INTRODUCTION — Renal cell carcinoma (RCC) is divided into two major groups based on histology: clear cell or non-clear cell RCC (ie, RCC of variant histology). Clear cell and non-clear cell RCCs are distinguished using morphology, growth pattern, cell of origin, and, where they are known, underlying biological and clinical characteristics.
Tumor dedifferentiation can develop in any RCC, independent of histology [1]. Sarcomatoid dedifferentiation, the most common form of tumor dedifferentiation, consists of cell components that are spindled or otherwise resemble sarcoma cells [1,2]. However, sarcomatoid RCC is not classified as a distinct tumor subtype because it can be seen in any histologic subtype of RCC [1,2]. Rather, these tumors are characterized by distinct molecular and biological characteristics, including clinical response to systemic therapies. (See "Epidemiology, pathology, and pathogenesis of renal cell carcinoma".)
This topic will review the epidemiology, pathology, clinical presentation, and management of RCC with sarcomatoid features. The management of clear cell RCC and non-clear cell RCC histologies are discussed in detail separately.
●(See "Overview of the treatment of renal cell carcinoma".)
●(See "Systemic therapy of advanced clear cell renal carcinoma".)
●(See "The treatment of advanced non-clear cell renal carcinoma".)
EPIDEMIOLOGY — RCC with sarcomatoid dedifferentiation occurs in approximately 5 to 15 percent of all patients with RCC [3-7]. Most patients present between 54 and 63 years of age [8]. Sarcomatoid RCCs occur more commonly in men than women [8] and in patients of White ethnicity compared with those of Black or Hispanic ethnicity [9].
The prevalence of RCC with sarcomatoid features also depends on the background histology and stage of disease:
●Background histology – Sarcomatoid dedifferentiation occurs mainly in clear cell histologies but can also be seen in non-clear cell histologies. For example, a majority (over 70 percent) of sarcomatoid RCCs occurs in clear cell tumors, the most common histologic subtype of RCC [4].
Sarcomatoid dedifferentiation occur in RCC histologies at the following frequencies [3,4,6-8]:
•Clear cell histologies – 5 to 13 percent
•Non-clear histologies:
-Papillary – 2 to 7 percent
-Chromophobe – 9 to 13 percent
-Unclassified – 11 to 26 percent
-Collecting duct – 29 percent
Sarcomatoid dedifferentiation is extremely rare in translocation RCCs, a subtype of non-clear cell tumors [10].
●Stage – RCC with sarcomatoid features can occur in patients presenting at all stages of disease but are more common in patients with metastatic disease. In observational series, sarcomatoid features occur in up to 15 percent of patients with metastatic RCC [4,5] and 5 to 6 percent of those with localized disease [3,7]. (See "Clinical manifestations, evaluation, and staging of renal cell carcinoma", section on 'TNM staging system'.)
PATHOLOGIC FEATURES — The pathologic features of RCC with sarcomatoid features, including histology and molecular alterations, are discussed separately. (See "Epidemiology, pathology, and pathogenesis of renal cell carcinoma", section on 'Renal cell carcinoma with sarcomatoid features'.)
CLINICAL PRESENTATION AND STAGING — Patients with sarcomatoid RCC are more likely to present with locally advanced or metastatic disease than other RCC histologies, due to the aggressive nature of the disease. A majority of patients (approximately 90 percent) are also symptomatic at presentation. The most common presenting symptoms are flank or abdominal pain, hematuria, weight loss, anorexia, fatigue, and night sweats [7,8,11].
The clinical presentation and staging of sarcomatoid RCC is otherwise similar to other RCC histologies and is discussed separately. (See "Clinical manifestations, evaluation, and staging of renal cell carcinoma", section on 'Clinical manifestations'.)
TREATMENT OF LOCALIZED DISEASE — The general approach to treatment of localized (American Joint Committee on Cancer eighth edition stage I to III (table 1)) sarcomatoid RCC is surgical resection, which offers the best chance of cure. However, the presence of sarcomatoid features (as detected on intraoperative frozen section or on preoperative biopsy) often warrants more aggressive surgical treatment, including radical nephrectomy and extended lymphadenectomy. Further details on the surgical management of sarcomatoid RCC are discussed separately. (See "Definitive surgical management of renal cell carcinoma", section on 'Radical nephrectomy' and "Definitive surgical management of renal cell carcinoma", section on 'Retroperitoneal lymph nodes'.)
TREATMENT OF METASTATIC DISEASE — Approximately 50 percent or more of patients with sarcomatoid RCC present with locally advanced, unresectable or metastatic disease, compared with just 15 percent of all patients with RCC [6,7,11]. Common sites of metastatic disease in patients with sarcomatoid RCC include lungs, bone, lymph nodes, liver, and brain [8]. (See "Clinical manifestations, evaluation, and staging of renal cell carcinoma", section on 'Symptoms and signs'.)
Treatment-naïve disease — There are limited high quality data on the efficacy of systemic therapies for patients with metastatic sarcomatoid RCC, due to the rarity of these tumors. Most evidence is based on subgroup analyses of randomized clinical trials conducted and retrospective studies conducted in clear cell histologies. As an example, one meta-analysis of four randomized clinical trials suggested that regimens containing checkpoint inhibitor immunotherapy demonstrate exceptional clinical efficacy in those with sarcomatoid RCC [12]. By contrast, patients with sarcomatoid RCCs respond poorly to antiangiogenic or targeted therapies such as vascular endothelial growth factor receptor (VEGFR) or mechanistic target of rapamycin (mTOR) inhibitors.
Nivolumab plus ipilimumab (preferred) — For patients with treatment-naïve metastatic sarcomatoid RCC, who are eligible for immunotherapy, we recommend checkpoint inhibitor-based immunotherapy regimens rather than VEGFR inhibitors. Our preferred immunotherapy regimen is nivolumab plus ipilimumab (table 2), which results in high complete response rates and improves overall survival (OS). This combination is approved by the US Food and Drug Administration (FDA) for the initial treatment of patients with intermediate- and poor-risk metastatic clear cell RCC, based on the International Metastatic RCC Database Consortium (IMDC) criteria (table 3). (See "Systemic therapy of advanced clear cell renal carcinoma", section on 'Risk stratification'.)
Most patients with sarcomatoid RCC typically present with intermediate- and poor-risk disease and thus are eligible for this therapy. We also offer this combination in patients with sarcomatoid RCC and favorable-risk disease because of the high rate of durable complete responses with this therapy, although such tumors are less common [5]. (See "Systemic therapy of advanced clear cell renal carcinoma", section on 'Nivolumab plus ipilimumab'.)
In patients with sarcomatoid tumors, the combination of nivolumab plus ipilimumab improves both OS and progression-free survival (PFS) over VEGFR inhibitor therapy, based on data from a randomized phase III trial (CheckMate 214). In a post hoc subset analysis of this study, 139 patients with intermediate- or poor-risk advanced RCC (table 3) with sarcomatoid features received either nivolumab plus ipilimumab followed by maintenance nivolumab (table 4), or sunitinib [12-15]. In preliminary results, at minimum follow-up of five years, relative to sunitinib, the combination of nivolumab plus ipilimumab demonstrated the following, independent of programmed cell death ligand 1 (PD-L1) status [16]:
●Improved OS (five-year OS 47 versus 21 percent, median OS 49 versus 14 months, hazard ratio [HR] 0.46, 95% CI 0.29-0.71)
●Improved PFS (five-year PFS 46 versus 12 percent, median PFS 26 versus 5 months, HR 0.5, 95% CI 0.32-0.8)
●Higher objective (61 versus 23 percent) and complete (23 versus 6 percent) response rates
●Treatment was well tolerated, with toxicity profiles similar to previously reported studies [13]
Further details regarding the administration of nivolumab plus ipilimumab, efficacy in patients with clear cell RCC based on IMDC subgroups, and expected toxicities are discussed in more detail separately. (See "Systemic therapy of advanced clear cell renal carcinoma", section on 'Nivolumab plus ipilimumab' and "Toxicities associated with checkpoint inhibitor immunotherapy".)
Pembrolizumab plus axitinib — In patients with treatment-naïve metastatic sarcomatoid RCC, pembrolizumab (table 5) plus axitinib is an appropriate alternative to nivolumab plus ipilimumab, although an OS advantage has not been established in this population.
In preliminary results from a phase III trial (KEYNOTE-426), 861 patients with treatment-naïve non-clear cell histologies were randomly assigned to either pembrolizumab plus axitinib or to single-agent sunitinib [17]. At median follow-up of 13 months, in the subset of 105 patients with sarcomatoid features, pembrolizumab plus axitinib improved objective response rates (59 versus 32 percent) and complete response rates (12 versus 0 percent) relative to sunitinib. While survival data are immature, there was a nonstatistically significant trend towards improved OS and PFS, which would be clinically meaningful if true (one-year OS 83 versus 80 percent, HR 0.58, 95% CI 0.21-1.59; one-year PFS 57 versus 26 percent, HR 0.54, 95% CI 0.29-1.00).
Pembrolizumab plus axitinib has regulatory approval from the US FDA for patients with treatment-naïve advanced RCC, regardless of risk stratification. Further details on the efficacy of pembrolizumab plus axitinib based on such risk stratification are discussed separately. (See "Systemic therapy of advanced clear cell renal carcinoma", section on 'Pembrolizumab plus axitinib'.)
Avelumab plus axitinib — In patients with treatment-naïve metastatic RCC, the combination of avelumab plus axitinib is an appropriate alternative to nivolumab plus ipilimumab. However, an OS advantage has not been established in this population, potentially due to the rarity of this tumor.
In the phase III JAVELIN RENAL 101 trial, 886 patients with treatment-naïve metastatic clear cell RCC were randomly assigned to avelumab plus axitinib or sunitinib [18]. At a median follow-up of approximately 12 months, in preliminary results from the subset of 108 patients with sarcomatoid RCC, avelumab plus axitinib improved PFS (median PFS 7 versus 4 months; HR 0.57, 95% CI 0.33-1.00), objective (47 versus 21 percent), and complete (4 versus 0 percent) response rates. OS data were not reported for the sarcomatoid subgroup [19].
Avelumab plus axitinib has regulatory approval from the US FDA for patients with treatment-naïve advanced RCC, regardless of risk stratification or PD-L1 expression. Further details on the efficacy of avelumab plus axitinib based on these subgroups are discussed separately. (See "Systemic therapy of advanced clear cell renal carcinoma", section on 'Avelumab plus axitinib'.)
Less preferred regimens — Other less preferred immunotherapy options for patients with metastatic sarcomatoid RCC include atezolizumab plus bevacizumab, pembrolizumab (table 5), or nivolumab (table 4).
Atezolizumab plus bevacizumab — The combination of atezolizumab plus bevacizumab is also active in those with sarcomatoid RCC [20]. However, this combination does not have regulatory approval as initial therapy for advanced RCC, and its use remains investigational.
In a phase III trial (IMmotion 151), 915 patients with treatment-naïve metastatic clear cell RCC were randomly assigned to atezolizumab plus bevacizumab or to single-agent sunitinib [21]. At median follow-up of 13 months, in a subgroup of 142 patients (16 percent) with sarcomatoid histology, atezolizumab plus bevacizumab improved PFS (one-year PFS 39 versus 22 percent, median PFS eight versus five months, HR 0.52, 95% CI 0.34-0.79), overall response rates (49 versus 14 percent), and complete response rates (10 versus 3 percent) relative to sunitinib [22]. While OS data are immature, there was a nonstatistically significant trend towards improved OS, which would be clinically meaningful if true (18-month OS 56 versus 45 percent, median OS 22 versus 15 months, HR 0.64, 95% CI 0.64-1.01).
Further data on the efficacy of atezolizumab plus bevacizumab in other patient subgroups with advanced RCC are discussed separately. (See "Systemic therapy of advanced clear cell renal carcinoma", section on 'Atezolizumab plus bevacizumab'.)
Pembrolizumab — Single-agent pembrolizumab (table 5) has clinical efficacy in metastatic sarcomatoid RCC, but its use remains investigational. Single-agent pembrolizumab has not been directly compared with VEGFR inhibitors or other immunotherapy-based regimens in this patient population.
The efficacy of single-agent pembrolizumab (table 5) in sarcomatoid RCC was demonstrated in preliminary results of an open-label, nonrandomized phase II trial (KEYNOTE-427) consisting of two cohorts. Cohort A had 110 patients with treatment-naïve clear cell RCC, including 11 patients (10 percent) with sarcomatoid features [23] and cohort B had 165 patients with non-clear cell RCC, including 38 (23 percent) with sarcomatoid features [24]. At median follow-up of 36 months, in the cohort A subset, the objective and complete response rates for pembrolizumab in those with sarcomatoid RCC were 64 and 0 percent, respectively (versus 36 and 4 percent in the overall cohort). At median follow-up of 32 months, in the cohort B subset, objective and complete response rates for pembrolizumab in those with sarcomatoid RCC were 42 and 8 percent, respectively (versus 27 and 7 percent in the overall cohort).
Further details from this study on the efficacy of pembrolizumab in other non-clear cell histologies are discussed separately. (See "The treatment of advanced non-clear cell renal carcinoma", section on 'Pembrolizumab'.)
Ineligible for immunotherapy (targeted therapy) — For patients who are not eligible for immunotherapy-based regimens, we offer antiangiogenic therapy with VEGFR inhibitors rather than chemotherapy, although this approach has limited efficacy in those with sarcomatoid features. The choice of VEGFR inhibitors in this population is similar to their use in those with clear cell RCC. (See "Antiangiogenic and molecularly targeted therapy for advanced or metastatic clear cell renal carcinoma", section on 'Preferred VEGFR inhibitors'.)
One observational series derived from the IMDC identified 230 patients with sarcomatoid features [25]. Among the approximately 93 percent of patients treated with VEGFR-directed therapy as initial therapy, the overall response rate was 21 percent; median PFS and OS were 5 and 10 months, respectively.
The effectiveness of mTOR inhibitors for the treatment of sarcomatoid RCC are also limited [4,5]. Although mTOR inhibitors are approved for the treatment of metastatic RCC, immunotherapy-based regimens should be preferred whenever possible for sarcomatoid RCC. (See "Antiangiogenic and molecularly targeted therapy for advanced or metastatic clear cell renal carcinoma", section on 'Inhibitors of the mTOR pathway'.)
Is there a role for other approaches?
Cytoreductive nephrectomy — We do not offer upfront cytoreductive nephrectomy in patients with sarcomatoid RCC, as data suggest poor outcomes with this approach [26]. Upfront cytoreductive nephrectomy is preferred in patients with good performance status, and low disease burden; patients with sarcomatoid RCC are less likely to meet these criteria. Alternatively, select patients with sarcomatoid RCC and a deep partial or complete response of disease outside the kidney to initial systemic immunotherapy could subsequently be offered cytoreductive nephrectomy and surgical resection of residual sites of metastatic disease. (See "Role of surgery in patients with metastatic renal cell carcinoma", section on 'Cytoreductive nephrectomy'.)
Chemotherapy — There is no established role for cytotoxic chemotherapy alone or in combination with targeted therapy in those with RCC with sarcomatoid features. As an example, some studies demonstrated clinical activity for the combination of doxorubicin and gemcitabine in patients with RCC with sarcomatoid features [27], but data overall has not consistently shown clinical efficacy for this approach [28-32].
Active surveillance — Active surveillance is generally reserved for patients with IMDC favorable-risk disease (table 3) who are asymptomatic or minimally symptomatic, and have a low disease burden. Active surveillance is not typically offered to those with sarcomatoid RCC because they are unlikely to fit these criteria. (See "Systemic therapy of advanced clear cell renal carcinoma".)
Subsequent therapy
Treatment approach — Our approach to subsequent therapy in patients with metastatic sarcomatoid RCC depends on the choice of initial therapy. Clinical trials are encouraged where available, given the rarity of these tumors.
Our approach is as follows:
●Progression on nivolumab plus ipilimumab – For patients who have progressed on initial treatment with nivolumab plus ipilimumab, we offer treatment that contains a VEGFR inhibitor, either as a single agent or in combination with immunotherapy (eg, pembrolizumab plus axitinib, avelumab plus axitinib). However, the use of immunotherapy-based regimens in this setting remains under investigation. The choice of single-agent VEGFR inhibitor therapy in this setting is similar to the choice of treatment in those with clear cell RCC and is discussed separately. (See "Antiangiogenic and molecularly targeted therapy for advanced or metastatic clear cell renal carcinoma".)
●No prior immunotherapy – For those who are eligible for immunotherapy and have not yet received it (eg, those previously treated with VEGFR inhibitors alone), we offer immunotherapy-based regimens. While the preferred regimen is nivolumab plus ipilimumab (table 2), another alternative is single-agent nivolumab. (See 'Treatment-naïve disease' above and 'Nivolumab' below.)
●Progression on combined immunotherapy plus VEGFR inhibitor – For those with progression on combination immunotherapy plus VEGFR inhibition (eg, pembrolizumab plus axitinib, avelumab plus axitinib) or sequential use of these agents, our preferred option is nivolumab plus ipilimumab (table 2). Other reasonable options include single-agent nivolumab [33], or alternative antiangiogenic therapy, either as a single agent (cabozantinib) or in combination (lenvatinib plus everolimus). (See "The treatment of advanced non-clear cell renal carcinoma", section on 'Cabozantinib' and "Antiangiogenic and molecularly targeted therapy for advanced or metastatic clear cell renal carcinoma", section on 'Lenvatinib plus everolimus'.)
The choice of subsequent therapy in patients with treatment-refractory clear cell RCC is discussed separately. (See "Systemic therapy of advanced clear cell renal carcinoma", section on 'Treatment approach for subsequent therapy'.)
Nivolumab — Nivolumab monotherapy is reserved for the subsequent treatment of patients with metastatic RCC who have progressed on initial therapy with antiangiogenic agents, and it has regulatory approval in this setting from the US FDA. Single-agent nivolumab is also an option for patients who previously received immunotherapy, as observational data also suggest that patients with metastatic RCC can respond to immunotherapy rechallenge (including monotherapy) in the subsequent-line setting [33].
In a pooled analysis of a phase II (CheckMate 010) [34] and phase III (CheckMate 025) [35] trials, single-agent nivolumab was compared to everolimus in a subset of 120 patients with previously treated metastatic sarcomatoid RCC. Compared with everolimus, nivolumab improved objective response rates (24 versus 2 percent). While OS (two-year OS 38 versus 21 percent; HR 0.72, 95% CI 0.49-1.07) and PFS (18-month PFS 14 versus 1 percent; HR 0.97, 95% CI 0.65-1.45) were higher with nivolumab, the results were not statistically significant, potentially due to the limited number of patients, but would be clinically meaningful if true [4].
Further details on these trials, including the efficacy of nivolumab as subsequent therapy in clear cell RCC, are discussed separately. (See "Systemic therapy of advanced clear cell renal carcinoma", section on 'Nivolumab'.)
ASSESSMENT OF TREATMENT RESPONSE — We assess the treatment response of patients with sarcomatoid RCC as follows:
●For most patients, we obtain computed tomography (CT) imaging of the chest and abdomen (with or without pelvic imaging) every two to three months. Brain imaging (eg, magnetic resonance imaging [MRI] or CT brain) may be obtained as clinically indicated (ie, based on neurologic symptoms). However, since sarcomatoid histology appears to be a risk factor for developing brain metastases, it is reasonable also to offer surveillance brain imaging in asymptomatic patients with metastatic disease [36].
●For patients with clinically aggressive disease at baseline, we image more frequently with a CT chest, abdomen, pelvis, and brain imaging every six to eight weeks.
●For patients with prolonged deep partial (ie, greater than 80 percent regression of disease outside the kidney) or complete responses to immune checkpoint inhibitor-based regimens, we reduce the frequency of imaging to every four months to six months, depending upon the duration of response. (See "Principles of cancer immunotherapy".)
PROGNOSIS — Historically, the prognosis of patients with advanced, unresectable, or metastatic sarcomatoid RCC has been poor and treatment has been palliative. Sarcomatoid RCC is associated with limited responsiveness to targeted therapies, such as vascular endothelial growth factor receptor (VEGFR) inhibitors or mechanistic target of rapamycin (mTOR) inhibitors [5].
However, both the prognosis and treatment of these patients are evolving in the era of checkpoint inhibitor immunotherapy, and some of these patients may have durable responses. Sarcomatoid RCC generally responds better to immunotherapy-based regimens than nonsarcomatoid RCC, regardless of background histology (ie clear cell versus non-clear cell). There is currently no evidence that background histology alters management. In patients with sarcomatoid RCC, immunotherapy extends median overall survival to over three years and improves complete response rates, suggesting the potential for cure.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cancer of the kidney and ureters".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Kidney cancer (The Basics)")
●Beyond the Basics topics (see "Patient education: Renal cell carcinoma (kidney cancer) (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Sarcomatoid dedifferentiation – Sarcomatoid dedifferentiation is the most common form of tumor dedifferentiation in renal cell carcinoma (RCC) and can be seen in both clear cell and non-clear cell histologies. (See 'Epidemiology' above and 'Pathologic features' above.)
●Clinical presentation – Patients with sarcomatoid RCC typically present with locally advanced or metastatic disease. The most common presenting symptoms are flank or abdominal pain, hematuria, weight loss, anorexia, fatigue, and night sweats. (See 'Clinical presentation and staging' above.)
●Treatment of localized disease – Patients with localized sarcomatoid RCC are treated with surgical resection. However, the presence of sarcomatoid features often warrants more aggressive surgical treatment, including radical nephrectomy and extended lymphadenectomy. (See "Definitive surgical management of renal cell carcinoma", section on 'Radical nephrectomy' and "Definitive surgical management of renal cell carcinoma", section on 'Retroperitoneal lymph nodes'.)
●Initial therapy for advanced or metastatic disease – For patients with treatment-naïve advanced or metastatic RCC with sarcomatoid features who are eligible for immunotherapy, we recommend nivolumab plus ipilimumab (table 2) rather than sunitinib, a vascular endothelial growth factor receptor (VEGFR) inhibitor, as initial therapy (Grade 1B). (See 'Treatment of metastatic disease' above and 'Nivolumab plus ipilimumab (preferred)' above.)
•Alternative options to nivolumab plus ipilimumab include combinations of immunotherapy with VEGFR inhibitors such as pembrolizumab plus axitinib or avelumab plus axitinib. However, nivolumab plus ipilimumab is the only regimen that has demonstrated an overall survival and clinically significant complete response benefit in relation to a VEGFR inhibitor. (See 'Pembrolizumab plus axitinib' above and 'Avelumab plus axitinib' above.)
•For those who are not eligible for immunotherapy, we offer antiangiogenic therapy with VEGFR inhibitors rather than chemotherapy, although this approach has limited efficacy in those with sarcomatoid features. The use of VEGFR inhibitors in this population is similar to their use in those with clear cell RCC. (See "Antiangiogenic and molecularly targeted therapy for advanced or metastatic clear cell renal carcinoma".)
●Assessment of treatment response – For most patients, we assess treatment response using computed tomography (CT) imaging of the chest, abdomen, (with or without pelvic imaging) every two to three months. We obtain brain imaging (eg, magnetic resonance imaging [MRI] or CT brain) as clinically indicated (ie, based on neurologic symptoms). However, it is reasonable also to offer surveillance brain imaging in asymptomatic patients with metastatic disease, since sarcomatoid histology appears to be a risk factor for developing brain metastases. (See 'Assessment of treatment response' above.)
