Renal cell carcinoma of variant histology: Biology and therapies

Introduction

Renal cell carcinomas (RCCs) are divided into distinct subtypes characterized by specific molecular alterations.¹ Clear cell renal cell carcinoma (ccRCC) is the most common subtype consisting of ~75% of RCC cases, while the remaining 25% is classified under the umbrella term variant histology renal cell carcinomas (vhRCCs) also known as non-clear cell RCCs.¹ The prognosis and efficacy of therapies can widely vary between vhRCC subtypes thus posing a challenge to clinicians managing these tumors. Herein, we provide guidance on how to choose appropriate treatment options for vhRCCs based on our evolving clinical and biological knowledge. We will restrict our focus to RCCs and not address non-RCC histologies that can arise from the kidney, such as Wilms tumors (nephroblastomas), malignant rhabdoid tumors (MRTs), urothelial carcinomas of the renal pelvis, and kidney sarcomas. We will also prioritize the more common vhRCC subtypes that practicing oncologists are likely to encounter at least once in their careers including papillary RCC (PRCC), chromophobe RCC (CHRCC), microphthalmia transcription factor (MiTF) family RCC (TRCC), renal medullary carcinoma (RMC), fumarate hydratase-deficient RCC (FH-RCC), collecting duct carcinoma (CDC), unclassified RCC (URCC), and vhRCCs with sarcomatoid and rhabdoid dedifferentiation.¹

Systemic Therapies for vhRCC

There are four broad categories of systemic therapies typically used for RCCs: cytokine-based immunotherapies, cytotoxic chemotherapies, targeted therapies, and immune checkpoint therapies (ICTs). Cytokine-based immunotherapies such as high-dose IL-2 or interferon-alpha do not typically yield responses in vhRCCs and are therefore currently not recommended for any vhRCC subtype.² Each vhRCC histology has a different sensitivity to each of the remaining three therapeutic modalities (Table 1).^1,3–5 The randomized controlled trials (RCTs) comparing the anti–vascular endothelial growth factor (VEGF) multireceptor tyrosine kinase inhibitor (TKI) sunitinib with mechanistic target of rapamycin (mTOR) inhibitors such as everolimus or temsirolimus in vhRCCs^6–9 were previously reviewed and summarized with the results weakly favoring sunitinib over mTOR inhibition although the benefit was modest using either modality across vhRCC subtypes.¹

Table 1.

Sensitivity of vhRCC subtypes to systemic therapy modalities.

Histology	Potentially sensitive to cytotoxic chemotherapy	Potentially sensitive to targeted therapies developed for clear cell renal cell carcinomas	Potentially sensitive to currently available immune checkpoint therapies
PRCC	No	Yes	Yes
CHRCC	No	Yes*	Yes*
FH-RCC	No	Yes	Yes*
TRCC	No	Yes#	Yes#
RMC	Yes	No	No
CDC	Yes	Yes#	Yes#
URCC	No	Yes#	Yes#

^*Low probability of response based on currently available evidence

^#Probability of response may depend on specific biological driver

Abbreviations: ccRCC, clear cell renal cell carcinoma; CDC, collecting duct carcinoma; CHRCC, chromophobe renal cell carcinoma; FH-RCC, fumarate hydratase-deficient renal cell carcinoma; PRCC, papillary renal cell carcinoma; RCC, renal cell carcinoma; RMC, renal medullary carcinoma; vhRCC, variant histology renal cell carcinoma;

For this chapter, we have updated the previously reported 2021 meta-analysis¹ of objective response rates (ORR) of ICTs in PRCC and CHRCC, the two most common vhRCC subtypes, based on a review of the literature in PubMed, Medline, and abstracts from the Proceedings of the European Society for Medical Oncology (ESMO) and the American Society of Clinical Oncology (ASCO) between September 2012 and January 2023 (Figure 1).^10–24 The results suggest that although PRCC demonstrates lower response rates (ORR 25.7% with 95% confidence interval [CI] of 17.7% to 34.4%) to ICT-based regimens than what has been observed in ccRCC,^1,25 it is nevertheless far more likely to respond to such therapies than CHRCC (ORR 6.3% with 95% CI of 1.9% to 12.4%).

Figure 1.

Forest plots summarizing the reported objective responses to immune checkpoint–based therapies of papillary and chromophobe renal cell carcinomas.

Management of Papillary Renal Cell Carcinoma

PRCC is a heterogeneous malignancy that was previously subclassified into the papillary type 1 and papillary type 2 morphologic subtypes. Type 1 PRCC is clinically more indolent and biologically more associated with activating MET mutations and copy number gains of the MET gene on chromosome 7, suggesting that c-MET inhibitors such as cabozantinib may be particularly effective for this subtype. The entity formerly defined as type 2 PRCC is clinically more aggressive and more biologically heterogeneous.¹ As mentioned in the chapter by Matar et al in this book, there is a major shift following the recent WHO 2022 classification from characterizing PRCC as type 1 or 2, to a therapeutically-focused classification based on the potential dependence on the MET pathway.

As reviewed in detail elsewhere,¹ a number of TKIs targeting c-MET have been investigated in PRCC, including foretinib,²⁶ crizotinib,^27,28 tivantinib,²⁹ savolitinib,^28,30,31 and cabozantinib.²⁸ The practice-changing randomized, multicenter, four-arm, phase 2 PAPMET trial was designed to compare cabozantinib versus crizotinib, sunitinib, or the selective c-MET inhibitor savolitinib in patients with PRCC who had received up to one prior systemic therapy that did not include VEGF-directed or MET-directed drugs.²⁸ However, the savolitinib and crizotinib arms were found to underperform during an interim analysis and PAPMET was thus modified into a two-arm, randomized, phase 2 trial focused on comparing cabozantinib versus sunitinib.²⁸ Following accrual completion, there was an efficacy signal favoring the primary endpoint of progression-free survival (PFS) with a covariate-adjusted hazard ratio (HR) of 0.6 and 95% CI 0.37 to 0.97.³² The estimates for the secondary endpoint of overall survival (OS) were inconclusive with HR = 0.84, 95% CI 0.47 to 1.51.²⁸

Cabozantinib is now a standard for PRCC given the biological rationale and robust efficacy signal, including the fact that it has demonstrated responses in cases that are resistant to savolitinib.³³ Although not as effective as in ccRCC, ICT-based combination therapies such as nivolumab + ipilimumab are approved therapies for RCC and can yield responses in patients with PRCC (Figure 1). Cabozantinib-based combination ICT regimens such as nivolumab + cabozantinib that have shown efficacy in PRCC (Figure 1) should be prioritized in patients with particularly aggressive PRCC that needs to quickly respond to at least one of the drugs in the regimen as it is unlikely that there will be time to administer these therapies sequentially. PAPMET2 will help answer the question whether such a combination would be a robust recommendation for all or most patients with PRCC. Emerging data also suggest that lenvatinib + pembrolizumab is another ICT + TKI regimen that can yield high response rates in PRCC (Figure 1).²⁴

Other TKI-based regimens include the combination of lenvatinib + everolimus which yielded objective responses in 3/20 (15%) of patients with treatment-naïve PRCC.³⁴ While data in the salvage setting for PRCC are scarce,³⁵ lenvatinib + everolimus has shown efficacy in ccRCC refractory to prior anti-VEGF TKIs, including cabozantinib.³⁵ While the combination of bevacizumab with the anti-epidermal growth factor receptor (anti-EGFR) TKI erlotinib appears to be particularly effective against FH-RCC, it can also produce objective responses in 35% of patients with PRCC (95% CI 22.1% to 50.6%).³⁶ Molecular testing may also help further subclassify PRCC tumors, particularly those not showing a morphologically classic pattern, and guide tailored management. For example, heavily pretreated patients with PRCC harboring ALK-EML4 fusions have shown responses to the ALK inhibitor alectinib.³⁷

Management of Chromophobe Renal Cell Carcinoma

CHRCC is typically more indolent than either ccRCC or PRCC. However, between 5–10% of patients with CHRCC will develop metastatic disease that is particularly refractory to the ICT and TKI regimens developed for ccRCC.^1,38–40 The presence of sarcomatoid dedifferentiation, noted in ~20% of patients with metastatic CHRCC,⁴⁰ is associated with a particularly aggressive and treatment-refractory clinical course.^1,41 (Figure 1).^38,41 Novel pathways of interest include the targeting of ferroptosis as a metabolic vulnerability of ChRCC.⁴²

TKIs such as sunitinib and cabozantinib are generally less effective against chRCC but can occasionally produce responses.^5,33,43 Uniquely compared with other RCCs such as ccRCC and PRCC, the mutation landscape of metastatic CHRCC includes a large proportion of TP53 mutations (58% of cases), PTEN mutations (24%) and imbalanced chromosome duplications.³⁹ In addition other mTOR pathway mutations can be found less commonly in CHRCC in TSC1, TSC2, and mTOR.³⁹ This provides a mechanistic rationale for using mTOR inhibitors such as everolimus in CHRCC.^6,9 To that end, lenvatinib + everolimus has yielded a signal of increased efficacy against CHRCC with 4 of 9 patients responding to therapy³⁴. Notably, lenvatinib + everolimus did not produce responses in a retrospective report of five patients with sarcomatoid CHRCC.³⁸ Furthermore, emerging data suggest that the combination of lenvatinib with pembrolizumab yields far less responses in CHRCC compared with other histologies such as PRCC (Figure 1).²⁴

The overall poor response of CHRCC to the currently available systemic therapies motivates the use of definitive local therapies such as metastasectomy in oligometastatic CHRCC. Of note, CHRCC is almost twice as likely to spread to the liver than ccRCC.⁴⁴

Management of MiTF Renal Cell Carcinomas

The MiTF family of transcription factors is comprised of TFE3, TFEB, TFEC, and MiTF.⁴⁵ Aberrant activation of these transcriptions can happen either via translocations leading to oncogenic fusions or via copy number amplifications.⁴⁶ TRCCs can occur most commonly due to TFE3 translocations, TFEB amplifications (second most common), and TFEB translocations (third most common).⁴⁷ The list of fusion partner genes for TFE3 and TFEB continues to be expanded, and each fusion partner confers distinct histomorphological and biological features.⁴⁶ TFE3 translocation TRCC is the most common pediatric RCC comprising more than 40% of RCCs in children and young adults. TFE3 translocation TRCCs in adults may be more clinically aggressive and likely to harbor more genetic alterations such as 17q gain compared with the pediatric population.¹ In approximately 20% of TFE3 translocation TRCC cases, a history of prior chemotherapy during childhood for malignancies, autoimmune disorders, or conditioning for bone marrow transplant.¹ TRCCs can be challenging to diagnose because they can mimic other RCC subytpes such as clear cell RCC and PRCC on histologic examination.⁴⁶ TRCC should be suspected in children and young adults, particularly women, with RCCs that contain mixed clear cell and papillary morphologies, especially if they have a history of chemotherapy during childhood.

Responses to dual ICT therapies are typically low with one retrospective study reporting ORR to dual ICT in 1/18 TRCC patients (5.5%), whereas ICT + TKI yielded objective responses in 4/11 patients (36%).⁴⁸ Conversely, another retrospective study of 23 patients with TRCC who received either ICT monotherapy or dual ICTs as salvage therapy noted partial responses in 3 patients (13%) and stable disease in 3 patients (13%) for a disease control rate of 26%.⁴⁹

Oncogenic TFE3 fusions can upregulate the MET pathway and one recent multi-center retrospective study of 52 patients with TRCC reported ORR 17.3% with cabozantinib, including 2 complete responses,⁵⁰ A retrospective study of salvage therapy with mTOR inhibitor monotherapy showed a durable objective response in one heavily pretreated patient with TRCC and stable disease in the remaining 6 patients for a median PFS of 3 months.⁵¹ Therefore, mTOR inhibition alone or in combination with TKIs such as lenvatinib may have a role in TRCC therapy.

Management of Fumarate Hydratase-Deficient Renal Cell Carcinoma

FH-RCC is an aggressive RCC that most commonly arises in individuals with germline inactivating mutations in the fumarate hydratase (FH) gene as part of the hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome.^52,53 Up to 35% of individuals with HLRCC syndrome will develop FH-RCC.⁵⁴ Less than 20% of FH-RCC cases will occur due to sporadic FH mutations in individuals without HLRCC.^52,55 FH-RCC will typically be negative for FH by immunohistochemistry (IHC). Because FH inactivation results in aberrant succination of cellular proteins due the high fumarate levels, this stable chemical modification can be detected by IHC for S-(2-succino)-cysteine (2SC).⁵⁴ All FH-RCC cases will show strong cytoplasmic and nuclear 2SC expression, with negative IHC staining in the background non-tumor cells making this another highly sensitive assay for FH-RCC.^54,56

Because FH is a critical metabolic enzyme in the Krebs cycle, its inactivation in FH-RCCs results in a Warburg-like metabolism characterized by aerobic glycolysis and a subsequent dependence on glucose.⁵⁷ The combination of bevacizumab with erlotinib was developed to inhibit glucose uptake by the tumor cells,⁵⁷ and has been shown to yield an ORR of 72.1% (95% CI 57.2% to 83.4%) and a median PFS of 21.1 months (95% CI 15.6 to 26.6) in patients with FH-RCC.³⁶ FH-RCC also often harbors copy number gains of chromosome 7q, where MET is located,^58,59 and retrospective data suggest that cabozantinib can yield higher efficacy than ICT regimens or mTOR inhibitors in FH-RCC.⁶⁰ Furthermore, cabozantinib in combination with nivolumab yielded objective responses in 5/5 patients with FH-RCC treated in a single-center phase 2 study.²¹ Emerging retrospective data also suggest that lenvatinib in combination with either everolimus or pembrolizumab can yield responses in patients with FH-RCC.⁵⁵ Anecdotal experience suggests that at least some patients with FH-RCC may demonstrate deep responses to ICT monotherapy or combination ICT + anti-VEGF TKI.^61,62 Given that bevacizumab + erlotinib has shown excellent efficacy in anti-VEGF TKI-refractory FH-RCC,³⁶ it may be reasonable to start with first-line ICT combinations and use bevacizumab + erlotinib as a salvage regimen.

Management of Renal Medullary Carcinoma

RMC is a highly aggressive malignancy that mainly occurs in young individuals with sickle hemoglobinopathies such as sickle cell trait, Sβ, SC, or sickle cell disease.^3,63 All sickle hemoglobinopathies appear to confer a similar risk for RMC. However, because sickle cell trait is far more prevalent than the other sickle hemoglobinopathies, most patients with RMC will harbor the sickle cell trait.⁶³ RMC is more common in men than women (~2:1 ratio) and arises from the right kidney in ~75% of cases due to the increased risk of renal medullary infarcts in the right kidney in the setting of sickle hemoglobinopathies.^63,64 High-intensity exercise may increase RMC risk by aggravating renal medullary hypoxia induced by red blood cell sickling.⁶⁴ Less than 10% of RMC cases occur in patients without sickle hemoglobinopathies, and these tumors are designated as RCC unclassified with medullary phenotype (RCCU-MP) to distinguish from typical RMC associated with sickle hemoglobinopathies.³ All RMC tumors demonstrate loss of INI1 (encoded by the SMARCB1 gene) by IHC.^3,65

Platinum-based cytotoxic chemotherapy such as carboplatin + paclitaxel is the preferred first-line therapy for RMC as it has occasionally led to complete responses in patients with metastatic RMC.³ Due to the high propensity of RMC to metastasize even when the primary tumor size is small, upfront cytotoxic chemotherapy is strongly recommended even in radiologically localized RMC. The only exception may be the rare cases where the primary tumor is ≤ 4 cm in greatest dimension and the disease is clearly confined to the kidney.³ Patients whose tumors respond to upfront chemotherapy can subsequently undergo nephrectomy with curative intent.

The response rates of RMC to platinum-based cytotoxic chemotherapy are approximately 29% and can often be brief.⁶⁶ Retrospective data reported that gemcitabine in combination with doxorubicin yielded partial responses in 3/16 (19%) patients with platinum-refractory RMC making this a viable second-line option.⁴ A recently completed clinical trial (NCT03587662) will report on the efficacy of adding the proteasome inhibitor ixazomib to gemcitabine + doroxubicin. The EGFR pathway is significantly upregulated in RMC,⁶⁵ and retrospective experience noted that EGFR targeting with erlotinib in combination with bevacizumab can produce objective responses in heavily pretreated patients with RMC who had progressed on prior platinum-based chemotherapy followed by gemcitabine + doxorubicin.⁶⁷ This approach is therefore a reasonable third-line option for patients with RMC. Regarding ICT, the efficacy of nivolumab + ipilimumab in RMC was prospectively investigated in a clinical trial that stopped early for futility (NCT03274258). Due to the notably high upregulation of LAG3 in RMC, an ongoing phase 2 clinical trial is testing high doses of the LAG3 inhibitor relatlimab in combination with nivolumab in patients with RMC (NCT05347212).

Management of Collecting Duct Carcinoma.

Other malignancies such as RMC, FH-RCC, NF2-mutant RCC (see below section on Management of URCC) and ALK-translocation RCC should be excluded prior to making a diagnosis of CDC.⁵² Platinum-based cytotoxic chemotherapy such as gemcitabine plus cisplatin or carboplatin plus paclitaxel can be effective in CDC.^1,68 In contrast to RMC, CDCs can be sensitive to VEGF inhibition with cabozantinib demonstrating ORR of 35% (including one complete response) in a phase 2 single-center trial in 23 patients with CDC (BONSAI).⁶⁹ The addition of bevacizumab to platinum-based chemotherapy may also improve outcomes but increase toxicity.⁷⁰ ICTs have also anecdotally produced responses in patients with CDC.^13,15 HER2 amplification has also be noted in up to 45% of CDC tumors and the triple combination of capecitabine + lapatinib + trastuzumab produced a partial response in a case report of a patient with CDC.^71,72 Loss of chromosome 9p, where CDKN2A and CDKN2B are located, confers poor prognosis in CDC⁷³ and a partial response lasting more than 6 months with the CDK4/6 inhibitor palbociclib was reported in a patient with metastatic CDC harboring homozygous CDKN2A/B deletion.⁷⁴

Management of Unclassified Renal Cell Carcinoma

Aggressive URCC variants frequently harbor mutations in NF2 (18%), SETD2 (18%), BAP1 (13%), KMT2C (10%), and mTOR (8%).⁷⁵ URCCs with NF2 mutations may nowadays be considered a distinct subtype of NF2-mutated RCCs that can occasionally show dramatic responses to ICT⁷⁶ and may be susceptible to therapeutic targeting of the Hippo pathway. NF2-mutated RCCs may also respond to inhibition of the mTOR^77–79 and EGFR⁸⁰ pathways. Prior to making a diagnosis of URCC, clinicians should look for clues in the patient’s clinical and family history that can point to a specific vhRCC subtype. For example, a personal history of prior chemotherapy in childhood may point to a diagnosis of TRCC. IHC for ALK can occasionally establish the diagnosis of ALK-translocation RCC.⁸¹

Sarcomatoid or/and Rhabdoid Dediffentiation

Sarcomatoid or rhabdoid dedifferentiation is associated with worse prognosis than RCCs without such morphological features and can occur across vhRCC subtypes.^41,82 The presence of sarcomatoid dedifferentiation attenuates responses to mTOR inhibitors and anti-VEGF TKIs.^82,83 The addition of cytotoxic chemotherapy agents such as gemcitabine to TKIs such as sunitinib or axitinib increases toxicity and is typically not favored.⁸⁴ RCCs with sarcomatoid and rhabdoid dedifferentiation often harbor higher PD-L1 expression and increased density of tumor-infiltrating lymphocytes.^85,86 Accordingly, ICT combinations such as nivolumab + ipilimumab can produce durable complete responses in up to 18% of patients with sarcomatoid ccRCC,⁸⁷ making such regimens the contemporary therapeutic mainstay for this histology. However, the role of ICT is less well defined in vhRCCs with sarcomatoid or rhabdoid dedifferentiation. There is anecdotal evidence of durable and deep responses to ICT in PRCCs with sarcomatoid and rhabdoid dedifferentiation.⁸⁸ Conversely, sarcomatoid CHRCC typically responds poorly to currently available ICT regimens, consistent with the overall experience with this vhRCC subtype (Figure 1).³⁸

Adjuvant Therapy Considerations

The KEYNOTE-564 phase 3 RCT randomized patients with ccRCC to either adjuvant pembrolizumab or placebo and found a strong signal of benefit with adjuvant pembrolizumab for the primary endpoint of disease-free survival leading to the FDA approval of this regimen across RCCs.⁸⁹ However, data are urgently needed on the efficacy of adjuvant pembrolizumab in particular vhRCC histologies. In the absence of such data, clinicians can use structured frameworks, reviewed extensively elsewhere and may occasionally extrapolate from Keynote-427, a first-line study of single agent pembrolizumab in vhRCC and inform patient-centered decisions.^14,90

Conclusions

Each vhRCC subtype has distinct clinical and biological characteristics that influence management as summarized in Table 2. Accurate diagnosis is therefore critical because certain histologies such as RMC are refractory to the therapies established for ccRCC and are instead sensitive to cytotoxic chemotherapy. Trials dedicated to each vhRCC subtype should emphasize RCTs for the more heterogeneous and common entities such as PRCC requiring robust inferences, and biology-driven interventional studies, including umbrella and basket trials,⁹¹ for the more rare and homogeneous vhRCCs driven by well-defined biological drivers.

Table 2.

Specific considerations for each vhRCC subtype.

Histologic subtype	Incidence among all RCCs	Median age	Common Molecular Alterations	Clinical Considerations	Systemic Therapy Options
Papillary renal cell carcinoma (PRCC)	10–20%	62	c-MET pathway: MET amplifications Chromosome 7 gain HGF amplifications MET kinase domain mutations 9p loss NF2 loss (may be included in NF2-RCC subtype) ALK translocations (ALK translocation RCC subtype)	Clinically and molecular heterogeneous “PRCC of classic pattern” (formerly type 1 PRCC) is more frequently associated with c-MET pathway alterations	Cabozantinib +/−ICT ICT alone Lenvantinib + everolimus after cabozantinib Bevacizumab + erlotinib (less response than FH-RCC)
Chromophobe renal cell carcinoma (CHRCC)	5%	58	PTEN and TP53 mutations Imbalanced chromosome duplications mTOR pathway alterations Low TMB	5%−10% of patients with CHRCC will develop metastatic disease Metastatic CHRCC with sarcomatoid features is highly aggressive	Suntinib or Cabozantinib have limited efficacy Lenvatinib + everolimus yields high ORR though efficacy in presence of sarcomatoid features unknown Currently available ICTs are not effective. Local definitive therapies such as surgical metastasectomy are preferred whenever feasible in oligometastatic CHRCC
Microphthalmia transcription factor (MiTF) family renal cell carcinoma (TRCC)	Up to 1%	31–49	Defined by MiTF alterations. Most commonly in TFE3 and less commonly in TFEB. 9p21.3 homozygous deletions found in ~20% of cases TFEB translocation confers a better prognosis compared to TFE3 translocation TFEB amplification is common and more aggressive TFE3 fusions upregulate the MET pathway TFE3 fusions may upregulate the PI3K/AKT/mTOR pathway Typically low TMB	Most common RCC in children and young adults. Adults may have worse prognosis. More common in women. Prior chemotherapy during childhood is a risk factor. Should always be considered in RCC cases with histomorphological features of both clear cell and papillary histologies. The FISH assay used to detect TFE3 alterations is different from the one used to detect TFEB alterations. These assays cannot provide information on the specific fusion partners in TFE3 or TFEB translocation cases	TKIs such as cabozantinib mTOR inhibitors alone or in combination with lenvatinib ICTs have shown heterogeneous albeit generally modest efficacy.
Fumarate hydratase-deficient renal cell carcinoma (FH-RCC)	< 1%	39–45	FH inactivation in all cases 7q gain 9p loss NF2 loss Low TMB	Between 20–35% of patients with germline FH mutations (HLRCC syndrome) will develop FH-RCC. Between 11–16% of FH-RCC cases will occur due to sporadic FH mutations Loss of FH by IHC is highly specific but not as sensitive as positive 2SC staining by IHC in diagnosing FH-RCC	Cabozantinib alone or in combination with ICT appears Lenvatinib in combination either ICT or everolimus Bevacizumab + erlotinib can be used either in first-line or in the salvage setting
Renal medullary carcinoma (RMC)	< 1%	27	All RMC cases are characterized by loss of INI1 encoded by the SMARCB1 gene 8q gain Low TMB but high focal copy number alterations	Highly aggressive Right kidney is more commonly involved More often in men than women Mainly afflicts young individuals with sickle cell trait or other sickle hemoglobinopathies Often associated with history of high-intensity exercise	Refractory to anti-VEGF TKIs Refractory to standard ICT Regimens Carboplatin + paclitaxel is the preferred first-line therapy Gemcitabine + doxorubicin effective second line EGFR pathway targeting with erlotinib can yield responses in heavily pretreated patients
Collecting duct carcinoma (CDC)	Very rare	65	HER2 amplification can be found in up to 45% of cases Loss of CDKN2A gene located in chromosome 9p is found in up to 62% of cases	Diagnosis of exclusion. Necessary to rule out specific subtypes such as RMC and FH-RCC Occurs in older individuals than RMC Expresses INI1 and FH by IHC and is not associated with sickle hemoglobinopathies	Platinum-based cytotoxic chemotherapy or anti-VEGF TKIs such as cabozantinib are reasonable options Addition of bevacizumab to cytotoxic chemotherapy may improve responses but increase toxicity ICTs can anecdotally produce responses in some CDC cases Capecitabine + lapatinib + trastuzumab can be considered in CDCs with HER2 overexpression CDK4/6 inhibitors such as palbociclib can be considered in CDCs with 9p loss
Unclassified renal cell carcinoma (URCC)	< 5%	50–55	Molecularly heterogeneous NF2, SETD2, BAP1, KMT2C, and/or mTOR mutations are found in aggressive URCC variants	Diagnosis of exclusion. Necessary to rule out specific vhRCC subtypes such as TRCC IHC for ALK may establish the diagnosis of ALK-translocation RCC	ICTs and targeted therapies are the therapeutic mainstays NF2-mutated RCCs are emerging as a distinct subtype that may respond to ICTs and targeting of the mTOR and EGFR pathways ALK-translocation RCC may respond to ALK inhibitors

Abbreviations: 2SC, S-(2-succino)-cysteine; ALK, anaplastic lymphoma kinase; CDC, collecting duct carcinoma; ccRCC, clear cell renal cell carcinoma; EGFR, epithelial growth factor receptor; FISH, fluorescence in situ hybridization; FH, fumarate hydratase; HLRCC, hereditary leiomyomatosis and renal cell carcinoma; ICT, immune checkpoint therapy; IHC, immunohistochemistry; MiTF, micropthalmia transcription factor family; vhRCC, variant histology renal cell carcinoma; PD-L1, programmed death-ligand 1; Pt, patient; CHRCC, chromophobe renal cell carcinoma; PRCC, papillary renal cell carcinoma; RCC, renal cell carcinoma; RMC, renal medullary carcinoma; TKIs, tyrosine kinase inhibitors; Tumor mutation burden, TMB; VEGF, vascular endothelial growth factor.

Key Points:

• Accurate pathologic subclassification is needed to guide management of variant histology renal cell carcinomas.

• Unclassified renal cell carcinoma and collecting duct carcinoma are diagnoses of exclusion.

• Each vhRCC subtype responds differently to cytotoxic chemotherapy, immune checkpoint inhibitors, and targeted therapies such as tyrosine kinase inhibitors.

• Due to its poor response to systemic therapies, local therapies such as surgical metastasectomy may be preferred in certain vhRCC subtypes, in oligometastatic disease.

• Platinum-based cytotoxic chemotherapy is the preferred first-line option for certain rare subtypes such as renal medullary carcinoma and collecting duct cancers.

Synopsis.

The term variant histology renal cell carcinomas (vhRCC), also known as non-clear cell renal cell carcinomas, refers to a diverse group of malignancies with distinct biologic and therapeutic considerations. The management of vhRCC subtypes is often based on extrapolating results from the more common clear cell renal cell carcinoma studies or basket trials that are not specific to each histology. Herein, we discuss how tailored recommendations can be made for each vhRCC histology informed by ongoing research to improve our biologic understanding and clinical experience. The unique management of each vhRCC subtype necessitates accurate pathologic diagnosis and dedicated research efforts.

CLINICS CARE POINTS.

• Identifying the specific vhRCC subtype for each patient is critical for proper management.

• Although most vhRCC histologies are refractory to cytotoxic chemotherapy, it is the preferred treatment strategy for certain rare subtypes such as renal medullary carcinoma.

• Certain vhRCC subtypes such as renal medullary carcinoma are refractory to the targeted therapies and immune checkpoint blockade strategies developed for clear cell renal cell carcinoma.