Malignant Renal Tumors Part One

Malignant Renal Tumors

Dr Prashant Bansal

Historical Considerations


The first documented nephrectomy was done in 1861 by Wolcott, who operated

with the mistaken assumption that the tumor mass was a hepatoma.

In 1867, Spiegelberg removed a kidney incidentally in the course of excising an

echinococcus cyst.

1st planned nephrectomy: by Simon in 1869 for persistent ureteral fistula, and this

patient survived with cure of fistula

One year later (1870), nephrectomy was successfully accomplished by Gilmore in

Mobile, Alabama, for treatment of atrophic pyelonephritis and persistent urinary

tract infection

In 1855, Robin examined solid tumors apparently arising in kidney and concluded

that renal carcinoma arose from renal tubular epithelium.


Theoretical and practical considerations of renal tumors were confused by Grawitz

(1883), who contended that such apparent renal tumors arose from adrenal rests

within the kidney. He introduced the terminology struma lipomatodes aberrata

renis as descriptive nomenclature for the tumors of clear cells that he believed

were derived from the adrenal glands.

In 1894, Lubarch endorsed the idea of a suprarenal origin of renal tumors

Term hypernephroid tumors, indicating origin above the kidneys, was advocated by

Birch-Hirschfeld

This mistake led to introduction of term hypernephroma

Some clarification of the histopathology of renal tumors was derived from the work

of Albarran and Imbert (1903), and the four-volume contribution of Wolff (1883),

written between 1883 and 1928, added further historical significance to the

understanding of renal tumors

Epidemiology

Epidemiology

Incidence: 12/100,000 per year

M : F = 3 : 2

Primarily a disease of elderly

Presentation in 6th and 7th decades of life

Incidence: 10% to 20% higher in African Americans

Mostly: sporadic

Familial: 2% to 3%

RCC in childhood

Uncommon (only 2.3% to 6.6% of all renal tumors in children)

Mean age at presentation = 8 to 9 years

Incidence in Boys = Girls

Although Wilm’s tumor is much more common in younger children, RCC is as

common as Wilm’s tumor during 2nd decade of life

More likely to be symptomatic and to exhibit papillary histology, and a predilection for

locally advanced, high-grade disease, and unfavorable histologic subtypes

TFE3 protein overexpression

Correlates with presence of ASPL-TFE3 and PRCC-TFE3 gene translocation

events (involving Chromosomes X and 1)

Relatively common in children and young adults with RCC and is unique to this

population

Clinical significance of TFE3 protein overexpression is not well defined

(Preliminary data suggest that these tumors may show differential sensitivity to

certain chemotherapeutic agents)

RCC in childhood

Stage for stage, children and young adults with RCC may respond better to surgical

therapy

A number of long-term survivors have been reported after radical nephrectomy

and lymphadenectomy for LN + disease

An aggressive surgical approach (Radical Nephrectomy + formal lymphadenectomy)

has thus been recommended when RCC is suspected in children or young adults

Etiology

Etiology

Established

Tobacco exposure

Obesity

Hypertension

Putative

Lead compounds

Various chemicals (e.g., aromatic

hydrocarbons)

Trichloroethylene exposure

Occupational exposure (metal,

chemical, rubber, and printing

industries)

Asbestos or cadmium exposure

Radiation therapy

Dietary (high fat/protein and low

fruits/vegetables)

Tobacco

Most generally accepted environmental risk factor for RCC

Relative risk = modest (1.4 to 2.5)

All forms of tobacco use have been implicated

Risk increases with cumulative dose or pack-years

Relative risk is directly related to duration of smoking and begins to fall after

cessation

Accounts for 20% to 30% of cases of RCC in men and 10% to 20% in women

Obesity

Accepted as another major risk factor

Relative risk of 1.07 for each unit of rising body mass index

Increased prevalence of obesity likely contributes to increased incidence of RCC in

Western countries

Estimated that > 40% of cases of RCC in US may be causally linked to obesity

Potential mechanisms

Lipid peroxidation leading to DNA adducts

Increased insulin-like growth factor-1 expression

Increased circulating estrogen levels

Increased arterionephrosclerosis and local inflammation

Hypertension

Third major etiologic factor

Proposed mechanisms

hypertension-induced renal injury and inflammation

metabolic or functional changes in the renal tubules that may increase

susceptibility to carcinogens

Familial RCC and Molecular Genetics

SYNDROME GENETIC

ELEMENT

MAJOR CLINICAL

MANIFESTATIONS

von Hippel-Lindau VHL gene

Chromosome 3p25-26

Clear cell RCC

Hemangioblastomas of CNS

Retinal angiomas

Pheochromocytoma (PCC)

Hereditary papillary

RCC

c-MET proto-oncogene

Chromosome 7q31

Type 1 papillary RCC

Familial Leiomyomatosis

and RCC

Fumarate hydratase

Chromosome 1q42

Type 2 papillary RCC

Cutaneous leiomyomas

Uterine leiomyomas

Birt-Hogg-Dubé BHD1 gene

Chromosome

17p12q11

Chromophobe RCC

Oncocytoma

Transitional tumors*

Occasional clear cell RCC

Cutaneous fibrofolliculomas

Lung cysts

Spontaneous pneumothorax

von Hippel-Lindau Disease

“Familial form of clear cell RCC”

Rare Autosomal dominant disorder

1 per 36,000 population

ORGAN SYSTEM LESION INCIDENCE (%)

Eye Benign retinal angiomas 49 – 59

Ear Endolymphatic sac tumor 10

CNS Benign Hemangioblastomas 42 – 72

Kidney Clear cell RCC

Renal cysts

25 – 70

22 – 59

Adrenal Pheochromocytoma 18

Pancreas Islet cell tumors

Malignant islet cell tumor

Pancreatic cysts

12

2

21 – 72

Epididymis Cystadenoma 10 – 26


All of these tumor types are highly vascular and can lead to substantial morbidity

Increased incidence of neuroendocrine tumors of pancreas

CNS lesions paralysis or death

Retinal lesions blindness

RCC in VHL

Develops in about 50%

Early age at onset (3rd, 4th or 5th decade of life)

B/L and multifocal involvement

Due to improved management of CNS complications, RCC is now the major cause

of mortality in VHL


VHL tumor suppressor gene

Located at chromosome 3p25-26

Tumor suppressor gene for both sporadic and familial forms of clear cell RCC

Gene consists of three exons, and it encodes a protein of 213 amino acids.

A large number of common mutations or “hot spots” have been identified

Direct correlation b/w genotype and phenotype has been established in some cases

For instance, missense mutations (type 2 mutations) that result in a full-length but

non-functional protein are commonly found in families with VHL that develop

pheochromocytomas, whereas deletions leading to a truncated protein (type 1

mutations) are typically found in families that do not develop pheochromocytomas

Both alleles must be mutated/inactivated for development of disease

Incidence of Major Manifestations of VHL

by Mutation Status

DISEASE

TYPE

HEMANGIOB

LASTOMA

RCC PCC GERMLINE MUTATION TYPES

1 High High Low Full gene deletions

Partial gene deletions

Nonsense mutations

Splice acceptor mutations

2A High Low High Missense mutations in specific areas

2B High High High Partial gene deletions

Nonsense mutations

Missense mutations

2C No No High Missense mutations in other specific

areas


VHL protein

Binds to elongins B and C, CUL-2 and RBX1 forms an E3 ubiquitin ligase complex

This complex modulates degradation of important regulatory proteins

A critically important function of the VHL protein complex is to target the hypoxia-

inducible factors 1 and 2 (HIF 1 and 2) for ubiquitin-mediated degradation

keeping the levels of HIFs low under normal conditions (HIFs are intracellular proteins

that play an important role in regulating cellular responses to hypoxia, starvation, and

other stresses)

Inactivation/mutation of VHL gene dysregulated expression of HIFs HIF

accumulation several fold upregulation of VEGF expression pronounced

neovascularity

HIFs also upregulate the expression of TGF-α, PDGF, glucose transporter (Glut 1),

erythropoietin and carbonic anhydrase IX (CA-IX)

Biologic functions of VHL protein


Other genes potentially involved in development of sporadic clear cell RCC

Additional loci on short arm of chromosome 3 (3p)

Loss of heterozygosity (LOH) at 3p12-p14 and 3p21.2- p21.3; particularly

common in tumors with wild-typeVHL status

Candidate tumor suppressor gene at 3p12 has been described and may

contribute to aVHL-independent pathway to RCC

TP53 and PTEN tumor suppressor genes

Increased immunostaining for TP53 in 6% to 40%. Some studies suggest a

correlation with tumor grade and stage

Loss of PTEN constitutive activation of mTOR promotes tumorigenesis

Familial Papillary RCC

= Familial Type 1 papillary RCC (Type II in HLRCC)

Do not develop tumors in other organ systems

Autosomal dominant

Median age at diagnosis = 45 years

Non–clear cell histotypes

Multifocal and bilateral papillary RCC

Gene for HPRCC = Chromosome 7q31 (Missense mutations of c-MET proto-

oncogene at 7q31)

Inciting event is activation of a proto-oncogene, rather than inactivation of a tumor

suppressor gene

Trisomy for chromosomes 7 and 17

Abnormalities on chromosomes 1, 12, 16, 20 andY

Chromosome 3 and VHL gene abnormalities uncommon

Familial Papillary RCC

Protein product of c – MET proto-oncogene

= receptor tyrosine kinase for hepatocyte growth factor (also known as scatter

factor)

Activation leads to cellular proliferation and other tumorigenic effects

Most of the mutations in HPRCC have been found in tyrosine kinase domain of

c-MET apparently lead to constitutive activation

Tumors in HPRCC tend to be less aggressive than their sporadic counterparts. But

some can metastasize and become lethal

CT is the preferred imaging modality for patients with HPRCC because it has the

greatest sensitivity for detecting the small, hypovascular lesions

Hereditary Leiomyomatosis and RCC

= Cutaneous and uterine leiomyomas + type 2 papillary RCC

Autosomal dominant

Renal tumors in this syndrome are different from other familial RCC because

Often solitary and unilateral

More likely to be aggressive than other forms of familial RCC

Collecting duct RCC has also been observed

Histologic hallmark

Large, prominent eosinophilic nuclei and nucleoli with perinucleolar clearing

HLRCC locus

A region on 1q 42-44

= Site of Fumarate hydratase gene (Fumarate hydratase is an essential enzyme in

Krebs cycle)

This appears to be a tumor suppressor gene rather than an oncogene

Hereditary Leiomyomatosis and RCC

Penetrance for RCC in HLRCC

Lower than for cutaneous and uterine manifestations

Only 20% develop RCC

In contrast, almost all individuals develop cutaneous leiomyomas and uterine

fibroids (if female), manifesting by 20 - 35 yr age.

Prompt surgical management of renal tumors is recommended in this

syndrome (tendency toward invasive and aggressive behavior)

Birt-Hogg-Dubé Syndrome

Cutaneous fibrofolliculomas + lung cysts + spontaneous pneumothorax + variety of

renal tumors (primarily derived from distal nephron)

Autosomal dominant

The renal tumors typically include chromophobe RCC, oncocytomas and hybrid or

transitional tumors that exhibit features of both of these entities.

However, other forms including clear cell RCC have been observed

Overall penetrance for renal tumors is 20% to 40%, but when they occur they are

often bilateral and multifocal

Average age at renal tumor diagnosis is approximately 50 years

Most renal tumors have limited biologic aggressiveness

BHD gene

Chromosome 17p12q11.2

Appears to be a tumor suppressor gene

Function is still under investigation

Gene product = folliculin

One hypothesis is that folliculin may interface with the mTOR pathway

Germline mutations in this gene have been found in 88% of kindreds

Genetic testing is now available

Birt-Hogg-Dubé Syndrome

Tumour Biology

RCC is a prototype of chemorefractory tumors

Tumor Biology and Clinical Implications

BIOLOGIC

CHARACTERISTIC

CLINICAL IMPLICATIONS

Expression of multidrug

resistance

•Contributes to chemorefractory nature of RCC

Immunogenic •10%-20% response rate with IFN or IL-2

•3%-5% complete response rate with high-dose IL-2

Angiogenic •Vascular invasion can lead to venous tumor thrombus

•20%-40% response rates with agents targeting VEGF (bevacizumab)

or the VEGF receptor (sunitinib, sorafenib, etc.)

•Prolonged recurrence-free survival and overall survival with some

antiangiogenic agents

Dependence on mTOR

pathway

•Agents targeting mTOR prolong survival in patients with poor-risk

RCC (temsirolimus) and demonstrate responses in patients failing

prior targeted molecular therapies (everolimus)

1. Resistance to Cytotoxic Therapy

RCC is a prototype of the chemorefractory tumor (limited or modest responses to

traditional chemotherapeutics)

Expression of multidrug resistance (MDR) proteins

E.g.: MDR-1 (also known as P-glycoprotein) and MDR-related proteins

Act as energy-dependent efflux pumps for a wide variety of hydrophobic

compounds

Contribute to chemorefractory nature of advanced RCC

However there seems to be some redundancy in these resistance mechanisms:

RCC is also resistant to drugs like cisplatin and others (that are not handled by

MDR proteins)

Downregulation of MDR-1 in high-grade tumors and metastases

2. Immunobiology

Evidence demonstrates that RCC is immunogenic

Tumor-infiltrating immune cells can be readily isolated from RCC, including

CytotoxicT cells with specificity for antigens on tumor cells

Dendritic cells and TH cells: express IL-1 and IL-2 and function as APCs

Clinical observations which support immunogenicity of RCC

Validated responses to immunotherapy

Prolonged disease stabilization

Occasional spontaneous tumor regression

Response of RCC to immunomodulators, such as IL-2, INF and tumor-

infiltrating lymphocytes. Infact, high-dose IL-2 is the only treatment with curative

potential for metastatic RCC, with durable and complete regression in 3 - 5%

Estimated incidence of spontaneous regression of RCC: 0.3 - 7%

Most spontaneous regressions have been noted in

Pulmonary mets after cytoreductive nephrectomy

Regression of primary RCC has also been reported in absence of any treatment

2. Immunobiology

CA-IX/Carbonic anhydrase IX/ MN-9 (antigen)

Of the tumor-associated antigens for RCC, CA-IX = most specific

CA- IX is recognized by G250 monoclonal antibody

Expressed almost ubiquitously by clear cell RCC and rarely by other subtypes

IHC analysis of CA-IX expression has been investigated as a diagnostic and a

prognostic marker for clear cell RCC

Normally expressed in: gastric mucosa, large bile ducts, and pancreas

Expression in normal renal epithelial cells is suppressed by wild-type VHL protein

CA-IX has also been investigated for RT-PCR detection of circulating RCC cells

in peripheral blood

CA-IX based tumor vaccine protocols have been developed

Radioactively labelled G250: shown promise for detection of RCC mets by

radionuclide scanning, and more recently by PET

All these potential applications of CA-IX are promising but experimental

2. Immunobiology

B7 family (cell surface glycoproteins)

A second class of factors that may modulate immunotherapeutic responses

Expressed on various immune and nonimmune cells

B7-H1 is a T-cell coregulatory molecule that is normally expressed by

macrophage lineage cells, can be induced on activated T lymphocytes, and is

aberrantly expressed by RCC

Tumor-associated B7-H1 impairs antigen-specific T-cell function

Blockade of B7-H1 has been shown to potentiate antitumoral responses in

preclinical models

Thompson and associates (2006) have shown that B7-H1 expression by clear cell

RCC tumors correlates with aggressive pathologic features and is associated

with an increased risk of disease progression

2. Immunobiology

ImmuneTolerance

Response rates of immunotherapy for RCC have been disappointing

Range from 15% to 20%

Impaired immune surveillance is seen in RCC

Defective NF-κB (nuclear factor-kappa B) signalling

Defects in transcriptional regulation via NF-κB are present in tumor-infiltrating

lymphocytes and dendritic cells in 60% RCC

Impairs lymphocyte function predisposes lymphocytes to apoptosis leads

to deficient recruitment and activation of dendritic cells

For example, in addition to its antiangiogenic activity, sunitinib also appears to

stimulate antitumor immunity by reversing myeloid-derived suppressor cell

mediated immunosuppression

3. Angiogenesis and Targeted Pathways

RCC = one of the most vascular cancers

Primary angiogenesis inducer in clear cell RCC appears to beVEGF

Increased levels ofVEGF have been found in serum and urine

Levels correlate with stage and grade

Functional relevance ofVEGF:

Increased levels ofVEGF transcript in most hypervascular tumors

Hypovascular counterparts exhibit reduced expression ofVEGF

Elevated serum basic fibroblast growth factor (bFGF) and other putative

angiogenesis inducers also seen


VEGF (A family consisting of several subtypes)

Bind to 1 or more of correspondingVEGF receptors

Regulated by HIFs andVHL

Suppressed by the wild-typeVHL protein normally

Dramatically upregulated during tumor development

Upon binding of ligand (VEGF) to VEGFR, key tyrosine residues along the

intracellular portion of VEGFR are phosphorylated binding of specific

intracellular factors activation of corresponding pathways

Pathways known to be activated by phosphorylation ofVEGFRs include

Raf-MEK-Erk pathway

Phosphatidylinositol-3-kinase /Akt /mTOR pathway (promote endothelial cell

survival and proliferation)

VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1) are receptor tyrosine kinases that are

the target of several multi–tyrosine kinase inhibitors (TKIs)


However, the promiscuity of interactions between the various ligands, receptors,

and downstream effectors leads to a host of effects that may be difficult to predict

This promiscuity is likely a major reason that two therapeutic agents that have the

“same” mode of action are found to have disparate clinical or off-target effects.

Initial clinical trials identified several antiangiogenic compounds such as TNP-470,

roquinimex, and thalidomide with limited activity in patients with advanced RCC.

Thalidomide

Has shown only rare response despite its potent antiangiogenic effects

Toxicity: can be substantial (thrombotic events and neurologic morbidity).

Multiple kinase inhibitors (that target theVEGF pathway)

Substantial activity in advanced RCC

2 agents approved by USFDA – Sunitinib and Sorafenib

Bevacizumab (humanized antiVEGF monoclonal antibody)

Monoclonal antibody that binds to VEGF (not to its receptor) and

sequesters the ligand so that it cannot interact withVEGFR

More promising initial results were reported

Significant delay in time to progression in met-RCC compared with placebo

Therapy commonly leads to shrinkage in the total tumor burden

Partial responses were uncommon and there were no complete responses

Tumoristatic rather than a tumoricidal mechanism of action.


Neovascularity associated with RCC. Renal angiogram shows left renal mass exhibiting markedly

increased neovascularity within renal tumor

4. Signal Transduction, Cell Cycle Regulation,

and Other Targeted Molecular Pathways

Aberrant activation of additional signal transduction pathways in RCC may also

contribute to altered cell cycle kinetics

mTOR pathway (mammalian target of rapamycin)

Interfaces with Akt (protein kinase B) and the PTEN tumor suppressor gene

Expression of mTOR is upregulated by

Various growth factors

Mutation or loss of PTEN

mTOR pathway increased expression of HIF-1 and other growth-promoting

sequelae

Inhibition of mTOR with Temsirolimus (FDA approved) prolonged survival in

poor-risk, metastatic RCC

Other important growth regulatory elements in RCC

Insulin-like growth factor

Telomerase

BCL2

Insulin-like growth factor receptor expression

Correlates with decreased survival

Increased telomerase activity

Found in 56% to 93% of RCCs

Affects cell cycle by maintaining telomere length

Progressive telomere loss occurs each time a normal cell divides growth inhibition

and cellular senescence

Increased expression of BCL2 (which protects against programmed cell death)

May contribute to tumor viability and treatment failure



Proliferative index

Defined by proliferating cell nuclear antigen (PCNA) or Ki-67 staining

Correlates with pathologic parameters and clinical outcomes

EGFR

Increased expression of TGF-α and its receptor tyrosine kinase (epidermal

growth factor receptor - EGFR), have been reported in RCC and may contribute

to tumorigenesis through an autocrine mechanism

C225 monoclonal antibody

Neutralizes EGFR and blocks tumor growth and metastasis

Anti EGFR agents

Erlotinib, Gefitinib and ABX-EGF

Phase II clinical trials lack of substantial activity in advanced RCC

May have a role in cancers that express high levels of EGFR



Hepatocyte Growth Factor and its Receptor (c-MET proto-oncogene)

Normally expressed by proximal tubular cells (PCT)

Normal Function

Branching tubulogenesis of developing kidney

Regeneration after renal injury

In vitro mitogenic and morphogenic effects on renal epithelial cells

May also contribute to pathogenesis of RCC

Role of activating mutations of c-MET proto-oncogene in HPRCC is well known

Increased levels are seen in most RCCs, independent of histologic subtype

Its activation (by phosphorylation at two sites) is a/w cancer progression

However, constitutive activation of receptor appears to be primarily limited

to familial papillary RCC only



5. Proteases, Adhesion and ECM

Interactions among cancer cells, adjacent cells and surrounding matrix can stronglyinfluence their pathogenic potential.

Altered intracellular processing and secretion of fibronectin and other matrixproteins is found in RCC (one consequence ofVHL gene mutation)

Proteases (Plasmin and matrix metalloproteinases)

Increased expression correlates with reduced survival

May contribute to aggressive behavior of RCC

Adhesion Molecules (E-cadherin and Cadherin-6)

Normally mediate adhesion between cancer cells

Downregulation correlates with poor outcomes

α-catenins

Cytoplasmic proteins that bind cadherins

Mediate their effects on the cytoskeleton

Aberrant regulation correlates with compromised survival

Sialyl-Lewis X (endothelial leukocyte adhesion molecule-1) and VLA-4 (vascularcell adhesion molecule-1) interactions regulate this process

Pathology

Pathology

Traditionally thought to arise from PCT (clear cell and papillary variants)

However, other histologic subtypes of RCC, such as chromophobe and collecting

duct RCC, are derived from the more distal components of the nephron

Gross

Most RCCs are round to ovoid and circumscribed by a pseudocapsule of compressed

parenchyma and fibrous tissue rather than a true histologic capsule

Most RCCs are not grossly infiltrative (unlike TCC)

Exception = collecting duct RCC and some sarcomatoid variants

Size ~ 4 - 8 cm

Tumors < 3 cm were previously classified as benign adenomas, but some small

tumors have been a/w mets

With exception of oncocytomas and some small (<1 cm) low-grade papillary

adenomas, there are no reliable histologic or ultrastructural criteria to differentiate

benign from malignant renal epithelial tumors

Yellow, tan or brown tumor interspersed with fibrotic, necrotic, or hemorrhagic

areas. Very few are uniform in gross appearance.

Cystic degeneration

Found in 10% to 25%

Appears to be a/w better prognosis (compared with purely solid RCC)

Calcification

Stippled or Plaque-like

10% to 20%

Pathology

HPE

Nuclear features can be highly variable

Grading has been based primarily on nuclear size and shape and the presence or

absence of prominent nucleoli

Fuhrman’s system

Most generally adopted

It is an independent prognostic factor for RCC (clear cell RCC particularly)

Fuhrman’s Classification System for Nuclear Grade in Renal Cell Carcinoma

GRADE NUCLEAR

SIZE

NUCLEAR OUTLINE NUCLEOLI

1 10 mm Round, uniform Absent or inconspicuous

2 15 mm Slightly Irregular

Contours

Small

Visible at 400 x magnification

3 20 mm Moderate to Markedly

Irregular Contours

Prominent

Visible at 100 x magnification

4 >20 mm Bizarre, often

multilobed

Large and Prominent

Heavy chromatin clumps present

Behaviour Aggressive local behavior is common

Frank invasion and perforation of renal capsule, renal sinus, or collecting system ~ 20%

Displacement of these structures is MC

Adjacent organs or abdominal wall spread is # by Gerota fascia

Venous System Involvement

Unique feature of RCC

Found in 10% of RCCs (MC than any other tumor)

MC manifests as a contiguous tumor thrombus extending into IVC or even RA

Many such tumor thrombi are highly vascularized by arterial blood flow

Directly invasion of wall of renal vein or IVC correlates with compromisedprognosis

Most sporadic RCCs are unilateral and unifocal

Bilateral:

Can be synchronous or asynchronous

2 - 4% of sporadic RCCs. MC in familial RCCs

Multicentricity

10% to 20%

MC with papillary histology and familial RCC

Satellite lesions

are often small and difficult to identify by preoperative imaging, IOUS or visual

inspection

main factor contributing to local recurrence after partial nephrectomy

Microsatellite analysis suggests that

There is a clonal origin for multifocal RCC within same kidney

But tumor in C/L kidney is likely to be

An independent growth if it is synchronous

Metastasis if it is asynchronous

Molecular analysis (e.g. - gene expression profiling)

Helps to determine whether an asynchronous tumor is a second primary tumor

or a metastasis

Behaviour

All RCCs by definition are adenocarcinomas derived from renal tubular epithelial

cells

Most RCCs share ultrastructural features with normal PCT cells, such as

Surface microvilli

Complex intracellular junctions

This information applies primarily to clear cell and papillary subtypes.

Other histologic subtypes appear to be derived from more distal elements of

nephron

Histologic Classification


Traditionally, RCC was divided into four histologic subtypes

Clear cell

Granular cell

Tubulopapillary

Sarcomatoid

Newer classification scheme was proposed by Kovacs (1993)

In this system

1. Granular cell tumors were reclassified into other categories based on distinct

histopathologic features

2. Chromophobe RCC was recognized as a new RCC subtype

3. Sarcomatoid features were categorized as variants of other histologic subtypes

rather than a distinct tumor type

Current practice is to identify primary histologic subtype and comment on

presence and extent of sarcomatoid differentiation, although the prognostic

implications have not changed

Depending on well-defined histologic and ultrastructural criteria, granular celltumors were reclassified as papillary RCC, eosinophilic variants of chromophobeRCC, or combined with clear cell RCC

Another important development was the identification of renal medullarycarcinoma that is common in young African-Americans with sickle cell trait

With additional advances in ancillary pathologic studies, including EM, IHC,molecular genetics and cytogenetics, several additional unique subtypes of RCChave been identified since 1993.

Based on these findings, an updated classification of malignant epithelial tumors ofthe kidney was presented by the WHO in 2004

Important changes include

Addition of several RCC subtypes that were previously grouped within“conventional” or unclassified RCC, such as

RCC associated with XP11.2 translocations/TFE3 gene fusions, which hasmicroscopic features of both clear cell and papillary RCC and occurs primarily inchildren and young adults

indolent mucinous tubular and spindle cell carcinoma


WHO Classification 2004Histology Clear Cell RCC (70 – 80 %)

Familial Forms von Hippel-Lindau disease

VHL gene (3p25-26) mutation or hypermethylation

Chromosome 3p deletions

Also, loss of chromosome 8p, 9p, 14q; gain of chromosome 5q

Gross Well-circumscribed, lobulated, golden yellow tumor when bivalved

Necrosis and hemorrhage common

Venous involvement also common

Cystic degeneration

HPE Hypervascular tumor

Network of delicate vascular sinusoids interspersed b/w Nests/ Sheets/ Acini

of clear cells

IHC†: low MWCKs,‡ vimentin, EMA, CA-IX

Other features Originate from PCT

Aggressive behavior more common

Tumor shrinkage common with targeted molecular therapy

May respond to immunotherapy

Clear Cell Renal Cell Carcinoma Formerly known as “conventional” RCC

Microscopic examination can include

Clear cell, granular cell, or mixed types

Clear cells

Round or polygonal with abundant cytoplasm

Contain glycogen, cholesterol, cholesterol esters, and phospholipids, all ofwhich are readily extracted by the solvents used in routine HPE (Hence the clear appearance)

Granular cells

Eosinophilic cytoplasm + abundant mitochondria

Sarcomatoid features 2 to 5 %

More likely to exhibit venous tumor extension than any other subtype

Worse prognosis compared with papillary or chromophobe

Most responders in immunotherapy protocols have had clear cell RCC, and theseprotocols are now being reserved primarily for this population

Clear Cell RCC

Clear cell RCC with typical golden yellow color

Clear Cell RCC

Clear cell RCC with typical golden yellow color and renal sinus fat invasion

Clear Cell RCC

Low-grade clear cell RCC

Delicate vascular network interspersed within homogeneous nests of cells with clear cytoplasm

Low-power view

Clear cell RCC

Deletion of 3p as the only karyotype change

Histology Papillary RCC (10%-15%)

Familial Forms Type 1: HPRCC

Type 2: HLRCC

Activation of c-MET oncogene (7q31-34) by mutation common in HPRCC

but uncommon (~10%) in sporadic cases

Trisomy of chromosome 7 and 17; loss of Y

Gross Fleshy tumor with fibrous pseudocapsule

Necrosis and hemorrhage are common

HPE Hypovascular tumor

Papillary structures with single layer of cells around fibrovascular cores

Type 1: basophilic cells with low-grade nuclei

Type 2: eosinophilic cells with high-grade nuclei

IHC: LMWCKs, CK7 (type 1 > type 2), AMACR

Other features Originate from PCT

Commonly multicentric

Common in ARCD

Type 1: good prognosis Type 2: worse prognosis

WHO Classification 2004

Papillary Renal Cell Carcinoma

These 2 subtypes appear to represent distinct entities

Subclassification into type 1 and type 2 is not routinely practiced

Type 1 papillary RCC Type 2 papillary RCC

MC Less Common

Basophilic cells with scant cytoplasm Eosinophilic cells and abundant granular

cytoplasm

Potentially more aggressive variants

A/w HPRCC syndrome A/w HLRCC syndrome

Better Survival as compared to HLRCC

Sporadic Type I comparison with Sporadic Type

II is NA

Poor Survival as compared to HPRCC

Sporadic Type I comparison with Sporadic Type

II is NA


Aka chromophilic RCC

2nd most common histologic subtype

10% to 15% of all RCCs

More commonly found in patients with ESRD and acquired renal cystic disease

On microscopic examination

Basophilic or eosinophilic cells arranged in papillary or tubular configuration

Previously, > 50 - 75% of tumor had to exhibit such architectural features to

qualify as a papillary RCC

One unique feature of papillary RCC is its tendency toward multicentricity, (~ 40%)


Cytogenetic abnormalities

Trisomy of chromosomes 7 and 17

Loss of theY chromosome

Gain of chromosomes 12, 16, and 20 and loss of heterozygosity on chr 14

VHL mutations are rare

More likely to be hypovascular (lack of VHL mutations)

Activating mutations of the c-MET proto-oncogene (chromosome 7) which encodes

the receptor for hepatocyte growth factor

These mutations have been detected in only ~ 10% of sporadic papillary RCCs


Prognosis: Controversial

Tendency towards low-grade disease

80% are confined to kidney

Recent studies: increased proportion of high-grade and advanced tumors

Although venous tumor thrombus is less common than clear cell RCC, outcomes in

this subgroup are compromised.

Conversely, although lymph node involvement is more common than clear cell

RCC, patients have higher cancer-specific survival at 5 years (65% vs. 19%, P = .03)

At present, most authors believe that papillary RCC, and type 1 papillary RCC in particular,

carry a better prognosis than clear cell RCC when compared grade for grade and stage for

stage


Papillary adenomas

Small (≤5 mm) tumors that resemble papillary RCC

Commonly found at autopsy

Possess many of the same genetic alterations as papillary RCCs

Benign neoplasms

Papillary RCC

Multiple

Small

Mildly enhancing renal tumors

Type 1

Papillary RCC

Basophilic cells with scant cytoplasm

Low-grade nuclei

Microscopic appearance

Type 2

Papillary RCC

Eosinophilic cells with abundant granular cytoplasm

High-grade nuclei

Microscopic appearance

Trisomy 7, 12, 13, 16, 17 and 20 and

deletion of 21 and Y

Histology Chromophobe RCC (3%-5%)

Familial Forms Birt-Hogg-Dubé syndrome

Fumarate hydratase gene

(1q42-43) mutation

Loss of multiple chromosomes (1, 2, 6, 10, 13, 17, 21)

Gross Well-circumscribed, homogeneous

Tan or light brown cut surface

HPE “Plant cells” with pale cytoplasm

Perinuclear clearing or “halo”

Nuclear “raisins”

Prominent cell borders

Positive Hale colloidal iron staining

IHC: diffuse CK7

Other features Originate from intercalated cells of collecting duct

Generally good prognosis

Sarcomatoid variant associated with poor prognosis


Chromophobe Renal Cell Carcinoma

First described by Theones and colleagues in 1985

appears to be derived from the cortical portion of collecting duct

3% to 5% of all RCCs

The tumor cells typically exhibit a relatively transparent cytoplasm with a fine

reticular pattern that has been described as a “plant cell” appearance

The chromophobic nature of this classic variant is responsible for the name of this

histologic subtyp

However, eosinophilic variants of chromophobic RCC have also been described and

constitute about 30% of cases

In either case, a perinuclear clearing or “halo” is typically found and electron microscopic

findings consist of numerous 150- to 300-nm microvesicles, which are the single most

distinctive and defining feature of chromophobe cell carcinoma

These microvesicles characteristically stain positive for Hale colloidal iron, indicating the

presence of a mucopolysaccharide unique to chromophobe RCC


IHC

Stain positive for various cytokeratins

Negative forVimentin

Genetic analysis

Multiple chromosomal losses

MC = whole chromosomes 1, 2, 6, 10, 13, 17, and 21

Flow cytometric analysis: hypodiploid DNA content in most cases

An increased incidence of TP53 mutations

Upregulated expression of the c-KIT oncogene

Commonly seen in Birt-Hogg-Dubé syndrome, but most cases are sporadic


Behaviour

Generally presents at an earlier stage

> 90% of patients remain cancer free for 5 or more years after treatment

Tendency to remain localized despite growth to large size

Predominance of low-grade disease

Better prognosis for localized chromophobe RCC than clear cell RCC

Poor outcome in patients with sarcomatoid features or metastatic disease

In High Grade Disease:

LN and distant metastases are common

Systemic disease is poorly responsive to IL-2

Temsirolimus may have some activity against metastatic chromophobe RCC

(Initial data for Metastatic Non Clear Cell RCC)

Chromophobe

RCC

Well-circumscribed

Homogeneous

Tan tumor

Chromophobe

RCC

Mixture of classic

(chromophobic) and

eosinophilic cells

Characteristic features:

Distinct cytoplasmic

borders

Perinuclear halos

Nuclear “raisins”

The classic variant is

notable for its “plant

cell” appearance

Chromophobe

RCC

Stains positive for Hale

colloidal iron

Demonstrates multiple

microvesicles on

electron microscopy

Histology Multilocular cystic clear cell RCC (uncommon)

Familial Forms Identical to clear cell RCC

Gross Well-circumscribed mass of small and large cysts

HPE Cysts lined by single layer of grade 1 clear cells

No expansive nodules of tumor cells

Other features Almost uniformly benign clinical behavior


Histology Collecting duct carcinoma (<1%)

Familial Forms Unknown

Multiple chromosomal losses

Gross Firm, centrally located tumor with infiltrative borders

Light gray to tan-white

HPE Complex, highly infiltrative cords within inflamed (desmoplastic) stroma

High-grade nuclei, mitoses

Other features Originate from collecting duct

Poor prognosis

May respond to chemotherapy

Collecting Duct Carcinoma

Carcinoma of the collecting ducts of Bellini

Rare (less than 1% of all RCCs)

Younger patients; often in 3rd, 4th or 5th decades of life

Most patients are symptomatic at presentation

Up to 50% have metastatic disease at the time of detection

Ulex europaeus agglutinin 1 reactivity and positivity for E-cadherin and c-KIT help

to distinguish this entity from aggressive papillary RCC, but this staining profile can

also be present in urothelial carcinoma

Expression of high-molecular-weight cytokeratin (HMWCK) was initially believed to

support a collecting duct origin, but more recent studies suggest that this is not a

reliable marker

Small collecting duct carcinomas can arise in a medullary pyramid, but most are

large, infiltrative masses and extension into the cortex is common

Collecting Duct Carcinoma

On microscopic examination

Mixture of dilated tubules and papillary structures typically lined by a single layer

of cuboidal cells, often creating a cobblestone appearance

Genetics

Deletion on chromosome 1q

Monosomy of chromosomes 6, 8, 11, 18, 21, andY

Most cases: high grade, advanced stage and unresponsive to conventional therapies

Reflecting the fact that collecting duct RCC may share features in common with

TCC, some patients with advanced collecting duct RCC have responded to

cisplatin- or gemcitabine -based chemotherapy

Histology Renal medullary carcinoma (rare)

Familial Forms Associated with sickle cell trait

Gross Infiltrative, gray-white

Extensive hemorrhage and necrosis

HPE Poorly differentiated cells with lacelike appearance

Inflammatory infiltrate

Other features Originate from collecting duct

Dismal prognosis


Histology Unclassified RCC (1 - 3%)


Gross Varied

HPE Varied

Other features Origin not defined

Generally poor prognosis

Renal Medullary Carcinoma

Occurs almost exclusively in association with the sickle cell trait.

Diagnosed in young African- Americans

Often in 3rd decade of life

Many cases are both locally-advanced and metastatic at the time of diagnosis

Most patients do not respond to therapy and succumb to their disease in a few to

several months

Mean survival ~ only 15 weeks

Histology

Shares many histologic features with collecting duct carcinoma

Some consider it a subtype of collecting duct carcinoma

Thought to arise from calyceal epithelium near renal papillae but is often highly

infiltrative

The site of origin (renal papillae) and association with sickle cell trait suggest that a

relatively hypoxic environment may contribute to tumorigenesis

Unclassified Renal Cell Carcinoma

<3%

Presumed RCC with indeterminate features even after careful analysis

Poorly differentiated

Highly aggressive biologic behavior

Particularly poor prognosis

Included within this “catch-all” category are RCCs with extensive sarcomatoid

differentiation and no discernible epithelial component.


Histology RCC associated with Xp11.2 translocations/TFE3 gene fusions

(rare)

Familial Forms Various mutations involving chromosome Xp11.2 resulting in TFE3 gene

fusion

Gross Well-circumscribed, tan-yellow tumor

HPE Variable; often clear cells with papillary architecture

IHC: nuclear TFE3

Other features Occur in children and young adults

40% of pediatric RCC

t(X;17) present with advanced stage and follow indolent course

t(X;1) can recur with late lymph node metastases

Xp11 translocation carcinomas


Histology Post-Neuroblastoma RCC (rare)


Gross Well circumscribed

HPE Oncocytic or clear cells with solid and papillary architecture

Other features Occurs exclusively in children with prior Neuroblastoma

Histology Mucinous tubular and spindle cell carcinoma (rare)


Gross Well-circumscribed, tan-white-pink tumors centered in medulla

HPE Mixture of tubules and spindle-shaped epithelial cells; mucin background

Other features Favorable prognosis

Sarcomatoid Differentiation Sarcomatoid differentiation is found in 1% to 5% of RCCs

Most commonly in a/w clear cell RCC or chromophobe RCC

Represent poorly differentiated regions of other histologic subtypes of RCC rather thanindependently derived tumors

A thorough search for epithelial-derived malignant components is almost always fruitful;it is rare to find a truly pure sarcomatoid renal mass. For this reason, it is no longerrecognized as a distinct histologic subtype of RCC.

Characterized by

Spindle cell histology

Positive staining for vimentin

Infiltrative growth pattern

Aggressive local and metastatic behavior

Poor prognosis

Invasion of adjacent organs is common, and median survival is < 1 year

Multimodal approaches should be considered if performance status allows

Extremely poor prognosis with surgery alone

Modestly improved response rates in patients receiving IL-2–based immunotherapy,chemotherapy or targeted molecular therapy after surgery

Clear Cell RCC with

Sarcomatoid

Differentiation

Clear cell RCC with

sarcomatoid

differentiation

Demonstrating

extension into the

perinephric fat

Normal tissue

Tumor

extension into perinephric fat

High-grade RCC with

typical spindle-cell

appearance on the left

indicating a component

of sarcomatoid

differentiation

Clear Cell RCC with

Sarcomatoid

Differentiation

Clinical Presentation

Clinical Presentation

Many renal masses remain asymptomatic and nonpalpable until they are advanced

More than 50% of RCCs are now detected incidentally on routine radiology imaging

Presentation Modes

Incidental

Local Tumor Growth

Hematuria

Flank pain

Abdominal mass

Perirenal hematoma

Metastases

Persistent cough

Bone pain

Cervical lymphadenopathy

Constitutional symptoms

Weight loss/fever/malaise

Obstruction of IVC

Bilateral lower extremity edema

Nonreducing or right-sided varicocele

Paraneoplastic Syndromes

Hypercalcemia

Hypertension

Polycythemia

Stauffer’s syndrome

Classic triad of flank pain, gross hematuria and palpable abdominal mass is nowrarely found

Paraneoplastic syndromes

Found in 20%

RCC was previously referred to as the internist’s tumor because of the predominance ofsystemic rather than local manifestations

Now, a more appropriate name would be the radiologist’s tumor, given thefrequency of incidental detection

Under normal circumstances, the kidney produces 1,25-dihydroxycholecalciferol,renin, erythropoietin, and various prostaglandins, all of which are tightly regulated tomaintain homeostasis

RCC may produce these substances in pathologic amounts, and it may alsoelaborate a variety of other physiologically important factors, such as PTRrP, Lupus-type anticoagulant, hCG, insulin, and various cytokines and inflammatory mediators

These substances are believed to be responsible for the development ofconstitutional symptoms such as weight loss, fever, and anemia as well as some ofthe distinct paraneoplastic syndromes observed with this malignancy


Incidence of Systemic Syndromes Associated with RCC

SYNDROME %

Elevated erythrocyte sedimentation rate 55.6

Hypertension 37.5

Anemia 36.3

Cachexia, weight loss 34.5

Pyrexia 17.2

Abnormal liver function 14.4

Hypercalcemia 4.9

Polycythemia 3.5

Neuromyopathy 3.2

Amyloidosis 2.0



Hypercalcemia

Upto 13% of patients with RCC

Can be due to either paraneoplastic phenomena or osteolytic mets

Etiology

MC = Production of PTHrP

Others = Tumor derived 1,25-dihydroxycholecalciferol and prostaglandins

Expression of PTHrP is suppressed by wildtypeVHL protein,

These peptides may act as potent growth factors for RCC

Patients with RCC who present with hypercalcemia have a compromised prognosis,

with a relative risk of death from cancer progression of 1.78 compared with

patients with normal serum calcium levels

The signs and symptoms of hypercalcemia are often nonspecific and include nausea,

anorexia, fatigue, and decreased deep tendon reflexes.

Medical management

Vigorous hydration followed by diuresis with furosemide

Selective use of bisphosphonates, corticosteroids or calcitonin

Bisphosphonate therapy

is now established as standard of care for patients with hypercalcemia of

malignancy, as long as renal function is adequate

Zoledronic acid, 4 mg intravenously every 4 weeks

Indomethacin has also proved useful in a minority of cases

More definite management includes nephrectomy and occasional

metastasectomy,.

Systemic therapy to reduce the burden of disease is also desirable but difficult

Osteolytic Mets

Hypercalcemia related to extensive osteolytic mets is much more difficult to

palliate because it is not amenable to surgical approaches, but many such patients

may respond to bisphosphonate therapy


Some patients benefit from focused radiation therapy if limited sites of involvement

can be identified

Hypertension

Etiology

Increased production of renin directly by the tumor

Compression or encasement of renal artery or its branches, effectively leading to

renal artery stenosis;

Arteriovenous fistula within tumor

Less common = polycythemia, hypercalcemia, ureteral obstruction, and increased

intracranial pressure associated with cerebral metastases

Polycythemia

Due to increased production of erythropoietin

directly by tumor or by adjacent parenchyma in response to hypoxia induced by

tumor growth


Stauffer Syndrome

Nonmetastatic hepatic dysfunction

3% to 20% of cases

elevated serum alkaline phosphatase ~ 100 %

67% have elevated prothrombin time or hypoalbuminemia

20% to 30% have elevated serum bilirubin or transaminase levels

Other common findings = thrombocytopenia and neutropenia

S/S = fever and weight loss

Many patients have discrete regions of hepatic necrosis

Hepatic mets must be excluded

Biopsy, when indicated, often demonstrates nonspecific hepatitis associated with aprominent lymphocytic infiltrate

Elevated serum IL-6

Hepatic function normalizes after nephrectomy in 60% to 70%

Persistence or recurrence of hepatic dysfunction is almost always indicative of thepresence of viable tumor and thus represents a poor prognostic finding


Other less common paraneoplastic syndromes

Cushing syndrome

Hyperglycemia

Galactorrhea

Neuromyopathy,

Clotting disorders

Cerebellar ataxia

In general, treatment of paraneoplastic syndromes associated with RCC has

required surgical excision or systemic therapy and, except for hypercalcemia,

medical therapies have not proved helpful


Screening and Clinical

Associations

Why it is not done?

The primary factor that limits widespread screening for RCC is relatively low

incidence of RCC in the general population (~ 12/100,000 population/year)

In this setting a screening test must be almost 100% specific to avoid an unacceptably

high false-positive rate

Even if test were 100% sensitive and specific, the yield from screening would be so

low that it would not be cost effective

Even with established risk factors for RCC, such as male sex, increased age, and

heavy tobacco use, generalized screening would be difficult to justify because the

increase in relative risk associated with each of these factors is at best twofold to

threefold

Another confounding factor substantial prevalence of clinically insignificant

tumors such as renal adenomas, which are found at autopsy in 10% to 20%

Studies on use of dipstick analysis for hematuria and USG/CT for screening

supports these conclusions

Urine Screening

Urinalysis is simple and inexpensive, but the yield is exceedingly low

Because small RCCs are often not associated with hematuria (gross or

microscopic) because this is a parenchymal rather than urothelium-based

The incidence of RCC in ultrasound or CT screening studies has ranged from 23 to

300 per 100,000 population

Although the yield of RCC has been higher than expected, it is still relatively low;

and it is unlikely that such efforts would be considered cost effective

Novel molecular assays to detect rcc-related biomarkers in the urine or serum

Microsatellite alterations in the DNA

VHL gene mutations or hypermethylation

Expression of rcc-specific proteins such as CA-9

Upregulation of angiogenic factors, includingVEGF

Proteomic profiling of urine to detect rcc-specific markers also holds much

promise

Target Populations Examples: ESRD and acquired renal cystic disease,TS and familial RCC

ESRD

80% of patients with ESRD develop acquired renal cystic disease (ACKD)

1-2% of this ACKD subgroup develop RCC

Overall, RR of RCC ~ 5-20 fold higher than general population

15% of RCC in the setting of ESRD have mets at presentation and many die of malignant

progression

Problems associated with screening this population

Concerns about short life expectancy

Increased incidence of adenomas (20-40% vs. 10-20% in general population)

Complexity of imaging (given the altered architecture a/w ACKD)

Inevitable cost-related issues

Elevated serum levels ofVEGF in dialysis patients with RCC (potential biomarker)

Renal transplant recipients remain at high risk for RCC in the native kidneys

Recommended: continued periodic radiologic screening even after transplantation

Target Population

Patients with ESRD •Screen only patients with long life expectancy and minimal major

comorbidities.

•Perform periodic ultrasound examination or CT scan beginning

during third year on dialysis

Patients with Known

VHL Syndrome

•Obtain biannual abdominal CT or ultrasound study beginning at age

15 to 20 years.

•Perform periodic clinical and radiographic screening for nonrenal

manifestations.

Relatives of Patients

with VHL

•Obtain genetic analysis.

•If positive, follow screening recommendations for patients with

known von Hippel-Lindau syndrome.

•If negative, less stringent follow-up is required

Relatives of Patients

with Familial RCC

•Obtain periodic ultrasound or CT study and consider genetic

Analysis

Patients with Tuberous

Sclerosis

•Perform periodic screening with ultrasound examination or CT scan

Patients with ADPKD •Routine screening is not justified

Target Population

Tuberous Sclerosis

Autosomal dominant

Epilepsy + Mental Retardation + Adenoma Sebaceum +AML + renal cysts

Increased incidence of RCC

RCC in TS: early onset and multifocal

Gene for TS in humans = TSC2 (Tumor Suppressor gene) (action is analogous to

VHL protein)

Develop RCC at high frequency

Eker rat (mutant for rodent homologue of TSC2 gene)

TSC2- deficient knockout mice

Increased incidence of TSC2 mutations has been found in human RCC

Loss of TSC2 mTOR and HIF-2α–mediated mechanisms upregulated

expression ofVEGF

A reasonable conclusion is that periodic renal imaging should be pursued in TS

Target PopulationADPKD

previously recommended, not now

More recent studies suggest no significantly increased risk

imaging is extremely difficult in this population

Increased incidence of adenomas

VHL

This syndrome should be considered in any patient with early-onset or multifocalRCC or RCC in combination with any of the following: a history of visual orneurologic disorders; a family history of blindness, central nervous system tumors,or renal cancer; or coexistent pancreatic cysts, epididymal lesions, or inner eartumors

Patients suspected of VHL, or appropriate relatives of those with documenteddisease, should strongly consider genetic evaluation

Patients with germline mutations can be identified and offered clinical andradiographic screening identify major manifestations at a presymptomatic phase decreasing associated potential morbidity

National Institutes of Health recommendations:

1. Annual physical examination and ophthalmologic evaluation beginning in infancy

2. Urinary catecholamines at age of 2 years and every 1 to 2 years thereafter

3. MRI of CNS biannually beginning at age of 11 years

4. USG abdomen and pelvis annually beginning at the age of 11 years, followed by

CT every 6 months if cysts or tumors develop

5. Periodic auditory examinations

Individuals who are found to be wild type for both alleles of VHL also benefit because

they can be spared much of the expense and anxiety a/w such intensive surveillance

protocols.

Target Population

Familial RCC

Molecular screening

Individuals at risk =

presence of mutations of the c-MET proto-oncogene or other relevant genetic

alterations

those with suggestive clinical or family histories

Abdominal USG/CT at periodic intervals.

Further testing according to syndrome/system involved

Target Population

Staging

Staging

Until the 1990s, most commonly used staging system was Robson’s modification of

Flocks and Kadesky system.

Limitations of this classification scheme

In stage III, tumors with lymphatic mets (very poor prognostic finding) were

combined with those with venous involvement (treated and potentially cured

with an aggressive surgical approach)

Extent of venous involvement was not delineated

Tumor size, an important prognostic parameter, was not incorporated

The net effect was that the prognostic significance of the various stages was

blunted, with some studies reporting equivalent survival for patients with stage II

and stage III tumors

The TNM system proposed by the Union International Contre le Cancer (UICC)

represented a major improvement because it separated tumors with venous

involvement from those with lymphatic invasion and defined the anatomic extent of

disease more explicitly

Another advantage of the TNM system is that it has facilitated comparison of

clinical and pathologic data from various centers across the globe

In 2009 the American Joint Committee on Cancer (AJCC) proposed a revision of

the TNM system that is now the recommended staging system for RCC

In 1997 the previous division of stages T1 and T2 at tumor size of 2.5 cm was

abandoned because several studies showed no prognostic significance at this level.

Staging

SEER demonstrated survival differences associated with 5, 7.5 and 10-cm cut points

7-cm cut point between stages T1 and T2 was adopted because it reflected the

mean tumor size in the database

In the 2002 version stage T1 was subdivided:

T1a represents tumor size of 4 cm or less

T1b represents tumor size between 4 and 7 cm

Excellent outcomes for patients with small (≤4 cm), unilateral, confined tumors

managed by either partial or radical nephrectomy

The most recent change for organ-confined tumors is a subdivision of T2 tumors:

T2a tumor represents tumors between 7 and 10 cm

T2b represents tumors greater than 10 cm

Staging

Other major revisions in 2009 included a reclassification of tumors with adrenal

metastasis, venous thrombi, and lymphatic involvement

Poor prognosis of adrenal involvement is well documented

Contiguous extension of tumor into ipsilateral adrenal gland is now T4

Metastatic involvement of either adrenal as M1

The favorable prognosis of isolated renal venous thrombi prompted a downgrading

From stage T3b to stage T3a in 2009 version

Finally, lymphatic extension

Previously subdivided based on number of involved nodes

Now been compressed to simplify this aspect

Because prognostic relevance of previous version was not observed

Staging

TNM staging classically is defined by the most advanced feature demonstrated by

the tumor

Important prognostic information can be lost in the process

Many tumors exhibit multiple adverse findings, such as high-level tumor thrombus

along with ipsilateral adrenal involvement

Clinical staging disease begins with a thorough history, physical examination, and

judicious use of laboratory tests

Presentation with systemic symptoms such as significant weight loss (>10% of body

weight), cachexia, or poor performance status all suggest advanced disease, as do

physical examination findings of a palpable mass or lymphadenopathy.

A non-reducing varicocele and lower extremity edema suggest venous involvement.

Abnormal liver function test results, elevated serum alkaline phosphatase or lactate

dehydrogenase level or sedimentation rate, hypercalcemia, and significant anemia

point to the probability of advanced disease

Staging

T: Primary Tumor

TX Primary tumor cannot be assessed

T0 No evidence of primary tumor

T1 Tumor ≤7.0 cm and confined to the kidney

T1a Tumor ≤4.0 cm and confined to the kidney

T1b Tumor >4.0 cm and ≤7.0 cm and confined to the kidney

T2 Tumor >7.0 cm and confined to the kidney

T2a Tumor >7.0 cm and ≤10.0 cm and confined to the kidney

T2b Tumor >10.0 cm and confined to the kidney

T3 Tumor extends into major veins or perinephric tissues but not into the ipsilateral adrenal gland and not beyond the Gerota fascia

T3a Tumor grossly extends into the renal vein or its segmental (muscle containing) branches or tumor invades perirenal and/or renal sinus fat but not beyond the Gerota fascia

T3b Tumor grossly extends into the vena cava below the diaphragm

T3c Tumor grossly extends into the vena cava above the diaphragm or invades the wall of the vena cava

T4 Tumor invades beyond the Gerota fascia (including contiguous extension into the ipsilateral adrenal gland)

Staging

N: Regional Lymph Nodes

NX: Regional lymph nodes cannot be assessed

N0: No regional lymph nodes metastasis

N1: Metastasis in regional lymph node(s)

M: Distant Metastases

MX Distant metastasis cannot be assessed

M0 No distant metastasis

M1 Distant metastasis present

Staging

Radiographic staging of RCC


High-quality abdominal CT

Routine chest radiograph

Selective use of MRI

Other studies as indicated

MRI: For patients with locally advanced malignant disease, equivocal venous

involvement, or allergy to intravenous contrast


Perinephric Fat

CT findings suggestive of extension into perinephric fat

Perinephric stranding (nonspecific)

Distinct soft tissue density within perinephric space (definitive but uncommon)

Overall accuracy of CT/MRI for detection of involvement of perinephric fat is low,

reflecting the fact that extracapsular spread often occurs microscopically

Many of these potentially locally advanced cases are managed with radical

nephrectomy, so the clinical relevance of this imprecision in staging is blunted.

Adrenal involvement

Ipsilateral adrenal involvement can be assessed with reasonable accuracy through a

combination of preoperative CT and intraoperative inspection

Patients at risk for ipsilateral adrenal involvement

1. Enlarged or indistinct adrenal gland on CT

2. Extensive malignant replacement of kidney

3. Palpably abnormal adrenal gland

Should be managed accordingly


Lymph nodes and adjacent organs

Enlarged hilar or retroperitoneal lymph nodes 2 cm or more in diameter on CT

almost always harbour malignant change

This should be confirmed by surgical exploration or percutaneous biopsy if the

patient is not a surgical candidate

Many smaller nodes prove to be inflammatory rather than neoplastic

MRI:

Adds specificity to evaluation of retroperitoneal nodes by distinguishing vascular

structures from lymphatic ones

Still the premier study for evaluation of invasion into adjacent structures and

surgical planning

Obliteration of fat plane between tumor and adjacent organs (e.g., the liver) can

be a misleading finding on CT and should prompt further imaging with MRI

Surgical exploration is often required to make an absolute differentiation.


Venous tumor thrombus

Sensitivities of CT for detection of renal venous tumor thrombus and IVC

involvement are 78% and 96%, respectively

CT findings suggestive of venous involvement include

Venous enlargement, abrupt change in the caliber of the vein, and intraluminal

areas of decreased density or filling defects

The diagnosis is strengthened by demonstration of collateral vessels

Most false-negative findings occur in patients with right-sided tumors in whom the

short length of the vein and the mass effect from the tumor combine to make

detection of the tumor thrombus difficult

MRI is well established as the premier study for the evaluation and staging of IVC

tumor thrombus

MRI and multiplanar CT are equivalent

MRI and multiplanar CT are noninvasive methods that provide reliable information

about both the cephalad and caudal extent of the thrombus and can often

distinguish bland from tumor thrombus


Venous tumor thrombus

Venacavography

For patients with equivocal MRI or CT findings

Who cannot tolerate or have other contraindications to cross-sectional imaging

Transesophageal echocardiography also appears to be accurate for establishing the

cephalad extent of the tumor thrombus, but it is invasive and provides no distinct

advantages over MRI or CT

Doppler ultrasonography is operator dependent and does not provide the anatomic

resolution available with MRI or multiplanar CT


Metastatic evaluation

Should include a routine chest radiograph, careful and systematic review of the

abdominal and pelvic CT or MRI findings, and liver function tests

Bone scintiscan: for patients with elevated alkaline phosphatase/bone pain

Chest CT: for patients with pulmonary symptoms/abnormal chest radiograph

However, patients with locally advanced disease, enlarged retroperitoneal lymph

nodes, or significant comorbid disease may mandate more thorough imaging to rule

out metastatic disease and to aid in treatment planning

Performance status is a powerful predictor of bone metastasis

Patients with good performance status (Eastern Cooperative Oncology Group

performance status score of 0), no evidence of extraosseous metastases, and no

bone pain were at extremely low risk and did not benefit from bone Scintigraphy.

They recommended a bone scintiscan for all other patients, and the incidence of

bone metastasis in this group was above 15%.


Positron emission tomography (PET)

For patients with high risk of metastatic RCC

Good specificity but suboptimal sensitivity

At present its best role is for patients with equivocal findings on conventional

imaging

In this setting an abnormal PET scan may indicate metastatic disease and could

strongly influence further evaluation and management

PET/CT combined with radiolabeled monoclonal antibody to CA-9 is also being

explored in this population for molecular imaging of clear cell RCC

Biopsy of the primary tumor and/or potential metastatic sites is also selectively

required as part of the staging process


Prognosis

Important prognostic factors for cancer-specific survival in patients with localized

RCC include

specific clinical signs or symptoms

tumor-related factors

various laboratory findings

Overall, tumor-related factors such as pathologic stage, tumor size, nuclear grade,

and histologic subtype = independent

Patient-related factors, such as age, CKD, and co-morbidity, have a significant impact

on overall survival

Clinical findings s/o compromised prognosis in presumed localized RCC:

Symptomatic presentation

Weight loss of more than 10% of body weight

Poor performance status

Prognostic factors in RCC


Anemia, thrombocytosis, hypercalcemia, albuminuria, elevated serum alkaline

phosphatase, C-reactive protein, lactate dehydrogenase, or erythrocyte

sedimentation rate, and other paraneoplastic signs or symptoms have also

correlated with poor outcomes

Abnormal values are more common in patients with advanced RCC

Independent predictors of cancer-specific mortality in localized clear cell RCC

Hypercalcemia

Anemia

Elevated erythrocyte sedimentation rate

Pathologic stage

Single most important prognostic factor

5-year survival rates

70% to 90% for organ-confined disease

15% to 20% reduction in survival associated with invasion of perinephric fat


Pathologic stage (contd)

Renal sinus involvement is classified along with perinephric fat invasion as T3a

These patients may be at even higher risk for metastasis related to increasedaccess to the venous system

Collecting system invasion has also been shown to confer poorer prognosis inotherwise organ-confined RCC

Most patients with direct or metastatic ipsilateral adrenal involvement, which isfound in 1% to 2% of cases, eventually succumb to systemic disease progression,suggesting a hematogenous route of dissemination or a highly invasive phenotype

The most recent staging system now reclassifies tumor as T4 if there is directinvasion of the adrenal gland or otherwise as M1, to reflect this poor prognosis

Venous involvement was once thought to be a very poor prognostic finding.Many patients can be salvaged with an aggressive surgical approach.

45% to 69% 5-year survival rates for patients with venous tumor thrombi as longas the tumor is otherwise confined to the kidney

84% 5-year survival in tumor thrombus limited to the main renal vein and tumorotherwise confined to the kidney



Patients with venous tumor thrombi and concomitant lymph node or systemic

metastases have markedly decreased survival, and those with tumor extending

into the perinephric fat have intermediate survival

The prognostic significance of the cephalad extent of tumor thrombus has been

controversial

Incidence of advanced locoregional or systemic disease increased with the

cephalad extent of the tumor thrombus, accounting for the reduced survival

associated with tumor thrombus extending into or above the level of the hepatic

veins

Cephalad extent of tumor thrombus is not of prognostic significance as long as

the tumor is otherwise confined

Direct invasion of the wall of the vein appears to be a more important prognostic

factor than level of tumor thrombus and is now classified as pT3c independent of the

level of tumor thrombus



The major drop in prognosis when tumor extends beyond Gerota fascia to

involve contiguous organs (stage T4)

Rarely associated with 5-year survival

Lymph node involvement (Poor sign)

5 yr SR = 5 - 30%

10 yr SR = 0 – 5%

Systemic metastases (poor prognosis)

1-year survival of less than 50%

5-year survival of 5% to 30%

10-year survival of 0% to 5%,

Synchronous metastases = worse. Patients die of disease progression in a year

In patients with asynchronous metastases, mets-free interval = useful

prognosticator because it reflects the tempo of disease progression


Other important prognostic factors for systemic mets

Performance status, number and sites of metastases, anemia, hypercalcemia,

elevated alkaline phosphatase or lactate dehydrogenase levels, thrombocytosis,

and sarcomatoid histology

The presence of bone, brain, and/or liver metastases, and multiple metastatic

sites further compromise in prognosis

These factors have been used to effectively categorize patients with metastatic

RCC as low, intermediate, and poor risk, with corresponding differences in

median survival

These risk groups provide important information for determining the likelihood

of benefit a patient may expect to receive after cytoreductive nephrectomy

and/or resection of other metastatic disease.


Tumor Size

Another significant prognostic factor

independent prognostic factor for both organ-confined and invasive RCC

5-year survival rates

84% for patients with tumor diameter less than 5 cm

50% for tumors between 5 and 10 cm

0% for tumors more than 10 cm in diameter.

Larger tumors more likely to exhibit clear cell histology + high nuclear grade

Favorable prognosis for unilateral pT1a tumors

Such tumors are associated with > 95% 5-year cancer-specific survival rates,

whether they were managed with nephron-sparing surgery or radical

nephrectomy


Nuclear grade, histologic subtype and symptomatic presentation

Several grading systems

Interobserver variability is common

No ideal classification system

Nuclear grade has proved in most cases to be an independent prognostic factor

Fuhrman’s classification system (MC adopted system)

5-year survival rates for grades 1 to 4 = 64%, 34%, 31%, and 10%, respectively

Nuclear grade = most significant prognostic factor for organ-confined tumors

Subsequent reports have demonstrated correlations between Fuhrman’s

nuclear grade and tumor stage, tumor size, venous tumor thrombi, and lymph

node and systemic metastases


Histologic subtype

Also carries prognostic significance

The presence of sarcomatoid differentiation or collecting duct, renal medullary,

or unclassified histologic subtype denotes a poor prognosis

Several studies now suggest that clear cell RCC may have a worse prognosis on

average compared with papillary or chromophobe RCC

Several subtypes of RCC are predictably indolent, including multiloculated cystic

clear cell RCC and mucinous tubular and spindle cell carcinoma.


For patients with clinically localized disease, mode of presentation (incidental vs.

symptomatic) can be combined with other predictive elements to better stratify

patients after primary surgical management

In addition, patients with systemic symptoms suggestive of metastatic spread have

significantly poorer outcomes than those with only local symptoms, such as

hematuria or flank pain

Dozens of genes that may have prognostic or therapeutic significance for patients

with RCC have been identified

Gene expression profiling (cDNA microarrays) can quantify the levels of thousands

of individual messenger RNA transcripts within an individual tumor sample.

Alterations in gene expression can then be correlated with the amount and location

of specific gene products (proteins) using immunohistochemical staining of cancer

specimens

Construction of tissue microarrays can facilitate the screening of hundreds of

tumors, but interpretation of results can be challenging due to tumor heterogeneity

and the selection of only a small amount of tissue for analysis


Molecular markers

Independent prognostic factors for RCC

CA-IX, which is regulated by the VHL gene and overexpressed in most clear cell

RCCs

Although initial studies indicated that decreased expression of CA-IX is

independently associated with poorer survival in patients with metastatic RCC

this association does not appear to apply for patients with localized disease

CA-IX also may serve as a marker for response to systemic therapy

B7-H1 a strong independent predictor of disease progression for RCC

Increased proliferative index as assessed by Ki-67 has also been correlated with

reduced survival in clear cell RCC

Although initial data indicated that Ki-67 expression was a surrogate for

histologic necrosis, more recent studies have found Ki-67 to be an independent

predictor and have incorporated it into predictive algorithms


Molecular markers (contd.)

Other factors that appear to be useful include

Cell cycle regulators, such as the tumor suppressor TP53

Growth factors and their receptors, including members of the VEGF family

adhesion molecules

Survivin


Nomograms

Tools that combine various prognostic factors and predict survival

Kattans Nomogram

Kattan and colleagues (2001) have combined

Manner of presentation (incidental vs. local or systemic symptoms),

Tumor histology

Tumor size

Pathologic stage

Predicts cancer-free survival after nephrectomy

Tumor grade was not included (role for non– clear cell RCC not clearlydefined)

Subsequent analysis focused only on patients with clear cell RCC

incorporated tumor grade, assessment of tumor necrosis, and vascularinvasion to further improve prognostication

Several predictive algorithms incorporate histologic necrosis but the utility ofthis predictor has been called into question


Pantuck and colleagues (2001a)

Integrated analysis of prognostic factors for all stages of RCC

revealed three independent prognostic factors that were most robust for

predicting outcomes

TNM stage,

Performance status

Tumor grade

UCLA integrated staging system (UISS) was subsequently modified to identify

patients with localized or metastatic disease at low, intermediate, and high risk of

disease progression and has been validated internally and externally

Molecular factors such as TP53, Ki-67, VEGF family members, and CA-IX have

also been incorporated into UISS-based algorithms to predict outcomes for

patients with localized or metastatic RCC


SSIGN Score

Another predominant model that provides individualized information for

patients with clear cell RCC is the SSIGN score, which incorporates 1997 TNM

stage, tumor size, nuclear grade, and presence of tumor necrosis to predict

recurrence and survival after radical nephrectomy

BioScore

Most recently, the group at Mayo Clinic has developed a sequential approach in

which the predicted outcomes for patients at various risk of recurrence

according to clinical and pathologic factors can be further stratified based on

molecular data incorporated into a BioScore

The expression of B7-H1, survivin and Ki-67 each added independent predictive

ability after accounting for either the UISS or SSIGN score, especially for

patients at intermediate or high risk of recurrence


Education

Malignant Renal Tumors Part One