Renal cell carcinoma

Non-clear cell renal cell carcinoma (RCC) encompasses diverse subtypes, each requiring tailored therapeutic approaches. Papillary RCC may benefit from immunotherapy or vascular endothelial growth factor receptor (VEGFR) inhibitors. Chromophobe RCC often sees mTOR inhibitors or VEGFR inhibitors as initial treatments. For collecting duct and renal medullary carcinomas, cytotoxic chemotherapy is recommended.

Translocation RCC may respond well to lenvatinib plus pembrolizumab, while unclassified RCC patients might consider immunotherapy-based regimens. Sarcomatoid features in non-clear cell RCC lean towards immunotherapy.

Clinical trials are encouraged due to limited high-quality data, emphasizing the need for personalized strategies based on histologic subtypes. Overall, these recommendations aim to optimize outcomes in the diverse landscape of non-clear cell RCC.

1. Dr SUMIT KUMAR Assistant Professor NEIGRIHMS

2. Grouping of Renal Tumors : Papillary Renal Tumors : Type 1 and Type 2 PRCC no longer recommended. Type 1 now termed classic PRCC. Type 2 recognized as various entities (e.g., FH deficient RCC, acquired cystic disease-associated RCC). Morphologic spectrum expanded, including biphasic PRCC and Warthin-like PRCC. Papillary renal neoplasm with reverse polarity recognized as a separate entity. Oncocytic and Chromophobe Renal Tumors : New Category: Other Oncocytic Tumors : Includes emerging entities like low-grade oncocytic tumor (LOT) and eosinophilic vacuolated tumor (EVT). Includes oncocytic renal neoplasms of low malignant potential (NOS) and hybrid oncocytic tumors (HOT) in a hereditary setting. Collecting Duct Tumors : No specific changes mentioned. Other Renal Tumors : Clear Cell Papillary Renal Cell Tumor: Replaces clear cell papillary renal cell carcinoma due to benign behavior . Molecularly Defined Renal Carcinomas: TFE3 rearranged RCC and TFEB altered RCC separated into distinct entities. New entities introduced: ESC RCC, ELOC-mutated RCC, ALK rearranged RCC. Grading of Renal Carcinomas: Based on the single high-power field showing the greatest pleomorphism. WHO/ISUP grading varies in significance across RCC subtypes, categorized based on grading value.

3. Von Hippel-Lindau (VHL) Gene: ccRCC : Often characterized by VHL gene mutations or inactivation, leading to dysregulation of hypoxia-inducible factor (HIF) and subsequent angiogenesis. ncRCC : VHL mutations are less frequent in non-clear cell subtypes. MET Gene: Papillary RCC: Frequently associated with MET gene mutations. CD117 (c-KIT): Chromophobe RCC: CD117 expression is often seen in chromophobe RCC but is typically negative in ccRCC . Carbonic Anhydrase IX (CAIX): ccRCC : CAIX is commonly expressed in clear cell RCC, making it a potential marker for distinguishing ccRCC from other subtypes. PAX8: ccRCC : Positive for PAX8, a marker often used in the immunohistochemical evaluation of renal tumors . ncRCC : Also positive for PAX8, making it less helpful in subtype differentiation. Cytokeratins (CKs): Papillary RCC: Positive for CK7, while clear cell RCC is typically negative.

4. RCC Significance: 3% to 4% of adult malignancies. Clear cell RCC ( ccRCC ) predominant (70-90%). ncRCC Subtypes: Papillary (10–15% of RCCs). Chromophobe (5-7%). Collecting duct (1-2%). Renal medullary (<1%). Translocation RCC tumors (<1%).

5. Primary tumor (T) T category T criteria TX Primary tumor cannot be assessed T0 No evidence of primary tumor T1 Tumor <_ 7 cm in greatest dimension, limited to the kidney T1a Tumor <_4 cm in greatest dimension, limited to the kidney T1b Tumor >4 cm but < 7 cm in greatest dimension, limited to the kidney T2 Tumor >7 cm in greatest dimension, limited to the kidney T2a Tumor >7 cm but < 10 cm in greatest dimension, limited to kidney T2b Tumor>10 cm , limited to kidney T3 Tumor extends into major veins or perinephric tissues, but not into the ipsilateral adrenal gland and not beyond Gerota’s fascia T3a Tumor extends into the renal vein or its segmental branches, or invades the pelvicalyceal system, or invades perinal and/ or renal sinus fat but not beyond Gerota’s fascia T3b Tumor extends into the vena cava below the diaphragm T3c Tumor extends into the vena cava above the diaphragm or invades the wall of the vena cava T4 Tumor invades beyond Gerota’s fascia ( including contiguous extension into the ipsilateral adrenal gland) Regional lymph nodes (N) N category N criteria NX Regional lymph node cannot be assessed N0 No regional lymph node metastases N1 Metastasis in regional lymph node(s) Distant metastasis (M0 M ctegory M criteria M0 No distant metastasis M1 Distant metastasis

6. Stage I Stage II Stage III Stage IV TNM Staging : Prognostic Groups T2NOMO T1NOMO T1-T2N1MO T3NX,NO-N1MO T4 Any N MO Any T Any N M1

7. Suspicious Mass STAGE I T1a STAGE I T1b STAGE II STAGE III STAGE IV Partial nephrectomy (preferred) Ablative techniques Active surveillance Radical nephrectomy Partial nephrectomy Ablative techniques Active surveillance Radical nephrectomy Partial nephrectomy (preferred) Radical nephrectomy Radical nephrectomy (preferred) Partial nephrectomy surveillance Adjuvant pembrolizumab surveillance Clear cell histology Adjuvant pembrolizumab surveillance Non Clear cell histology H&P Urinanalysis Abdomen +/-pelvis CT or MRI Chest CT Scan surveillance

8. Clear cell histology Surgically unresectable Potentially surgically resectable primary Consider tissue sampling Systemic therapy ( preferred in clear cell histology Tissue sampling Clinical trial First line systemic therapy Metastasectomy or SBRT BST Cytoreductive nephrectomy in selected patient Stage IV Non- Clear cell histology Clinical trial First line systemic therapy Metastasectomy or SBRT BST

9. Nephron-Sparing Surgery (Partial Nephrectomy): Recommended for: Unilateral stage I–III tumors (where technically feasible). Uninephric state, renal insufficiency, bilateral renal masses, and familial renal cell cancer. Patients at relative risk for progressive chronic kidney disease (young age, medical risk factors). Surgical Techniques: Open, laparoscopic, or robotic approaches for radical and partial nephrectomies. Lymph Node Dissection: Optional but should be considered for resectable adenopathy on preoperative imaging or palpable/visible adenopathy. Adrenalectomy: Omitted if adrenal gland is uninvolved. Inferior Vena Cava Involvement: Specialized teams or referral to high-volume centers may be required for extensive involvement. Thermal Ablation: Options include cryosurgery, radiofrequency ablation, and microwave ablation. Considered for clinical stage T1 renal lesions. Clinical T1b masses in select patients not eligible for surgery.

10. Stereotactic Body Radiation Therapy (SBRT): O ption for medically inoperable patients with stage I, II, or III kidney cancer (Category 2B for stage I, Category 3 for stage II and III). Active Surveillance: Considered for clinical stage T1 renal lesions, especially: Small renal masses (<3 cm) with high rates of benign tumors . T1a tumors (≤4 cm) with a predominantly cystic component. Patients with T1 masses and significant competing risks for intervention-related morbidity or mortality. Involves serial imaging with timely intervention if the mass shows changes indicating increasing metastatic potential. Periodic metastatic survey, including blood work and chest imaging, is recommended. Cytoreductive Nephrectomy: Candidates typically have: Excellent performance status (ECOG PS <2). No brain metastasis. Considered prior to systemic therapy. Systemic Therapy: Recommended before cytoreductive nephrectomy for patients with: Large-volume distant metastases. Tumors with significant sarcomatoid burdens.

11. Characteristic Clear Cell Carcinoma Non-Clear Cell Carcinoma Histology Clear cytoplasm Diverse morphology based on specific subtype Prevalence 70-80% of RCC cases Less common, various subtypes collectively Genetics Associated with VHL mutations Heterogeneous genetic alterations by subtype Prognosis Variable, often less favorable Variable, subtypes may have different outcomes Molecular Features VHL mutations common Genetic variations specific to each subtype Clinical Approach Targeted therapies often developed Individualized approach based on subtype Examples of Subtypes Clear cell, clear cell papillary Papillary, chromophobe, collecting duct, etc.

12. Surgery: Nephron-Sparing Surgery: Considered whenever feasible to preserve renal function. Radical Nephrectomy: In cases where nephron-sparing surgery is not possible or for more aggressive subtypes. Systemic Therapy: Targeted Therapies: Depending on the specific histologic subtype. Papillary RCC: Tyrosine kinase inhibitors (TKIs) like sunitinib or pazopanib. Chromophobe RCC: Limited evidence, but potential response to TKIs. Collecting Duct Carcinoma: Chemotherapy may be considered. Other Subtypes: Limited data, and treatment may vary. Immunotherapy: Checkpoint Inhibitors: May be considered for certain subtypes, with immunotherapy agents like nivolumab or pembrolizumab. Clinical Trials: Participation in clinical trials exploring novel treatments and targeted therapies is encouraged, given the limited evidence for standard treatments in ncRCC . Radiation Therapy: Adjuvant or Palliative Radiation: Depending on the extent and location of the disease. Active Surveillance: For selected cases with indolent tumors or those not amenable to immediate intervention. Cytoreductive Nephrectomy: Considered in metastatic disease, especially if there's potential for a significant reduction in tumor burden. Genetic Testing: Consideration for genetic testing, as certain genetic mutations may guide treatment decisions. Patient Considerations: Age, overall health, and comorbidities play a crucial role in treatment decisions. The general approach to treatment of localized (stage I to III)non-clear cell renal cell carcinoma (RCC) is similar to that of clear cell RCC.

13. A ) Classical features of pRCC type 1, with delicate papillae covered by cells with scant pale cytoplasm and nuclei arranged in a single layer. ( B ) Notice the frequent psammomatous calcifications (arrows) and macrophages filled with hemosiderin pigment; pRCC is relatively hypovascular in comparison with cRCC

14. Characteristic Type 1 pRCC Type 2 pRCC Histological Characteristics Single-layered cells, oval nuclei, scant basophilic cytoplasm Large pseudostratified cells, eosinophilic, prominent nucleoli Immunohistochemistry CK7, MUC1, vimentin expressions common CK20, E-cadherin expressions more frequent Molecular Profile Largely driven by MET pathway alterations Multiple subtypes, distinct molecular profiles Genomic Clusters (NGS) Lower-grade, higher rates of chromosomal gains in 7p and 17p Different copy number alterations, subtypes identified Cell Origin Diversity Primarily from proximal tubule (PT) cells Multiple cell origins, some tumors from collecting duct (CD) cells Clinical Associations Generally lower grade May have higher-grade subtypes, varied clinical associations Examples Classic pRCC Includes HLRCC, translocation RCC, diverse subtypes

15. Abandonment of Type 1 and Type 2 Subtyping: Traditional subtyping of PRCC into Type 1 and Type 2 is no longer recommended. "Type 1 PRCC" is now termed "classic PRCC." Recognition of Distinct Entities: Tumors previously labeled as "Type 2" PRCC exhibit morphologic variability and diverse clinical behaviors . Many tumors with prominent papillary architecture previously classified as "Type 2" are now recognized as separate entities: Sporadic FH-deficient RCC MiTF family translocation RCC ALK-rearranged RCC Acquired cystic disease-associated RCC (ACD-RCC) Eosinophilic solid and cystic RCC Prognostic Value of WHO/ISUP Grade: Recent evidence questions the clinical significance of "Type 1 and 2" PRCC, emphasizing the prognostic value of WHO/ISUP grade. Emerging biomarkers like ABCC2 are also considered for prognosis. Expanded Morphologic Spectrum: The morphologic spectrum of PRCC is expanded to include new patterns: Biphasic (alveolar/ squamoid ) PRCC with solid growth Papillary renal neoplasm with reverse polarity (formerly " oncocytic low-grade PRCC") Warthin-like PRCC mimicking salivary gland Warthin tumor Association with Immunohistochemical Features and Molecular Alterations: Specific patterns like papillary renal neoplasm with reverse polarity are consistently positive for GATA3 and negative for vimentin. Molecular alterations, such as recurrent KRAS mutations, are observed, even in small tumors .

16. Trial Name Comparative Arms Findings ARCC Trial IFN vs. Temsirolimus Temsirolimus showed superiority over IFN in terms of PFS and OS in pRCC. RAPTOR Trial Everolimus Everolimus demonstrated an OS benefit, with a longer duration of SD contributing to positive outcomes. SUPAP Trial Sunitinib Sunitinib demonstrated effectiveness in terms of response rates, PFS, and OS in patients with pRCC. AXIPAP Trial Axitinib Axitinib showed activity in both type 1 and type 2 pRCC, with significant responses and PFS. ESPN Trial Sunitinib vs. Everolimus Sunitinib showed superior PFS compared to everolimus in nccRCC , including pRCC . ASPEN Trial Sunitinib vs. Everolimus Sunitinib showed improved PFS compared to everolimus in the intention-to-treat cohort, with significant benefits in pRCC . SAVOIR Trial Savolitinib vs. Sunitinib Savolitinib showed a numerically superior response rate to sunitinib in a biomarker-driven approach for MET inhibition in pRCC. PAPMET Trial Cabozantinib vs. Sunitinib Cabozantinib demonstrated superior median PFS and response rates compared to sunitinib. KEYNOTE-427 Trial Pembrolizumab Pembrolizumab monotherapy demonstrated activity in non-clear cell histology, including a significant ORR in pRCC. CheckMate-374 Trial Nivolumab Nivolumab demonstrated an ORR and impressive OS in patients with treatment-refractory advanced/metastatic nccRCC. CheckMate-920 Trial Nivolumab plus Ipilimumab Nivolumab plus ipilimumab showed activity in previously untreated advanced/metastatic nccRCC .

17. Among other histologies mostly papillary. Phase III, randomized, open-label study ARM 1 ARM 1 IFN (3 million units [MU] subcutaneously three times weekly, N: 207 Other histology: 36 temsirolimus (25 mg intravenously weekly) N:209 Other histology: 37 FOR OTHER Median Months :1.8 Overall response: 8.3% OS:4.3 Clinical Benefit:8.3% FOR OTHER Median Months :7.0 Overall response: 5.4% OS:11.6 Clinical Benefit: 40.5% Dutcher J.P., De Souza P., McDermott D., Figlin R.A., Berkenblit A., Thiele A., Krygowski M., Strahs A., Feingold J., Hudes G. Effect of temsirolimus versus interferon- α on outcome of patients with advanced renal cell carcinoma of different tumor histologies . Med. Oncol. 2009;26:202–209.

18. Open-label phase 2 trial of first-line everolimus monotherapy in patients with papillary metastatic renal cell carcinoma: RAPTOR final analysis Bernard Escudier   1 ,  Vincent Molinie   2 ,  Sergio Bracarda   3 ,  Pablo Maroto   The RAPTOR study, a phase 2 trial, evaluated first-line everolimus in previously untreated patients with papillary metastatic renal cell carcinoma ( mRCC ). Key findings: Patient Characteristics: 92 patients enrolled; 78% were men. Mean age: 60 years. Papillary histology confirmed in 78% (type 1, 32%; type 2, 64%). Treatment and Endpoints: Everolimus 10 mg once daily until progression or toxicity. Primary endpoint: 6-month PFS rate (34%). Results: Median PFS: 4.1 months (95% CI 3.6-5.5). 65% achieved stable disease. Median OS: 21.4 months (95% CI 15.4-28.4). Type 1 histology: Median PFS 7.9 months; Median OS 28.0 months. Type 2 histology: Median PFS 5.1 months; Median OS 24.2 months. Adverse Events: Common grade >2 events: Asthenia (13%), anemia (7%), fatigue (5%). Interpretation: Everolimus showed clinical benefit in papillary mRCC . Central pathological review emphasized for this rare tumor.

19. Everolimus versus sunitinib for patients with metastatic non-clear-cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomised phase 2 trial Andrew J Armstrong ,  Susan Halabi ,  Tim Eisen ,  Samuel Broderick ,  Walter M Stadler , Participants: 108 patients with metastatic non-clear-cell renal cell carcinoma (papillary, chromophobe, or unclassified). Patients were randomly assigned (1:1) to receive everolimus (10 mg/day) or sunitinib (50 mg/day; 6-week cycles of 4 weeks with treatment followed by 2 weeks without treatment) Parameter Sunitinib (N=51) Everolimus (N=57) PFS 8.3 months (80% CI 5.8–11.4) 5.6 months (5.5–6.0) Hazard Ratio 1.41 (80% CI 1.03–1.92), p=0.16 - Adverse Events Hypertension 24% 2% Infection 12% 7% Diarrhea 10% 2% Pneumonitis 9% 9% Stomatitis 9% - Hand-Foot Syndrome 8% -

20. A comparison of sunitinib with cabozantinib , crizotinib , and savolitinib for treatment of advanced papillary renal cell carcinoma: a randomised, open-label, phase 2 trial Prof Sumanta K. Pal , MD, 1   Prof Catherine Tangen , DrPH, 2,3   Ian M. Thompson, Jr. , MD, 4 Study Design: Randomized, open-label, phase II trial. 152 patients enrolled (April 2016 to December 2019). Treatment Arms: Sunitinib (46), Cabozantinib (44), Crizotinib (28), Savolitinib (29). Patient Characteristics: Median age: 66 years; 76% male. 147 eligible patients in the intention-to-treat population. Prior therapy received by 7%. Sunitinib: 50 mg 4 weeks on, 2 weeks off, with dose reductions to 37.5 mg and 25 mg permitted. Cabozantinib : 60 mg oral daily with dose reductions to 40 mg and 20 mg permitted. Crizotinib : 250 mg twice daily with dose reductions to 200 mg twice daily and 250 mg once daily permitted. Savolitinib : 600 mg oral daily with dose reductions to 400 mg and 200 mg oral daily permitted

21. Parameter Sunitinib Cabozantinib Crizotinib Savolitinib Efficacy Median PFS (months) 5.6 9.0 2.8 3.0 Overall Response Rate (%) 4 23 3 Median Overall Survival (months) 16.4 20.0 19.9 11.7 Adverse Events Discontinuation due to Adverse Events (%) 24 23 16 10 Common Side Effects (> Grade 2) Hypertension 17% 32% - - Fatigue 21% 13% 7% - Hand-foot Syndrome - 20% - - Anemia 13% 10% - - Thromboembolic Event 2% 2% - - Diarrhea - 63% - - Hyponatremia - - - 10% Increase in ALT Levels - - 7% - Limb Swelling - - - 7%

22. Type: French multicentre phase II study Patients: Untreated mPRCC patients with measurable disease, ECOG performance status ≤ 1, and adequate organ functions. Treatment: Axitinib administered orally at 5 mg twice daily . Patients Screened: 56 Patients Included: 44 (13 type 1, 30 type 2, 1 non-specified) Follow-up: Median 32.0 months (13.1-39.9) 24w-PFR (Primary Endpoint): 45.2% (95% CI, 32.6% to +∞) Objective Response Rate: 28.6% (95% CI, 15.7%-44.6%) Type 1: 7.7% Type 2: 35.7% Progression-Free Survival (Overall Median): 6.6 months (95% CI, 5.5-9.2) Type 1: 6.7 months Type 2: 6.2 months Overall Survival: Median 18.9 months (95% CI, 12.8-not reached) Grade 3-4 Treatment-Related Adverse Events: Rare, except for hypertension (27%) Negrier S., Rioux-Leclercq N.,., et al. Axitinib in first-line for patients with metastatic papillary renal cell carcinoma: Results of the multicentre, open-label, single-arm, phase II   Eur. J. Cancer.  2020;129:107–116. Conclusion: Axitinib demonstrated encouraging efficacy in mPRCC patients, particularly in type 2 PRCC. Manageable toxicity profile. Axitinib may be a promising first-line treatment option and warrants further investigation, potentially in combination with immunotherapy

23. Study Type: Single-arm, international phase II trial Patients Enrolled: 158 Histology: Advanced non-clear cell RCC of varying histologies Treatment: Lenvatinib plus pembrolizumab Results (Papillary Histology Subgroup): Patients with Papillary Histology: 93 Objective Responses: 54% Complete Responses: 9% One-Year Progression-Free Survival (PFS): 67% Follow-up: Median Follow-up: 15 month Albiges L, Gurney H, Atduev V, et al. Pembrolizumab plus lenvatinib as first-line therapy for advanced non-clear-cell renal cell carcinoma (KEYNOTE-B61): a single-arm, multicentre, phase 2 trial. Lancet Oncol 2023; 24:881.

24. Phase II N= 47 Patients: Advanced non–clear-cell RCC, 0-1 prior systemic therapies (excluding immune checkpoint inhibitors). Treatment: Cabozantinib 40 mg once daily plus nivolumab 240 mg q2w or 480 mg q4w. Results: Cohort 1 (Papillary, Unclassified, Translocation-Associated RCC): ORR: 47.5% (median follow-up: 13.1 months). Median progression-free survival: 12.5 months. Median overall survival: 28 months. Mutations: NF2 and FH. Promising efficacy, with common mutations in NF2 and FH associated with objective responses. Cohort 2 (Chromophobe RCC): No responses; one patient had stable disease > 1 year. Safety: Grade 3/4 treatment-related adverse events: 32%. Discontinuation due to toxicity: 13% for cabozantinib , 17% for nivolumab. Conclusion: Cabozantinib plus nivolumab demonstrated promising efficacy in non–clear-cell RCC variants, especially those with papillary features. Lee CH, Voss MH, Carlo MI, et al. Phase II Trial of Cabozantinib Plus Nivolumab in Patients With Non-Clear-Cell Renal Cell Carcinoma and Genomic Correlates. J Clin Oncol 2022; 40:2333.

25.  Ongoing Trials in pRCC

26.  Ongoing Trials in pRCC

27. Introduction: 5% of kidney cancers are chRCC . Estimated 3,700 new cases in the USA (2020). Clinical Presentation: Less aggressive than clear cell RCC. Often asymptomatic, detected incidentally. Common metastases to liver and lungs. Genetic Syndromes: Linked to Birt -Hogg- Dubé syndrome and others. Pathology: Arises from collecting duct cells. Microscopic variants: pale and eosinophilic cells. Immunohistochemistry markers: CD117, CK7. Molecular Characteristics: Aneuploidy with chromosome losses. Loss of HNF1B and TP53 mutation noted. Infrequent PDL1 expression (5.6%). Conclusion: Ongoing research on genetic and molecular features. Accurate diagnosis involves clinical, pathological, and molecular assessments. High-power photomicrograph of the classic variant of chRCC demonstrates uninucleated (black arrow) and binucleated (red arrow) cells with a polymorphous character, including raisinoid nuclei and perinuclear clearing. ( Hematoxylin -eosin stain; original magnification, ×200.)

28. Clinical Presentation: Often incidental finding. Local symptoms: abdominal/flank pain (34–67%), abdominal mass (27%), hematuria (17–40%). Systemic symptoms: fever, cachexia, fatigue, weight loss (20–33%). Majority low-stage cancers at diagnosis. Epidemiology: Estimated global RCC incidence in 2018: 400,000 with 175,000 deaths. U.S. annual chRCC incidence: 3,250 cases. Mean age at diagnosis: 58–60 years. Slight male sex predilection. Birt -Hogg- Dubé (BHD) Syndrome: Associated with chRCC . Autosomal dominant with FLCN gene mutations on chromosome 17. RCC incidence 7x higher in BHD. RCCs in BHD: bilateral, multifocal, slow-growing. Often hybrid oncocytic tumors or pure chRCCs . Imaging Features (CT): Well-circumscribed mass, smooth/lobular contours. Solid or mostly solid appearance. Calcification in 14–34%. Central scar in 19–34%. Isoattenuating to slightly hyperattenuating on noncontrast CT. Moderate enhancement, peaks in nephrographic phase. Enhances less than ccRCC but more than papRCC . chRCC may have a central scar (black * in 

29. Chromophobe renal cell carcinoma Localised disease Metastatic disease Radical nephrectomy (ablation if feasible for tumors <3 cms ) Surveillance No proven benefit with adjuvant therapy Consider cytoreductive nephrectomy if ECOG PS 0-1 AND SYMPTOMATIC RENAL MASS Systemic therapy: Sunitinib or Everolimus Preferred first-line options Also consider: Genomic testing, clinical trials, temsirolimus , immunotherapy for sarcomatoid variants

30. The general approach for the  treatment  of localized chRCC is surgery, similar to that of ccRCC Localized chRCC has better prognosis when compared to ccRCC . The 5-year recurrence-free survival and cancer-specific survival rates were 89.3 % and 93 %, respectively . However, advanced stage IV chRCC has no survival benefit compared to ccRCC Axial contrast-enhanced excretory phase CT image shows a hypoenhancing mass (arrow) with nonenhancing central necrosis (*).

31. Collecting Duct RCC: Aggressive tumor with similarities to urothelial carcinoma. Responds to platinum-based chemotherapy. Limited clinical trial data; further studies needed. Phase II trial with gemcitabine plus cisplatin showed 26% objective responses, median survival ~11 months. Renal Medullary Carcinoma: Aggressive variant associated with sickle cell trait. Limited treatment data; platinum-based chemotherapy commonly used. Response rates around 30% in observational studies. Two-year overall survival in one series: 13%. Limited activity with anthracyclines, bortezomib, and VEGFR inhibitors. General Recommendations: Cytotoxic chemotherapy (cisplatin plus gemcitabine, carboplatin plus gemcitabine, or carboplatin plus paclitaxel) suggested for both histologies . Immunotherapy with checkpoint inhibitors investigational; limited data available. Encourage enrollment in clinical trials for both types.

32. Initial Treatment: Suggest immunotherapy-based regimens for high objective response rates. Options include combination therapy (nivolumab plus ipilimumab; lenvatinib plus pembrolizumab) or single-agent immunotherapy (pembrolizumab or nivolumab). Alternative for Immunotherapy Decline: VEGFR inhibitors, either as single-agents (e.g., sunitinib or cabozantinib ) or combination therapy ( lenvatinib plus everolimus ), are reasonable. Immunotherapy Regimens: Nivolumab plus ipilimumab: Observational data report 20-44% objective response rates. Lenvatinib plus pembrolizumab: Phase II trial showed 52% objective response in unclassified RCC. Pembrolizumab: Phase II trial reported 31% objective response and durable responses. Nivolumab: Phase II trial demonstrated 30% objective response in unclassified RCC. VEGFR Inhibitors: Sunitinib: Improved progression-free survival (PFS) twofold relative to everolimus in randomized trials. Cabozantinib : Retrospective study reported 13% objective responses and 36% 12-month overall survival in unclassified RCC subset. Other Regimens: Lenvatinib plus everolimus : Phase II trial showed partial responses in unclassified RCC. Bevacizumab plus everolimus : Phase II trial reported 43% objective response rate and 14 months median PFS in unclassified RCC with papillary features.

33. Initial Therapy: Suggest lenvatinib plus pembrolizumab for high objective response rates. Single-agent VEGFR inhibitor (e.g., sunitinib) is a reasonable alternative for those declining or ineligible for immunotherapy. Translocation RCC Characteristics: Rare non-clear cell carcinoma variant with TFE3 gene fusions. Fusions activate microphthalmia-associated transcription factor (MITF). Limited Data on Optimal Therapy: Rarity hinders data collection. Lenvatinib plus pembrolizumab phase II trial showed a 67% objective response rate. No direct comparison with single-agent VEGFR inhibitors in randomized trials. Lenvatinib Plus Pembrolizumab: KEYNOTE-B61 phase II trial demonstrated 67% objective response in papillary histology. International trial with 158 patients, systemic therapy-naïve advanced non-clear cell RCC. Sunitinib: Observational studies support initial use in translocation RCC. Nonrandomized study showed 27% partial responses with sunitinib. Longer progression-free survival compared to cytokine therapy (median PFS eight versus two months).

34. Histologic Subtypes: Main subtypes include papillary, chromophobe, collecting duct, unclassified, and translocation carcinomas. Sarcomatoid features can be present in any histologic subtype. Treatment Approach: Tailored to histologic subtype due to limited data. Encourage enrollment in clinical trials whenever possible. Papillary RCC: Immunotherapy-based therapy (e.g., nivolumab plus ipilimumab) or VEGFR inhibitor as initial therapy. Consider nivolumab plus ipilimumab for immunotherapy, extrapolating from clear cell RCC data. Cabozantinib is suggested for those opting for targeted antiangiogenic therapy or ineligible for immunotherapy. Preferred therapy for hereditary leiomyomatosis -related papillary RCC: bevacizumab plus erlotinib. Chromophobe RCC: Limited evidence due to rarity. Initial treatment with mTOR inhibitor (e.g., everolimus ) or VEGFR inhibitor (e.g., sunitinib). Alternatives include combination therapy ( lenvatinib plus pembrolizumab or lenvatinib plus everolimus ).

35. Collecting Duct and Renal Medullary Carcinoma: Cytotoxic chemotherapy as initial therapy over VEGFR inhibitors. Platinum-based chemotherapy options: cisplatin plus gemcitabine, carboplatin plus gemcitabine, or carboplatin plus paclitaxel. Translocation RCC: Lenvatinib plus pembrolizumab preferred over single-agent VEGFR inhibitor. Consider single-agent VEGFR inhibitor (e.g., sunitinib) for those declining or ineligible for immunotherapy. Unclassified RCC: Immunotherapy-based regimens recommended over VEGFR inhibitors. Options: combination therapy (nivolumab plus ipilimumab; lenvatinib plus pembrolizumab) or single-agent immunotherapy (pembrolizumab or nivolumab). VEGFR inhibitors are reasonable alternatives for those declining or ineligible for immunotherapy. Non-Clear Cell RCC with Sarcomatoid Features: Prefer immunotherapy-based regimens for treatment-naïve cases.