Diagnostic accuracy and clinical outcomes of patients diagnosed with clear cell papillary renal cell tumour at renal mass biopsy

Abstract

Background

Clear cell papillary renal cell tumour (CCPRCT) is a clinically indolent neoplasm. The diagnosis of CCPRCT at renal mass biopsy (RMB) may facilitate conservative management; however, this can be challenging in small samples and there are limited data on the outcome of patients managed conservatively. This study aimed to: (1) evaluate concordance between RMB and nephrectomy for the diagnosis of CCPRCT, and (2) determine the clinical outcomes of patients with CCPRCT, particularly those who have undergone conservative management.

Methods and Results

We reviewed all cases at our institution where CCPRCT was diagnosed or included in the differential diagnosis at RMB. In all, 65 RMB with a diagnosis/differential diagnosis of CCPRCT were identified, including 25 patients who had subsequent surgical resection. Of cases where CCPRCT was the likely or favoured diagnosis on RMB (n = 19), the final diagnosis was concordant in 16/19 (84%). Discordant cases comprised clear cell renal cell carcinoma (ccRCC) (n = 1) and RCC with fibromyomatous stroma (n = 2). In all, 15 patients were managed with active surveillance (median follow‐up 34 months) and 26 were treated with ablation (median follow‐up 37 months). There was no recurrence, metastasis, or death in the cohort.

Conclusion

CCPRCT can be reliably diagnosed at RMB in most cases if strict morphologic and immunohistochemical (IHC) criteria are applied. Furthermore, there was no adverse behaviour among patients managed nonsurgically in our cohort. It is important, however, to recognize the limitations of RMB, particularly given that occasional examples of ccRCC can show foci resembling CCPRCT. Pathologists and treating clinicians should be aware of the limitations of RMB when considering conservative management.

Clear cell papillary renal cell tumours can be identified on renal mass biopsy if strict morphologic and immunohistochemical criteria are used. We found a high concordance between the biopsy and resection diagnoses of these tumours and that patients treated nonsurgically had favourable clinical outcomes.

Abbreviations

CCPRCT

clear cell papillary renal cell tumour

ccRCC

clear cell renal cell carcinoma

RCC FMS

renal cell carcinoma with fibromyomatous stroma

WHO

World Health Organization

Introduction

Clear cell papillary renal cell tumour (CCPRCT) is a distinct renal neoplasm that is typically discovered incidentally as a small renal mass. ¹ , ² Previously known as clear cell papillary renal cell carcinoma, this was revised in the 2022 World Health Organization (WHO) ³ with removal of the ‘carcinoma’ label to better reflect its indolent clinical behaviour. Until recently, there was no well‐documented case of recurrence or metastasis of CCPRCT, although a report by Gupta et al. ⁴ suggests that there may be very rare exceptions. Most studies have focused on surgically treated cases, while data on CCPRCT diagnosis on renal mass biopsy (RMB) and outcomes following nonsurgical management are limited. ⁵

The diagnostic features of CCPRCT are well described. ⁶ Morphologically, they are composed of clear cells with low‐grade nuclei, often with luminal nuclear orientation, arranged in a variety of architectural patterns, including tubules, papillae, nests, and cysts (Figure 1). The expected immunohistochemical (IHC) profile includes diffuse positivity for CK7 and CA‐IX in a ‘cup‐like’ membranous distribution, while other stains, such as GATA3 and high molecular weight cytokeratin, may also be positive. Several other tumour entities can be considered in the differential diagnosis, with clear cell renal cell carcinoma (ccRCC) being the most common. Importantly, this distinction can occasionally be challenging, as some tumours may exhibit overlapping features. ⁷ , ⁸ , ⁹

Figure 1.

Example of the typical architectural and immunohistochemical features of CCPRCT on RMB that was confirmed on subsequent nephrectomy. (A,B) H&E stain showing tubular and papillary architectures with low‐grade nuclear features and luminal nuclear orientation (see arrows in B). (C,D) CAIX immunohistochemistry showing membranous basolateral ‘cup‐like’ pattern (see arrows in D). (E) CK7 immunohistochemistry showing diffuse cytoplasmic staining. (F) Positivity for HWMK. (G) Positivity for GATA3. (H) Absence of membranous staining with CD10 immunohistochemistry. [Color figure can be viewed at wileyonlinelibrary.com]

RMB is increasingly used to identify patients with benign or indolent renal tumours who may be good candidates for active surveillance (AS) or nonsurgical ablative therapies. While most pathologists are comfortable diagnosing CCPRCT on resection specimens, the diagnosis in RMB can be more challenging, due to the potential for misclassification with limited tissue sampling and overlap with ccRCC. Moreover, outcomes for patients with CCPRCT managed nonsurgically have only been reported in a small number of cases. ⁵ This study aimed to:1) evaluate concordance between RMB and nephrectomy for the diagnosis of CCPRCT, and 2) determine the clinicopathologic features and outcomes of patients following a diagnosis of CCPRCT on RMB, including those managed conservatively.

Methods

The study was approved by the Institutional Research Ethics Board (CAPCR 22‐5436). Cases were identified from the Institutional Laboratory Information System between 2010 and 2023. The study cohort included all in‐house cases of RMB with a diagnosis or differential diagnosis that included CCPRCT. The diagnostic certainty based on the original report was recorded as: (i) consistent with/favour CCPRCT, or (ii) CCPRCT in differential diagnosis. As this study was focused on RMB, patients with a diagnosis of CCPRCT on surgical resection who did not undergo preoperative RMB were not included.

Slides were reviewed by a urologic pathologist (S.P.) to confirm the original diagnosis and IHC was performed as required based on morphologic features. Concordance with final classification was evaluated in patients with subsequent resection. Discordance was defined as RMB consistent/favour CCPRCT and alternate diagnosis after resection. Patients with CCPRCT in differential diagnosis and an alternate diagnosis after resection were not considered discordant.

Tumour size was based on the documented radiologic measurement at the time of RMB for patients undergoing surveillance/ablation or the macroscopic pathologic measurement for patients undergoing nephrectomy. Pathologic stage at nephrectomy was assigned based on AJCC 8th edition parameters.

IHC was performed using 4 μm‐thick formalin‐fixed paraffin‐embedded sections pretreated with Cell Conditioning 1 solution (Roche Diagnostics, Tucson, AZ, USA). Incubation with primary antibodies was performed using Roche Benchmark ULTRA followed by visualization with OptiView DAB IHC Detection Kit (Roche DiagnosticsA). Primary antibodies used were CK7 (clone OV‐TL12/30, Dako/Agilent, Santa Clara, CA, USA), CAIX (clone TH22, Leica Biosystems, Deer Park, IL, USA), GATA3 (clone: L50‐823, Intermedico, Markham, ON, CA), HMWK (clone 34BE12, Dako/Agilent); CD10 (clone 56C6; Leica Biosystems, Newcastle Upon Tyne, UK). Molecular analysis was not routinely performed; however, next‐generation sequencing (NGS) was conducted on one resected tumour with overlapping features.

Clinical and follow‐up data were obtained from the electronic patient records including age at diagnosis, sex, treatment, length of follow‐up, recurrence, metastasis, and vital status at last follow‐up.

Results

The study cohort comprised 65 tumours from 64 patients (one patient had RMB of two separate tumours). The median patient age at diagnosis was 63 years (range 26–90) and the male: female ratio was 1.03:1.0. Median tumour size was 2.1 cm (range 0.9 to 5.5 cm). The RMB diagnosis was consistent with or favoured CCPRCT in 53/65 (82%) cases, while in 12/65 (18%) cases CCPRCT was in the differential. The latter included one case where ccRCC was favoured and one case where RCC with fibromyomatous stroma (RCC FMS) was favoured, while the remaining 10 cases were reported descriptively with a list of differentials that included CCPRCT. The initial management was AS (n = 15, 23%), ablation (n = 26, 40%), or nephrectomy (n = 24, 37%), see Table 1.

Table 1.

Initial management

Initial management	N (%)	Median tumour size (range), cm
Active surveillance	15 (23)	1.5 (0.9–3.7)
Ablation	26 (39)	2.1 (1.3–3.3)
Radiofrequency ablation	18 (27)
Cryoablation	8 (12)
Nephrectomy	24 (37)	2.5 (1.0–5.5)
Partial	18 (28)
Radical	6 (9)
Total cohort	65	2.1 (0.9–5.5)

Outcome of patients managed nonsurgically

Follow‐up information was available for 14/15 (93%) patients initially managed with AS with a median follow‐up of 34 months (mean 43 months; range 1–142 months). All patients managed with AS had an initial tumour size <4 cm. One patient proceeded to partial nephrectomy due to increasing tumour size (5.5 cm at resection) and patient factors; the diagnosis of CCPRCT was confirmed at resection. Eleven patients remained on surveillance at last follow‐up, while two patients died of other causes.

Of patients treated with ablation, follow‐up information was available for 25/26 (96%) with a median follow up of 37 months (mean 44 months; range 1–120 months). One patient underwent a second ablation due to residual viable tumour postprocedure. There was no evidence of recurrence or metastasis among the cohort.

Concordance with subsequent surgical resection

Of the entire cohort, 25 patients (37%) had subsequent surgical resection (including one patient initially managed with AS, as noted above). The final diagnosis at resection was CCPRCT in 18/25 (72%); RCC FMS in 5/25 (20%); ccRCC in 1/25 (4%); and multilocular cystic renal neoplasm of low malignant potential in 1/25 (4%). Of these, the original biopsy report did not commit to or favour a specific diagnosis in six cases (CCPRCT was in the differential with other low‐grade clear cell neoplasms) and these were therefore not considered discordant. Among cases where CCPRCT was the likely or favoured diagnosis on RMB (n = 19), the final diagnosis was concordant in 16/19 (84%). The three discordant cases were classified as ccRCC (1/19, 5%) and RCC FMS (2/19, 10%) at resection.

The IHC profile for all 18 cases confirmed to be CCPRCT at resection were: CK7‐positive (18/18, 100%), CA‐IX cup‐like‐positive (18/18, 100%), AMACR‐negative (18/18, 100%), 34BE12‐positive (16/16 tested, 100%), CD10‐negative (16/17 tested, 94%), and GATA3‐positive (11/14 tested, 79%).

Postsurgical follow‐up was available for 21 patients (84%), including the three discordant cases, and there was no evidence of recurrence or metastasis with a median follow‐up period of 60 months (range 10–118 months).

Discordant cases

Details of the three discordant cases are outlined in Table 2. At resection, the discordant case with a final diagnosis of ccRCC showed CCPRCT‐like areas admixed with conventional ccRCC (Figure 2). NGS performed on this case confirmed the presence of a VHL mutation. Retrospective review of this case showed positivity for CD10 and negativity for GATA3.

Table 2.

Features of three discordant cases

	Case 1	Case 2	Case 3
Nephrectomy diagnosis	ccRCC	RCC FMS	RCC FMS
Tumour size (cm)	3.1	2.5	1.1
ISUP/WHO grade	2	2	2
Pathologic stage	pT1a	pT1a	pT1a
CAIX	Cup‐like in areas	Cup‐like in areas	Cup‐like in areas
CK7	Positive	Positive	Positive
34BE12	Negative	Negative	Focal positive
CD10	Positive	Negative	Focal positive
AMACR	Focal positive	Negative	Negative
GATA3	Negative	Negative	Negative

Figure 2.

Discordant case (Case 1) which was diagnosed as ccRCC at resection. H&E sections demonstrating low‐power view (A), admixed CCPRCT‐like and ccRCC areas (B), higher‐power view of ccRCC (C), and CCPRCT‐like (D) areas. [Color figure can be viewed at wileyonlinelibrary.com]

Discussion

CCPRCT was originally described in patients with endstage renal disease (ESRD) ¹⁰ and subsequently found to occur sporadically, ¹¹ with one series reporting it as the fourth‐most common RCC subtype. ¹² While the indolent nature of this tumour has been recognized for some time, the 5th WHO classification ³ formally removed the carcinoma label, suggesting that it can be managed as a benign neoplasm. The diagnosis of CCPRCT on RMB can be challenging, and most series to date have focused on surgically resected tumours. In this study we aimed to evaluate the accuracy of RMB for the diagnosis of CCPRCT and to assess clinical outcome for patients managed nonsurgically.

Most studies have demonstrated that CCPRCT is an indolent neoplasm with very favourable prognosis. ¹¹ , ¹³ , ¹⁴ Occasional tumours can show locally advanced features in the form of renal vein/sinus/pelvicalyceal involvement, but this does not appear to confer an adverse prognosis. ¹⁵ While previous rare reports of metastatic behaviour could not be fully substantiated, ⁵ , ¹⁶ Gupta et al. ⁴ recently reported a patient who developed metastasis 13 years post nephrectomy. In this case both the primary and metastatic tumour were extensively characterized, supporting the existence of rare cases with adverse behaviour. This may be similar to oncocytoma where rare, well‐characterized examples of metastasis also exist. ¹⁷ Despite this, the overwhelming majority of CCPRCT appear to have a benign outcome, although most studies have focused on surgically resected tumours. Our series provides further data on patients managed nonsurgically, with no adverse behaviour among those placed on surveillance and treated with ablation.

In 18% of our cases the RMB reported a differential only, highlighting the challenges that exist due to the overlapping features of various low‐grade clear cell renal neoplasms.

Of cases in our series where CCPRCT was the likely or favoured diagnosis at RMB, the final diagnosis at resection was concordant in 84% (16/19). It is recognized that occasional ccRCC can show morphologic overlap with CCPRCT, ⁷ , ⁸ , ⁹ leading to caution against making a definite diagnosis of CCPRCT on RMB. ³ In line with this, one case in our series where the favoured diagnosis at RMB was CCPRCT was ultimately classified as ccRCC at final diagnosis, although it can be noted that low‐grade pT1a ccRCC also has a generally favourable outcome. ⁴ CCPRCT consistently shows diffuse CK7 and CAIX expression, typically in a cup‐like distribution, which differs from classic ccRCC. However, in our experience distinguishing cup‐like vs circumferential CAIX staining can sometimes be difficult in limited biopsy samples and some ccRCC can show more diffuse CK7 staining. ¹⁸ CCPRCT is also expected to show negative or minimal labelling with AMACR and CD10 and is frequently positive for HMWK and GATA3. Retrospective review of the discordant case showed variable positivity for CD10 and negativity for GATA3, highlighting the importance of performing a complete IHC work‐up of possible CCPRCT cases before favouring a diagnosis on RMB.

RCC FMS is not currently recognized as a distinct tumour entity, but describes a group of neoplasms with shared histopathologic features including those with ELOC and TSC1/2 alterations. ¹⁹ In this series, two discordant cases were ultimately classified as RCC FMS. Features that distinguish RCC FMS include elongated and frequently branching tubules without significant luminal nuclear orientation, intervening fibromuscular stroma, circumferential CA‐IX staining, and more frequent CD10 positivity. ⁶ , ¹⁹ However, these tumours can show considerable overlap with CCPRCT, even on resection and distinguishing features may not be represented on limited biopsy material. It is also worth noting that molecular testing was not available at the time of reporting. Studies to date have reported favourable outcomes for these tumours, particularly in the absence of high‐grade nuclear features. ²⁰ , ²¹

In cases where a diagnosis of CCPRCT is being considered on RMB, we would advocate performing a complete IHC panel where possible to include CK7, CAIX, GATA3, CD10, and HMWK. Based on our experience, tumours with characteristic morphology and supportive IHC findings can be reported as ‘consistent with’ or ‘favouring’ CCPRCT, accompanied by communication in the form of a comment or multidisciplinary discussion to convey possible limitations of RMB in this setting. In tumours with overlapping or ambiguous findings at RMB, our practice is to provide a descriptive diagnosis such as ‘clear cell renal neoplasm with low‐grade features’ with the differential described as appropriate. In all cases, management decisions should involve the integration of clinical, radiological, and RMB findings and shared decision‐making with the patient. ²² , ²³ , ²⁴

A limitation of the present study was that the diagnoses were based on morphologic and IHC findings, with additional molecular testing not performed in the majority of cases. CCPRCT does not have specific molecular findings but lacks alterations characteristic of other tumour types, such as VHL, ELOC, or TSC mutations. However, in clinical practice molecular analysis is not routinely performed for diagnostic purposes and many laboratories do not have access to such testing. Furthermore, the utility of this type of testing in limited RMB samples is uncertain. For patients managed nonsurgically, the diagnosis was based on RMB only and it's possible that some of these cases would be reclassified on resection. Despite this, the lack of adverse behaviour among the cohort is reassuring.

In conclusion, CCPRCT can be reliably diagnosed at RMB in the majority of cases if strict morphologic and IHC criteria are applied and there was no adverse behaviour among patients managed nonsurgically in our cohort. However, it's important to recognize the limitations of RMB, particularly given that occasional examples of ccRCC can show foci resembling CCPRCT. Our findings suggest that conservative management may be considered for patients with a diagnosis of CCPRCT at RMB in the appropriate multidisciplinary setting.

Conflict of interest

There are no conflicts of interest to declare for any of the study's authors. The study was approved by the Institutional Research Ethics Board (CAPCR 22–5436).

Data availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.