Malignant Renal Tumors - Campbell-Walsh Urology, 11th Edition

Campbell-Walsh Urology, 11th Edition

PART X

Neoplasms of the Upper Urinary Tract

57 Malignant Renal Tumors

Steven C. Campbell; Brian R. Lane

Questions

What is the most accurate imaging study for characterizing a renal mass?
Intravenous pyelography
Ultrasonography
Computed tomography (CT) with and without contrast enhancement
Magnetic resonance imaging (MRI)
Renal arteriography
A hyperdense renal cyst may also be termed a:
probable malignancy.
Bosniak II cyst.
Bosniak III cyst.
Bosniak IV cyst.
probable angiomyolipoma.
The most generally accepted indication for fine-needle aspiration of a renal mass is a suspected clinical diagnosis of:
renal cell carcinoma (RCC).
renal oncocytoma.
renal cyst.
renal metastasis.
renal angiomyolipoma.
Recommended postoperative radiographic surveillance of the chest after radical nephrectomy for T1N0M0 RCC is:
no imaging studies.
chest radiograph at 1 year.
chest radiograph annually for 3 years.
chest CT at 1 year and then chest radiograph annually for 2 years.
chest radiograph annually for 5 years.
The European Organisation for Research and Treatment of Cancer 30904 study randomly assigned patients to radical versus partial nephrectomy. Which of the following was an inclusion criterion?
Clinical T1a tumor (< 4.0 cm)
Tumor size < 5.0 cm
Estimated glomerular filtration rate (GFR) > 60 mL/min/1.73 m²
No hypertension
Age < 70 years
Following partial nephrectomy for pathologic stage T3aN0M0 RCC, it is recommended to perform surveillance abdominal CT scanning with what frequency?
Never
Every 6 months for at least 3 years and then annually to year 5
Every year to year 5
Every 2 years
Every year for 2 years and then at year 5
Following partial nephrectomy of a solitary kidney, what is the most effective method of screening for hyperfiltration nephropathy?
Urinary dipstick test for protein
24-hour urinary protein measurement
Iothalamate GFR measurement
Serum creatinine measurement
Renal biopsy
The most accurate and practical assessment of renal function for routine use after nephrectomy is:
serum creatinine measurement.
urinary dipstick test for protein.
24-hour urinary protein measurement.
iothalamate GFR measurement.
serum creatinine–based estimation of GFR, such as CKD-EPI formula.
What is an important prerequisite for successful cryoablation of a renal tumor?
Slow freezing
Rapid thawing
A single freeze-thaw cycle
A double freeze-thaw cycle
Freezing of tumor to a temperature of − 10° C
Which two imaging modalities are the preferred and most accurate for demonstrating the presence and extent of an inferior vena caval tumor thrombus?
Abdominal ultrasonography and CT
MRI and renal artery angiography
CT and MRI
MRI and contrast venacavography
Contrast venacavography and transesophageal ultrasonography
In patients undergoing complete surgical excision of an RCC, the lowest 5-year survival rate is associated with which factor?
Perinephric fat involvement
Microvascular renal invasion
Subdiaphragmatic inferior vena caval involvement
Intra-atrial tumor thrombus
Lymph node involvement
A 45-year-old man has a 5-cm RCC in the upper pole of a solitary left kidney and a single 2-cm left lower lung metastasis. What is the best treatment?
Initial targeted therapy, then partial nephrectomy
Partial nephrectomy, then targeted therapy
Staged partial nephrectomy and pulmonary lobectomy
Simultaneous partial nephrectomy and pulmonary lobectomy
Simultaneous radical nephrectomy and pulmonary lobectomy
A healthy 79-year-old man is referred after renal biopsy of a 3.0-cm centrally located renal mass. The biopsy is definitive for renal oncocytoma. The other kidney is normal, the serum creatinine level is 1.0 mg/dL, and there is no evidence of metastatic disease. What is the best next step?
Open radical nephrectomy
Laparoscopic nephroureterectomy
Percutaneous thermal ablation
Partial nephrectomy
Observation with follow-up renal imaging in 6 to 12 months
Tuberous sclerosis is similar to von Hippel-Lindau disorder in which of the following respects?
Propensity toward development of seizure disorders
Similarity of cutaneous lesions
Common development of adrenal tumors
Frequent involvement of cerebral cortex with vascular lesions
Mode of genetic transmission
A 48-year-old woman with a history of seizure disorder presents with recurrent gross hematuria and left flank pain. Abdominal CT shows a large left perinephric hematoma associated with a 3.0 cm left renal angiomyolipoma. There are also multiple right renal angiomyolipomas ranging in size from 1.5 to 6.5 cm. What is the best management of the left renal lesion?
Selective embolization
Radical nephrectomy
Observation
Partial nephrectomy
Laparoscopic exposure and renal cryoablative therapy
Which of the following statements is TRUE regarding cystic nephromas occurring in adults?
They are complex cystic lesions that are typically classified as Bosniak II to III.
They are malignant 2% to 5% of the time.
They are more common in men than in women.
When suspected, they should be treated by radical nephrectomy.
They are readily differentiated from cystic RCC on the basis of appropriate imaging studies.
Which environmental factor is most commonly accepted as a risk factor for RCC?
Radiation therapy
Antihypertensive medications
Tobacco use
Diuretics
High-fat diet
Which of the following manifestations is restricted to certain families with the von Hippel-Lindau disorder?
RCC
Pancreatic cysts or tumors
Epididymal tumors
Pheochromocytoma
Inner ear tumors
RCC develops in what percentage of patients with the von Hippel-Lindau disorder?
0% to 20%
21% to 40%
41% to 60%
61% to 80%
81% to 100%
What is the most common cause of death in patients with the von Hippel-Lindau syndrome?
Renal failure
Cerebellar hemangioblastoma
Unrelated medical disease
Pheochromocytoma
RCC
The von Hippel-Lindau syndrome tumor suppressor protein regulates the expression of which of the following mediators of biologic aggressiveness for RCC?
Basic fibroblast growth factor
Vascular endothelial cell growth factor
Epidermal growth factor receptor
Hepatocyte growth factor (scatter factor)
P-glycoprotein (multiple drug resistance efflux protein)
What do the hereditary papillary RCC syndrome and von Hippel-Lindau syndrome have in common?
The mode of genetic transmission
Chromosome 3 abnormalities
A propensity toward tumor formation in multiple organ systems
Inactivation of a tumor suppressor gene
Nearly complete penetrance
Mutation of the metproto-oncogene in hereditary papillary RCC leads to:
increased expression of hepatocyte growth factor.
increased sensitivity to vascular endothelial growth factor.
inactivation of a tumor suppressor gene that regulates cellular proliferation.
constitutive activation of the receptor for hepatocyte growth factor.
increased expression of vascular endothelial growth factor.
P-glycoprotein is a transmembrane protein that is involved in:
immunotolerance.
resistance to high-dose interleukin-2 (IL-2) therapy.
resistance to cisplatin therapy.
resistance to radiation therapy.
efflux of large hydrophobic compounds, including many cytotoxic drugs.
Pathology demonstrates venous involvement limited to the main renal vein along with contralateral adrenal involvement with RCC. There is also a 6-cm bulky retroperitoneal lymph node replaced with cancer. What is the stage?
pT3aN1M0
pT3aN2M0
pT3aN1M1
pT3bN1M1
pT4N2M0
Which of the following is most likely to demonstrate an infiltrative growth pattern?
Clear cell RCC
Sarcomatoid variants of RCC
Papillary RCC
Chromophobe RCC
Oncocytoma
What is the most common mutation identified in sporadic clear cell RCC?
Activation of the metproto-oncogene
Activation of the von Hippel-Lindau tumor suppressor gene
Inactivation of the von Hippel-Lindau tumor suppressor gene
Inactivation of p53
Inactivation of genes on chromosome 9
Which of the following cytogenetic abnormalities is among those commonly associated with papillary RCC?
Trisomy of chromosome 7
Trisomy of the Y chromosome
Loss of chromosome 17
Loss of all or parts of chromosome 3
Loss of chromosome 7
What percentage of RCCs are chromophobe cell carcinomas?
0% to 2%
4% to 5%
8% to 10%
12% to 15%
18% to 25%
Most renal medullary carcinomas are:
found in patients with sickle cell disease.
diagnosed in the fifth decade of life.
responsive to high-dose chemotherapy.
genetically and histologically similar to papillary RCC.
metastatic at the time of diagnosis.
Which paraneoplastic syndrome associated with RCC can often be managed or palliated medically?
Polycythemia
Stauffer syndrome
Neuropathy
Hypercalcemia
Cachexia
A healthy 64-year-old man is found to have a 6.0-cm solid, heterogeneous mass in the hilum of the right kidney. CT of the abdomen and pelvis shows interaortocaval lymph nodes enlarged to 2.5 cm. A chest radiograph and a bone scan are negative, and the contralateral kidney is normal. The serum creatinine level is 1.0 mg/dL. What is the best next step?
Right radical nephrectomy and regional or extended lymph node dissection
Abdominal exploration, sampling of the enlarged lymph nodes, and possible radical nephrectomy pending frozen section analysis
CT-guided percutaneous biopsy of the lymph nodes
CT-guided percutaneous biopsy of the tumor mass
Systemic therapy followed by radical nephrectomy
Which of the following patients would be the best candidate for percutaneous biopsy or fine-needle aspiration of a renal mass?
A 42-year-old man with a 2.5-cm Bosniak III complex renal cyst
An 88-year-old man with unstable angina and a 1.7-cm solid, enhancing renal mass
A 32-year-old woman with bilateral solid, enhancing renal masses ranging in size from 1.5 to 4.0 cm
A 48-year-old woman with a 3.5-cm solid, enhancing renal mass with fat density present
A 38-year-old woman with a fever, a urinary tract infection, and a 3.5-cm solid/cystic, enhancing renal mass
A 67-year-old man undergoes radical nephrectomy and inferior vena caval thrombectomy (level 2 tumor thrombus). The primary tumor is otherwise confined to the kidney, and the lymph nodes are not involved. What is the approximate 5-year cancer-free survival rate?
15% to 25%
26% to 35%
36% to 45%
46% to 65%
66% to 80%
Which of the following is NOT a predictor of cancer-specific survival after nephrectomy for RCC?
Pathologic stage
Tumor size
Fuhrman nuclear grade
Patient age
Histologic necrosis
Which of the following statements about renal lymphoma is TRUE?
Five percent to 10% of all lymphomas involving the kidney are primary tumors
The radiographic patterns manifested by renal lymphoma are diverse and can be difficult to differentiate from RCC
Percutaneous biopsy is rarely indicated if renal lymphoma is suspected
Renal failure associated with renal lymphoma is most often due to extensive parenchymal replacement by the malignancy
The most common pattern of renal involvement is from direct extension from adjacent retroperitoneal lymph nodes
Which of the following would be considered diagnostic for renal angiomyolipoma (AML)?
Hyperechoic pattern on ultrasonography
Enhancement of > 30 Hounsfield units on CT scan
Small area measuring less than − 20 Hounsfield units on nonenhanced CT
Aneurysmal changes on renal arteriogram
Positive signal on T2 images of MRI
The main limitation of renal mass biopsy is:
risk of needle tract seeding.
difficulty differentiating the eosinophilic variants of RCC from renal oncocytoma.
risk of pneumothorax.
risk of hemorrhage.
high incidence of inadequate tissue sampling.
Which of the following tumors is most likely to be a malignant RCC?
2.5-cm hyperechoic complex cyst, with no enhancement with IV contrast
6.0-cm complex cyst with four thin septae
5.0-cm cyst with thin, curvilinear calcification
11-cm cyst with water density and homogeneous nature
3.0-cm solid lesion with fat associated with calcification
A common and pathogenic cytogenetic finding in children with RCC is:
VHLmutation.
B cMEToncogene mutation.
p53mutation.
TFE3gene fusions.
PTENmutations.
The central mediator for loss of VHL protein function is:
hypoxia-inducible factor (HIF) alpha.
platelet derived growth factor (PEGF).
erythropoietin.
vascular endothelial growth factor (VEGF).
p53.
Most tumors at various sites in the von Hippel-Lindau syndrome share the following characteristic:
Malignant behavior
Hypervascularity
Rapid growth rate
High nuclear grade
Symptomatic presentation
One major difference between hereditary papillary RCC syndrome and von Hippel-Lindau syndrome is:
pattern of genetic inheritance.
age of onset.
gender distribution.
incidence of metastasis.
incidence of associated tumors in nonrenal organ systems.
Which syndrome is most likely to exhibit aggressive behavior of RCC?
von Hippel-Lindau syndrome
Hereditary papillary RCC syndrome
Hereditary leiomyomatosis and RCC syndrome
Birt-Hogg-Dubé syndrome
Familial oncocytosis
Spontaneous pneumothorax is occasionally observed in which of the following?
von Hippel-Lindau syndrome
Hereditary papillary RCC syndrome
Hereditary leiomyomatosis and RCC syndrome
Birt-Hogg-Dubé syndrome
Familial oncocytosis
Chromophobe RCC shares many characteristics with:
oncocytoma.
type 2 papillary RCC.
clear cell RCC.
mesoblastic nephroma.
mixed epithelial and stromal tumor of the kidney.
A finding that is diagnostic for collecting duct carcinoma is:
central location and infiltrative growth pattern.
aggressive clinical course.
p53mutation.
positive staining for Ulex europaeuslectin.
sensitivity to chemotherapy.
Sarcomatoid differentiation is most commonly observed with which histologic subtypes of RCC?
Clear cell and papillary
Papillary and chromophobe
Clear cell and collecting duct
Clear cell and chromophobe
Chromophobe and collecting duct
Which of the following factors has greatest utility for predicting bone metastasis from RCC?
Tumor size
Tumor grade
Performance status
Elevated alkaline phosphatase
Invasion of the perinephric fat
The prognosis for a 3-cm tumor infiltrating the renal sinus fat is:
similar to a pT1bN0 tumor.
similar to a pT2aN0 tumor.
similar to a pT3a tumor with invasion of the perinephric fat laterally.
worse than a pT3a tumor with invasion of the perinephric fat laterally.
similar to a tumor with ipsilateral adrenal involvement.
The single most important prognostic factor for RCC is:
tumor size.
tumor grade.
tumor stage.
histologic subtype.
performance status.
The most accurate assessment of prognosis for patients with RCC is usually provided by:
tumor size.
clinician judgment.
tumor stage.
integrated analysis of prognostic factors.
performance status.
Which of the following indicates a tumor that is NOT correctly staged according to the 2009 TNM staging system for RCC?
Localized RCC, 8.5 cm: pT2a
RCC with direct ipsilateral adrenal involvement: pT3a
RCC with metastatic involvement of the adrenal gland: pM1
RCC with tumor thrombus within a segmental branch of the renal vein: pT3a
RCC with three lymph node metastases: pN1
Risk of local recurrence is highest in which of the following situations?
pT3btumor after radical nephrectomy and inferior vena cava (IVC) thrombectomy
von Hippel-Lindau patient after partial nephrectomy with wedge resection of a single tumor
4.5-cm tumor after partial nephrectomy with focal positive parenchymal margin
3.5-cm tumor after cryoablation
2.5-cm centrally located tumor after radiofrequency ablation
What is the most common form of renal sarcoma?
Liposarcoma
Rhabdomyosarcoma
Fibrosarcoma
Leiomyosarcoma
Angiosarcoma
The most useful prognostic factors for renal sarcoma are:
tumor size and grade.
tumor stage and grade.
histologic subtype and stage.
tumor stage and ploidy status.
margin status and grade.
Which of the following renal tumors has the best prognosis?
Sarcoma
Carcinoid
Adult Wilms
Primitive neuroectodermal tumor
Small cell
Patients with which RCC subtype are most likely to benefit from targeted therapy, such as tyrosine kinase inhibitors?
Papillary RCC
Clear cell RCC
Renal medullary carcinoma
Collecting duct carcinoma
Chromophobe RCC
Standard postoperative adjuvant therapy for patients at high risk of recurrence following nephrectomy includes which of the following?
High-dose IL-2
Targeted molecular therapy
Autologous tumor vaccine
Observation
Interferon-α (IFN-α)
Agents targeting which of the following signaling pathways in clear cell RCC have significant antitumor effects in patients with metastatic disease?
VEGF and epidermal growth factor receptor (EGFR)
p53and EGFR
VEGF and mammalian target of rapamycin (mTOR)
mTOR and transforming growth factor-α (TGF-α)
All of the above
Of the following, which is the greatest determinant of renal function after partial nephrectomy?
Surgical approach (open vs. minimally invasive)
Tumor size
Absence of a functioning contralateral kidney
Renal function before partial nephrectomy
Gender
Which of the following statements is TRUE regarding chronic kidney disease (CKD)?
CKD due to surgery has the same impact as CKD due to medical causes
Serum creatinine below 1.4 mg/dL excludes the possibility of CKD
CKD can be diagnosed based on a single estimated GFR value less than 60 mL/min/1.73 m²
Increasing CKD stage has been associated with an increase in morbid cardiovascular events for subjects in the general population
Choice of intervention for localized renal malignancy has little impact on development or progression of CKD
Which of the following is an indication for adrenalectomy at the time of partial nephrectomy?
6-cm upper pole renal tumor
4-cm adrenal lesion measuring − 20 Hounsfield units on noncontrast CT scan
Bilateral adrenal hyperplasia
3-cm renal tumor adjacent to the adrenal gland on CT scan, but readily separable from the adrenal gland at surgery
1.5-cm adrenal lesion that is bright on T2-weighted MRI

Pathology

A 49-year-old man has a biopsy of a peripheral lower pole exophytic 4-cm mass of the right kidney. The histology is depicted in Figure 57-1and is read as clear cell carcinoma. Metastatic workup is negative. He should be advised to:

FIGURE 57-1 (From Bostwick DG, Cheng L. Urologic surgical pathology. 2nd ed. Edinburgh: Mosby; 2008.)

receive targeted chemotherapy.
have a radical nephrectomy.
have the tumor ablated with cryotherapy.
have a partial nephrectomy.
receive radiation therapy.
A 48-year-old woman has a right radical nephrectomy for a 6-cm mass. Preoperative metastatic workup was negative. The pathology is illustrated in Figure 57-2and is read as collecting duct carcinoma. She should be advised to:

FIGURE 57-2 (From Bostwick DG, Cheng L. Urologic surgical pathology. 2nd ed. Edinburgh: Mosby; 2008.)

receive targeted chemotherapy.
receive radiation therapy to the nephrectomy bed.
receive platinum-based chemotherapy.
follow up with her primary care physician.
be followed closely because the development of metastatic disease is likely.

Imaging

See Figure 57-3. A 55-year-old man with hematuria has this contrast-enhanced CT scan for evaluation. The most appropriate therapy is:

FIGURE 57-3

laparoscopic nephron-sparing surgery.
radical nephrectomy.
open nephron-sparing surgery.
radiofrequency ablation.
cryoablation.
See Figure 57-4. A 45-year-old man with no urinary symptoms has this axial contrast-enhanced CT scan. What is the most likely diagnosis?

FIGURE 57-4

Bosniak II-F lesion—short-interval imaging follow-up
Bosniak IV—cystic RCC
Bosniak II cyst
Bosniak III cyst
Bosniak I cyst

Answers

c. Computed tomography (CT) with and without contrast enhancement.A dedicated (thin-slice) renal CT scan remains the single most important radiographic image to delineate the nature of a renal mass. In general, any renal mass that enhances with administration of intravenous contrast material on CT scanning should be considered a renal cell carcinoma until proved otherwise.
b. Bosniak II cyst.Category II lesions are minimally complicated cysts that are benign but have some radiologic findings that cause concern. Classic hyperdense renal cysts are small (< 3 cm), round, sharply marginated, and do not enhance after administration of contrast material. Hyperdense cysts that are 3 cm or larger are classified as Bosniak II-F lesions.
d. Renal metastasis.The traditionally accepted indications for needle aspiration or biopsy of a renal mass are when a renal abscess or infected cyst is suspected, or when differentiating RCC from metastatic malignancy or renal lymphoma. Fine-needle aspiration or biopsy is now performed with increased frequency for the evaluation of renal masses in other circumstances, particularly for patients in whom a wide variety of treatment options are under consideration.
c. Chest radiograph annually for 3 years.Surveillance for recurrent malignancy after radical nephrectomy for RCC can be tailored according to the initial pathologic tumor stage. This patient is low risk (pT1N0M0) and the American Urological Association (AUA) Guidelines recommend an annual chest radiograph for 3 years and only as clinically indicated beyond that time period.
b. Tumor size < 5.0 cm.A solitary tumor and a normal contralateral kidney were also required, but criteria for the latter were not well defined.
b. Every 6 months for at least 3 years and then annually to year 5.Surveillance for recurrent malignancy after nephron-sparing surgery for RCC can be tailored according to the initial pathologic tumor stage. This patient is intermediate to high risk and the AUA Guidelines recommend a baseline abdominal scan (CT or MRI) within 3 to 6 months following surgery with continued imaging (ultrasonography, CT, or MRI) every 6 months for at least 3 years and annually thereafter to year 5. Imaging beyond 5 years may be performed at the discretion of the clinician.
b. 24-hour urinary protein measurement.Patients who undergo nephron-sparing surgery for RCC may be left with a relatively small amount of renal tissue. These patients are at risk for long-term renal functional impairment from hyperfiltration renal injury. Because proteinuria is the initial manifestation of the phenomenon, a 24-hour urinary protein measurement should be obtained yearly in patients with a solitary remnant kidney to screen for hyperfiltration nephropathy.
e. Serum creatinine–based estimation of GFR, such as CKD-EPI formula. At present, there are several formulas in clinical use, including the MDRD, Cockcroft-Gault, and CKD-EPI formulas, each of which is an improvement over using serum creatinine alone for identification of patients with or at risk for chronic kidney disease.Serum levels of creatinine are dependent on gender, muscle mass, and other factors and can therefore lead to an underappreciation of kidney disease in certain populations, such as thin, elderly women. Urinary creatinine measurement is impractical and provides only marginally more valuable information than serum creatinine. Urinary protein measurement can identify patients with early signs of kidney disease (proteinuria) but is not the best screening test. Direct measurement of GFR using iothalamate (or other agents) is costly and not routinely available; it is therefore impractical in most settings.
d. A double freeze-thaw cycle.Renal cryosurgery is an ablative nephron-sparing treatment option for RCC that can be performed percutaneously under radiographic guidance or laparoscopically under direct vision and ultrasound guidance. The aim of cryosurgery is to ablate the same predetermined volume of tissue that would have been removed had a conventional surgical excision been performed. Established critical prerequisites for successful cryosurgery include rapid freezing, gradual thawing, and a repetition of the freeze-thaw cycle.
c. CT and MRI.Both CT and MRI are noninvasive and accurate modalities for demonstrating both the presence and the distal extent of vena caval involvement. Although MRI has been recommended as the test of choice at most centers, several recent studies have demonstrated that multiplanar CT also provides sufficient information for surgical planning, and it has become the preferred diagnostic study at many centers.
e. Lymph node involvement. In most studies, the presence of lymph node or distant metastases has carried a dismal prognosis that is much more pronounced than the other distractors.
d. Simultaneous partial nephrectomy and pulmonary lobectomy.The subset of patients with metastatic RCC and a solitary metastasis, estimated at between 1.6% and 3.2% of patients, may benefit from nephrectomy with resection of the metastatic lesion. This patient also needs partial nephrectomy to preclude the need for dialysis.
e. Observation with follow-up renal imaging in 6 to 12 months.Renal mass biopsy is now performed with increased frequency and should be considered in an elderly patient such as this. For those in whom nonextirpative options are being considered, biopsy can provide important information, such as a definitive nonmalignant diagnosis (as in this example). Given the benign nature of renal oncocytomas, the best answer is observation with follow-up imaging in 6 to 12 months.
e. Mode of genetic transmission.Approximately 20% of angiomyolipomas are found in patients with the tuberous sclerosis (TS) syndrome, an autosomal dominant disorder characterized by mental retardation, epilepsy, and adenoma sebaceum, a distinctive skin lesion. TS, similar to von Hippel-Lindau, is transmitted in an autosomal dominant manner.
a. Selective embolization.Most patients with acute or potentially life-threatening hemorrhage will require total nephrectomy if exploration is performed, and if the patient has TS, bilateral disease, preexisting renal insufficiency, or other medical or urologic disease that could affect renal function in the future, selective embolization should be considered. In such circumstances, selective embolization can temporize by controlling hemorrhage and in many cases will prove to be definitive treatment.
a. They are complex cystic lesions that are typically classified as Bosniak II to III. Cystic nephromas are benign renal neoplasms that occur most commonly in middle-aged women.They appear to be genetically related to mixed epithelial and stromal tumors (MESTs) but generally have a somewhat different radiographic appearance. Unlike MESTs, which contain a solid stromal component and often appear as solid or Bosniak IV lesions on cross-sectional imaging, cystic nephromas are typically characterized as complex cystic lesions without a solid component.
c. Tobacco use.The most generally accepted environmental risk factor for RCC is tobacco use, although the relative associated risks have been modest, ranging from 1.4 to 2.3 when compared with controls. All forms of tobacco use have been implicated, with risk increasing with cumulative dose or pack-years. Other well-established risk factors include obesity and hypertension.
d. Pheochromocytoma. The familial form of the common clear cell variant of RCC is the von Hippel-Lindau syndrome. Major manifestations include the development of RCC, pheochromocytoma, retinal angiomas, and hemangioblastomas of the brainstem, cerebellum, or spinal cord.Penetrance for all of these traits is far from complete, and some, such as pheochromocytomas, tend to be clustered in certain families but not in others.
c. 41% to 60%. RCC develops in about 50% of patients with von Hippel-Lindau syndrome and is distinctive for early age at onset, often developing in the third, fourth, or fifth decades of life, and for bilateral and multifocal involvement.
e. RCC.With improved management of the central nervous system manifestations of the disease, RCC has now become the most common cause of mortality in patients with von Hippel-Lindau syndrome.
b. Vascular endothelial cell growth factor. Inactivation or mutation of the von Hippel-Lindau gene leads to dysregulated expression of hypoxia inducible factor-1, an intracellular protein that plays an important role in regulating cellular responses to hypoxia, starvation, and other stresses. This in turn leads to a severalfold upregulation of the expression of vascular endothelial growth factor (VEGF), the primary proangiogenic growth factor in RCC, contributing to the pronounced neovascularity associated with this carcinoma.
a. The mode of genetic transmission.Studies of families with hereditary papillary renal cell carcinoma (HPRCC) have demonstrated an autosomal dominant mode of transmission, similar to von Hippel-Lindau syndrome. Von Hippel-Lindau syndrome is caused by inactivation or mutation of a tumor suppressor gene, whereas HPRCC is caused by activation of an oncogene.
d. Constitutive activation of the receptor for hepatocyte growth factor.Missense mutations of the met proto-oncogene at 7q31 were found to segregate with the disease, implicating it as the relevant genetic locus. The protein product of this gene is the receptor tyrosine kinase for the hepatocyte growth factor (also known as scatter factor), which plays an important role in regulating the proliferation and differentiation of epithelial and endothelial cells in a wide variety of organs, including the kidney. Most of the mutations in hereditary papillary RCC have been found in the tyrosine kinase domain of met and lead to constitutive activation.
e. Efflux of large hydrophobic compounds, including many cytotoxic drugs.P-glycoprotein is a 170-kDa transmembrane protein expressed by 80% to 90% of RCCs that acts as an energy-dependent efflux pump for a wide variety of large hydrophobic compounds, including several cytotoxic drugs.
c. pT3aN1M1. Isolated renal vein involvement is now classified as T3a and nodal classification has been simplified such that all nodal involvement is now classified as N1.Contiguous invasion of the ipsilateral adrenal is now classified as T4, but metastatic involvement of the contralateral (or ipsilateral) adrenal gland is classified as M1, reflecting a likely hematogenous pattern of dissemination.
b. Sarcomatoid variants of RCC.Most RCCs are round to ovoid and circumscribed by a pseudocapsule of compressed parenchyma and fibrous tissue rather than a true histologic capsule. Unlike upper tract transitional cell carcinomas, most RCCs are not grossly infiltrative, with the notable exception of some sarcomatoid variants.
c. Inactivation of the von Hippel-Lindau tumor suppressor gene. Chromosome 3 alterations and von Hippel-Lindau mutations are common in conventional RCC, and mutation or inactivation of this gene has been found in over 75% of sporadic cases.
a. Trisomy of chromosome 7.The cytogenetic abnormalities associated with papillary RCC are characteristic and include trisomy of chromosomes 7 and 17 and loss of the Y chromosome.
b. 4% to 5%. Chromophobe cell carcinoma is a distinctive histologic subtype of RCC that appears to be derived from the cortical portion of the collecting duct.It represents 4% to 5% of all RCCs.
e. Metastatic at the time of diagnosis. Renal medullary carcinoma is a rare histologic subtype of RCC that occurs almost exclusively in association with sickle cell trait.It is typically diagnosed in young African Americans, often in the third decade of life. Many cases are both locally advanced and metastatic at the time of diagnosis. Most patients have not responded to therapy and have succumbed to their disease in a few to several months.
d. Hypercalcemia. Hypercalcemia has been reported in up to 13% of patients with RCC and can be due to either paraneoplastic phenomena or osteolytic metastatic involvement of the bone. The production of parathyroid hormone–like peptides is the most common paraneoplastic etiology, although tumor-derived 1,25-dihydroxyvitamin D₃and prostaglandins may contribute in a minority of cases. Medical management includes vigorous hydration followed by diuresis with furosemide and the selective use of bisphosphonates, corticosteroids, and/or calcitonin.
a. Right radical nephrectomy and regional or extended lymph node dissection.An aggressive surgical approach is still preferred because it will likely prolong survival and represents the only realistic chance for a cure. Lymph nodes in this size range are most likely malignant, and this patient will likely need to consider adjuvant clinical trials. An extended lymph node dissection includes the interaortocaval nodes and nodes alongside and behind the ipsilateral great vessel from the crus of the diaphragm to the ipsilateral common iliac artery.
e. A 38-year-old woman with a febrile urinary tract infection and a 3.5-cm solid/cystic, enhancing renal mass.Patients with flank pain, a febrile urinary tract infection, and a renal mass may be considered for percutaneous biopsy or aspiration to establish a diagnosis of renal abscess rather than malignancy.
d. 46% to 65%.Venous involvement was once thought to be a poor prognostic finding for RCC, but more recent studies suggest that most patients with tumor thrombi can be salvaged with an aggressive surgical approach. These studies document 45% to 69% 5-year survival rates for patients with venous tumor thrombi as long as the tumor is otherwise confined to the kidney.
d. Patient age.Although patient age and comorbidity are important predictors of overall survival in patients with RCC and strongly affect the choice of treatment in these patients, they have no effect on the likelihood of dying of cancer-specific causes. Each of the other factors has been incorporated into one or more RCC prognostic algorithms for cancer-specific outcomes.
b. The radiographic patterns manifested by renal lymphoma are diverse and can be difficult to differentiate from RCC.Five different radiographic patterns have been described for lymphoma involving the kidney, including a solitary mass that can be difficult to differentiate from RCC.
c. Small area measuring less than − 20 Hounsfield units on nonenhanced CT. The presence of even a small focus of fat, as evidenced by a density less than − 20 HU on a nonenhanced CT scan, is diagnostic for AML.The findings described in a, b, and d are all suggestive but not diagnostic for renal AML.
b. Difficulty differentiating the eosinophilic variants of RCC from renal oncocytoma.The main limitation of renal mass biopsy is difficulty differentiating renal oncocytoma, the most common benign renal mass, from eosinophilic variants of conventional, papillary, and chromophobe RCC on biopsy material. The risk of complications is low in the modern era with the use of smaller gauge needles, and needle tract seeding with RCC appears to be a rare event.
e. 3.0-cm solid lesion with fat associated with calcification.Tumors with calcification associated with fat are uncommon but are almost always malignant RCC. In this setting the fat is thought to be a reactive process related to tumor necrosis. Calcification is virtually never seen in association with AML. The lesions described in a–c are Bosniak II renal cysts, with risk of malignancy of < 10%. The lesion described in d is a simple cyst and highly likely to be benign despite its large size.
d. TFE3gene fusions. Mutations or translocations resulting in TFE3 gene fusions are common in RCC occurring in the pediatric population. Although these cancers often present with advanced stage, the t(X;17) variant frequently follows an indolent course while t(X;1) cancers can recur with late lymph node metastases.
a. Hypoxia-inducible factor (HIF) alpha.Inactivation of the VHL protein or loss of its function allows HIF-2 alpha to accumulate, leading to a variety of downstream events including upregulation of VEGF, erythropoietin, and PEGF. HIF-2 alpha is the primary mediator of these events.
b. Hypervascularity.Tumors in the von Hippel-Lindau syndrome include adrenal pheochromocytoma, retinal angiomas, cerebellar and brainstem hemangioblastoma, RCC, and others. Most are relatively slow growing and asymptomatic if patients are evaluated and screened in a proactive manner. The common feature is that almost all are hypervascular.
e. Incidence of associated tumors in nonrenal organ systems.The incidence of nonrenal tumors is low in the hereditary papillary RCC syndrome in contrast to von Hippel-Lindau syndrome, in which patients commonly develop tumors in the eyes, spinal cord, cerebellum, adrenal glands, inner ear, epididymis, and pancreas.
c. Hereditary leiomyomatosis and RCC syndrome.Malignant behavior is particularly common in the hereditary leiomyomatosis and RCC syndrome, and proactive and aggressive surgical management is recommended.
d. Birt-Hogg-Dubé syndrome.Lung cysts and spontaneous pneumothoraces are well described and relatively common findings in the Birt-Hogg-Dubé syndrome.
a. Oncocytoma. Both chromophobe RCC and renal oncocytoma are derived from the distal tubules and both are commonly observed in the Birt-Hogg-Dubé syndrome.There are also some overlapping cytogenetic changes, all suggesting a potential relationship between these renal tumors.
d. Positive staining for Ulex europaeuslectin. Ulex europaeus lectin is expressed by the normal collecting duct, and tumor staining suggests origin from this structure. Most collecting duct carcinomas are centrally located and exhibit an infiltrative growth pattern and aggressive clinical course, but this is also true for poorly differentiated transitional cell carcinomas (TCCs) of the renal pelvis or centrally located sarcomatoid RCC.
d. Clear cell and chromophobe.Sarcomatoid differentiation is most commonly found in association with clear cell and chromophobe RCC.
c. Performance status.Poor performance status (PS) can be used to segregate patients when deciding whether to obtain a bone scan for metastatic RCC. Shvarts and colleagues (2004)* have shown that patients with good performance status (ECOG performance status = 0), no evidence of extraosseous metastases, and no bone pain were extremely low risk for bone metastasis and did not benefit from bone scanning. They recommended a bone scan for all other patients, and the incidence of bone metastasis in this group was > 15%.
d. Worse than a pT3a tumor with invasion of the perinephric fat laterally.Invasion of the perisinus fat medially has been shown to be a poor prognostic sign. Medial invasion places the tumor in proximity to the venous system and likely increases the risk of metastatic dissemination. Ipsilateral adrenal involvement is even worse, and these are now classified as pT4 if due to direct local extension, or pM1 otherwise, consistent with a hematogenous route of dissemination.
c. Tumor stage.Although not truly a single factor because it combines tumor size with several other pieces of information obtained from final pathologic analysis, tumor stage is the most powerful individual predictor of oncologic outcomes. When incorporated into a multi-predictor analysis, such as a nomogram or other multivariable analysis, the predictive ability increases further.
d. Integrated analysis of prognostic factors.Integrated analysis of a variety of factors such as tumor size, stage, and grade, performance status, and histologic subtype has yielded the most accurate prognostication for RCC. Several studies have documented that nomograms and other algorithms outperform traditional staging systems, clinical opinion, individual risk factors, and chance.
b. RCC with direct ipsilateral adrenal involvement: pT3a.Several studies have demonstrated that RCC directly invading the adrenal gland is associated with poorer prognosis than RCC with perinephric or renal sinus fat invasion. Direct ipsilateral adrenal involvement is now grouped with other RCCs that extend beyond Gerota fascia as pathologic stage T4 (pT4). These patients have a high risk for disease recurrence or progression.
b. von Hippel-Lindau patient after partial nephrectomy with wedge resection of a single tumor.Local recurrence after partial nephrectomy for von Hippel-Lindau disease is common if patients are followed long-term due to multifocal tumor diathesis. These kidneys have been shown to harbor several hundred incipient tumors, and the risk of local recurrence is thus high during longitudinal follow-up after partial nephrectomy.
d. Leiomyosarcoma.Leiomyosarcoma is the most common histologic subtype of renal sarcoma, accounting for 50% to 60% of such tumors. The most common type of sarcoma in the retroperitoneum is liposarcoma.
e. Margin status and grade.Margin status and tumor grade are the primary prognostic factors for sarcoma. Patients with high-grade disease are at risk for systemic metastasis and those with low-grade disease are at risk for local recurrence. Wide local excision with negative margins is essential for minimizing the risk of recurrence for sarcomas because these tumors are derived from the mesenchymal tissues and are typically infiltrative, and thus do not respect natural barriers.
b. Carcinoid.All of these tumor types have a relatively poor prognosis except for renal carcinoid, which tends to be associated with good outcomes in most patients.
b. Clear cell RCC.Targeted molecular therapies, such as tyrosine kinase inhibitors, mostly target VEGF and thus the pathways that are typically upregulated in clear cell RCC. Most objective responses have been observed in individuals with clear cell RCC. Standard of care for the treatment of metastatic non–clear cell RCC is not well defined at present.
d. Observation.All randomized postoperative adjuvant trials in patients with resected RCC have failed to demonstrate an improvement in survival or time to progression. Several ongoing clinical trials are evaluating whether targeted molecular therapy will show a benefit, but the results are not available at present. The standard of care continues to be surveillance with periodic radiographic and clinical observations, although enrollment in a clinical trial is highly preferred.
c. VEGF and mammalian target of rapamycin (mTOR).Several clinical trials indicate that agents targeting VEGF signaling, including sunitinib, sorafenib, and pazopanib, and mTOR pathway signaling, including temsirolimus and everolimus, demonstrate substantial tumor responses or significant improvement in progression-free or overall survival.
d. Renal function prior to partial nephrectomy.When compared with radical nephrectomy, partial nephrectomy has been associated with better renal functional outcomes. The main determinants of renal function after partial nephrectomy are the quality of the kidney prior to surgery and the quantity of vascularized parenchymal mass that is preserved after excision of the tumor and reconstruction of the kidney. Warm ischemia time, if prolonged, can also contribute to a decline in renal function after partial nephrectomy.
d. Increasing chronic kidney disease (CKD) stage has been associated with an increase in morbid cardiovascular events, hospitalization and death on a longitudinal basis for subjects in the general population.In this setting, CKD is predominantly due to medical causes. CKD due to surgical causes appears to be more stable than that due to medical causes.
e. 1.5-cm adrenal lesion that is bright on T2-weighted MR imaging.Several pathologic adrenal lesions can be diagnosed based on their radiographic characteristics without histologic confirmation. Lesions that are bright on T2-weighted MR imaging are suspicious for pheochromocytomas and should be surgically removed. Careful preoperative and intraoperative management are essential for safe management in this circumstance.

Pathology

d. Have a partial nephrectomy.Notice the clear cytoplasm due to glycogen characteristic of clear cell carcinoma of the kidney. Because of the patient's young age, a nephron-sparing approach is preferred. Because the tumor is located in the lower pole, is peripheral, and is exophytic, it is ideal for this approach. These tumors are not sensitive to radiation therapy, cryotherapy does not have long-term extended follow-up, and targeted chemotherapy is not appropriate for a surgically curable lesion.
e. Be followed closely because the development of metastatic disease is likely.Collecting duct cancers have a high likelihood of being metastatic at diagnosis. None of the other therapies listed are helpful in this disease.

Imaging

b. Radical nephrectomy.The images demonstrate a large mass in the lower pole of the right kidney, with tumor extension into the right renal vein, extending to the junction of the right renal vein with the inferior vena cava. The renal vein is enlarged, and tumor vessels are seen within the thrombus in the renal vein. These findings make radical nephrectomy the best option.
b. Bosniak IV—cystic RCC. Notice the enhancing nodules within the cyst wall with foci of dystrophic calcification making cystic renal cell carcinoma the most likely diagnosis.

Chapter review

A solid mass on CT scan that enhances more than 15 Hounsfield units is suggestive of RCC.
Twenty percent of small solid enhancing masses on CT are benign.
Hyperdense cysts (Bosniak II) contain old blood and are benign.
Clear cell RCCs originate from the proximal tubule; oncocytomas and chromophobe RCCs originate from the distal tubule.
There is ample evidence for impaired immune surveillance in RCC.
Bilateral involvement in RCC either synchronously or metachronously occurs in 2% to 4% of patients.
RCC pathologically is classified as clear cell: 70% to 80%; papillary: 10% to 15%; chromophobe: 3% to 5%; collecting duct: less than 1%; and medullary: rare.
Alterations in chromosome 3 are common in clear cell renal carcinoma.
Papillary renal cell cancer has a tendency to multifocality.
Paraneoplastic syndromes include hypercalcemia, hypertension, polycythemia, and hepatic dysfunction (Stauffer syndrome).
Stauffer syndrome is a perineoplastic syndrome associated with RCC that results in elevated liver function tests. If hepatic function does not normalize after nephrectomy, persistent hepatic dysfunction is indicative of persistent disease.
Enlarged perirenal lymph nodes noted on CT may be inflammatory, particularly if they are less than 2 cm in diameter. Lymph nodes larger than 2 cm generally contain metastases.
Extended lymphadenectomy for renal cell carcinoma has not been shown to be beneficial for the majority of patients over conventional lymphadenectomy, which includes the renal hilar and adjacent paracaval or para-aortic lymph nodes.
Fuhrman grading system from 1 to 4 is used to grade the renal tumor and is based on nuclear characteristics.
There is an increased incidence of renal cell carcinoma in patients with acquired renal cystic disease.
RCC involving the vena cava that infiltrates the wall of the vena cava has an extremely poor prognosis.
A patient with a tumor thrombus involving the vena cava associated with metastatic regional nodal disease has a very poor prognosis.
A patient with a tumor thrombus involving the vena cava in which the nodes are negative and there is no invasion of the vein wall (except the ostia) has a good prognosis.
Ipsilateral adrenalectomy as part of a radical nephrectomy is not necessary unless there is CT evidence of adrenal involvement, contiguous spread of the tumor to the adrenal, or large upper pole renal masses that are adjacent to the adrenal gland.
The risk for developing recurrent malignant disease is greatest in the first 3 years after surgery.
In a partial nephrectomy, the amount of renal parenchyma taken with the tumor appears to be immaterial provided the margin itself is negative.
RCCs less than 3.5 cm in general grow less than 0.5 cm per year; some may grow up to 1 cm per year.
Incomplete excision of a large primary tumor or debulking is rarely indicated as a sole treatment.
Sarcomas typically have a pseudocapsule that cannot be relied on for a plane of dissection because tumor will be left behind.
Metastatic tumors to the kidney are common, appearing in 12% of patients who die of other cancers; the most common primary lesions are those of the lung, breast, or gastrointestinal tract, melanoma, or hematologic.
Positron emission tomography scanning using radiolabeled anticarbonic anhydrase IX is taken up by clear cell renal carcinoma.
Major poor prognostic indicators include tumors that extend beyond Gerota fascia, involve contiguous organs, have lymph node involvement, or are metastatic.
Patients with von Hippel-Lindau disease should have their tumors treated when they reach 3 cm in size.
Patients with a significant reduction in renal mass are at risk for developing long-term renal functional impairment from hyperfiltration renal injury. These patients should have their urinary protein excretion monitored because proteinuria is the initial manifestation of hyperfiltration injury.
Established critical prerequisites for successful cryosurgery include rapid freezing, gradual thawing, and a repetition of the freeze-thaw cycle.
Approximately 20% of angiomyolipomas are found in patients with the tuberous sclerosis (TS) syndrome, an autosomal dominant disorder characterized by mental retardation, epilepsy, and adenoma sebaceum, a distinctive skin lesion. TS, similar to VHL, is transmitted in an autosomal dominant manner.
Cystic nephromas are benign renal neoplasms that occur most commonly in middle-aged women.
The von Hippel–Lindau syndrome's major manifestations include the development of renal cell carcinoma, pheochromocytoma, retinal angiomas, and hemangioblastomas of the brain stem, cerebellum, or spinal cord.
Inactivation or mutation of the von Hippel–Lindau gene leads to dysregulated expression of hypoxia inducible factor-1, an intracellular protein that plays an important role in regulating cellular responses to hypoxia, starvation, and other stresses. This in turn leads to a several-fold upregulation of the expression of vascular endothelial growth factor (VEGF).
Hereditary papillary renal cell carcinoma has an autosomal dominant mode of transmission.
Chromosome 3 alterations and von Hippel–Lindau mutations are common in conventional renal cell carcinoma, and mutation or inactivation of this gene(VHL) has been found in over 75% of sporadic cases.
Renal medullary carcinoma is a rare histologic subtype of RCC that occurs almost exclusively in association with sickle cell trait.
Most collecting duct carcinomas are centrally located and exhibit an infiltrative growth pattern and aggressive clinical course.
Direct ipsilateral adrenal involvement is now grouped with other RCC's that extend beyond Gerota fascia as pathologic stage T4 (pT4).

^* Sources referenced can be found in Campbell-Walsh Urology, 11th Edition, on the Expert Consult website.

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