (SPSS Inc., Chicago, IL, USA). P-value > 0.05 was considered not statistically signi cant

Imaging ndings
All MESTKs demonstrated a variable proportion of multi-septate cystic and solid components, which appeared as delayed enhancement with a well-circumscribed margin on triphasic dynamic-enhanced MDCT (Fig 3, 4), except for two subjects that had gradual washout pattern. The CT attenuation was less than 20 HU in the cystic part. In the 17 cases, the tumor in 14 patients (77.8%) showed a regular shape, and 10 subjects (58.82%) demonstrated RSI ( Fig 5A). In addition, tumor capsule was present in 7 patients (41.1%) (Fig 5B), and regular or irregular septa was present in 4 patients (22.2%) (Fig 5C). The MDCT ndings are shown in Table 3.
The comparison of type A with type B In our study, 9 patients with MESTK were classi ed into type A (Fig 3) and 8 subjects into type B (Fig 4).

Discussion
As a member of the mixed epithelial and stromal tumor family, the imaging characteristics of MESTK and its connection with patients' management remain largely unknown (5). Most of the current literature on MESTK focused on its pathologic features (20,21), with only a small number of case reports and case series addressing its radiologic features (11,22). In our study, 17 patients with MESTK who had an MDCT were collected-the largest imaging series to the best of our knowledge to analyze the imaging and clinical features and with emphasis on providing a reference for patients' management based on the difference in the two types of MESTK.
The typical clinical symptomatology of MESTK includes ank pain, hematuria, or symptoms related to genitourinary infections (20). In our research, only ve patients with ank pain and 2 subjects with hematuria were found in the 17 MESTK cases.
However, most of them (10 patients, 58.82%) were detected MESTK incidentally without any symptoms, which was consistent with the ndings of Lane et al. (9). The possible reason may be advances in imaging modalities and the prevalence of health examinations. Also, MESTKs were found in 13 females (76.5%): 9 of whom were perimenopausal (69.23%). This suggests that perimenopausal females had the predominance of MESTK due to the serum estrogen level. The ndings are in accordance with previous studies (20,23,24). MESTKs are unilateral and single lesions with different proportions of solid components (8,11,12,16). Our cases demonstrated well-circumscribed expansile lesions with a variable proportion of multi-septate cystic and solid components, having delayed enhancement on triphasic dynamic-enhanced MDCT. The delayed enhancement may be related to the abundance of collagen bers, which restrict the diffusion of contrast agent within the tumor (4, 17). Lane et al. found that MESTK commonly tends to extend into the renal sinus (9). In our study, 10 subjects (55.5%) have demonstrated SFI, indicating that nephron-sparing surgery is not the best management plan for such tumors compared to those without the SFI.
In our study, Type A in MESTK is composed mainly of solid elements (> 63% for the ratio of the solid components' MD in the mass), while Type B consists principally of the cystic part (≤ 63% for the percentage of the solid element' MD in the tumor).
Interestingly, the MD of tumor in type B was greater than Type A. The reason may be that epithelial elements existed more in type B than type A. These epithelia then secret uid that accumulates in many various cysts due to the epithelial cells containing much spatulate papillary architectures and tiny crowded glands(4). In addition, our ndings showed that R.E.N.A.L-NS in type B was higher than type A (10.03 ± 0.50 vs. 8.95 ± 1.26, P 0.001), which implies that patients in type B had a higher risk for urine leakage when PN is performed (27

Consent for publication
Not applicable.

Availability of data and materials
The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests.  One or more enhancing nodule(s) ( 4-mm convex protrusion with obtuse margins, or a convex protrusion of any size that has acute margins) *Renal masses have abundant thick or nodular calci cations on MDCT; # Renal tumors are hyperattenuating, homogeneous, nonenhancing, and larger than 3cm on MDCT. Note: pre-= premenopausal; peri-= perimenopausal; post-=postmenopausal; PN=partial nephrectomy; RN=radical nephrectomy; The number in the parentheses was the beginning and endpoint of follow-up time; The creatinine level was normal from 53 to 132.6umol/l; The score standard for the evaluation of R.E.N.A.L. NS as follow: 1point (R ≤ 40mm; E ≥ 50%; N > 7mm; or L: entirely above the upper or below the lower polar line); 2 points (40<R< 70mm; E<50%; 4mm<N <7mm; or L: lesion crosses polar line); 3points (R ≥ 70mm; E = Entirely endophytic; N ≤ 4mm; L: >50% of mass is across polar line or mass crosses the axial renal midline or mass is entirely between the polar lines) [13].
Note: BC= Bosniak Classi cation; NA=not applicable; MD=maximal diameter of tumor; Re-=regular; Irre-=irregular; L=left R=right 1=entirely above the upper or below the lower polar line; 2= lesion crosses polar line; 3=>50% of mass is across polar line or mass crosses the axial renal midline or mass is entirely between the polar lines [13]. SFI = sinus fat invagination; GE = gradual enhancement; GW = gradual washout.   A 56-year-old woman with con rmed MESTK by pathological examination of surgical specimen (Case 3). Axial (Fig 2A) and coronal (Fig 2B, 2C) MDCT images in the excretory phase. The images show the solid-predominant mass extending into the pelvis and ureter (white arrow), which was con rmed histologically, Fig 2D (  A 52-year-old woman with ank pain (Case 13). A slightly hyperdense solid mass in the left kidney was found on the axial unenhanced MDCT (Fig 3A), which shows no enhancement on the corticomedullary phase (Fig 3B), slight enhancement on the nephrographic phase (Fig 3C), further enhancement on the excretion phase ( Fig 3D). It was con rmed as MESTK by histopathological staining with the epithelium and stroma ( Fig 3E) and immunohistochemical staining (   A 49-year-old woman with ank pain (Case 15), A cystic-solid mass is shown on an axial enhancement MDCT (Fig 4A), which displayed slight enhancement with multi-septate cystic and solid components on the corticomedullary phase (Fig 4B), prolonged