Younger Patient With Stage III Chromophobe RCC

History and Diagnosis

AT is a 37-year-old female with stage III chromophobe renal cell carcinoma (RCC).  

She was admitted to the hospital with preeclampsia and developed an infection after a C-section on September 22, 2024. This was her second child. The patient initially had a CT of the chest to evaluate for a pulmonary embolism, which was negative. On that same day, she underwent imaging with an ultrasound of the kidney and bladder, which found an 11 cm complex mass in the superior pole of the right kidney without internal blood flow.  

Ten days later, a CT-guided right renal mass biopsy was performed with pathology showing predominantly necrotic tissue, which appeared to consist of a solid sheet of monotonous cells, paired-box gene 8 (PAX-8) positive, which supports renal origin. Positivity for cytokeratin subtype CK7 and transmembrane tyrosine kinase receptor CD117 raises the possibility of chromophobe RCC or oncocytoma. Prior to this the care team felt that the patient might have septic thrombophlebitis.  

On November 14 of the same year, the patient underwent hand-assisted laparoscopic right radical nephrectomy. Pathology showed a stage III chromophobe renal cell carcinoma (9 cm), unifocal, that extended into the renal sinus and pelvicalyceal system.  

• Sarcomatoid and rhabdoid features were not identified 
• Tumor necrosis present (80%) 
• All margins negative for invasive carcinoma 
• pT3aNx 
• Six days later, the patient was admitted for shortness of breath and had a CT of the chest, abdomen, and pelvis.  

Chromophobe RCC is a rare subtype of non-clear cell renal cancer. Often found incidentally prior to any symptomology, it represents about 5% of all RCCs. It is found more frequently in females. It is generally less aggressive but when it does metastasize, it will often go to the liver, lungs, and less often, bone. Risk factors for metastasis include larger tumors and sarcomatoid differentiation. It may be associated with a rare genetic disorder called Birt-Hogg-Dubé syndrome, which causes benign, or noncancerous, growths in the skin.¹  

The patient’s family history includes a maternal grandmother who was diagnosed with what was believed to be pancreatic cancer at 60 years of age and a maternal great-grandmother who died of an unknown cancer. There is no family history of kidney cancer. The patient’s personal health history showed exposure to radiation at the Chernobyl nuclear disaster while her mother was pregnant with her. 

Discussion and Shared Decision-Making

The patient presents to medical oncology for a second opinion regarding her current diagnosis and treatment options. She has a history of migraine headaches, gestational radiation exposure from living near Chernobyl nuclear reactors, heart failure with reduced EF (45-50%), and preeclampsia. The first thing the care team recommended was further testing to confirm staging and check for residual cancer. Because of the history of headaches and the wish of the patient to reduce the amount of radiation exposure she receives, instead of a head or abdominal CT, a brain MRI was done to establish a baseline. CT scans of the head expose patients to the equivalent of ~1 year of natural radiation, which is ~100 times the radiation dose from a chest X-ray. Other CT examinations involve higher radiation doses, ranging up to 8x the dose received from background radiation in 1 year.²  

The care team discussed adjuvant treatment with the patient, first reviewing the pros and cons of the possible side effects of immunotherapy against the likelihood of recurrence. The KEYNOTE-564 trial found the most common serious treatment-related adverse events in the pembrolizumab group were adrenal insufficiency, and diabetic ketoacidosis.³ While immunotherapy may be recommended in some instances of RCC, especially in clear cell RCC where four therapies evaluated in the setting with pembrolizumab showed a survival advantage, in this case, there is no clear data to support pembrolizumab in RCC with sarcomatoid features. Although the NEMESIA trial found that a pembrolizumab-axitinib combination is an effective option for chromophobe RCC, further studies are needed to confirm the efficacy of novel treatments with combinations for non-clear RCC.⁴ Therefore, no adjuvant treatment was recommended. 

Regarding genetic (germline) testing, NCCN guidelines state that early age of RCC onset, family history of RCC (≥1 FDR/SDR with RCC), bilateral or multifocal RCCs, and suspicious RCC histology can prompt a referral to genetic counseling.⁵ Germline testing found that the patient was positive for two things that are of unknown significance: heterozygous for the c.4492_4494delTTA (p.L1498del) variant of unknown significance in the ATM gene and heterozygous for the p.I144T (c.431T>C) variant of unknown significance in the RAD51C gene, which may or may not contribute to this individual's clinical history. 

The patient was placed on surveillance. It was suggested to the patient that the most prudent maneuver in the setting would be to consider frequent radiographic evaluation, giving the care team a greater chance of catching any recurrence in a localized fashion and then implementing local therapy through radiation to address the recurrence. A CT scan of the chest, abdomen, and pelvis every 3 months for the first 3 years was recommended, with CT imaging every 6 months thereafter for an additional 2 years, totaling 5 years.  

According to the physician, a nationally renowned expert in renal cell cancer and clinical trials, there are no adjuvant studies or other clinical trials that would be appropriate for the patient’s chromophobe RCC.  

References

1. Casuscelli J, Becerra MF, Seier K, et al. Chromophobe renal cell carcinoma: Results from a large single-institution series. Clin Genitourin 2019;17(5):373-379.e4.
2. Computed tomography (CT) - What patients need to know. International Atomic Energy Agency. Accessed February 27, 2024. ttps://www.iaea.org/resources/rpop/patients-and-public/computed-tomography#:~:text=CT%20scans%20of%20the%20head,background%20radiation%20in%20one%20year.
3. Powles T, Tomczak P, Park SH, et al. Pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for clear cell renal cell carcinoma (KEYNOTE-564): 30-month follow-up analysis of a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial [published correction appears in Lancet Oncol. 2023 Jan;24(1):e10]. Lancet Oncol. 2022;23(9):1133-1144.
4. Stellato M, Buti S, Maruzzo M, et al. Pembrolizumab plus axitinib for metastatic papillary and chromophobe renal cell carcinoma: NEMESIA (Non Clear MEtaStatic Renal Cell Carcinoma Pembrolizumab Axitinib) Study, a Subgroup Analysis of I-RARE Observational Study (Meet-URO 23a). Int J Mol Sci. 2023;24(2):1096. Published 2023 Jan 6. doi:10.3390/ijms24021096
5. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Kidney Cancer. Version 3.2023. Plymouth Meeting, PA: National Comprehensive Cancer Network, 2022. chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf