The Classification and Treatment of
Non-Clear Cell Renal Cell Carcinoma






Sandy T. Liu, MD1,4,5, Karlton Wong, MD,1 Gavin Hui, BA,2 Kristen Kelley, MD,3
Allan J. Pantuck, MD,4,5 Alexandra Drakaki, MD, PhD1,4,5

1Division of Hematology-Oncology, Department of Medicine, David Geffen
School of Medicine at University of California Los Angeles, Los Angeles, California
2David Geffen School of Medicine at University of California Los Angeles,
Los Angeles, California
3Division of General Internal Medicine, Department of Medicine, David Geffen
School of Medicine at University of California Los Angeles, Los Angeles, California
4Institute of Urologic Oncology, Department of Urology, David Geffen
School of Medicine at University of California Los Angeles, Los Angeles, California
5Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at
University of California Los Angeles, Los Angeles, California

Key Words: Non-clear cell renal cell carcinoma; classification, subtypes, papillary, chromophobe, collecting duct, medullary,translocation, unclassified, treatment, VEGF receptor inhibitor, mTOR inhibitor.

Corresponding author: Allan J. Pantuck, MD, MS, FACS, Department of Urology, David Geffen School of Medicine at UCLA, Wasserman Building, Third Floor, 300 Stein Plaza,
Los Angeles, CA 90095 Email:


Renal cell carcinoma (RCC) is the 8th most common cancer in the United States with an estimated incidence of 63,990 causing 14,400 deaths in 2017 according to the National Cancer Institute’s Surveillance, Epidemiology, and End Result (SEER) program data.1 From 1975 to 2014, the incidence of RCC increased from 7 to 15 per 100,000 people. This finding is likely due in part to the increased use of imaging studies leading to the detection of small, asymptomatic renal tumors.  Recently, Welch and colleagues found that hospital referral regions that utilized computerized tomography (CT) with greater frequency also experienced higher rates of nephrectomy, presumably reflecting the increased rate in detection of incidental renal masses.2

Cigarette smoking, increased body mass index (BMI), and high blood pressure are all established risk factors for the development of renal cell carcinoma. Smoking cessation and also possibly treatment of hypertension are associated with a reduction in risk.3 Increased risk of developing RCC has also been observed in some studies in patients with diabetes mellitus,4 increased parity,5 and in patients with history of trichloroethylene exposure.6 Conversely, an inverse relationship has been suggested between physical activity and alcohol consumption and the development of RCC. The study of the relationship between diet and RCC has yielded conflicting results with some data suggesting a protective effect from a diet rich in fruits and vegetables and increased risk associated with high fat diets or intake of processed meats.7 RCC affects males twice as often as females and typically affects older adults with a median age at diagnosis of 64.8 Higher incidence is found among Blacks, American Indians, Alaska Natives, Whites, and Hispanics as compared to Asians and Pacific Islanders.9

Among all malignant renal neoplasms, renal cell carcinoma (RCC) represents 90% of cases.10 RCC itself is a heterogeneous group of malignant epithelial neoplasms that is further categorized based on histopathologic, genetic features and clinical behavior ranging from indolent to highly aggressive.  RCC is primarily comprised of clear cell type, representing about 75%, while non-clear cell RCC represents approximately 25%.11 Non-clear cell renal carcinomas can be further subdivided into, papillary (10-15%), chromophobe (5%), collecting duct (1%), medullary (<1%), translocation (1-3%), and unclassified (5% ) types.11-12 A clear understanding of the different characteristics of these subtypes of non-clear cell RCC is critical for prognostication and for identification of suitable treatments.

Classification of Non-Clear Cell RCC
Non-clear cell RCC subtypes are classified according to cell of origin, histology, immunohistochemical staining, molecular biology, and tumor genetics (Table 1. To view a larger version of this table, click here). The main subtypes of non-clear cell RCC include papillary, chromophobe, collecting duct, medullary, translocation, and unclassified. Sarcomatoid features, once thought to represent a distinct subtype but now better understood to represent a nonspecific pattern of high-grade morphology, can be seen in any histologic subtype of RCC. Additionally, there are other types of non-epithelial malignancies that can arise from the kidney including lymphoma, sarcoma, and carcinoid tumors. These tumor types are beyond the scope of the paper and will not be included in the discussion.

The papillary subtype of non-clear cell RCC can be further subdivided into type 1 and type 2 papillary RCC. Type 1 papillary RCC tumors are typically multifocal but slow growing and have low metastatic potential thus patients with type 1 papillary RCC are typically diagnosed at lower stages of disease.15 These tumors arise from the proximal convoluted tubules of nephrons and demonstrate a predominantly papillary growth pattern with small, basophilic cells of low nuclear grade.10,12

Data from The Cancer Genome Atlas (TCGA) has identified alterations in the MET oncogene to be prevalent in most type 1 papillary RCCs.13-14 Familial types of type 1 papillary RCC are commonly associated with germline MET mutations on chromosome 7 while sporadic type 1 papillary RCCs are more often associated with MET amplification rather than mutation.11 Both types of papillary RCC are found to have trisomies of chromosomes 7 and 17 and variability in chromosomes 1, 12,16, 20, and Y.12 Other mutations identified as having a possible association with the papillary subtypes include NF2, SLC5A3, PNKD, CPQ, LRP2, CHD3, SLC9A3R1, SETD2, and CRTC1.16

Type 2 papillary RCC is a more aggressive variant with worse outcomes15 and is histologically distinct with eosinophilic cells with granular cytoplasm and high nuclear grade.12 This subtype has been noted to have genetic alterations such as CDKN2A silencing, SETD2 mutations, TFE3 fusions, and increased expression of the NRF2-antioxidant response pathway.13-14 CDKN2A silencing and the CpG island methylation phenotype are associated with a poorer prognosis.13 Type 2 papillary RCC may exhibit greater VEGF expression and is more often associated with -1p, -3p, and +5q than type 1.17 This type of RCC can be associated with a germline mutation in the genes involved in the tricarboxylic acid cycle.18 For example, hereditary leiomyomatosis and RCC syndrome results in a loss-of-function mutation in the fumarate hydratase enzyme. Patients with this syndrome present with skin lesions, uterine leiomyoma, and solitary RCC lesions.18 Additionally, there have been reports of an association between loss of fumarate hydratase and HIF-1 overexpression and poorer prognosis.19

Chromophobe RCC has a solid, tubular, or sarcomatoid growth pattern with cells arising from the intercalated cells of the distal tubules of nephrons.10,12 The cells are eosinophilic and contain microvesicles that stain for Hale colloidal iron.12 Commonly seen cytogenetic aberrations include multiple monosomies and loss of chromosomes -1, -2, -6, -10, -13, -17, -21.20 This type of RCC is typically slow growing, and rarely metastatic, although sarcomatoid histology is associated with a more aggressive phenotype.  Common mutations associated include TP53, ND5, and Folliculin20 and PTEN, FAAH2, PDHB, PDXDC1, and ZNF765 have also been found to be contributory.17 Birt-Hogg-Dube syndrome is a rare autosomal-dominant disease associated with the Folliculin mutation on chromosome.17-21 Patients with this disorder present with hamartomas, renal and/or pulmonary cysts, and chromophobe or mixed oncocytoma RCC.21 Chromophobe RCC has also associated with Cowden syndrome characterized by PTEN mutations.22

Collecting Duct RCC or Bellini duct carcinoma is a rare, aggressive tumor that typically metastasizes early and has an overall poor prognosis.23 The majority of patients with this type are diagnosed with metastatic disease with a median survival of only a few months once metastasized.23 The cell of origin is the epithelial cell of the collecting ducts. These tumors typically display a tubular or papillary growth pattern. Cells of this tumor type often have positive staining for E-cadherin and c-KIT.12 The histology and genetics of these cells have features that overlap with transitional cell carcinomas.10 For example, collecting duct carcinomas can display Her-2 overexpression.12

Medullary RCC is another rare subtype similar in morphology to that of collecting duct RCC. It is commonly seen in younger patients who have been diagnosed with sickle cell disease or trait.  Medullary RCCs arise from calyceal epithelium and have cystic morphology and inflammation present.12 Similar to collecting duct RCC, this type is also aggressive, and in fact has a worse median survival than collecting duct RCC.24 Medullary RCC is associated with a loss of function mutation of the SMARCB1/INI1 gene, which is a chromatin remodelling regulator and repressor of cyclin D1 transcription.25 Medullary RCC can also be differentiated from collecting duct RCC by the presence of OCT3/4 protein on immunohistochemistry.24,26

Translocation associated RCC are classified on the basis of the chromosome involved (X or 6). The translocation involves fusion of the TFE3 transcription gene with ASPL or PRCC, configuring a distinctive RCC subtype.27 Most Xp11.2 translocation RCCs occur in pediatric populations however in adults, it presents at an advanced stage and displays an aggressive clinical behavior.28

Unclassified RCC represents 5% of non-clear cell RCC. RCC tumors that do not fit other genetic and histopathologic classifications would be categorized as unclassified RCC. Unclassified renal cell carcinoma, which includes tumors that are 100% sarcomatoid in appearance and for which a more definitive tumor histology cannot be assigned, is associated with distinct and highly aggressive biological behavior, and poor clinical outcome. In a single institution study, compared to clear cell carcinoma, patients with unclassified RCC had more metastatic disease at diagnosis, larger tumors, increased risk of adrenal gland involvement, direct invasion to adjacent organs, bone involvement, regional and nonregional lymph node metastases. Unclassified histology was a significant indicator for poor prognosis. Median survival in patients with advanced or metastatic unclassified renal cell carcinoma was 4.3 months.29

Current Treatment Landscape for Non-clear Cell RCC
Nephrectomy plays an important and potentially curative role in localized, and an important cytoreductive role in metastatic, non-clear RCC given the suboptimal efficacy of systemic therapy. In metastatic disease, cytoreductive nephrectomy (CN) for non-clear cell RCC showed significantly lower cancer-specific mortality and all-cause mortality among 64% of the patients in the SEER database between 2000 and 2009.1 Additionally, Vaishampayan and colleagues analyzed advanced non-clear cell RCC cases between 2000 and 2013 from SEER which showed a higher risk of death in patients with non-clear cell RCC when compared to clear cell with a median OS 5 and 7 months respectively.18 There were 10% more patients with distant-stage non-clear cell RCC who underwent CN and despite this increase, OS outcomes were worse for non-clear cell RCC.30

On the other end of the spectrum, small renal masses with an indolent subtype that are known to be either papillary type 1 or chromophobe could be observed or ablated in selected patients. Currently, outside a clinical trial setting, there is no role for adjuvant systemic therapy as there was no benefit in disease-free survival or overall survival seen with either sunitinib or sorafenib as compared to placebo from the double-blind randomized ECOG 2805 study that evaluated a subgroup of non-clear cell patients (550 of 1943) with localized RCC post nephrectomy.30 In high-risk patients with medullary, or collecting duct carcinoma, adjuvant platinum-based chemotherapy should be considered.31

For patients with advanced recurrent or metastatic disease, the treatment of choice is systemic therapy. Although there have been significant advances in the treatment of metastatic RCC in the post-cytokine era, the majority of studies to date have mostly involved clear-cell RCC with a subset of patients with non-clear cell histology. It is noteworthy to mention that the efficacy of the same agents in non-clear cell RCC is reduced with decreased response rates and shorter durations of response.30 Given the fatal disease and the lack of randomized clinical trials as well as no specific FDA approvals, the general approach to management of non-clear cell metastatic RCC is similar to that of clear cell; however subtype specific clinical trials are evolving (Table 4. To view a larger version of this table, click here).

The phase II ASPEN trial is one of the largest trials that support the use of VEGF inhibitors in papillary cancer (Table 2. To view a larger version of this table, click here). In this study 108 previously untreated non-clear cell RCC patients (68 with papillary, 16 with chromophobe, and 22 with unclassified) were randomized to either sunitinib or everolimus. Median PFS, which was the primary endpoint, was longer in patients assigned to the sunitinib arm. Compared with everolimus, sunitinib showed a longer PFS (8.3 vs 5.6 months), and higher objective response (18% versus 9%).  Interestingly, subgroup analysis for the good and intermediate-risk group had longer PFS (14 months versus 5.7 months for good risk and 6.5 versus 4.9 months for intermediate-risk), compared to the poor-risk group that had shorter PFS with sunitinib compared with everolimus (4.0 versus 6.1 months).32

The ESPN trial is a phase two study that randomly assigned treatment with everolimus or sunitinib to 73 patients with metastatic non-clear cell RCC (27 papillary, 12 chromophobe, 7 translocation, 10 unclassified, and 12 sarcomatoid) with crossover to the other arm at disease progression. The study concluded that everolimus was not superior to sunitinib as both PFS and overall survival did not show any statistical difference between the two groups (16.2 versus 14.9 months) for the initial treatment with sunitinib and everolimus respectively.33

RECORD-3 trial is a phase two study that compared the sequence of sunitinib followed by everolimus versus everolimus followed by sunitinib in first-line metastatic RCC (including both clear cell and non-clear cell type. A total of 66 non-clear cell RCC patients were included in the analysis and there was a trend toward a longer PFS with sunitinib as the initial treatment as compared with everolimus (7.2 versus 5.1 months).34

A phase II PANORAMA trial of pazopanib in non-clear cell RCC reported an 81% disease control rate and partial responses in 27% of patients (10 of 37). Median PFS was 15.9 and OS were 17.2 months.35

In 2015, the SUPAP phase two study enrolled 61 patients with metastatic papillary RCC (15 with type 1 and 46 with type 2) who were treated with sunitinib with results showing overall survival of 17.8 and 12.4 months and PFS of 6.6 and 5.5 months, in type 1 and 2 papillary RCC, respectively.36  Subsequently, the phase 2 RAPTOR trial in 2016 enrolled 92 patients with papillary RCC treated with everolimus demonstrating an overall survival of 21 months, and PFS of 3.9 months.37

A phase II trial that was presented in 2014 European Organisation for Research and Treatment of Cancer-National Cancer Institute-American Association for Cancer Research (EORTC-NCI-AACR) included 41 patients with papillary RCC who were treated with bevacizumab in combination with erlotinib (an epidermal growth factor receptor). This combination demonstrated a 30% objective response rate both groups that had sporadic disease and hereditary leiomyomatosis and renal cell cancer. The median PFS was 24 months for those with hereditary leiomyomatosis compared to only seven months with sporadic papillary RCC.38

As discussed previously met oncogene plays a significant role in papillary cancer. With that knowledge, several clinical trials with MET directed-therapies have shown activity in papillary RCC.

In a recent EORTC 90101 CREATE phase II trial, the ALK-inhibitor crizotinib, which appears to have affinity for MET kinase, has shown activity among MET-positive papillary RCC type 1. Schöffski and colleagues treated 23 eligible patients out of 41. The response rate was 50% for patients that were MET-positive (2 out of 4 patients) with a mean treatment duration noted to be longer in the MET altered cohort (11.9 versus 5.3 months).39

Additionally, a randomized phase II SWOG 1500 PAPMET clinical trial will evaluate a total of 180 patients with metastatic type 1 and type 2 papillary RCC to receive either sunitinib, crizotinib, cabozantinib (a dual VEGFR2/ MET inhibitor), or savolitinib (a distinct and more specific MET inhibitor). This study is currently ongoing and recruiting patients.40

Foretinib is a multi-targeted TKI that targets MET and VEGF receptors that has demonstrated some benefit in papillary RCC based on a phase II trial that included 74 patients. The ORR was 13.5% and the median PFS was 9.3 months. However, the RR was 50% in patients with germline MET mutation. The OS was 70% at one year.41

In a similar phase II trial that evaluated another MET inhibitor, Savolitinib, for 109 patients with papillary RCC, there was an ORR of 7% and tumor shrinkage in 20%.  For the 40% of patients with MET-driven disease, the ORR was noted to be 18% (8 out of 44 patients) and tumor shrinkage in 61%. The median PFS was 6.2 months compared to 1.4 months with MET-negative papillary RCC which was statistically significant with a hazard ratio of 0.33 in favor of MET-driven papillary RCC as compared to the non-MET driven disease. Additionally, there were no partial responses seen in the 46 tumors that were not driven by MET.42 Currently, there is an ongoing phase III SAVOIR trial, comparing savolitinib with sunitinib to determine whether or not savolitinib has selective activity in a MET-selected population (NCT03091192).43 There is another randomized trial evaluating the clinical efficacy of three distinct targeted therapies including volitinib (MET inhibitor), cabozantinib (VEGF, MET, AXL inhibitor), and crizotinib (ALK-1 and MET inhibitor) with sunitinib as the comparator control arm (NCT02761057).44 If either of these studies is positive, it would herald a change in the current standard of care for frontline treatment in metastatic papillary RCC.

“In general, the current treatment of choice for non-clear cell RCC is a vascular endothelial growth factor (VEGF) receptor inhibitor followed by a mammalian target of rapamycin (mTOR) inhibitor at the time of progression. Immunotherapy with checkpoint inhibitors is not yet FDA approved for non-clear cell RCC.”

As the landscape of treatment for clear cell RCC has shifted to immunotherapy due to the CheckMate 214 that suggested an OS advantage with the combination of nivolumab/ipilimumab over sunitinib in the first-line setting, there is biological rationale to extrapolate the activity of immunotherapy in non-clear cell RCC. Choueiri et al. have evaluated 101 patients with a variety of non-clear cell subtypes and found varied expression levels of PD-L1 in this cohort, with 10% of papillary patients expressing PD-L1 in tumor cells.45 Additionally, A retrospective analysis with a PD-1 inhibitor, nivolumab monotherapy, was done for 41 patients with non-clear cell histology that included 16 papillary, 14 unclassified, 5 chromophobe, 4 collecting duct, and 1 Xp11 translocation. There were 20% of patients that had a PR and 29% with stable disease. Responses were observed in unclassified, papillary, and collecting duct subtypes which lend support to the use of nivolumab for patients with non-clear cell RCC.59 Currently there are studies of dual immuno- therapy that include a non-clear cell arm that will provide additional insight into the activity of checkpoint inhibitors in this population. There are ongoing phase II studies with a PD-L1 inhibitor, atezolizumab, in combination with a VEGF inhibitor, bevacizumab, in patients with advanced non-clear cell RCC (NCT02724878), thought no results have yet been reported.46

Overall, for papillary RCC, VEGR-targeted therapies seem to be the most effective first-line treatment for both type 1 and type 2 papillary RCC. mTOR inhibitor, however, has been shown to have activity in treating papillary type RCC and can be used as a second-line therapy option.

Both VEGF receptor inhibitors and mammalian target of rapamycin (mTOR) inhibitors have been used to treat chromophobe RCC.  In the ASPEN trial, subgroup analysis of chromophobe RCC demonstrated better clinical outcomes with everolimus therapy.32 In 2008, a study looked at 53 patients with non-clear cell RCC (41 with papillary and 12 with chromophobe) treated with sunitinib or sorafenib. The results for the 12 chromophobe type RCC (7 treated with sunitinib and 5 with sorafenib) showed a response rate of 25% to sunitinib or sorafenib, PFS of 10.6 months (sorafenib treated group had a longer median PFS of 27.5 months).47 In the ESPN trial, which included 12 chromophobe RCC subtype, there was an objective response rate of 2.8% and 6%, and overall survival was 25.1 and 31.6 months for the everolimus and sunitinib treated groups, respectively.33

Collecting Duct
Collecting duct RCC, due to its similarities with transitional cell carcinoma, is treated with chemotherapy with a platinum based regimen as well as with combination chemotherapy and bevacizumab. In 2007, a phase two prospective multicenter study evaluated 23 patients with metastatic collecting duct carcinoma treated with gemcitabine plus either cisplatin or carboplatin. Results of the study demonstrated an objective response of 26%, with a PFS of 7.1 months and an overall survival 10.5 months.48 Another study in 2013, enrolled 5 patients with metastatic collecting duct RCC who were treated with gemcitabine plus a platinum-based agent in addition to bevacizumab. Three of the cases had partial response, one with stable disease, and another one with a complete remission. Median overall survival was 27.8 months and PFS was 15.1 months.49

Medullary RCC is typically treated with a platinum-based chemotherapy regimen, but because it is such a rare disease, data is still lacking to clearly support a first line regimen. There are multiple case reports of medullary RCC responding to combination chemotherapy with gemcitabine, paclitaxel and a platinum agent.50-51 Treatment with a topoisomerase II chemotherapy, such as etoposide has shown efficacy based on a patient who achieved complete response for 9 months after receiving a topoisomerase II therapy.52 Another case report looked at two patients with renal medullary carcinoma receiving combination platinum-based therapy with bortezomib, a proteasome inhibitor, with promising results: one patient passing away 7 years after diagnosis, while another remains disease free nearly 2 years from diagnosis.53 In 2004 a phase two study recruited 37 patients with metastatic renal cell RCC (25 clear cell, 6 papillary, 1 collecting duct, 1 medullary, and 4 unspecified) who were treated with bortezomib.54  On a follow up report to this study, the patient with medullary RCC received 7 months of bortezomib, achieved a complete response, and remain without evidence of disease after 27 months.55

There are scant data available for unclassified and translocation RCC. Although no prospective trials have been conducted in this setting, there are case reports that document the activity of VEGF-targeted agents. For patients with Xp11.2 translocation, one study reported 15 patients with had received VEGF-directed therapies. Three patients (20%) achieved a partial response. The median PFS was 7.1 months and medians OS was 14.1 months.56  The Juvenile RCC network reported a series of 11 patients who received sunitinib in the first-line setting with a median PFS of 8.2 months.57

With no clear standard of care FDA approved agents, non-clear cell RCC represents a significant and long ongoing unmet medical need. Patients should be encouraged to participate in clinical trials whenever possible, though given the heterogeneity of this disease, investigators should not make the mistake of combining numerous non-clear cell RCCs in prospective trial designs. Instead, each non-clear cell histology has its unique characteristics and should be studied individually. In general, the current treatment of choice for non-clear cell RCC is a vascular endothelial growth factor (VEGF) receptor inhibitor followed by a mammalian target ofrapamycin (mTOR) inhibitor at the time of progression. Immunotherapy with checkpoint inhibitors is not yet FDA approved for non-clear cell RCC; however, there are ongoing studies that show promising results, notably in papillary RCC with sarcomatoid and rhabdoid features. Combinations with a PD-1 inhibition with CTLA-4 inhibitors, or ido-1 inhibitors are noteworthy and currently in study. As we gain a better understanding of the biology through the discovery of molecular and genomic testing, collaborative efforts will be essential for the therapeutic development of targeted pathways  and agents to further advance this orphan disease.

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