renal cancer

RENAL AND UROLOGY II

Renal cancerMark Haynes

AbstractRenal cell cancer is the seventh most common cancer in males and ninth

most common in females in the UK. Although it classically presents with

haematuria, loin pain and a palpable mass, increasingly small renal

cancers are being detected incidentally. Curative treatment for the disease

remains surgical, with, until recently, few effective additional treatments.

Recent advances in the molecular/genetic understanding of the disease

have enabled the development of effective treatments for advanced

disease. Surgery for renal cancer remains technically challenging and

increasing detection of small tumours is necessitating the development

of lower morbidity, nephron-sparing techniques. This article discusses

current understanding of renal cancer, modes of diagnosis and various

treatment options available.

Keywords Haematuria; nephrectomy; partial nephrectomy; renal cell

cancer; von HippeleLindau

Introduction

Surgery remains the only curative treatment option for renal

cancer presenting at any stage of disease and this has led to the

development of surgical techniques to treat very advanced

disease (e.g. right atrial involvement) alongside techniques to

treat very small incidentally detected tumours while minimizing

damage to normal renal parenchyma. The most important aspect

of the clinical management of patients presenting with renal

cancer is selection of the most appropriate treatment for the

individual patient, balancing information from their preoperative

imaging with their co-morbidities and expectations. This article

aims to introduce renal cell cancer, describe the genetics of the

most common genetic form of the disease, outline staging

investigations appropriate to the disease and discuss treatment

options available to the treating urological surgeon.

Epidemiology

Kidney cancer accounts for 2e3% of new cancer diagnoses in

adults in the UK (excluding non-melanoma skin cancer) and

approximately 90% of these are renal cell carcinomas. In 2007,

8228 patients were diagnosed with kidney cancer with a male-

to-female ratio of 5:3 making it the seventh most common cancer

in men and ninth most common cancer in women in the UK.

Kidney cancer accounted for 3848 cancer-related deaths in the

UK in 2008, approximately 2% of all cancer-related deaths in the

UK. Male incidence has risen from 4.3 per 100,000 in 1971 to 6.0

per 100,000 in 2008; female rates have increased over the same

Mark Haynes MB BCh MD FRCS(Urol) is a Consultant Urological Surgeon,

Royal Hallamshire Hospital, Sheffield, UK. Conflicts of interest: none

declared.

SURGERY 28:12 605

period from 2.1 to 3.1 per 100,000. Approximately 75% of cases

occur in individuals over 60 years old, but it can affect younger

individuals with hereditary familial renal cancer (see below).

Risk factors

� Cigarette smoking: approximately 24e32% of renal cell

cancer cases in men and 9e16% in women can be attributed

to smoking. Risk increases with the number of cigarettes

smoked, smoking 20/day increases the risk of renal cancer by

60e100% compared with non-smokers.

� Obesity: risk of renal cell cancer increases by 7% for each unit

increase of body mass index (BMI). Approximately 25% of

renal cell carcinomas (RCC) are attributable to being

overweight.

� Acquired cystic kidney disease: patients receiving dialysis are

at an increased risk of renal cancer of up to sevenfold after

10 years of dialysis. Renal transplant patients are also at an

increased risk for cancer in the native kidneys.

� Family history: siblings have a four- to sevenfold risk of renal

cancer.Therearealsoanumberof familial conditions (seebelow).

Pathology

Most renal cancers are ovoid and circumscribed by a pseudo-

capsule comprising compressed renal parenchyma and fibrous

tissue. When bivalved they are yellow, brown or tan with areas of

necrosis and haemorrhage (Figure 1). All RCC are adenocarci-

nomas derived from renal tubular epithelium. There are four main

subtypes of RCC and each subtype has differing clinical charac-

teristics and genetic origins (Table 1). RCCs are graded according

to the Fuhrman nuclear grading system from grade 1 to 4.

Hereditary kidney cancer

There are several types of inherited kidney cancer:

� von HippeleLindau (VHL)

� hereditary papillary renal cell carcinoma

� hereditary leiomyoma renal cell carcinoma

� BirteHoggeDube syndrome.

Figure 1 Typical renal cell carcinoma bivalved, tumour is at the upper pole

and yellow/tan in colour with a central cystic area. Normal kidney is seen

at the bottom of the image.

� 2010 Elsevier Ltd. All rights reserved.

http://dx.doi.org/10.1016/j.mpsur.2010.09.001

Histological subtypes of renal cell carcinoma

Histology Genetics Characteristics

Clear cell (70e80%) VHL gene mutations

Deletion of 3p

Gain of 5q

Loss of 8p, 9p and 14q

From proximal tubule

Hyper-vascular

Familial ¼ VHL

Papillary (10e15%) Trisomy 7 and 17

Abnormalities of met proto-oncogene

Loss of 14 and Y

Gain of 12, 16 and 20

From proximal tubule

Hypo-vascular

Multi-centric

Type 2 worse prognosis

Occur in acquired cystic disease

Familial ¼ HPRCC (type 1) and HLRCC (type 2)

Chromophobic (3e5%) Loss of 1, 2, 6, 10, 13, 17 and 21 From intercalated cells of collecting duct

Good prognosis

Familial ¼ BirteHoggeDube syndrome

Collecting duct (1%) Loss of 1, 6, 8, 11, 18, 21, and Y

Gain of 7, 12, 17, and 20

From collecting duct

Poor prognosis

Table 1

Presentation of renal cell carcinoma

Common symptoms and signsC Haematuria (40%)

C Flank pain (40%)

C Palpable abdominal mass (25%)

Other signs and symptoms

C Weight loss (33%)

C Pyrexia of unknown origin (20%)

C Hypertension (20%)

C Hypercalcaemia (5%)

C Lethargy/malaise

C Varicocele, usually left-sided, due to obstruction of the testicular

vein (2% of males)

Paraneoplastic syndromes (5%)

C Non-specific (toxic) syndromes (e.g. anaemia)

C Non-metastatic abnormal liver function tests (Stauffer’s

syndrome)

C Immunological syndromes (e.g. neuropathy)

C Specific endocrine syndromes; occur as a result of hypersecretion

of renal hormones (e.g. renin, erythropoietin) or non-renal

hormones (e.g. parathormone, gonadotrophin)

Table 2


The most common and most studied, VHL has an autosomal

dominant inheritance with an annual incidence of 1 per 35,000

population in the UK. Peak presentation is between the ages of 40

years and 50 years. Classically, these patients develop bilateral,

multifocal renal tumours and cysts. VHL has associated tumours,

including:

� haemangioblastomas of the cerebellum and spine

� phaeochromocytomas

� pancreatic islet cell tumours

� retinal haemangiomas

� epididymal cystadenomas.

The gene associated with VHL is on the short arm of chromo-

some 3 (3P 25). The VHL gene has characteristics of a tumour

suppressor gene that requires ‘two hits’ to lose its function.

Tumour suppressor genes actively stop tumour growth until they

are altered or mutated. In VHL, mutation on one gene is inherited

and mutation on the wild type allele occurs, allowing the disease

to develop. Screening begins in childhood and includes:

� annual ultrasound of the kidneys and abdomen

� annual ophthalmology review

� urinary catecholamines and magnetic resonance imaging

(MRI) of the head and spine every 3 years.

Inherited renal cancer is difficult to manage because of the

multiplicity of tumours and the earlier age of presentation.

Diagnosis

Up to 50% of RCCs are detected incidentally and do not cause

symptoms in early stages. Classically RCC causes a triad of flank

pain, a palpable renal mass and haematuria, but RCC can present

with a wide variety of symptoms and paraneoplastic conditions

(Table 2). Figure 1 shows the common and uncommon presen-

tations of this disease. At presentation up to 30% of patients with

renal cell carcinoma already have metastatic disease (even those

patients detected incidentally). Typically RCCs are identified as

solid lesions within the renal parenchyma on ultrasound, but

they may also have cystic components making the distinction

between benign cystic disease and RCC difficult. The Bosniak

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classification of complex cysts (Table 3) and computed tomog-

raphy (CT) imaging with contrast allows accurate identification

of most lesions.

Staging

Tumour stage at presentation is the best prognostic guide and

radiological staging is imperative before surgery. The TNM

classification of renal tumours is shown in Table 4.



Bosniak classification of renal cysts

Class I Simple benign cysts. Lesions have round or oval

shape, are unilocular with the uniform density of

water, have no perceptible wall and do not show

enhancement on radiographs taken after giving

contrast medium.

Class II Probable benign cystic lesions that are minimally

complicated. Lesions include septated cysts,

minimally calcified cysts, infected and high-density

cysts.

Class III More complicated cystic lesions. Cysts exhibit some

findings seen in malignancy, such as thick, irregular

calcifications, irregular borders, multilocular form,

thickened or enhancing septa, uniform thickening of

the wall, or small, non-enhancing nodules.

Class IV Clearly malignant cystic masses. Appearances of

these lesions result from necrosis and liquefaction of

a solid tumour or a tumour growing into the wall.

Lesions are heterogeneous, with a shaggy

appearance, thickened walls or enhancing nodules.

Table 3

Renal cancer TNM staging

T Primary tumour

TX Primary tumour cannot be assessed

T0 No evidence of primary tumour

T1 Tumour �7 cm in greatest dimension, limited to the

kidney

T1a Tumour �4 cm in greatest dimension, limited to the

kidney

T1b Tumour >4 cm, but �7 cm in greatest dimension

T2 Tumour >7 cm in greatest dimension, limited to the

kidney

T2a Tumour >7 cm, but �10 cm in greatest dimension

T2b Tumours >10 cm limited to the kidney

T3 Tumour extends into major veins or directly invades

adrenal gland or perinephric tissues but not into the

ipsilateral adrenal gland and not beyond Gerota’s fascia

T3a Tumour grossly extends into the renal vein or its

segmental (muscle-containing) branches or tumour

invades perirenal and/or renal sinus (peripelvic) fat but

not beyond Gerota’s fascia

T3b Tumour grossly extends into the vena cava below the

diaphragm

T3c Tumour grossly extends into vena cava above the

diaphragm or invades the wall of the vena cava


Ultrasonography

T4 Tumour invades beyond Gerota’s fascia (including

contiguous extension into the ipsilateral adrenal gland)

N Regional lymph nodes

NX Regional lymph nodes cannot be assessed

N0 No regional lymph node metastasis

N1 Metastasis in a single regional lymph node

Ultrasonography is the first-line investigation in any patient in

whom a renal mass is suspected. It enables the detection of solid

renal masses and cysts. It also allows synchronous assessment of

the inferior vena cava, para-aortic nodes and the liver.Where a solid

renal mass, or a complex cyst is identified then further radiological

assessment is indicated to enable accurate categorization.

N2 Metastasis in more than one regional lymph node

M Distant metastasis
Contrast enhanced CT
M0 No distant metastasis

M1 Distant metastasis

Table 4

Contrast enhanced CT (Figure 2) is the gold standard radiological

investigation for staging renal carcinoma. Any contrast

enhancing solid renal mass should be considered to be renal cell

cancer until proven otherwise. CT allows assessment of exten-

sion into the renal vein or inferior vena cava (IVC), extra-renal

extension, involvement of adjacent organs, nodal disease and

adrenal metastases. Standard imaging for a suspected renal

cancer also includes CT of the chest as this is a common site for

metastasis.

MRI

MRI is used for the assessment of IVC involvement and may be

used in place of CT in patients with renal insufficiency or allergy

to intravenous contrast.

Isotope bone scans

Isotope bone scans can be used to assess for bony metastases.

Where bony metastases are present at diagnosis they are typi-

cally symptomatic or the serum alkaline phosphatase is raised so

bone imaging is only carried out in these situations.

Treatment e localized renal cancer

Nephron-sparing surgery (partial nephrectomy)

Figure 2 Contrast-enhanced computed tomography demonstrating small

(radiologically T1a) renal mass of the left kidney (circled).

Nephron-sparing surgery (partial nephrectomy) should be

considered in all patients presenting with small (T1a) renal

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tumours and is the treatment of choice in patients presenting

with bilateral disease (as is often the case in familial renal cancer

syndromes), tumour in a solitary functioning kidney and RCC in

patients with pre-existing renal insufficiency. Cancer cure rates




are similar to radical nephrectomy in small tumours, but more

intense follow-up is required as local recurrence can occur.

Partial nephrectomy can be performed by open or laparoscopic

approaches and the tumour is removed with a thin margin of

normal adjacent renal tissue. Laparoscopically the procedure is

technically challenging and most surgeons would advocate an

open approach in patients with a solitary kidney or RCC with pre-

existing renal insufficiency.

Radical nephrectomy

Radical nephrectomy is the standard, often curative, therapy for

localized renal cell cancer. As first described by Robson it

involves removal of the kidney, adrenal gland, perirenal fat, and

Gerota’s fascia, with a regional lymph node dissection.

However, randomized clinical trials suggest that the ipsilateral

adrenal gland can be left in situ with T1 and T2 tumours of the

lower pole because the risk of spread with a normal preoperative

CT is very low. The role of lymphadenectomy in localized renal

cancer is controversial. In earlier series, patients undergoing

radical nephrectomy had a 20e30% incidence of positive nodes,

and extended lymphadenectomy was claimed to improve

survival in this group. With the diagnosis of smaller incidental

tumours, this incidence is considerably less, and while it allows

accurate pathological staging it probably does not impact on

survival.

Laparoscopic radical nephrectomy

Laparoscopic radical nephrectomy is now the first-line surgical

approach for radical nephrectomy. Cancer cure rates are equiv-

alent to the open procedure but perioperative morbidity is

reduced with a reduction in blood loss, reduced analgesic

requirements, reduced length of stay in hospital and an earlier

return to normal activities. It can be performed via trans-

peritoneal or retroperitoneal approaches. Technically the proce-

dure is the same as an open radical nephrectomy. The specimen

is placed in a bag at the end of the procedure (port site metas-

tases have been reported in early series) and removed through

a grid iron incision. While enthusiasts perform IVC thrombec-

tomy via a laparoscopic approach, most urological surgeons

would advocate open radical nephrectomy for larger tumours

(>7 cm) and renal vein/IVC involvement.

Renal vein/IVC involvement

Renal vein/IVC involvement occurs in up to 20% and 10% of

patients, respectively. Inferior vena cava thrombus requires

modification in the surgical approach so that control of the

inferior vena cava below and above the tumour can be achieved.

Thrombus above the diaphragm entering the right atrium

requires veno-venous or complete cardiopulmonary bypass; this

intervention has a high morbidity and mortality, and careful

consideration should be made (in addition to detailed discussions

with the patient and family).

Locally invasive disease (T4)

Locally invasive disease (T4) has a very poor prognosis even

without demonstrable metastatic disease. Radical surgical exci-

sion is the only treatment, but rarely achieves satisfactory

survival rates. Surgery can be indicated in symptomatic patients

for palliation.

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Alternative (non-surgical) approaches

With increasing numbers of small incidentally detected tumours

being identified, alternative approaches offering lower morbid-

ities have been studied. In particular these approaches are useful

in patients who are unfit for standard surgical treatments. A

variety of ablative approaches have been studied and at present

radiofrequency ablation and cryotherapy are the two in most

widespread use. Both treatments are delivered radiologically

under local anaesthetic. While cure rates from both techniques

are good, local recurrence is more common than after partial

nephrectomy.

It is recognized that small renal cancers grow at a slow rate

and metastasis is extremely rare in tumours <3 cm. Observation

alone is an option in the management of small incidentally

detected renal masses in the unfit or very elderly. The principal

advantage is the avoidance of any procedure-related morbidity

and many of these patients will die with these small tumours

rather than of them.

Treatment e metastatic disease

Thirty percent of newly diagnosed patients with renal cell

carcinoma have metastatic disease at presentation. In the

remaining patients who present initially with local disease, 30%

will develop metastatic disease. These patients have an average

survival of 4 months and all will die within 5 years.

Resection of the primary tumour and solitary metastasis

appears to be justified in the 2e4% of patients in whom this is

found, because the survival rates are about 30% at 5 years.

Palliative nephrectomy may be done for the control of severe

bleeding or pain or in patients with symptomatic paraneoplastic

syndromes. Angio-infarction is a safer and less invasive method

than surgery for managing severe haemorrhage and other severe

symptoms.

Targeted molecular therapies

Targeted molecular therapies directed at the hypoxic response

pathway (the same molecular pathway affected in VHL patients)

include tyrosine kinase inhibitors (sunitinib, sorafenib) and

mTOR inhibitors (temsirolimus) and vascular endothelial growth

factor (VEGF) inhibition (bevacizumab) are effective in the

management of patients with metastatic renal cell cancer offering

an improved progression free and overall survival. The side

effects of these targeted treatments are considerably lower than

the immunotherapies and they are now the first-line agents in the

management of metastatic RCC. Potential roles for these agents

in adjuvant treatment of intermediate and high-risk RCC are

currently under investigation in randomized controlled trials.

Immunotherapy

Immunotherapy prior to the emergence of targeted molecular

therapies immunotherapeutic agents were the only available

treatment for metastatic disease. Interferon-a has immunosti-

mulatory and anti-angiogenic antitumoural mechanisms and

promotes an immune response. Interferon-a is approved in

Europe for the treatment of renal cell carcinoma, with a reported

partial response of 11e15%, and a complete response rate of 2%.

Recently combination treatment with bevacizumab and inter-

feron-a has shown increased response rates (31% in




combination arm versus 13% in interferon alone arm) and

increased progression free survival (10.2 months vs 5.4 months).

Interleukin-2

Interleukin-2 has higher toxicity than interferon but complete

responses have been achieved in 5% of patients, while 15%

showed a partial response using high-dose regimens.

Radiotherapy

Radiotherapy can be used for the palliative treatment of painful

skeletal metastases. Radiation therapy appears to have no role as

a primary or adjunctive treatment.

Chemotherapy

Chemotherapy has little role to play in the management of RCC

as response rates are extremely poor.

Follow-up

Follow-up regimens (post-surgical treatment) are varied and

most centres are using risk stratification (e.g. Mayo risk criteria)

to guide the use of surveillance imaging. There is no single

universally accepted follow-up protocol. Recurrence/metastases

in low-risk patients typically occurs early and follow-up may

involve cross-sectional imaging at 1 year and 5 years post-

treatment. Recurrence/metastases is much more common in

intermediate and high-risk patients, therefore their follow-up

SURGERY 28:12 609

may involve yearly cross-sectional imaging. Detection of solitary

isolated metastases/renal bed recurrence may be amenable to

further surgery.

Summary

The treatment of renal cancer is challenging. Studies of the

hereditary forms of RCC aid the understanding of the genetic

basis of this disease and continue to guide research and novel

treatment strategies. The gold standard of treatment for local

disease is surgical excision, with partial nephrectomy recom-

mended for smaller tumours and the laparoscopic radical

nephrectomy where nephron sparing surgery is not feasible.

Open radical nephrectomy is reserved for large tumours and IVC

involvement. The prognosis is poor if metastatic disease is

confirmed, but recent advances have led to the development of

effective treatments which delay the progression of disease. A

FURTHER READING

Ljungberg B, Cowan N, Hanbury DC, et al. European association of urology

guidelines on renal cell carcinoma. Taneja SS, ed. Urol Clin North Am

2010; 30: 423e668. August 2003.

Weiss RM, George NJR, O’Reilly PH, eds. Comprehensive urology. London:

Mosby, 2001.



renal cancer

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