Navigating the Current Landscape of Non-Clear Cell Renal Cell Carcinoma: A Review of the Literature

Round 1

Reviewer 1 Report

The authors reported a comprehensive review of the literature on molecular pathogenic mechanisms pertaining to each nccRCC subtype. The topic is interesting, underexplored, and worthy of interest. Some amendments are required, as follows: 

- I believe that the introduction is a section for background and study aims. Please do not present results, conclusions, figures, or tables. Eliminate the pr Table 1 for subtypes. You may present it in the result, discussion ect. 

- Genomic profiling and metabolic pathways is crucial to better understand molecular pathogenic mechanisms unique to individual nccRCC subtypes. Please include this interesting paper in the discussion and as reference: DOI: 10.3390/ijms232214360; PMID: 36430837. 

- Why did you not consider surgery, ablation, or any local therapy when presenting therapies strategy? clear cell CCR and nccCCR have been largely treated in this way, and oncologic data are currently available. Please explain. If you consider including this aspect please discuss the argument with those interesting paper 1: DOI: 10.23736/S2724-6051.22.05092-3; PMID: 36286402. 2: DOI: 10.1089/end.2022.0478; PMID: 36367175.

- Correct and check typos.

Author Response

We thank the reviewers for their valuable and constructive feedback regarding the submitted review. We have reviewed and edited the manuscript closely, in accordance to feedback and suggestions with annotations detailed below.

- I believe that the introduction is a section for background and study aims. Please do not present results, conclusions, figures, or tables. Eliminate the pr Table 1 for subtypes. You may present it in the result, discussion ect. 

Table 1 (subtypes of RCC) has been moved to the pathological, molecular and clinical features of nccRCC subtypes section to clearly incorporate this in the “review” section of the manuscript. Table 1 lays out the prevalence of nccRCC subtypes – of which the more frequent or clinically relevant subtypes discussed in detail.

- Genomic profiling and metabolic pathways is crucial to better understand molecular pathogenic mechanisms unique to individual nccRCC subtypes. Please include this interesting paper in the discussion and as reference: DOI: 10.3390/ijms232214360; PMID: 36430837. 

The paper above (Renal cell carcinoma as a metabolic disease: an update on main pathways, potential biomarkers and therapeutic targets) focuses on ccRCC but the biological themes are broadly applicable to nccRCC. We have have included a brief synopsis of the concept in the ‘Future directions’ section- see below:

Moreover, within the clear cell RCC context, recent data has highlighted the utility of metabolic profiling in predicting clinical outcomes including prognosis and response to therapies through a combination of metabolomics, lipidomics, and transcriptomics. There is therefore scope for similar investigation to be prospectively conducted in the non-clear cell RCC space

- Why did you not consider surgery, ablation, or any local therapy when presenting therapies strategy? clear cell CCR and nccCCR have been largely treated in this way, and oncologic data are currently available. Please explain. If you consider including this aspect please discuss the argument with those interesting paper 1: DOI: 10.23736/S2724-6051.22.05092-3; PMID: 36286402. 2: DOI: 10.1089/end.2022.0478; PMID: 36367175.

Thank you for this suggestion. We concur that mention of local therapy, which upon review of the literature is not clearly defined as different in approach to localized ccRCC, should be included in the overall therapy spectrum for nccRCC. We have included this statement in the introduction to the systemic therapy section:

Of note, local therapies such as surgery and ablative techniques (eg radiofrequency, microwave and cryoablation) can be utilized in the management of early stage nccRCC (Pandolfo). However, it is unclear if differences exist between outcomes in ccRCC and nccRCC managed with local therapies, as comparative studies have not been conducted. As such, systemic therapy will be the focus of this discussion.

Reviewer 2 Report

General comments to the paper entitled

“Navigating the current landscape of non-clear cell renal cell carcinoma: a review of the literature”

The author’s aim was to provide an overview of the literature to describe the molecular pathogenic mechanism of non-clear cell renal cell carcinoma (nccRCC) and the findings from clinical trials conducted with nccRCC patients.

Table 1. summarize 11 subtypes of nccRCC, but later discuss in detail only 5 out of 11 subtypes. This section also writes about “sarcomatoid and rhabdoid dedifferentiation” but not clear if it is considered as nccRCC and not mentioned in Table 1.

Table 3 summarizes the results of three clinical trials in connection with sarcomatoid subgroups of patients but considered as clear cell RCC phase III trials. Also not clear Table 2 shows the results of four clinical trials with ccRCC patients.

I suggest making it clear if the title defines the subject of the paper as the review of nccRCC why showing the results of ccRCC clinical trials.

Table 4. give a nice summary of several clinical trials with nccRCC patients. After showing the data I suggest giving a short conclusion on what would be useful for oncologists just like in line 222 when mentioned the “chromophobe tumors are indeed immunologically cold” and in lines 258-260 making clear the role of MET proto-oncogene.

line 23: misprint

line 78: misprint

line 222: Table, a misprint.

line 307 and 414: misprint: Non-clear

Author Response

Table 1. summarize 11 subtypes of nccRCC, but later discuss in detail only 5 out of 11 subtypes. This section also writes about “sarcomatoid and rhabdoid dedifferentiation” but not clear if it is considered as nccRCC and not mentioned in Table 1.

Thank you for the suggestion and we note that sarcomatoid/rhabdoid features cross clear vs non-clear subtyping. We have edited the ‘pathological, molecular and clinical features of nccRCC subtypes’ section, with the following:

Certain subtypes of metastatic nccRCC are associated with more aggressive disease behaviour and poorer survival outcomes compared to ccRCC. Within nccRCC, subtypes exhibit different clinical courses. The incidence of morphological subtypes of nccRCC are listed below (Table 1). Recent genomic sequencing studies of nccRCC have revealed molecular aberrations amongst different nccRCC subtypes that parallel different patterns of clinical behaviour, therapy response and prognosis. Subtypes with unique histological and molecular features have been discussed in further detail.

Specifically regarding: sarcomatoid/rhabdoid differentiation, we have made the difference with nccRCC clearer to the reader:

Though not categorized as subtypes of nccRCC, note should be made of the phenomena of sarcomatoid and rhabdoid dedifferentiation, which can be seen in approximately 10-15% of RCC, often co-existing with other RCC histologies (eg clear cell, papillary etc) [29]

Table 3 summarizes the results of three clinical trials in connection with sarcomatoid subgroups of patients but considered as clear cell RCC phase III trials. Also not clear Table 2 shows the results of four clinical trials with ccRCC patients.

I suggest making it clear if the title defines the subject of the paper as the review of nccRCC why showing the results of ccRCC clinical trials.

We concur this suggestion and therefore we have removed table 2 (key first line immunotherapy and combination therapy trials in metastatic RCC), and instead simply listed the landmark trial names:

Management paradigms within this space have historically consisted of cytokine therapy (such as interferon-alpha and IL-2) and oral targeted therapies (tyrosine kinase inhibitors, such as sunitinib), however immunotherapy (IO) has recently emerged as a mainstay of initial treatment of metastatic ccRCC [7]. This shift has occurred due to improvements in survival with immunotherapy in large randomized clinical trials (CheckMate-214, KEYNOTE-426, CheckMate-9ER, CLEAR and JAVELIN-101) [7-11].

We have also removed Table 3 (subgroup analyses of patients with sarcomatoid features in 1L immunotherapy/combination ccRCC phase 3 trials), and instead summarised in 1 line:

These tumours are known to have an ‘immune-inflamed phenotype’, typified by immune activation, higher PD-L1 expression, upregulation of antigen presenting machinery genes and enhanced infiltration of cytotoxic immune cells [29]. This translates into the clinical setting, as demonstrated through the responsiveness of these tumours to IO, with response rates of 47-61% and overall survival benefit over sunitinib seen in subgroup analyses of Phase III ccRCC trials [35-37].

Table 4. give a nice summary of several clinical trials with nccRCC patients. After showing the data I suggest giving a short conclusion on what would be useful for oncologists just like in line 222 when mentioned the “chromophobe tumors are indeed immunologically cold” and in lines 258-260 making clear the role of MET proto-oncogene.

Thank you for this comment which enhances the discussion. We have included a summary after the large list of retrospective studies as a point of reflection:

These data do not demonstrate major differences between survival outcomes with use of targeted therapies vs IO. Of note, poor outcomes were seen with mTOR inhibitors. Additionally, chromophobe tumours responded poorly to IO, although higher response rates were observed with combination ipilimumab/nivolumab in this subgroup. Results must be interpreted with caution, however, due to the heterogeneity of trial populations, small sample sizes and the retrospective nature of these studies.

Round 2

Reviewer 1 Report

The paper has been deeply improved. I am satisfied with this new version which is suitable for publication, in my opinion.