DR.KAZEMINEZHAD Associate professor of - PowerPoint Presentation

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DR.KAZEMINEZHADAssociate professor of Shahid Beheshti university Modarres Hospital

Updates in Pathologic

Staging and Histologic

Grading of Renal

Cell Carcinoma

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Renal cell carcinoma (RCC) ninth and fourteenth most common cancer in American men and women, respectivelythe most lethal of genitourinary tumorsa

collection

of diverse

tumors believed to recapitulate the phenotypes

of several parts of the

nephron

Each with

distinct histologic and genetic features.

in

contrast to many other

invasive cancers

often

spherical with subtle tongue-like

extensions into

renal veins

renal sinus

Perinephric tissue

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often without desmoplastic or destructive infiltrative responseWith advancement in imaging techniques, a majority of renal masses now present incidentally.Clinical and pathologic staging of RCC revised to reflect this changing

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Cancer staging in general :Tumor characteristics to stratify patients into clinically meaningful and prognostically relevant categories.predict survival, metastases, and

pattern of disease

recurrence

easy

to

reference and

nearly uniformly adopted

prognostic tool

a

common

language for

treatment, prognostication, and

publication purposes

important

to

weigh treatment

options, like nephron-sparing

surgery versus

radical

nephrectomy

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The AJCC TNM system is the most recent and commonly used staging system.The 8th edition of AJCC staging system defines TNM as:local extension of the primary tumor (T)tumor size

and its

extension into neighboring structures

involvement

of

regional lymph

nodes (N

)

presence

of distant

metastasis (M)

Currently

, most

RCC presents

in the localized stage (65

%)

16% having

regional lymph node

spread

16%

having distant metastases

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TUMOR SIZEMost oncological staging systems based on:size and anatomic extent of diseaseRenal sinus invasion,

vein invasion

, perinephric

fat

invasion

, tumor

thrombus

,

can

potentially upstage cases

S

urvival

is decreased by a factor of 3.5 when

the tumor

size is

doubled

b

ecause

7 cm seems

predictive of

poor

outcomes

More

than 90% of clear cell RCCs greater than or equal to 7

cm

invade the renal sinus increases the tumor to pT3a

Size

greater than 10 cm is classified as pT2b

Almost

all of these tumors found to have renal sinus, vein, or perinephric invasion with careful

sampling

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Tumor size is generally measured in the fresh gross pathologic specimen.There may be some variability between radiologic and pathologic tumor measurements.maximum tumor diameter by imaging 12.1

% greater than the measurement in

fresh specimens

, which, in turn, was 4.6% larger

than

formalin-fixed

specimens

Tumor

size recorded

after bisecting the specimen

along the

long

axis

preferably

in a plane through

either the

venous or collecting system, and

measuring the

greatest dimension of the tumor with a ruler

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The distance of tumor reaching beyond the kidney into perinephric tissue and the renal sinus is by convention included in this measurementRenal vein or vena cava tumor extension is excluded from the measurement.

When

multiple tumors are

present:

ISUP

guidelines

recommend sampling and

measuring at

least the 5 largest

tumors

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RENAL SINUS INVASIONlocated between the pelvicalyceal system and renal parenchymacontains the main lymphovascular

supply of the

kidney

Themost

critical step of RCC pathologic

staging:

tumor

is limited to the

kidney or

invades the perinephric fat, renal veins,

or the

renal

sinus

based

on

decreased cancer-specific

survival in patients with renal

sinus invasion

The

8th edition of AJCC TNM staging

system classifies

the presence of renal sinus

invasion as pT3a

This

has been added to the

pT

category since

the 2002 revision of the TNM

classification

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Renal sinus invasion potentially:subtle and significant interobserver variabilitysinus fat or vascular invasion may go undiagnosed if aggressive search is not undertaken and that this may have significant prognostic

implications.

In the AJCC 8th edition staging

manual:

renal sinus and

perinephric fat infiltration continue to

be considered

under same category (pT3a

)

there

is some evidence that

may

be a

difference in

prognosis between the

two

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Authors’ experience is that in clear cell RCC, perinephric fat invasion alone is uncommon in the absence of vein branch or renal sinus invasion.In larger tumors with equivocal vascular invasion on gross examination, extensive sampling or the entire renal sinus interface should be strongly considered, particularly for tumors larger

than 5

cm

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Renal sinus invasion can include direct invasion or LVI within

the renal

sinus

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SEGMENTAL RENAL VEIN BRANCH AND MAIN RENAL VEIN INVASIONRCC, especially clear cell RCC, has a predilection for intravenous growth in the form of so called tumor thrombus

finger-like

outpouching

or extension

into veins or vein

branches

in

4% to 10% of newly

diagnosed patients

The

8th edition of AJCC

classifies segmental

or main renal vein invasion as pT3a.

This was changed from pT3b in AJCC 6th

edition

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In previous editions of AJCC TNM stagingdemonstration of muscle in segmental veins was required, as was identification of vein invasion by Gross examinationThe AJCC 8th edition has removed the phrase, “muscle-containing,”

diameter

of sinus veins or the

presence or

absence of muscle in sinus veins

is a

poor indicator of the involved

vein segment

or its relationship to main renal vein.

The word, “grossly,” has also been

removed

whenever

renal vein

invasion is

present, it is always visible

grossly

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Early vein branch invasion

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INFERIOR VENA CAVA TUMOR INVOLVEMENTTumor can extend to inferior vena cava (IVC) superiorly up to the right atrium of the heartWhen this tumor does not invade the venous wall it

can

sometimes be retracted back from this

location and

resected with the

specimen

P

rognostic

importance of the cranial extent

of IVC

thrombus is

debated

Risk

of recurrence of RCC is increased if there is

tumor thrombus

versus no tumor

thrombus

Cancer-specific

survival of

localized RCC

was similar to patients with

subdiaphragmatic

extension

of tumor

thrombus

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Supradiaphragmatic extension associated with a significantly worse survival The 8th edition of AJCC

classifies:

Subdiaphragmatic

extension

of IVC tumor as

pT3b

Extension above

the level of diaphragm is classified

as pT3c

Because tumor invading the wall of the IVC is categorized together with

supradiaphragmatic

involvement as pT3c, it is important to also evaluate for wall invasion

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If IVC specimen sent for histopathologic examinationapproach is to search for vein wall tissue within or adherent to the tumor correlate histologic findings with the clinical

impression of

adherence to vein wall

overall

interpretation of pT3c stage

category

If

it is not clear whether IVC tissue

is included

part of the pathologic specimen, but

if surgical

impression is of extension into

the lumen (pT3b)

with

comment that IVC involvement is based

on clinical

findings.

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Finger like extension of a clear cell RCC tumor shows extension

in a

polypoid fashion

into the

venous system

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RETROGRADE VENOUS INVASIONTumor may grow in a retrograde fashion into the proximal of the renal veinEspecially when the main

renal vein

is occluded by the tumor

thrombus

May

lead to growth of cortical nodules

in noncontiguous

areas, separate from the

original tumor

Can

be a cause of misinterpretation of

tumor as

multifocal or of larger

size

if

the

intravenous spread

is not recognized as

such

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In contrast, true multifocal clear cell RCC was quite rareAny case of clear cell RCC with satellite lesions should be approached with cautionConsidering possibility that these may

represent:

hereditary syndrome

(such as von Hippel–Lindau

disease

intravenous spread

a variant mimicking

clear cell RCC, especially clear

cell papillary RCC

Although In

the AJCC 8th edition staging of

RCC:

retrograde venous

invasion is

not considered differently from vein

invasion

important to prevent misdiagnosis of multifocal or lower stage

(but

larger

)

RCC

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Retrograde venous invasion is principally diagnosed at gross

examination

satellite

tumor nodules

adjacent to

a main mass

in

locations

that conform

to the normal venous outflow of

kidney

(between

renal pyramids or at the

corticomedullary

junction)

Microscopic

confirmation:

l

ocation

relationship

to

veins

evidence

of preexisting

vein

Retrograde venous invasion

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RENAL VEIN OR INFERIOR VENA CAVAMARGINRCC tumors are often present within blood vessels as finger-like extensionssometimes be to a level at which the vessel can be transected andthe tumor removed, without transecting the tumor.

Combining

retracted back

tumor by

a surgeon

with artifacts of specimen

fixation and

vascular clipping or stapling by the

surgeon

it

is not unusual to encounter RCC specimens

for which

tumor is extending beyond the renal

vein margin or tumor

thrombus

extends close

to the vein margin

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Approach in this situation is:dissect the distal-most vein rim (if freely mobilef rom the tumor) and examine it microscopically to verify that no tumor is adherent to it

amputate

the distal-most section of

vein wall

containing tumor, to verify in the

histologic section

that the tumor is not

microscopically adherent

to the vein

wall

In

either of these

approaches, if

the tumor is

not adherent to,

or Invading the

vein

wall

interpret the vein

margin as negative

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Renal vein margin

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LYMPHOVASCULAR INVASIONRCC can have microvascular invasionpresence of tumor within the microscopic blood vessels or lymphatics AJCC 8th edition

mention

significance

of

LVI

:

p

redicting

cancer-specific

survival and disease-specific

survival

but

not

specifically included in

staging

system

.

It is recommended to report LVI whenever present

The incidence of LVI may differ from older literature, with more recent literature on this subject

usingmarkers

like

podoplanin

ISUP recommendations also note that any

LVI within

the renal sinus should be classified as renal sinus invasion (pT3a)

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LVI not necessarily alter the pathologic tumor

stage category

, unless it is

present in

the renal sinus

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PERINEPHRIC FAT INVASIONAJCC 8th edition again includes perinephric fat invasion in the pT3a stage categoryperinephric fat invasion is uncommon in the absence of venous or renal sinus invasion

in clear cell

RCC

The criteria for this includes

tumor cells in

contact with

fat or irregular tongues or nodules into

the perinephric

tissue

with

or

without

desmoplasia

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Perinephric fat invasion in clear cell RCC is less common in

the absence

of renal sinus

or renal

vein invasion

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In theory renal sinus provide increased opportunity for tumor dissemination compared with the perinephric:renal capsule more of a barrier to extrarenal spread than the renal sinus

renal

sinus

contains

abundant veins and

lymphatics

The

patients with renal sinus invasion 63% more likely to die of RCC compared with perinephric fat invasion

prognostic significance of perinephric fat involvement in small size tumors

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Tumors can bulge well beyond the normal contour of the kidney and this bulge remains encapsulated by a layer of normal or atrophic kidney tissueStrong agreement (90%) that a

spherical mass

bulging well into the perinephric

tissue did

not necessarily constitute perinephric fat

invasion, especially

if a layer of compressed

normal structures

could be appreciated

microscopically surrounding

the

tumor

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RENAL CAPSULE INVASIONRenal capsule is tough fibrous membrane surrounding the renal parenchyma and located below the adipose tissue or perirenal fat

RCC tumors

also

often surrounded by

a

pseudocapsule

at the interface with the renal

parenchyma

Renal

capsule

invasion defined as

presence

of tumor cells

within fibrous

renal capsule yet without

perirenal

fat

tissue

infiltration

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The significance of renal capsule invasion has been debatedSome studies showing impact on recurrenceRenal capsule invasion was significantly associated with an increased risk of recurrenceThe AJCC 8th edition does not include any specific categories for renal capsule invasion

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RENAL PELVIS INVASIONRenal pelvis invasion by RCC is uncommon Not been specifically addressed in prior AJCC systemsThe 8th edition added to the pT3a

category

Tumor invades

the

renal pelvis

would have likely extended through

other structures such

as renal sinus in most

cases

extension

to the tip

of medullary

papilla

leads

to renal pelvis extension

without involving

the renal

sinus

Prognosis for pelvis invasion is still considered debatable

.

Decreased survival

rates for tumors with renal pelvis

invasion

Both capsular invasion and pelvis/

pelvicalyceal

system invasion have significant impact on recurrence-free survival

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ADRENAL GLAND INVOLVEMENTIn modern surgical practice adrenal gland resected only if imaging or intraoperative findings suspect involvementAdrenal

gland

involvement by renal cancer

:

direct(invasion

) or indirect (

metastasis)

e

very attempt should

be made on gross examination

As in

previous

editions, the

AJCC 8th edition staging system

continues classify:

direct

adrenal gland invasion

as pT4

in

contrast to indirect invasion (a

metastatic nodule

) as

pM1

Direct

adrenal gland

invasion is rare with

an incidence of only 2.5

%

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LYMPH NODES7% to 17% of RCC tumors have hilar or locoregional lymph node metastases, including caval and aortic lymph

nodes

In

current

practice, dissection

is generally considered

unnecessary in

patients with clinically

negative lymph nodes

it

offers extremely

limited staging

information

and survival

or disease

recurrence

Dissection

is more frequently performed

:

younger

patients

locally

advanced

disease

cases

of open

surgery

Previously

, the

N category

has been divided on the basis on

size of

involved lymph

nodes

in

further

revisions reduced

to 2 categories only (

positive and

negative

)

Slide43

palpation and dissection emphasizing hilar area specifically is sufficientRandom histologic sections of fat that does not contain grossly appreciable lymph nodes not necessary

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HISTOLOGIC GRADINGThe Fuhrman grading system replaced with the modified ISUP grading systememphasis in tumor grade on the nucleolar

prominence

particularly

whether the nucleoli are

prominent at

100 magnification (10

microscope objective

) or only at higher magnification

ornot

at all, to distinguish grades 1 to

3

leaves

grade 4, including tumors with

extreme nuclear

pleomorphism

multinucleated giant cells

s

arcomatoid

feature

rhabdoid

feature

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GRADE 1GRADE 2

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GRADE3GRADE 4

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TUMOR NECROSISPotentially important prognostic parameterCombined grading scheme includes both the tumor histologic grade and presence or absence of necrosis:

grade

1: ISUP grade 1 and ISUP grade 2

without necrosis

grade

2: ISUP grade 2 with

necrosis and

ISUP grade 3 without

necrosis

grade 3:ISUP

grade 3 with necrosis and ISUP grade

4 without necrosis

grade

4: ISUP grade 4

with necrosis

or

sarcomatoid

/

rhabdoid

tumors

There

was

a significant difference in survival rates between each of the grades for clear cell RCC

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Similar results were not obtained for papillary RCC or chromophobe RCCOverall this system has not gained widespread use at present.Current recommendations:grade based on nucleolar

prominence

report presence

or absence of

necrosis

use the ISUP

system for clear cell, papillary, and

other RCCs

,

not

to use it for

chromophobe

RCC

inherent

cytologic

atypia but

often nonaggressive behavior

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