|Year : 2020 | Volume
| Issue : 1 | Page : 5-13
The reliability of leptin immunostain use for differentiating renal oncocytoma and chromophobe renal cell carcinoma
Yasmine Fathy Elesawy, Samar Ibrahim Ismail Amer, Ahmed Naeem Eesa
Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
|Date of Submission||18-Nov-2019|
|Date of Decision||14-Dec-2019|
|Date of Acceptance||27-Feb-2020|
|Date of Web Publication||16-Sep-2020|
MD Ahmed Naeem Eesa
Pathology Department, Faculty of Medicine, Cairo University, Cairo
Source of Support: None, Conflict of Interest: None
Background The discrimination between chromophobe renal cell carcinoma (ChRCC) and renal oncocytoma (RO) has been a topic of concern in medicine. Because ChRCC is a malignant tumor, whereas RO is a tumor with benign behavior, it is important to distinguish these two entities. We aimed to study the possible differentiation concepts between ChRCC and RO.
Aim We attempted to study the pathological features of RO and ChRCC and correlate them focusing on the reliability of leptin immunostain use as a tool in differentiation.
Materials and methods A total of 25 cases of renal tumors (17 RO cases and eight ChRCC ones) were studied for clinicopathological features’ correlation and leptin immunohistochemical expression.
Results The included cases’ mean±SD age was 53.1±12.7 years, with range of 28–72 years. The male sex slightly exceeded the female one in prevalence of studied renal neoplasms (52 vs. 48%, respectively). Regarding the size of oncocytoma tumors in gross examination, it had a mean±SD of 5±2 cm, whereas that of ChRCC was 7±4 cm. The central scar is present in only four (23.5%) cases of oncocytoma, being absent in most cases (13 cases, 76.5%). In ChRCC, the nuclear grade 2 is the most common in the studied group (62.5%). Regarding leptin immunostaining scores, positive score was found in 13/17 oncocytoma cases, and only 2/8 cases of ChRCC showed nuclear leptin stain, with significant P value of 0.028. Oncocytoma leptin-positive cases represented 86.70%, whereas those of ChRCC represented 13.30% of total cases. Leptin sensitivity was estimated to be 76.5%, specificity 75.0%, positive predictive value 86.7%, negative predictive value 60.0%, with overall accuracy of 76%.
Conclusion Leptin immunostain can be of an extreme help in differentiating ChRCC and RO.
Keywords: chromophobe renal cell carcinoma, leptin, renal oncocytoma
|How to cite this article:|
Elesawy YF, Amer SI, Eesa AN. The reliability of leptin immunostain use for differentiating renal oncocytoma and chromophobe renal cell carcinoma. Kasr Al Ainy Med J 2020;26:5-13
|How to cite this URL:|
Elesawy YF, Amer SI, Eesa AN. The reliability of leptin immunostain use for differentiating renal oncocytoma and chromophobe renal cell carcinoma. Kasr Al Ainy Med J [serial online] 2020 [cited 2020 Sep 30];26:5-13. Available from: http://www.kamj.eg.net/text.asp?2020/26/1/5/295198
| Introduction|| |
Renal tumors have heterogeneous morphology with a minimum of 16 known subtypes . Differentiation of benign renal oncocytomas (RO) from malignant chromophobe renal cell carcinomas (ChRCC) represents a potential diagnostic dilemma. Both RO and ChRCC arise from the intercalating cells of the distal renal tubules . The discrimination between the two tumors can be tedious owing to overlapping confusing pathologic features .
ChRCC was so termed to reflect the perinuclear cytoplasmic clearing unlike the complete one of clear cell RCC. It accounts for 4–6% of renal epithelial tumors. It is a malignant tumor with metastatic potential but still has a more favorable prognosis than other RCC subtypes. Grossly, it exhibits well-circumscribed encapsulated mass, which has a light-brown to tan colored section. It is traditionally solid, but cystification can occur. Central irregular fibrous bands may be seen. Histologically, the neoplastic cells are polygonal, arranged in sheet-like pattern with delicate fibrovascular septa and poor cellular cohesion. The cell membranes are prominent and thick with plant-like configuration. The nuclei are irregular, crinkled, and angulated, with perinuclear clearing and frequent binucleation. Virtually, there are two variants. In the classic variant, the cells show finely granular reticular pale cytoplasm. On the contrary, in the eosinophilic type, the cells display copious eosinophilic cytoplasm ,.
RO is a benign renal epithelial tumor, composing 6–7% of renal cortical neoplasms. Occasional metastasis was reported in the early literature. The current prevailing opinion is that ‘metastasizing’ oncocytoma is an incorrectly diagnosed RCC, notably chromophobe RCC or coexisting hybrid types. Grossly, they are also well-defined but unencapsulated. They were typically described as of mahogany brown coloration. One-third of cases had a central stellate scar. Cystic change or hemorrhage can be found, but no necrosis. Invasion of perinephric fat may be rarely detected. Cellular nests, tubules, acini, and microcysts can be histologically seen. The cells are large round polygonal with abundant eosinophilic cytoplasm, round nuclei, and inconspicuous nucleoli. Focal degenerative nuclear atypia can be encountered ,.
RO and ChRCC are often thought to be extremities of corresponding morphological spectrum. There are also coexistent cases of RO with ChRCC that are seen in sporadic cases of hybrid tumors, renal oncocytosis, and Birt–Hogg–Dube syndrome. Discrimination of RO and ChRCC, from other more threatening RCC subtypes, is critical for patients’ management and prognosis .
Accurate and conclusive diagnosis of renal mass core biopsy can be difficult owing to the limitation of sample. Pathologists usually build a diagnosis by seeing multiple aspects of tumor cytoarchitecture . Generally, if the lesion appears as ChRCC on small biopsy, some reported as such in an assured matter. In contrast, a lesion that resembles RO, some may think of incomplete sampling, differential diagnosis of eosinophilic variant of ChRCC, hybrid tumor, or oncocytoma-like areas in a ChRCC. Therefore, many would not diagnose RO depending on a needle biopsy. The possibility of ChRCC in other tumor areas is readily documented. Reliable preoperative use of biomarkers for RO and ChRCC may lead to decrease in surgical intervention for benign small renal lesions. Moreover, the pathological features after resection of these tumors usually overlap with confusing clues .
ChRCC can exhibit evident oncocytic features, resembling oncocytoma in frozen section and routine histopathology specimens. Differentiation is of extreme importance for the approach of surgery, for proper postoperative surveillance, and for prognosis of the patient. The pathologists have to be cautious and always consider that encountering a renal mass with oncocytic features or eosinophilic cytoplasm is not equivalent to a straightforward diagnosis of oncocytoma. A differential diagnosis of chromophobe RCC needs to be suggested with seeking correlation with other available data ,.
To date, none of the histochemical techniques, immunomarkers, or cytogenetic features have been ascertained to be reliable and specific . However, immunohistochemical markers may represent as a cost-effective and valuable tool to monitor disease for the sake of prognosis and treatment-planning regimens. The most popular immunohistochemical markers for the differentiation of renal tumors are vimentin, cytokeratin 7 (CK7), CD10, and marker for RCC. Vimentin is declared to be positive in clear cell renal cell carcinoma (ccRCC), whereas negative in ChRCC and RO. CK7 is seen to be positive in ChRCC but negative in RO and ccRCC. Marker for RCC and CD10 are positive in ccRCCs but negative in both ChRCCs and ROs. Hale’s colloidal iron staining is seen in ChRCC with diffuse reticular pattern and perinuclear halo but not in RO and ccRCC . Nevertheless, many differentiation pitfalls, staining assessing problems, and controversy around a reliable marker do exist.
Focusing on leptin (Ob), it is a peptide hormone secreted by fat, first and best identified for being an appetite suppressant, and energy balance regulator by hunger inhibition. Leptin is a small molecule, is mainly cleared by the kidney, through a megalin-mediated tubular uptake in the proximal convoluted tubule. This is followed by endocytosis and intracellular degradation. Therefore, little or no leptin appears in urine ,. Leptin also performs a role in carcinogenesis through cell proliferation, angiogenesis, apoptotic inhibition, and proinflammatory effects through its receptor interaction ,,.
Leptin is known to act as a mitogen, inflammatory, and pro-angiogenic factor that induces cancer cell proliferation and tumor angiogenesis. Moreover, leptin signaling induces cancer stem cells, which are involved in cancer recurrence and drug resistance. Aberrant expression of leptin and Ob-R is involved in pathogenesis and development of numerous cancers . We investigated leptin immunostaining in RO and ChRCC as an approach to unravel their diagnostic confusion.
| Aim|| |
The aims of the work are as follows:
- To study RO and ChRCC pathological features and correlate them.
- To examine leptin immunostaining patterns in these tumors, as an attempt to differentiate between them in a reliable manner.
| Materials and methods|| |
This retrospective institutional study was conducted by collecting data and tissue blocks from Kasr Al-Ainy Hospital, Cairo University. Pathologic records of patients who underwent nephrectomy tumors between 2013 and 2018 were assessed. The study was approved by the Ethics committee of the Faculty of Medicine, Cairo University, for use of patients’ samples for research purposes.
We retrieved 25 cases of targeted renal neoplasms (17 cases of RO and eight ones of ChRCC). Tumoral paraffin-embedded cell blocks were collected. Hematoxylin and eosin-stained slides were reviewed, and diagnosis was confirmed based on the presence of specific morphologic features. Selecting the tumor block with viable tumor tissue and preserved cellular architecture was done. Those with marked necrosis or poor fixation were excluded.
Serial sections (4 μm) were prepared from the tumor cell blocks and mounted on adhesive-coated glass slides for leptin staining. Primary antibody used is a rabbit antihuman polyclonal anti-leptin antibody (Chongqing Biospes Co., Jiangbei District, Chongqing, China) at 1 : 100 dilution. Immunohistochemistry autostainer (BenchMark ULTRA, Ventana, Arizona, USA) was used for immunohistochemistry staining.
Every staining run contained a slide section of placenta tissue, employed as a positive control. A negative control is done by omitting the primary antibody. The immunostained entire slide had been evaluated and subsequently scored by light microscopy, provided that the staining did not represent background or artifact.
Hematoxylin and eosin-stained sections were evaluated by light microscopy along with leptin immunohistochemically stained slides.
The available data were collected and tabulated, including patient’s age and sex, as well as pathological factors such as tumor size, central scar presence in gross picture, and nuclear grading in ChRCC.
Two grading systems were applied regarding ChRCC: the classic Fuhrman nuclear grading (FNG) and the novel chromophobe tumor one (illustrated in [Table 1]) ,,.
|Table 1 The criteria of two tumor grading system for chromophobe RCC |
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Immunohistochemical leptin staining evaluation was done by scoring leptin stain intensity, as well as cytoplasmic and nuclear localization. Staining was subjectively scored according to the intensity and percentage of cells stained to three-tiered system: (a) nil/weak focal, (b) moderate focal, and (c) intense diffuse. Marker’s positivity is estimated when there is cytoplasmic intense diffuse or moderate focal staining with prerequisite of nuclear stain evident localization .
Data management and statistical analysis were performed using the Statistical Package for Social Sciences, version 24 (Armonk, New York, United States).
Numerical data were summarized using means, SDs, and ranges. Data were explored for normality using Kolmogorov–Smirnov test and Shapiro–Wilk test. Categorical data were summarized as percentages. Comparisons between the two groups with respect to normally distributed numeric variables were done using the independent t test. For categorical variables, differences were analyzed with Fisher’s exact test. All P values are two sided. P values less than or equal to 0.05 were considered significant. The leptin immunomarker sensitivity, specificity, as well as overall accuracy with positive and negative predictive values were calculated.
| Results|| |
This paper seeks to analyze the possible differentiation concepts between ChRCC and RO, with special consideration for the applicability of leptin immunostain use.
The study includes 25 cases of renal neoplasms (17 oncocytoma cases and eight ChRCC). The included cases’ mean age±SD is 53.1±12.7 years, with range of 28–72 years ([Figure 1]). The male sex slightly exceeds the female one in the prevalence of studied renal neoplasms; male represents 52%, whereas female represents 48% of cases ([Table 2], Graphs 1 and 2). Regarding the size of oncocytoma tumors in gross examination, it has a mean±SD of 5 ±2 cm, whereas that of ChRCC is 7±4 cm. Five cases of ChRCC were T1 (62.5%), whereas three of them were T2 (37.5%).
|Figure 1 (a) Chromophobe renal cell carcinoma case showed sheet pattern of malignant cells with prominent cytoplasmic borders and wrinkled nuclei. (b) Oncocytoma case showed nests of cells with abundant eosinophilic cytoplasm and round nuclei (hematoxylin and eosin stain, ×400 and ×200).|
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Central stellate scars are characteristic of RO, but they are not a diagnostic feature. In our study, the central scar is present in only four (23.5%) cases of oncocytoma, being absent in most cases (13 cases, 76.5%). None of ChRCC showed a central scar grossly.
ChRCC has better prognosis than clear cell RCC. However, owing to irregular nuclei and nuclear pleomorphism, ChRCC’s high FNG can cause confusion to the clinicians owing to the inconsistency of good prognosis and high grade ,. Regarding the studied cases of ChRCC, the Fuhrman nuclear grade 2 was the most common in the studied group (62.5%), followed by nuclear grade 1 (25%), and then 3 (12.5%). By the application of chromophobe tumor grade (CTG) novel three-tier grading system, most cases showed grade 1 (80%), whereas the rest showed grade 2 (20%). None of the ChRCC cases showed grade 3 ([Figure 2]).
|Figure 2 (a) Chromophobe renal cell carcinoma case showed nuclear grade 1 without nuclear crowding. (b) Another case with nuclear grade 2 showed nuclear crowding and pleomorphism (hematoxylin and eosin stain, ×200).|
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Regarding leptin immunostaining scores in this study, leptin stain was assessed by different expression patterns and distribution. In most RO cases, it showed the highest intensity with cytoplasmic staining and a diffuse prominent nuclear localization. In contrast, leptin showed no apparent nuclear localization with weak intensity in most ChRCC cases. Surrounding compressed non-neoplastic renal tissue was seen in ten dissected tumoral blocks of the studied cases. This showed leptin focal cytoplasmic and nuclear staining with weak intensity ([Figure 3] and [Figure 4]).
|Figure 3 (a, c) Chromophobe renal cell carcinoma case showed subtle cytoplasmic immunostaining with no nuclear stain. (b, d) Oncocytoma case showed intense cytoplasmic immunostaining with nuclear stain accentuation (leptin immunostain, ×200 and ×400).|
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|Figure 4 (a) Adjacent non-neoplastic cortical renal tissue showed weak cytoplasmic immunostaining with focal nuclear localization. (b) A chromophobe renal cell carcinoma case showed weak granular cytoplasmic immunostaining with wide nuclear localization (leptin immunostain, ×400).|
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These tabulated results showed positive score in 13/17 oncocytoma cases, whereas only 2/8 cases of ChRCC showed nuclear leptin stain, with significant P value of 0.028. Oncocytoma-positive leptin cases represent 86.70%, whereas those of ChRCC represent 13.30% of total cases ([Table 3]). Leptin sensitivity was estimated by 76.5%, specificity 75.0%, positive predictive value 86.7%, negative predictive value 60.0%, with overall accuracy of 76%.
These results provide important insight to the possibility of leptin immunostain as a tool of discrimination between RO and ChRCC in histopathological evaluation.
| Discussion|| |
The identification of benign RO and its differentiation from malignant renal tumors are a continuous challenge for diagnostic disciplines, including pathology, radiology, and urology, because there are no absolute distinctive bases. This influences preoperative planning and acts as a nightmare stress factor for patients. This diagnostic dilemma is more aggravated by the presence of the eosinophilic or oncocytic subtypes as well as tumor regressive changes as cystification and necrosis ,.
As a contributing trial to solve this dilemma, our study included 25 cases of renal neoplasms (17 oncocytoma cases and eight ChRCC). The included cases’ mean±SD age was 53.1±12.7 years, with range 28–72 years. The male sex slightly exceeded the female one in the prevalence of studied renal neoplasms; male represents 52%, whereas female represents 48% of cases. Regarding the size of oncocytoma tumors in gross examination, it has a mean±SD of 5±2 cm, whereas that of ChRCC is 7±4 cm. Five (62.5%) cases of ChRCC were T1, whereas three (37.5%) of them were T2.
These findings were in concordance with previous studies. Romis et al.  in their multicentric oncocytoma study stated that oncocytoma usually occurs during the seventh decade of life, varying from 20 to 86 years of age, with predominance in males. According to the cohort of Ng et al. , male to female ratio was 2 : 1, median age was 64 (45–88 years), and median tumor size was 3.8 cm (range, 1.2–18 cm). T1 represented 62.7% of their studied ChRCC cases.
This is also in accordance with that found by Demirović et al.  who studied 37 cases in total (18 ChRCC and 19 RO). Their study of ChRCC cases showed patients’ age ranged from 34 to 76 years (mean, 56.9 years). Tumor size ranged from 1.7 to 17 cm (mean, 7.9 cm). For RO, patients’ age ranged from 47 to 80 years (mean, 65.2 years). Tumor size ranged from 0.9 to 8 cm (mean, 3.6 cm). However, the findings of the current study do not support the female sex predominance found by Demirović et al. . Among the patients with CRCC, 10 were females, and eight were males. Among patients with RO, 12 were females, and seven were males. This may be attributed to the geographic and genetic variability between patients .
Although the central stellate scar is considered a classic book-description for the gross surgical appearance and radiological imaging of oncocytoma, the studied cases of oncocytoma in our study showed that central scar is present in only 23.5% of cases. None of ChRCC showed a central scar grossly. This was also reported by Woo et al. , where only 33% of their oncocytoma cases, especially in lesions larger than 2.5 cm in diameter, showed central scar. They stated that its absence does not exclude oncocytoma diagnosis, as it is not a pathognomonic sign. A stellate fibrous segment cannot be differentiated on imaging from the central necrosis (a common finding in renal cell carcinoma).
As every day we acquire more knowledge in oncological morphology, new subtypes of RCC were defined by the WHO in 2016. It was realized that the FNG system had to be reanalyzed for validation for use of these RCC subtypes. It was proposed that this WHO/International Society of Urological Pathology grading system is only applicable for clear cell RCC and papillary RCC . To analyze grading systems in this study, most ChRCC cases showed FNG 2 (62.5%), followed by nuclear grade 1 (25%), then 3 (12.5%). By the application of CTG novel three-tier grading system, most cases showed grade 1 (80%), whereas the rest showed grade 2 (20%). None of the ChRCC cases showed grade 3. This finding corroborates the idea of Lin et al.  who studied 18 patients with ChRCC. The majority of these cases showed nuclear grades FNG 2 (56%) and CTG 1 (78%). This assured the delivered fact of good prognosis of ChRCC as compared with classic clear RCC.
An initial objective of this paper was to identify the reliability of leptin immunostain use in differentiating RO and ChRCC. Leptin stain was assessed by different expression patterns and distribution. Most RO cases showed intense staining with a diffuse prominent nuclear localization. In contrast, leptin showed no apparent nuclear localization with weak intensity in most ChRCC cases. The cases with surrounding compressed non-neoplastic renal tissue showed leptin focal cytoplasmic and nuclear staining with weak intensity.
These tabulated results showed positive score in 13/17 oncocytoma cases, whereas only 2/8 cases of ChRCC showed nuclear leptin stain, with significant P value of 0.028. Oncocytoma-positive leptin cases represent 86.70%, whereas those of ChRCC represent 13.30% of total cases. It was encouraging to find that the estimated leptin sensitivity was 76.5%, specificity 75.0%, positive predictive value 86.7%, negative predictive value 60.0%, with overall accuracy of 76%.
The findings of the current study are consistent with Ng et al.  who observed significant high nuclear leptin expression in RO compared with ChRCC and clear cell RCC.
Many studies in literature explored immunomarker use in differentiating oncocytic renal tumors. The majority of markers showed positive scores in ChRCC not in RO. There has been little analysis of positive immune markers in RO, which is an advantage of the current leptin study. Comparing leptin immune marker scoring with other markers used in RO and ChRCC differentiation, leptin showed comparable sensitivity and specificity to caspase 3 (CASP3) and CK7. CASP3 showed 75% specificity, whereas the sensitivity was 86%. Compared with RO, a higher percentage of the total ChRCCs stained positive for CK7 (67 vs. 22%, respectively) and CASP3 (86 vs. 25%). CK7 had high specificity (78%) and lower sensitivity (67%) as stated by Kowalski et al. . They declared that CASP3 was a promising marker in distinguishing ChRCC from RO and may represent an alternative for CK7. Cyclin D1, p16, survivin, CD138, and Ki-67 cannot be used to distinguish these neoplasms. In the study of Ohe et al. , comparing with RO, they found a significantly higher percentage of the total ChRCCs stained positive for CK7 (85 vs. 10%, respectively), CD82/KAI1 (90 vs. 10%), epithelial-specific antigen (95 vs. 10%), epithelial-related antigen (95 vs. 10%), and Claudin-7 (95 vs. 20%). We recommend that leptin nuclear immunostain can be added to the panel to discriminate RO.
On the contrary, Kuroda et al.  examined the expression of S100A1 protein in 18 renal tumors (four RO, 10 ChRCC, and four oncocytic papillary RCC). All the cases of RO and oncocytic papillary RCC showed a positive reaction for S100A1 with cytoplasmic pattern. In ChRCC, seven of 10 were completely negative for S100A1. They declared that S100A1 immunohistochemistry may be useful in distinguishing RO from chromophobe RCC, but it may be of no use in the differential diagnosis between RO and oncocytic papillary RCC. This finding cannot be evaluated by the current study, as it is limited by the lack of information on leptin immune stain in oncocytic papillary RCC which is beyond the scope of the studied cases.
Leptin immune stain can be a promising marker to distinguish RO and ChRCC, especially if used in a panel with other markers that stain ChRCC. This has an important effect in surgical management and patient prognosis.
Conclusions and recommendations
In close scrutiny, nuclear expression of leptin in RO had a significantly higher intensity versus ChRCC. This finding, though preliminary, suggests that leptin immunostain can be used as a reliable differentiating tool among the integration of the other diagnostic aspects. These data must be interpreted with caution, as further large-scaled multi-institutional studies are still needed for mass marker validation. More oncoytic subtypes of RCC, other than RO and ChRCC, should be also included.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3]