Incidence, Workup, Diagnosis, and Risk Categorization

Emily Lemke

For those APPs who are learning about renal cell carcinoma (RCC) for the first time or starting their practice, a comprehensive overview is always useful. I think it's underappreciated how common renal cell carcinoma is. It's one of the top 10 most common cancers in men and women, and the lifetime risk of developing RCC is about 2%.¹ The American Cancer Society estimates that there will be 76,000 new cases in 2021 and 13,780 deaths.¹ This is a real burden in the cancer world, and therefore it's important that both specialists and community oncologists alike are aware of the treatment modalities.

Thinking about risk factors that we associate with RCC, it probably comes as no surprise that smoking is one. Obesity is also up there. RCC is one of the 10 cancers that is linked to obesity; others risk factors include high blood pressure, family history, and workforce exposures. Interestingly, RCC is twice as common in men as women.¹ End-stage renal disease is also a risk factor, as well as hereditary syndromes such as VHL disease, HLRCC, and Birt-Hogg-Dubé. So you should always take a good history when meeting patients to make sure there's no red flags or suggestions that this could be a part of a familial disorder. Zita, in your experience, what are the most common presenting symptoms for RCC?

Zita Lim

It’s important to remember the triad of symptoms: hematuria, flank pain, and a palpable mass. But it turns out that the triad is probably not as common: only about 9% of patients will present with it.^2,3 Typically it's a sign that a patient has much more advanced disease. Hematuria itself is very common, as about 40% of patients will present with that symptom. It’s especially important to note that clot formation is a telltale sign of kidney cancer, as opposed to just bleeding from unrelated issues. The other things that we as APPs on the front lines should be aware of are any kind of anemia and also erythrocytosis, although this is less common, only seen in about 1% to 5% of patients.

About 20% of patients will present with fever associated with night sweats, anorexia, and unintentional weight loss. Another very interesting symptom that I think often is missed is scrotal varices in men. If a patient has a left varicocele, and especially if it fails to empty when the patient is recumbent, that's another telltale sign of a possible kidney tumor. Hypercalcemia is another sign, seen in about 50% of patients, and it can be associated with possible lytic bone metastases but also could be just part of the tumor process. Finally, another sign is thrombocytosis, which can signal poor prognosis. These are all things to be on the lookout for in a patient who may have kidney cancer.

Our workup entails a CT scan, ideally of the abdomen with contrast. Ultrasounds can be helpful in differentiating between a mass and a benign cyst or more complex cysts.

Our surgical colleagues may want an MRI of the abdomen to help with surgical planning, as the MRI can show if the tumor is invading into the renal vein or the inferior vena cava. A CT scan of the chest is ordered to evaluate any pulmonary metastases or mediastinal lymph node metastases. If patients are having bone pain or have an elevated alkaline phosphatase, you may want to do a bone scan. However, bone scans in kidney cancer can be notoriously misleading as RCC tumors are lytic lesions and therefore may not always show up on a bone scan.

Patients often ask us, "Well, don't we need to do a PET scan?" But typically we avoid PET scans because they don't inform us more than a thorough CT scan and are typically not reimbursed by insurance.

And then finally, there's the question of the biopsy. If a patient has metastatic disease, it would behoove us to biopsy a metastatic site. Alternatively, we may biopsy the primary site with the caveat that the center of the tumor may contain necrotic tissue and should be avoided. If a patient has no metastases, they may bypass the biopsy entirely and proceed directly to a nephrectomy. After biopsy, what are the most common histologies you encounter?

Emily Lemke

This lends itself to what you were just talking about, in that the value of a biopsy is really important because RCC isn't a homogenous disease; there are a number of different variant histologies. And what type of histology the patient has is really important because that reflects what their best treatment options are going to be.

Three of the more common types are clear cell, papillary type 1, and papillary type 2. Clear cell carcinoma is the most common—about 75% to 85% of all RCCs⁴—and what the majority of the treatments are geared towards. This is caused by a mutation in the VHL gene.

Next, we have papillary RCC, which accounts for about 10% of all RCCs and is further divided into pap type 1 and pap type 2. Generally pap type 2 has poorer outcomes than type 1 and is also associated with the hereditary syndrome HLRCC. Pap type 1 is caused by a MET mutation, which is important for therapeutic options. Pap type 2 is a little bit more complicated. It's usually associated with mutations in a CDKN2A, BAP1, and PBR1.

Those are the more common subtypes, but we have even more than those three. Zita, I know in your practice, you come across a lot of these rare subtypes.

Zita Lim

Yes, I do. So after pap type 1 and 2, the next most common is chromophobe, which accounts for 4% of kidney tumors.^5,6 It’s known to upregulate the c-KIT oncogene. Also these patients appear to have an upregulation of mTOR pathway, so some experts would recommend treating them with an mTOR inhibitor such as everolimus. There was a randomized phase 2 trial in that subset of patients where 16 patients (15%) had an overall response rate that was superior when using everolimus over sunitinib.⁷ Some physicians will start these patients, for instance, frontline on lenvatinib/everolimus as a combination as well. In general, chromophobe RCC doesn't seem to be very immune sensitive; it's more an immune silent tumor. So we have to continue doing research in this area.

The other tumor type that we see in our practice is renal medullary carcinoma (RMC)—the most aggressive variant of kidney cancers. Sadly, it affects young people and patients with sickle cell trait or sickle cell disease. Typically, these tumors are treated with cytotoxic chemotherapy, but even in our retrospective study in 2017 with our best treatments, these patients survived about 13 months.⁸

Collecting duct RCC is similar to RMC, but it does not have the SMARC B1 mutation. It's also quite aggressive but tends to present in older patients in the absence of a sickle cell background. These patients are also predominantly treated with a platinum-based chemotherapy. Then there’s translocation renal cell carcinoma, which is a rare variant even among non–clear cell subtypes, and it is characterized by the TFE3 gene fusion. The data that we have for this is mostly limited to observational studies. There was a trial comparing sunitinib versus interferon alpha in these patients showing a 27% response rate with sunitinib.⁹ But again, this is a subtype that that needs more focused research.

Emily, once you've established the tumor subtype, what's the next step. As medical oncology APPs, how do we interface with our surgery and radiation oncology colleagues?

Emily Lemke

Renal cell carcinoma necessitates a multidisciplinary approach requiring lots of subspecialists to be involved. The stage of disease at diagnosis impacts who's going to be involved, at least initially. When we think about localized RCC confined to the kidney, meaning stages I to III, treatment will be surgery and involve a urologic oncologist. Certainly if patients aren’t surgical candidates, or they have a very small mass, we might consider a nonsurgical approach such as cryoablation, radiofrequency ablation, radiation in some cases, or observation. However, any tumor larger than 3 cm in an appropriate surgical candidate should be removed. Right now there's no real involvement from medical oncology following a resection of a localized tumor, as adjuvant treatment hasn't yielded a meaningful survival benefit.

Metastatic or stage IV disease is when more subspecialists are involved. Medical oncology is going to be the quarterback of this team because generally systemic therapy is the mainstay of treatment. However, there is data to support resection for oligometastatic disease, so where there is a metastatic lesion guides what other subspecialists are going to be involved. For example, if they have a pancreatic lesion, we might involve our GI surgical colleagues. If they have a lung lesion, we might be involving a cardiothoracic surgeon.

Radiation is another somewhat nontraditional approach for the right patient. Sometimes stereotactic body radiation therapy is used to treat oligometastatic disease in patients who either are poor surgical candidates or have a lesion in an area that isn't amenable to surgery. Currently ongoing trials are looking at the combination of systemic treatment plus radiation therapy. So I think we're going to learn more in the next few years as to how those therapies complement each other and if there's a survival benefit. Also, if patients have painful metastatic lesions that can benefit from a palliative radiation dose, we consult radiation oncology. Interventional radiology can also be involved, depending on your institution, to handle the radiofrequency ablation or cryotherapy.

Lastly, in patients with metastatic disease, especially if they're symptomatic, it's important to involve a palliative care specialist. We know that patients who have metastatic cancer and have palliative care involved earlier on in their treatment have improved outcomes. So I always try and make sure if there's any symptomology from their disease itself, or sometimes even from the treatment, that we involve those subspecialists.

Another important area of workup is risk categorization. Zita, do you have a preference for IMDC or MSKCC risk criteria?

Zita Lim

The risk criteria are an important tool for us in treating kidney cancer patients, because, as we all know, not all stage IV cancers behave the same way. The MSKCC criteria includes anemia, performance status, hypercalcemia, and how soon a patient starts treatment after diagnosis, as well as LDH as a surrogate measure for tumor volume.

The newer International Metastatic Renal Cell Carcinoma Database Consortium was formed in 2009. This model includes KPS of 80% or better, time from diagnosis to initiation of therapy, anemia, hypercalcemia, neutrophilia, and thrombocytosis. So if you had zero of these risk factors, you are considered as having favorable risk. One to two is intermediate risk, and three to six is considered poor risk disease.