Malignant Renal Tumors

Renal cancers are common, accounting for an estimated 65,340 new diagnoses and 14,970 attributable deaths in 2018 in the United States.1 In the article, "Epidemiology and Etiology of Kidney Cancer" both topics are discussed at great length. Despite a large number of histologic tumors which may occur in the kidney, renal cell carcinoma (RCC) is the most prevalent histology.

Tumor biology

Research into the molecular genetics of hereditary RCC has yielded many insights which contribute to the treatment of sporadic RCCs. An understanding of the function of the von Hippel Lindau protein led to the identification of the importance of vascular endothelial growth factor (VEGF) and the mammalian target of rapamycin (mTOR) pathways. Identification of the importance of VEGF aided in both explaining the significant neovascularity associated with ccRCC and providing a therapeutic target for systemic therapy.

Other molecular insights have significant clinical implications as well. First, RCC expresses multi-drug resistance proteins, energy-dependent efflux pumps. These pumps prevent the intracellular accumulation of chemotherapeutics and contribute to the chemotherapy-resistance of RCC. Second, based on observations of tumor-infiltrating immune cells and neoantigens, RCC is highly immunogenic. Thus, immunotherapies beginning with interleukins and interferon and now immune checkpoint inhibitors are efficacious in RCC.

Unfortunately, none of these insights have to lead to validated diagnostic, prognostic, or predictive biomarkers to date.

Pathology

Renal cell carcinoma tends to form relatively spherical tumors with a surrounding pseudo capsule of compressed adjacent parenchyma and fibrosis. With rare exceptions (collecting duct carcinoma and sarcomatoid variants), RCC tends to be relatively well circumscribed without gross infiltrative features. This allows for local treatment, radiographically-guided approaches such as partial nephrectomy and tumor ablation (see linked article on non-surgical focal therapy of renal tumors). Grading of RCC is undertaken using Fuhrman’s system. While this approach was developed for ccRCC,2 more recent evidence suggests that it is prognostic in papillary RCC as well.3 Fuhrman’s grading system relies on the size and shape of the nucleus and the presence or absence of nucleoli.

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A relatively unique pathological characteristic of RCC is its propensity for the involvement of the venous system. This occurs in nearly 10% of all RCCs, at least in historical series, which is much higher than other tumor types.4

Histologic subgroups

A number of histological subtypes have been recognized including conventional clear cell RCC (ccRCC), papillary RCC, chromophobe RCC, collecting duct carcinoma, renal medullary carcinoma, unclassified RCC, RCC associated with Xp11.2 translocations/TFE3 gene fusions, post-neuroblastoma RCC, and mucinous tubular and spindle cell carcinoma. Conventional ccRCC comprises approximately 70-80% of all RCCs while papillary RCC comprises 10-15%, chromophobe 3-5%, collecting duct carcinoma <1%, unclassified RCC 1-3%, and the remainder are very uncommon.

Clear cell RCC is formerly described as “conventional” RCC. These tumors, as mentioned prior, are highly vascular and thus tend to respond well to vascular-targeted agents when systemic therapy is indicated. In general, ccRCC is more aggressive than papillary RCC or chromophobe RCC, even after accounting for stage and grade.5

Papillary RCC, formerly known as “chromophilic” RCC, may be subdivided into type 1 and type 2. Type 1 papillary RCC histologically is characterized by basophilic cells with low-grade nuclei. In contrast, type 2 papillary RCC has eosinophilic cells with high-grade nuclei. Correspondingly, type 1 papillary RCC is less aggressive and portends a more favourable prognosis than type 2 papillary RCC. Papillary RCC exhibits a predilection for multifocality.

Chromophobe RCC is histologically characterized by a perinuclear halo. While chromophobe RCC typically have a good prognosis, those with sarcomatoid features are associated with a poor outcome.6

Collecting duct carcinoma and renal medullary carcinoma are relatively rare variants of RCC which exhibit aggressive behaviour and have poor to dismal prognosis. Renal medullary carcinoma is notably found in patients with sickle cell trait.

Finally, rather than its prior classification as a distinct subtype, sarcomatoid differentiation is now noted as a feature accompanying an underlying histologic characterization.

Clinical presentation of RCC

Historically, RCC was diagnosed on the basis of a classic triad of flank pain, gross hematuria, and a palpable flank mass. However, nowadays most RCCs are diagnosed incidentally during abdominal imaging for a variety of nonspecific abdominal complaints.7 Symptoms may arise due to local tumor growth, hemorrhage, paraneoplastic syndromes, or metastatic disease.

While paraneoplastic syndromes are relatively uncommon in other tumors, these occur in 10-20% of patients with RCC. A wide variety of clinical manifestations due to endocrinologically-active compounds may occur including hypertension, electrolyte dysregulation, and cytokine-driven effects such as weight loss, fever, and anemia.

Screening for RCC

Due in large part to the relatively low incidence of RCC, widespread screening is not advocated.

However, certain populations at a much higher risk of RCC warrant screening. This including patients with end-stage renal disease and acquired renal cystic disease, those with tuberous sclerosis, and those with familial RCC syndromes. Patients with end-stage renal disease are generally recommended to undergo RCC screening upon reaching their third year on dialysis assuming that they do not have other major comorbidities which would be life-limiting.

Staging of RCC

Robson’s staging system was widely used until the 1990s. However, there are numerous limitations including the amalgamation of tumors with lymph node metastases and those with venous involvement as stage III and the omission of tumor size. Thus, the TNM (tumor, node, metastasis) system is now widely used.


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Notably, the involvement of the ipsilateral adrenal gland may be classified at T4 if contiguous or M1 if metastatic. Historically, lymph node involvement had been sub-stratified. However, this did not show the prognostic value. Thus, a single present/absent classification is now used.

As may be implied from the characteristics used in the staging schema, clinical staging involves a thorough history, physical examination, radiographic investigation and laboratory investigations (including liver function tests). Contrast-enhanced abdominal computed tomography and chest radiograph are considered standard imaging approaches.8 MRI may be indicated in patients with locally advanced disease, those with unclear venous involvement, and those for whom CT is contraindicated.8 For patients with suspected inferior vena cava involvement, MRI or multiplanar CT are reasonable imaging approaches.8 Doppler ultrasonography is an alternative. Venacavography is rarely utilized today. In patients with suspected metastatic disease, bone scintigraphy is indicated among those with elevated serum alkaline phosphate, bony pain, or poor performance status.9 Similarly, CT chest is indicated in patients with pulmonary symptoms or an abnormal chest radiograph.

A number of prognostic factors have been described for patients with RCC:10
  1. Clinical characteristics:
    1. Performance status
    2. Systemic symptoms
    3. Symptomatic (vs. incidental) presentation
    4. Anemia
    5. Thrombocytosis
    6. Hypercalcemia
    7. Elevated lactate dehydrogenase
    8. Elevated erythrocyte sedimentation rate
    9. Elevated C-reactive protein
    10. Elevated alkaline phosphatase
  2. Tumor anatomic characteristics:
    1. Tumor size
    2. Venous extension
    3. Contiguous invasion of adjacent organs (i.e. T4 stage)
    4. Adrenal involvement (i.e. T4 or M1 stage)
    5. Lymph node metastasis (i.e. N1 stage)
    6. Presence and burden of metastatic disease (i.e. M1 stage)
  3. Tumor histologic characteristics:
    1. Histologic subtype
    2. Presence of sarcomatoid differentiation
    3. Nuclear grade
    4. Presence of histologic necrosis
    5. Vascular invasion
    6. Invasion of perinephric or sinus fat
    7. Invasion of collecting system
    8. (post-operative) surgical margin status
Pathologic stage is the single most important prognostic factor in RCC.10 Interestingly, tumor size has additional independent prognostic value, beyond that which is conveyed in the tumor stage.11 Among patients with IVC thrombus, direct invasion into the caval wall appears to portend a worse prognosis.12

To date, no biomarkers have been adopted in clinical practice for prognostic or predictive purposes. However, a number of nomograms relying on clinical data have been proposed for risk prediction. They may be useful in predicting tumor histology, recurrence rates, and survival.

Treatment of RCC (localized)

There are a number of accepted treatment options for patients diagnosed with localized RCC. These include radical nephrectomy (whether open, laparoscopic or robotic), partial nephrectomy (whether open, laparoscopic, or robotic), surgical or non-surgical ablation, and active surveillance. The most appropriate treatment strategy will depend on the patient (host) and tumor characteristics.

The ability to distinguish between benign and malignant renal masses is relatively limited on the basis of clinical characteristics. The renal mass biopsy may, therefore, be indicated where the results of this test would modify treatment choices.

Radical nephrectomy was historically the treatment of choice for localized RCC. Partial nephrectomy was initially indicated for patients with imperative indications. However, today, partial nephrectomy is the standard of care for small renal masses. Radical nephrectomy remains indicated for patients with larger tumors and those where partial nephrectomy is not feasible (for example, a tumor in a very central location).13 The primary concern regarding radical nephrectomy is the loss of nephron mass and the corresponding risk of surgically induced chronic kidney disease (CKD). Such CKD may predispose to cardiovascular events and premature mortality. However, the only randomized controlled trial to compare radical and partial nephrectomy (EORTC 30904) demonstrated improved overall survival among patients undergoing radical nephrectomy and decreased rates of cardiovascular events.14 These results have proven controversial and have not dissuaded enthusiasm for partial nephrectomy.

A more fulsome discussion regarding nonsurgical renal mass ablation may be found entitled “Focal therapy for renal tumors.”

Finally, active surveillance has gained acceptance. This approach was first employed among asymptomatic elderly patients who were poor surgical candidates with small, incidentally detected RCCs.15 Subsequent follow-up has demonstrated that small renal masses grow quite slowly (0.1-0.3cm/year). AUA guidelines recommend serial abdominal imaging to both ascertain the growth and monitor for progression.16 Biopsy may be considered in order to inform surveillance strategies. For patients found to have biopsy-proven RCC, a chest radiograph may be added to the annual surveillance testing.

The American Urological Association offers a helpful algorithm to guide treatment decision making in patients with small renal masses
Written by: Christopher J.D. Wallis, MD, PhD
References:
  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA: a cancer journal for clinicians 2018;68:7-30.
  2. Fuhrman SA, Lasky LC, Limas C. Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol 1982;6:655-63.
  3. Sukov WR, Lohse CM, Leibovich BC, Thompson RH, Cheville JC. Clinical and pathological features associated with prognosis in patients with papillary renal cell carcinoma. The Journal of urology 2012;187:54-9.
  4. Skinner DG, Pfister RF, Colvin R. Extension of renal cell carcinoma into the vena cava: the rationale for aggressive surgical management. The Journal of urology 1972;107:711-6.
  5. Deng FM, Melamed J. Histologic variants of renal cell carcinoma: does tumor type influence outcome? The Urologic clinics of North America 2012;39:119-32.
  6. Klatte T, Han KR, Said JW, et al. Pathobiology and prognosis of chromophobe renal cell carcinoma. Urologic oncology 2008;26:604-9.
  7. Almassi N, Gill BC, Rini B, Fareed K. Management of the small renal mass. Transl Androl Urol 2017;6:923-30.
  8. Ng CS, Wood CG, Silverman PM, Tannir NM, Tamboli P, Sandler CM. Renal cell carcinoma: diagnosis, staging, and surveillance. AJR Am J Roentgenol 2008;191:1220-32.
  9. Shvarts O, Lam JS, Kim HL, Han KR, Figlin R, Belldegrun A. Eastern Cooperative Oncology Group performance status predicts bone metastasis in patients presenting with renal cell carcinoma: implication for preoperative bone scans. The Journal of urology 2004;172:867-70.
  10. Lane BR, Kattan MW. Prognostic models and algorithms in renal cell carcinoma. The Urologic clinics of North America 2008;35:613-25; vii.
  11. Kattan MW, Reuter V, Motzer RJ, Katz J, Russo P. A postoperative prognostic nomogram for renal cell carcinoma. The Journal of urology 2001;166:63-7.
  12. Zini L, Destrieux-Garnier L, Leroy X, et al. Renal vein ostium wall invasion of renal cell carcinoma with an inferior vena cava tumor thrombus: prediction by renal and vena caval vein diameters and prognostic significance. The Journal of urology 2008;179:450-4; discussion 4.
  13. Nguyen CT, Campbell SC, Novick AC. Choice of operation for clinically localized renal tumor. The Urologic clinics of North America 2008;35:645-55; vii.
  14. Van Poppel H, Da Pozzo L, Albrecht W, et al. A prospective, randomised EORTC intergroup phase 3 study comparing the oncologic outcome of elective nephron-sparing surgery and radical nephrectomy for low-stage renal cell carcinoma. European urology 2011;59:543-52.
  15. Abouassaly R, Lane BR, Novick AC. Active surveillance of renal masses in elderly patients. The Journal of urology 2008;180:505-8; discussion 8-9.
  16. Donat SM, Diaz M, Bishoff JT, et al. Follow-up for Clinically Localized Renal Neoplasms: AUA Guideline. The Journal of urology 2013;190:407-16.
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