Renal Cell Carcinoma

Updated by Phillip J. Gray and Thomas J. Guzzo

BACKGROUND

Order the following 5 tissues from outermost to innermost: renal cortex, Gerota’s fascia, adrenal gland, perirenal fat, and renal capsule.

From outermost to innermost:

1. Gerota’s fascia

2. Perirenal fat

3. Adrenal gland (which is embedded in the perirenal fat sup to the kidney)

4. Renal capsule

5. Renal cortex

Name 3 environmental risk factors for renal cell carcinoma (RCC).

Environmental risk factors for RCC:

1. Cigarette smoking

2. Phenacetin exposure (found in analgesics)

3. Heavy metal exposure

Name the most important nonenvironmental risk factor for RCC.

Obesity. The risk of RCC increases by 7% per unit increase in BMI. (Bergstrom A et al., Br J Cancer 2001)

Familial RCC makes up what % of RCC cases? Name 5 familial syndromes.

Familial RCC makes up ~4% of RCC cases. Familial syndromes:

1. Von Hippel-Lindau

2. Birt-Hogg-Dube syndrome

3. Tuberous sclerosis

4. Hereditary papillary RCC

a. HRCC (met proto-oncogene)

b. Familial leiomyomatosis

c. RCC (fumarate hydratase)

5. Familial clear cell RCC

What is the estimated annual incidence of new RCC cases in the U.S.?

~58,000 cases/yr of new RCC in the U.S.

Has the incidence of RCC been increasing or decreasing over the past 30 yrs? Is there a sex predilection?

The incidence of RCC has been increasing by 2%/yr over the past 30 yrs according to NCI SEER data. Men appear to be more commonly diagnosed with RCC than women.

In which decade of life is RCC typically diagnosed?

RCC is typically diagnosed in the 7^th decade of life.

RCC represents what % of all urinary tract tumors?

RCC represents ~6% of all urinary tract tumors.

What benign tumors can exist in the kidney?

Benign tumors of the kidney:

1. Angiomyolipomas

2. Fibromas

3. Lipomas

4. Lymphangiomas

5. Oncocytomas

6. Hemangiomas

What % of RCC pts will present with a palpable mass on physical exam?

~10% of RCC pts will have a palpable mass at the time at presentation.

RCC pts are at increased risk of having what other type of synchronous urinary cancer?

RCC pts have an RR of 1.5 of having a synchronous bladder cancer, though the authors do not screen for bladder cancer in RCC pts. This increased risk may be related to smoking.

What is the classic triad of RCC? With what other clinical Sx can pts with RCC present?

Pts with RCC present with classic triad Sx of hematuria, flank pain, and a palpable mass. Sx of fever, night sweats, and weight loss suggest the presence of metastatic Dz.

What are some paraneoplastic syndromes associated with RCC? In what % of pts would these syndromes be found?

Paraneoplastic syndromes associated with RCC:

1. Hypercalcemia

2. Elevated LFTs

3. Hypertension

These paraneoplastic syndromes arise in 20% of pts.

What % of RCC pts present with bilat kidney involvement?

3% of RCC pts will have bilat involvement at Dx.

What are 4 pathologic subtypes of RCC?

Pathologic subtypes of RCC:

1. Clear cell

2. Chromophilic (or papillary)

3. Chromophobic

4. Collecting duct

What is the most common pathologic subtype of RCC?

Clear cell is the most common subtype of RCC (~70%), demonstrating large clear cells with abundant cytoplasm.

What is the most common histologic grading system for RCC?

The most common histologic grading system for RCC is the Fuhrman grading system from I–IV based on nuclear roundness, size, nucleoli presence, and the presence of clumped chromatin.

Sporadic RCC is characterized by what genetic mutation?

Sporadic RCC is characterized by a mutation in the VHL tumor suppressor gene on chromosome 3p25, which is silenced in >50% of sporadic RCC.

WORKUP/STAGING

How is RCC diagnosed?

RCC requires a tissue Dx. Often, nephrectomy is both diagnostic and therapeutic. Percutaneous Bx can also be employed for surgically unfit pts, those considering active surveillance, or at the time of ablative therapy.

What % of biopsied pts have benign Dz?

~33% of small renal masses may be characterized as benign according to the specimen obtained. The risk of benign pathology is inversely proportional to the size of the renal mass.

What imaging is important in the initial workup of RCC?

Imaging workup typically includes contrast-enhanced CT or MRI scan of the abdomen and chest imaging. Consider bone scan and MRI brain if clinically indicated.

Summarize the AJCC 7^th edition (2011) T staging for RCC.

T1: limited to kidney and ≤7 cm

T1 a: ≤4 cm

T1b: 4–7 cm

T2: limited to kidney and >7 cm

T2 a: >7 cm but ≤10 cm

T2b: >10 cm

T3: invades into major veins or perinephric tissues but not into ipsilateral adrenal gland and not beyond Gerota’s fascia

T3 a: grossly extends into renal vein or its segmental branches, or extends into perirenal and/or renal sinus fat but not beyond Gerota’s fascia

T3b: extends into vena cava below diaphragm

T3 c: extends into vena cava above diaphragm or invades wall of vena cava

T4: invades beyond Gerota fascia, including contiguous extension into ipsilateral adrenal gland

Summarize the AJCC 7^th edition (2011) stage grouping for RCC.

Stage I: T1N0M0

Stage II: T2N0M0

Stage III: T1-2N1M0 or T3N0-1M0

Stage IV: T4 or M1

What other staging systems are widely used for RCC?

The Flocks and Kadesky system (with or without Robson modification) and Jewett-Strong classification system have been used to stage RCC.

Name 3 prognostic factors for RCC.

Prognostic factors for RCC:

1. TNM stage

2. Performance status

3. Fuhrman grade

TREATMENT/PROGNOSIS

Describe 5 invasive Tx for locally confined RCC.

Invasive Tx for locally confined RCC:

1. Open nephrectomy

2. Laparoscopic nephrectomy

3. Percutaneous CT-guided cryosurgery

4. Percutaneous radiofrequency ablation

5. Partial nephrectomy

Are there any studies comparing laparoscopic resection with that of open resection in pts with RCC?

Yes. There are retrospective data that compared laparoscopic resection vs. open resection of RCC. There was no difference in DFS. (Luo JH et al., World J Urol 2009; Marszalek M et al., Eur Urol 2009)

Are there surgical options for pts with bilat RCC or unilat RCC with a diseased contralat kidney?

Yes. Pts with bilat RCC or a diseased contralat kidney can be treated with a partial nephrectomy provided the lesion is amenable to a nephron-sparing approach.

When is recurrence most likely to occur following surgery for RCC?

The median time for recurrence after surgery for RCC is ∼2 yrs. Most recurrences occur within 5 yrs.

Name 4 predictors of RCC recurrence after nephrectomy.

Predictors of RCC recurrence after nephrectomy:

1. Nuclear grade (Fuhrman grade)

2. TNM stage

3. DNA ploidy

4. Genetic RCC syndromes

What are the most common sites of RCC recurrence after nephrectomy?

Most common sites of RCC recurrence after nephrectomy:

1. Lung

2. Bone

3. Regional LNs

What follow-up imaging is recommended for RCC pts after nephrectomy?

RCC pts after nephrectomy should be followed with CXR/CT chest and CT/MRI abdomen.

For how long should pts with RCC treated with nephrectomy be followed?

Pts with RCC treated with nephrectomy should be followed for life (sporadic RCC recurrences have been documented ≥40 yrs later).

Are there any prospective randomized studies examining the role for adj therapy in pts with RCC treated with initial nephrectomy?

Yes. IFN α-2b within 1 mo after surgery vs. Tx only after postsurgical relapse demonstrated no EFS or OS benefit. (Messing EM et al., JCO 2003) A phase III randomized comparison of adjuvant sunitinib, sorafenib, or placebo is ongoing.

What is the 1^st-line Tx for pts with metastatic RCC?

1^st-line Tx for pts with metastatic RCC:

1. Cytoreductive nephrectomy

2. Metastasectomy for oligometastases

3. Sunitinib

4. Temsirolimus

5. Bevacizumab and IFN

6. High-dose recombinant interleukin-2

7. Sorafenib

Cytotoxic chemo for non–clear cell histologies may be considered.

What is the mechanism of action of sorafenib? Of sunitinib?

Sorafenib inhibits multiple kinase pathways, including Raf kinase, PDGF, VEGF receptor 2 and 3, and c-Kit. Sunitinib also inhibits multiple kinase pathways, including PDGF, VEGF, c-Kit, RET, CSF-1R, and flt3.

Is there a role for palliative nephrectomy in pts with RCC?

Yes. Palliative nephrectomy is still encouraged to relieve local Sx of pain or intractable hematuria; as well as systemic Sx related to the primary tumor.

What are the data for using cytoreductive surgery in combination with immunotherapy?

Cytoreductive surgery utilized before immunotherapy may delay time to progression and improve survival of pts with metastatic Dz (median duration of survival 17 mos vs. 7 mos, SS). (Mickisch GH et al., Lancet 2001)

Is there a role for resection of metastatic lesions in pts with RCC?

Yes. A retrospective study by Kavolius JP et al. suggests that curative resection of metastatic lesions in pts with RCC improves survival compared with the subtotal resection of pts or those with noncurative salvage attempts (44%, 14%, and 11%, respectively). (JCO 1998)

Is there a role for RT in patients with RCC?

Yes. RCC is widely regarded as a radioresistant tumor. When clinically and technically appropriate, consider SRS for pts with RCC brain mets. (Jagannathan J et al., Neurosurgery 2010; Te BS et al., Clin Genitourin Cancer 2007) Several recent studies have identified good outcomes using stereotactic body radiotherapy to treat primary RCC in patients who are not operative candidates. Postoperative radiotherapy can improve local control but does not appear to affect OS or DFS. (Tunio MA et al., Ann Oncol 2010)