Non-clear cell renal cell carcinoma narrative review: where we are in 2024

Introduction

Background

Clear cell renal cell carcinoma (RCC) constitutes 75% of RCCs, while the remaining 25% is made up of dozens of distinct histologic variants such as papillary, chromophobe, translocation, unclassified, and medullary RCC which collectively constitute non-clear cell RCC (1).

Rationale and knowledge gap

While our understanding of the underlying molecular and genetic aberrations of RCC has greatly advanced in recent years, there remains significant disparity in knowledge between the more common clear cell RCC and the less common and heterogeneous group of variant histology.

Objective

This review will endeavor to provide an update on the molecular and pathologic characteristics of variant RCC histology, as well as review the available clinical trial data specific to non-clear cell RCC. We present this article in accordance with the Narrative Review reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-737/rc).

Methods

Relevant publications to the histopathologic diagnosis of RCC as well as the updated pathologic diagnostic definitions and evolving molecular and genetic signatures of variant histology RCC were searched for by the authors (Table 1). Additionally, the published clinical trial data including significant numbers of patients with non-clear cell RCC were collected, synthesized, and summarized by the authors for the creation of this narrative review.

Molecular and pathologic characteristics of variant RCC histology

Papillary RCC and its differential diagnosis

Papillary RCC is the most common non-clear cell variant, accounting for approximately 15% of RCC (1). The molecular pathogenesis of papillary RCC was first described when studying patients with inherited forms of RCC, an autosomal dominant condition with high penetrance that often results in multifocal and bilateral papillary RCC tumors. In the hereditary form, germline mutations in MET are frequently seen, while somatic mutations in MET are seen in 10–20% of the sporadic form (2-4). Altogether, MET alterations are seen in 81% of patients with papillary RCC and typically arise in the form of increased copy number of chromosome 7, splice variants, or gene fusion (4).

Papillary RCC is named for the typical papillary architecture observed histologically. However, areas of tumor with other architectural patterns including tubular and solid are commonly observed within papillary RCCs. The tumor cells demonstrate a spectrum of cytologic features ranging from smaller cuboidal cells with lower grade nuclear features [World Health Organization (WHO)/International Society of Urologic Pathologists (ISUP) grade 1 or 2] to larger cells with hyperchromatic nuclei and large nucleoli (WHO/ISUP grade 3). Sarcomatoid or rhabdoid differentiation (WHO/ISUP grade 4) is infrequently observed (5). While cytologic features previously informed the distinction between type I and type II papillary RCC, this distinction is no longer used in the 2022 WHO classification of renal tumors due to poor interobserver reproducibility and questionable clinical significance (6). Papillary RCCs typically express CK7, CD10, and p504S by immunohistochemistry.

Other RCC subtypes can show strikingly similar morphologic features to “type II” papillary RCC and may only be confidently distinguished by the use of immunohistochemical stains and/or cytogenetic or studies, such as translocation RCC and fumarate hydratase (FH)-deficient RCC (discussed later). Other distinct tumors of the kidney on the differential diagnosis with papillary RCC include the recently described papillary renal neoplasm with reverse nuclear polarity characterized by KRAS mutations, papillary urothelial carcinoma of the renal pelvis, and mucinous tubular and spindle cell RCC (7). Of note, the entity formerly known as clear cell papillary RCC, which typically has tubulopapillary architecture but more morphologic overlap with clear cell RCC than papillary RCC, has been renamed as clear cell papillary renal cell tumor in WHO 2022 to reflect its indolent nature.

Chromophobe RCC and its differential diagnosis

Chromophobe carcinoma develops from the intercalated cells located in the cortical collecting ducts, and typically have a favorable prognosis as only 5% are found to be metastatic at diagnosis (8). This subtype exhibits a wide variety of genetic alterations, including losses on chromosomes 1, 2, 6, 10, 13, 17, and 21. Frequently implicated genes are TP53, PTEN, and TERT (4,9). Chromophobe RCC is also associated with germline cancer syndromes such as Birt-Hogg-Dube syndrome and Cowden syndrome. In the former, there is an association with germline mutation in FLCN, and germline mutations in PTEN in the latter (10). A recent comprehensive genome study of chromophobe RCC found recurrent DNA rearrangement breakpoints within the TERT promoter region, which is a relatively unique mechanism compared to TERT point mutations seen in other malignancies (3).

Chromophobe RCC is characterized histologically by its prominent cell membranes imparting a “plant cell-like” appearance. The cytoplasm can either be clear to flocculent or eosinophilic. The tumor cells typically demonstrate nuclear abnormalities such as binucleation, perinuclear clearing, and irregular nuclear contours. Due to its inherent nuclear irregularity, the WHO/ISUP nuclear grading system is not applied to chromophobe RCC (5).

The main differential diagnostic consideration for an eosinophilic chromophobe RCC is oncocytoma. It lacks the widespread nuclear atypia of chromophobe RCC but can show degenerative atypia and in a minority of cases can represent a challenging distinction (5). Immunohistochemistry is extremely helpful in this scenario. While both tumors express c-kit (CD117), chromophobe is distinguished by diffuse CK7 expression. A spectrum of emerging entities with oncocytic cytoplasm, some morphologic resemblance to chromophobe or oncocytoma, and somatic tuberous sclerosis complex (TSC)/mammalian target of rapamycin (mTOR) mutations have recently been described. Eosinophilic, solid and cystic RCC is aptly named for its histologic features and distinctly expresses CK20. Eosinophilic vacuolated tumor shows high-grade nuclear features overlapping with chromophobe despite its indolent behavior but has cytoplasmic vacuolization and stromal edema and is typically negative for CK7 and CD117. Low grade oncocytic tumor shows small nests of bland eosinophilic tumor cells but may show focal perinuclear clearing which could prompt immunohistochemical workup for chromophobe RCC. If only CK7 is performed it will be diffusely positive and therefore could lead to the incorrect diagnosis of chromophobe RCC, but demonstration of negative CD117 stain helps ensure the correct diagnosis this indolent tumor. Succinate dehydrogenase (SDH)-deficient RCC associated with germline SDH mutations and autosomal dominant familial paraganglioma syndrome is rare and shows morphologic variability, but typically demonstrates pale cytoplasmic inclusions in an otherwise nested eosinophilic tumor (11). A high index of suspicion is necessary. Loss of SDH-B expression supports the diagnosis and molecular confirmation is helpful.

Translocation RCC and its differential diagnosis

Translocation RCC is an aggressive subtype of RCC that is more common in children but can also be seen across the age spectrum. It is characterized by gene fusions involving transcription factors in the MIT/TFE gene family (TFE3 or TFEB) (12). As such, it is occasionally referred to as MiTF-RCC.

These tumors are histologically heterogeneous. Xp11 TFE3 translocation RCC can often show features of both papillary architecture with thick fibrovascular cores mimicking papillary RCC, as well as areas of tumor with clear cytoplasm raising the possibility of clear cell RCC. The presence of psammoma bodies can be a clue to the diagnosis. They typically have high-grade nuclear features (4). TFE3 immunostain is theoretically helpful, but often shows equivocal staining. Fluorescence in situ hybridization (FISH) studies are the gold standard for confirming the diagnosis, but in a minority of cases the Xp11 FISH with TFE3 break-apart probes will be falsely negative (13).

6p21 TFEB translocation RCC tends to show nests of predominantly clear cells mimicking clear cell RCC, but with a more cellular biphasic component around scattered hyaline material. Most immunostains are negative in TFEB RCC, but the tumor expresses melanocytic markers and TFEB immunostain. TFEB FISH remains the gold standard confirmatory test.

FH-deficient RCC and its differential diagnosis

FH-deficient RCC is characterized by the biallelic loss of the FH gene, which can more commonly occurs in an inherited fashion, though biallelic somatic FH loss has been described. Loss of FH results in disruption of the tricarboxylic acid (TCA) cycle, increased cellular dependence on glycolysis, and increased fumarate which can disrupt normal DNA repair processes (14). Germline pathogenic variants in FH result in patients developing hereditary leiomyomatosis and RCC syndrome. This is critical because uterine leiomyomas and piloleiomyomas typically develop first at a younger age and could raise suspicion for this autosomal dominant syndrome and prompt aggressive screening before the development of RCC. Typically, these tumors have low mutational burden, and they behave aggressively with frequent metastatic presentation even with small tumor size (14,15).

The histologic diagnosis of FH-deficient RCC requires a high index of suspicion yet represents a diagnostic imperative. The tumor characteristically shows heterogeneous architecture within different areas of the same tumor, most commonly including papillary, tubulocystic, tubulopapillary, and solid. The tumor cells show high-grade nuclear features with macro-nucleoli imparting a “cytomegalovirus (CMV)-like” nuclear appearance. A few large laboratories offer immunohistochemical staining for FH (loss of expression) and 2-SC (gain of expression), but these stains are not widely available. Ultimately, molecular confirmation of germline FH mutation will clinch the diagnosis.

Historically these tumors were called type 2 papillary RCCs. This diagnosis must be considered in any high-grade tumor with papillary architecture, which includes not only papillary RCC but also translocation RCC. Tumors with features of tubulocystic carcinoma should also be evaluated for FH-deficiency.

Other non-clear cell RCCs

While there are too many distinct histologic subtypes of RCC to discuss in detail, a few high-grade distal nephron tumors are particularly worth mentioning. Collecting duct RCC is a highly aggressive tumor composed of poorly formed, infiltrative glands with high-grade nuclear features and often an associated inflammatory infiltrate. Immunostains are of limited help and these tumors are sometimes labeled as “unclassified RCC”. Renal medullary carcinoma occurs predominantly but not exclusively in young patients of African ancestry and with sickle cell disease or trait. These tumors show significant morphologic similarities to collecting duct and FH-deficient RCC. However, renal medullary carcinoma demonstrates loss of SMARCB1 (INI-1) nuclear expression. Anaplastic lymphoma kinase (ALK)-RCC is a more recently described distal nephron tumor which also occurs in patients with sickle cell trait (16). It has variable morphology but is generally high grade, shows tubulopapillary to sheetlike architecture, and has prominent mucin deposition. ALK immunostain is positive. Of note, TFE3 immunostain may be falsely positive and detection of ALK rearrangement with one of multiple partners supports the diagnosis. Specific classification as ALK-RCC may raise the possibility of ALK inhibitor therapy in patients with advanced disease.

Systemic therapy for variant RCC histology

Due to the disparate prevalence of clear cell RCC compared to non-clear cell RCC, Food and Drug Administration (FDA) approval of systemic therapies is heavily weighted towards clear cell RCC. Enrollment in clinical trials remains the preferred strategy in non-clear cell RCC. As it stands, the majority of clinical trial data guiding systemic therapy in non-clear cell RCC is from single-arm phase 2 trials with a relative paucity of randomized, multicenter phase 3 clinical trials.

Historically, the vascular endothelial growth factor (VEGF)-tyrosine kinase inhibitor (TKI) sunitinib and the mTOR inhibitor everolimus were considered standard therapies for advanced non-clear cell RCC. The ASPEN and ESPN trials were randomized, multicenter phase 2 trials that studied these drugs head-to-head. In the ASPEN trial, 108 patients with metastatic papillary, chromophobe, or unclassified non-clear cell RCC were enrolled in the first-line setting and were randomized to receive sunitinib or everolimus (17). Sunitinib significantly increased progression-free survival (PFS) compared to everolimus (8.3 vs. 5.6 months). The ESPN trial was similar in make-up and design, though crossover was allowed at disease progression (18). Median PFS was 6.1 months in the sunitinib arm and 4.1 months in the everolimus arm. Both trials included multiple types of non-clear cell RCC and noted differences in treatment response based on histology. In the ASPEN trial, patients with papillary histology had a median PFS of 8.1 months when treated with sunitinib compared to 5.5 months in the everolimus arm. In contrast, patients with chromophobe histology have a non-statistically significant increase in PFS in the everolimus arm (11.4 months) compared to the sunitinib arm (5.5 months). In the ESPN trial, patients in the sunitinib arm with papillary or translocation histology also had a prolonged PFS compared to those patients in the everolimus arm (5.7 vs. 4.1 months and 6.1 vs. 3.0 months, respectively). These data led to the widespread adoption of sunitinib, despite the relatively modest clinical benefit and heterogeneous and relatively small patient population.

When further discussing systemic therapy options, we will break down new clinical trial data by histology to further elucidate potential emerging treatment paradigms.

Papillary RCC

Papillary RCC is the most common variant histology of RCC, and as such it represents the majority of patients enrolled in non-clear cell RCC clinical trials.

Given the frequency with which MET pathway alterations are observed in papillary RCC, it is a clear choice for potential targeted therapies. SWOG 1500 is a randomized phase 2 trial comparing the MET-targeted TKIs cabozantinib, crizotinib, and savolitinib with sunitinib in patients with advanced papillary RCC who had previously received up to one previous line of systemic therapy (19). The savolitinib and crizotinib arms had incomplete assignment due to interim futility analysis. As seen in Table 2, Patients receiving cabozantinib had a significantly higher objective response rate (ORR) (23% vs. 4%) and prolonged median PFS (9 vs. 5.6 months).

The use of single-agent immune checkpoint inhibitors (ICIs) has been widely adopted across the solid tumor malignancy landscape, including advanced RCC. The single-arm phase II KEYNOTE-427 cohort B study enrolled 165 patients with advanced non-clear cell RCC to receive pembrolizumab 200 mg every 3 weeks (20). Patients could be newly diagnosed or have recurrent metastatic disease, as long as they were treatment naive. Most patients had papillary histology (71.5%) and intermediate or poor risk disease (67.9%). Most patients (61.8%) had PD-L1 expression by combined positive score (CPS) ≥1. At median follow-up of 32 months, there was an ORR of 28.8% for patients with papillary histology.

Investigators have sought to establish the role of doublet ICI in non-clear cell RCC, just as CheckMate 214 led to the adoption of combination CTLA-4 blockade with PD-1 inhibition in advanced/metastatic clear cell RCC (26). CheckMate 920 included a cohort of 52 patients with previously untreated advanced or metastatic non-clear cell RCC to be treated with combination ipilimumab and nivolumab (Ipi/Nivo) (21). Thirty-four percent of patients had papillary histology. At a median follow-up of 24.1 months, combination Ipi/Nivo had an ORR of 19.6%, median PFS of 3.7 months, and median OS of 21.2 months. Of the patients who obtained a partial response, 52% had papillary histology, as did one of the two patients with a complete response.

Based on the results of the CheckMate 9-ER and CLEAR trials, researchers have attempted to find a synergistic response between ICI and VEGF-TKI using a variety of combinations. KEYNOTE-B61 is a single-arm phase 2 trial that enrolled 158 previously untreated patients with stage IV non-clear cell RCC to pembrolizumab 400 mg every 6 weeks for up to 2 years and oral lenvatinib 20 mg once daily (22). At the present time, this represents the largest prospective clinical trial evaluating combination ICI and VEGF-TKI in the non-clear cell RCC population. The majority of patients (59%) had papillary histology, where the observed ORR was 52% and disease control rate (DCR) 85%. In a separate post-hoc analysis, median PFS for this group was 17.5 months, similar to the median PFS of 18 months observed for the entire study population.

At the ASCO General Meeting in 2023, Lee and colleagues presented an update to their phase 2 trial of cabozantinib and nivolumab in non-clear cell RCC (23). Forty patients with advanced non-clear cell RCC were given either cabozantinib with nivolumab 240 mg every 2 weeks or 480 mg every 4 weeks. The trial was initially designed to have a second arm containing patients with chromophobe histology, but that arm was closed early for lack of efficacy. Papillary histology made up 80% of the patients enrolled in the trial. These patients had an ORR of 47%, including 1 patient (3%) with a complete response, 14 (44%) with a partial response, and 17 (53%) with stable disease.

In an effort to further augment the response, doublet ICI in combination with VEGF-TKI therapy has been studied. McGregor and colleagues presented a phase 2 study of cabozantinib with Ipi/Nivo in patients with advanced non-clear cell RCC at the ASCO General Meeting 2023 (24). Patients could be treatment-naïve or previously received one line of therapy, as long as it was not immunotherapy or cabozantinib. Of the 38 patients enrolled in the study, 19 had papillary histology. When evaluating radiographic response by RECIST criteria, 32% exhibited a partial response, 47% had stable disease, and 21% had progressive disease.

Similarly, investigators have endeavored to understand the effects of combination mTOR and VEGF pathway inhibition. As such, everolimus and lenvatinib combination therapy was studied in a single-arm, multicenter phase 2 trial that enrolled 31 patients with unresectable advanced or metastatic non-clear cell RCC in the first-line setting (25). Again, papillary histology made up the majority of patients (64.5%). The ORR for patients with papillary histology was 15%, and 70% of patients showed stable disease. Of those patients with stable disease, 50% continued to exhibit stable disease for more than 23 weeks. Median PFS in this group was 9.2 months and median OS was 11.7 months.

Chromophobe RCC

Interpretation of clinical outcome data for patients with chromophobe, translocation, or unclassified RCC is limited by small numbers included in the aforementioned phase two trials. Table 3 outlines clinical outcomes of the most prominent clinical trials broken down by included histology subtype.

By far, the largest study with this histology is the study of single-agent pembrolizumab in KEYNOTE-427 cohort B, which enrolled 21 patients (12.7%) with chromophobe histology. At interim analysis with minimum follow-up of 34 months, they report an ORR of 9.5% for patients.

There were 7 patients (13.5%) with chromophobe histology included in CheckMate 920, which evaluated the use of Ipi/Nivo in non-clear cell RCC. No radiographic responses were noted in these patients.

In KEYNOTE-B61, which studied pembrolizumab and lenvatinib combination, the median PFS for patients with chromophobe histology was 12.5 months, inferior to the 17.5 months seen in papillary histology.

In the cabozantinib and Ipi/Nivo combination, only one out of 11 (9%) patients with chromophobe histology showed a partial response, and 5 patients (45%) showed progressive disease.

There were nine patients with chromophobe histology in the phase 2 trial of everolimus and lenvatinib. The ORR in this group was 44%, with another 33% showing stable disease. All patients with stable disease had a durable response lasting >23 weeks. Median PFS was 13.1 months.

Translocation RCC

Meaningful conclusions are hard to draw from the available data of patients with translocation RCC due to limited representation in clinical trials. In KEYNOTE-B61, there were only four patients with translocation RCC. Three of the four patients exhibited partial response to pembrolizumab and lenvatinib and the remaining patient experienced stable disease per RECIST criteria.

Similarly, in the phase 2 trial of cabozantinib and nivolumab, there were two patients with translocation RCC, where one patient had a partial response and the other showed stable disease.

Unclassified RCC

The response to systemic therapy in patients with unclassified RCC is variable, likely due to the lack of uniformity in diagnosis. The largest population of patients with unclassified RCC came in cohort B of KEYNOTE-427 (single-agent pembrolizumab). This group had a reported ORR of 30.8%.

In CheckMate 920, (doublet Ipi/Nivo), there were two patients with a complete radiographic response, one of which had unclassified histology. Out of those who obtained a partial response, 43% had unclassified histology.

In the phase 2 trial of cabozantinib and nivolumab, there were 6 patients with unclassified histology without papillary features. This distinction is important in that the papillary category included 16 patients with unclassified histology with papillary features. Of the six remaining patients, there was a 50% ORR, with three patients showing partial response, two with stable disease, and one with progressive disease.

It is challenging to evaluate the response of patients with unclassified RCC to combination cabozantinib and Ipi/Nivo as well as combination everolimus and lenvatinib. This is because there was only one patient and two patients, respectively. The one patient treated with cabozantinib and Ipi/Nivo had a partial response. Of the two patients treated with everolimus and lenvatinib, one had a partial response, and the other patient had a durable stable disease.

Conclusions

The therapeutic landscape of non-clear cell RCC continues to evolve. It has been shown that molecular targeted therapy with VEGF-TKIs and immunotherapy, either in combination or as monotherapy, have efficacy in this patient population. Variant histologies tend to have heterogeneous biology and exhibit a distinct molecular and mutational pattern that should be taken into account when recommending systemic therapy and designing future trials (Table 4). Considerate clinical trial design that allows for dedicated analysis of unique non-clear cell subgroups is necessary to help inform treatment decisions.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tcr.amegroups.org/article/view/10.21037/tcr-24-737/rc

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-737/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-737/coif). D.K. has received grants from Exelixis and Genentech, consulting fees from Exelixis, Janssen, Pfizer, Eisai, and honoraria from Janssen, Aveo, MJH Life Science, and Astellas. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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