PEComas

the

past

the

present

and

the

future

The

perivascular

epithelioid

cell

-LRB-

PEC

-RRB-

is

a

cell

type

constantly

present

in

a

group

of

tumors

called

PEComas

PEC

expresses

myogenic

and

melanocytic

markers

such

as

and

actin

Recently

recurrent

chromosomal

alterations

have

been

demonstrated

in

PEC

At

present

PEComa

is

a

widely

accepted

entity

In

the

past

years

the

use

of

this

term

has

allowed

to

report

and

describe

numerous

cases

permitting

to

start

highlighting

the

biology

of

this

group

of

lesions

PEComas

are

related

to

the

genetic

alterations

of

tuberous

sclerosis

complex

-LRB-

TSC

-RRB-

an

autosomal

dominant

genetic

disease

due

to

losses

of

-LRB-

-RRB-

or

-LRB-

-RRB-

genes

which

seem

to

have

a

role

in

the

regulation

of

the

pathway

There

are

some

open

questions

about

PEComas

regarding

its

histogenesis

the

definition

of

epithelioid

angiomyolipoma

and

the

identification

of

the

histological

criteria

of

malignancy

An

innovative

therapeutic

trial

using

rapamycin

is

under

way

for

tumors

occurring

in

TSC

such

as

renal

angiomyolipoma

and

lymphangioleiomyomatosis

Its

success

could

provide

the

rationale

for

the

use

of

the

same

drug

in

other

lesions

composed

of

PECs

especially

in

the

malignant

ones

What

is

the

perivascular

epithelioid

cell

The

perivascular

epithelioid

cell

-LRB-

PEC

-RRB-

-LRB-

Fig.

-RRB-

is

a

cell

type

constantly

present

in

a

group

of

tumors

including

angiomyolipoma

-LRB-

AML

-RRB-

clear-cell

sugar

tumor

-LRB-

CCST

-RRB-

of

the

lung

and

extrapulmonary

sites

lymphangioleiomyomatosis

clear-cell

myomelanocytic

tumor

of

the

falciform

ligament/ligamentum

teres

and

rare

clear-cell

tumors

of

other

anatomical

sites

Fig.

angiomyolipoma

perivascular

epithelioid

cells

arranged

around

a

blood

vessel

H&E

It

has

morphologic

immunohistochemical

ultrastructural

and

genetic

distinctive

features

such

as

an

epithelioid

appearance

with

a

clear

to

granular

cytoplasm

a

round

to

oval

centrally

located

nucleus

and

an

inconspicuous

nucleolus

PEC

has

mild

to

any

atypia

and

a

typical

perivascular

location

-LSB-

-RSB-

At

present

PEC

has

not

a

known

normal

counterpart

Immunohistochemically

PEC

expresses

myogenic

and

melanocytic

markers

such

as

microophtalmia

transcription

factor

-LRB-

Mitf

-RRB-

actin

and

less

commonly

desmin

-LSB-

-RSB-

Its

immunoreactivity

for

vimentin

is

usually

incospicuous

At

ultrastructural

analysis

PEC

contains

microfilament

bundles

with

electron-dense

condensation

numerous

mithocondria

and

membrane-bound

dense

granules

-LSB-

-RSB-

It

is

thought

that

PEC

can

modulate

its

morphology

and

immunophenotype

given

all

the

characteristics

described

above

-LRB-

Fig.

-RRB-

PEC

can

show

muscular

features

with

a

spindle

shape

and

a

stronger

positivity

for

actin

than

for

or

it

can

have

an

epithelioid

feature

with

a

strong

positivity

for

and

a

mild

if

any

reaction

for

actin

-LRB-

Fig.

-RRB-

PEC

can

also

become

vacuolized

acquiring

the

feature

of

an

adipocyte

Progesterone

receptor

positivity

has

been

described

in

PEC

with

spindle

morphology

this

suggests

a

possible

role

of

progesterone

in

this

morphologic

modulation

-LSB-

-RSB-

Fig.

demonstrating

the

modulation

of

morphology

and

immunophenotye

of

PECsFig

angiomyolipoma

strong

granular

immunoreactivity

in

perivascular

epithelioid

cells

Recently

recurrent

chromosomal

alterations

have

been

demonstrated

in

PEC

-LSB-

-RSB-

What

is

a

PEComa

The

World

Health

Organization

defines

PEComa

as

a

mesenchymal

tumor

composed

of

histologically

and

immunohistochemically

distinctive

perivascular

epithelioid

cells

-LSB-

-RSB-

At

present

this

neoplasm

is

a

widely

accepted

entity

However

some

authors

cast

doubts

on

the

existence

of

PEComa

as

a

distinctive

tumor

particularly

as

regards

the

uterine

ones

that

they

view

as

leiomyosarcoma

with

aberrant

expression

of

-LSB-

-RSB-

Although

we

understand

their

perplexity

we

would

like

to

underline

some

points

First

it

has

been

demonstrated

that

there

are

different

gene

expression

profiles

among

uterine

smooth

muscle

tumors

demonstrating

their

heterogeneity

-LSB-

-RSB-

Second

we

think

that

it

is

difficult

to

explain

in

uterine

smooth

muscle

neoplasms

both

and

Mitf

positivity

as

an

aberrant

expression

or

antibody

crossreactivity

involving

both

antigens

-LSB-

-RSB-

Third

we

think

that

the

absence

of

a

recognized

normal

counterpart

for

PEC

is

not

a

sufficient

reason

to

reject

the

concept

of

PEComa

in

fact

there

are

other

well-accepted

soft-tissue

neoplasms

such

as

alveolar

soft-part

sarcoma

and

epithelioid

sarcoma

that

still

have

not

a

known

normal

counterpart

Some

authors

have

questioned

about

the

use

of

the

term

PEComa

They

consider

it

ambiguous

because

it

is

not

clear

whether

this

term

should

be

restricted

to

purely

epithelioid

tumors

as

CCST

or

whether

the

term

should

be

more

broadly

applied

to

include

AML

and

lymphangioleiomyomatosis

-LSB-

-RSB-

We

believe

that

AML

CCST

and

pulmonary

lymphangioleiomyomatosis

are

composed

of

PECs

in

different

stages

of

modulation

and

these

lesions

together

with

clear-cell

myomelanocytic

tumor

of

the

falciform

ligament/ligamentum

teres

belong

to

the

same

family

of

tumors

the

PEComas

Nevertheless

we

think

that

it

is

better

to

continue

to

name

some

of

them

-LRB-

i.e.

AML

and

pulmonary

lymphangioleiomyomatosis

-RRB-

also

with

their

established

names

which

identify

their

clinical

and

morphological

aspects

and

are

well

known

by

clinicians

and

pathologists

-LSB-

-RSB-

Moreover

in

the

past

years

the

use

of

the

term

PEComa

has

permitted

to

report

and

describe

numerous

cases

with

the

morphological

and

immunohistochemical

features

of

this

tumor

permitting

to

start

to

understand

the

biology

of

this

group

of

lesions

PEC

and

tuberous

sclerosis

PEComas

are

related

to

the

tuberous

sclerosis

complex

-LRB-

TSC

-RRB-

or

better

to

the

genetic

alterations

of

TSC

an

autosomal

dominant

genetic

disease

due

to

losses

of

-LRB-

-RRB-

or

-LRB-

-RRB-

genes

-LSB-

-RSB-

and

characterized

by

mental

retardation

seizures

and

cellular

proliferations

-LRB-

AMLs

subependymal

giant

cell

tumors

cutaneous

angiofibromas

cardiac

rabdomyomas

lymphangioleiomyomatosis

pulmonary

multifocal

micronodular

hyperplasia

-RRB-

Similar

alterations

of

the

TSC

genes

have

been

demonstrated

in

a

significant

number

of

PEComas

both

occurring

within

the

TSC

and

in

sporadic

cases

In

recent

years

great

advances

have

been

made

in

our

knowledge

of

TSC

and

related

lesions

In

particular

TSC

genes

seem

to

have

an

important

role

in

the

regulation

of

the

pathway

-LSB-

-RSB-

Kenerson

et

al.

-LSB-

-RSB-

have

recently

demonstrated

increased

levels

of

a

marker

of

mTOR

activity

in

sporadic

AMLs

The

associated

reduced

phospho-AKT

expression

is

consistent

with

the

disruption

of

function

Similar

findings

were

obtained

analysing

extrarenal

PEComas

PEComa

the

past

PEC

was

first

described

in

by

Apitz

-LSB-

-RSB-

as

an

abnormal

myoblast

in

renal

AML

as

reported

by

Masson

-LSB-

-RSB-

in

his

famous

book

The

idea

of

a

possible

link

between

AML

and

other

two

lesions

CCST

and

lymphangioleiomyomatosis

came

from

the

fact

that

the

same

epithelioid

cell

was

observed

in

them

Moreover

this

cell

was

in

all

three

lesions

-LSB-

-RSB-

Later

ultrastructural

examination

revealed

the

presence

of

premelanosomes

both

in

CCSTs

of

the

lung

and

in

epithelioid

clear-cell

component

of

renal

and

hepatic

AMLs

-LSB-

-RSB-

In

addition

the

possibility

of

a

relationship

between

AML

and

lymphangioleiomyomatosis

was

suggested

by

the

fact

that

both

occur

in

TSC

-LSB-

-RSB-

We

proposed

that

CCST

should

be

also

included

in

this

syndrome

-LSB-

-RSB-

and

the

first

description

of

this

tumor

in

a

patient

with

TSC

confirmed

this

idea

-LSB-

-RSB-

In

we

described

the

first

case

of

pancreatic

CCST

and

suggested

the

name

PEComa

for

neoplasms

composed

of

a

pure

proliferation

of

PECs

-LSB-

-RSB-

Moreover

the

fact

that

the

same

clear

epithelioid

cell

composing

pulmonary

sugar

tumor

was

present

in

AML

and

was

the

only

component

of

some

small

renal

microhamartoma

-LRB-

Fig.

-RRB-

suggested

to

us

the

idea

of

the

existence

of

a

monotypic

epithelioid

AML

of

the

kidney

We

looked

for

them

and

we

found

them

-LSB-

-RSB-

Fig.

microhamartoma

completely

composed

of

perivascular

epithelioid

cells

H&E

PEComa

the

present

PEComas

have

been

described

in

different

organs

and

are

considered

ubiquitous

tumors

Kidney

PEComas

of

the

kidney

include

classic

AML

microscopic

AML

-LRB-

so-called

microhamartoma

-RRB-

intraglomerular

lesions

cystic

AML

epithelioid

AML

oncocytoma-like

AML

and

lymphangiomyomatosis

of

the

renal

sinus

Classic

angiomyolipoma

is

the

most

common

mesenchymal

tumor

of

the

kidney

Being

composed

of

a

variable

mixture

of

adipose

tissue

and

spindle

and

epithelioid

smooth

muscle

cells

mixed

together

with

abnormal

thick-walled

blood

vessels

AML

is

the

prototype

of

the

capacity

of

PEC

to

modulate

its

morphology

-LSB-

-RSB-

For

a

long

time

AML

has

been

considered

a

hamartoma

rather

than

a

true

neoplasm

but

at

present

its

clonal

nature

has

been

demonstrated

-LSB-

-RSB-

In

patients

with

TSC

renal

AMLs

are

found

in

both

sexes

in

the

third

and

fourth

decades

of

life

with

a

female

predominance

they

are

usually

asymptomatic

bilateral

small

and

multifocal

Sporadic

AMLs

occur

in

older

patients

in

the

fourth

to

sixth

decades

of

life

with

a

female

predominance

they

are

single

unilateral

and

larger

than

those

associated

with

TSC

-LSB-

-RSB-

Classic

AML

contains

more

than

one

cell

type

if

a

particular

cell

type

predominates

AML

is

consequently

named

-LRB-

lipoma-like

AML

or

leiomyoma-like

AML

-RRB-

-LSB-

-RSB-

Classic

AML

has

a

benign

outcome

Multifocality

and

regional

lymph

node

involvement

can

occur

and

this

is

considered

to

represent

a

multifocal

growth

pattern

rather

than

a

metastasis

-LSB-

-RSB-

Three

cases

of

sarcoma

developing

in

sporadic

AML

have

been

reported

Similar

cases

have

not

been

described

in

TSC

patients

-LSB-

-RSB-

Both

inherited

and

sporadic

AML

frequently

demonstrates

loss

of

heterozigosity

of

chromosome

-LRB-

containing

the

locus

-RRB-

The

gene

occasionally

shows

loss

of

heterozigosity

-LSB-

-RSB-

Microscopic

angiomyolipomas

-LRB-

so-called

microhamartomas

-RRB-

They

are

small

nodules

often

present

in

a

kidney

with

an

AML

They

are

not

homogeneous

in

appearance

and

display

all

the

heterogeneous

morphologic

aspects

of

AML

microscopic

AMLs

do

not

contain

thick-walled

blood

vessels

-LSB-

-RSB-

Intraglomerular

lesions

with

similar

features

of

AML

have

been

reported

in

patients

with

and

without

tuberous

sclerosis

and

in

the

contiguous

gene

syndrome

a

disease

with

a

deletion

disrupting

both

and

-LRB-

autosomal

dominant

polycystic

disease

gene

-RRB-

-LSB-

-RSB-

Cystic

angiomyolipoma

is

a

recently

described

variant

of

AML

-LSB-

-RSB-

It

is

a

solid-cystic

lesion

that

microscopically

is

composed

of

epithelial

cysts

lined

by

cuboidal

to

hobnail

cells

positive

for

cytokeratin

a

compact

subepithelial

cambium-like

layer

of

stromal

cells

positive

for

Melan-A

estrogen

and

progesterone

receptors

and

a

solid

extracystic

component

with

the

morphology

of

a

muscle-predominant

-LRB-

Fig.

-RRB-

AML

which

is

positive

for

estrogen

and

progesterone

receptors

smooth

muscle

actin

and

desmin

and

which

is

associated

with

irregular

blood

vessels

Some

authors

think

that

the

subepithelial

cambium-like

layer

is

a

manifestation

of

a

mullerian

differentiation

of

PEC

If

the

epithelial

cysts

represent

entrapped

renal

tubular

epithelium

-LSB-

-RSB-

or

are

also

related

to

PEC

is

unknown

Fig.

angiomyolipoma

strong

positivity

for

actin

in

the

solid

extracystic

component

SM

ACT

of

the

cases

described

to

date

had

a

history

of

TSC

-LSB-

-RSB-

Epithelioid

angiomyolipoma

is

another

recently

described

variant

of

AML

It

is

composed

of

purely

epithelioid

cells

with

melanogenesis

markers

immunoreactivity

arranged

in

sheets

Both

adipocytes

and

abnormal

blood

vessels

are

not

present

The

cytoplasm

of

the

neoplastic

cells

varies

from

faintly

eosinophilic

to

clear

Tumor

cells

can

display

considerable

nuclear

atypia

and

necrosis

can

be

present

This

tumor

can

recur

locally

and

metastasise

causing

death

On

the

basis

of

histology

alone

it

is

not

possible

to

predict

malignant

behaviour

in

these

neoplasms

and

further

data

are

needed

to

better

define

it

However

at

the

present

time

all

epithelioid

AMLs

should

be

closely

followed

clinically

Epithelioid

AMLs

has

been

described

in

patient

with

or

without

evidence

of

TSC

and

in

the

contiguous

gene

syndrome.Loss

of

heterozigosity

of

have

been

reported

in

some

cases

of

sporadic

epithelioid

AML

-LSB-

-RSB-

Oncocytoma-like

angiomyolipomas

are

tumors

composed

of

a

homogeneous

population

of

polygonal

cells

with

strongly

eosinophilic

cytoplasm

They

have

been

described

in

patients

with

and

without

TSC

Recognition

of

this

variant

is

important

because

oncocytomas

in

the

same

kidney

with

AMLs

have

been

reported

repeatedly

and

in

patients

with

TSC

oncocytomas

seem

to

occur

more

frequently

than

in

general

population

-LSB-

-RSB-

Lymphangiomyomatosis

of

the

renal

sinus

is

a

plaque-like

mass

in

the

wall

of

the

renal

pelvis

All

three

cases

reported

to

date

also

had

renal

AMLs

but

in

only

one

of

them

careful

postmortem

examination

of

the

lungs

revealed

pulmonary

lymphangiomyomatosis

-LSB-

-RSB-

Bladder

and

prostate

In

Pan

et

al.

-LSB-

-RSB-

have

reported

two

PEComas

of

the

genitourinary

tract

in

patients

without

TSC

Both

tumors

were

composed

of

a

variable

percentage

of

epithelioid

and

spindle

cells

with

clear

to

granular

cytoplasm

arranged

in

nests

separated

by

a

vascular

stroma

Neoplastic

cells

were

positive

for

but

not

for

epithelial

markers

vimentin

and

protein

The

prostatic

tumor

-LRB-

Fig.

-RRB-

showed

a

low

mitotic

activity

coagulative

necrosis

and

a

malignant

behaviour

whereas

the

neoplasm

of

the

bladder

-LRB-

Fig.

-RRB-

lacking

these

histologic

findings

behaved

in

a

benign

fashion

Another

case

of

primary

PEComa

of

the

bladder

has

recently

been

described

also

in

this

case

the

patient

is

well

and

alive

at

months

after

surgery

-LSB-

-RSB-

Fig.

PEComa

composed

of

epithelioid

cells

with

clear

cytoplasm

arranged

in

nests

H&E

PEComa

composed

of

epithelioid

cells

with

clear

cytoplasm

arranged

in

nests

H&E

Finally

Weinreb

et

al.

-LSB-

-RSB-

have

recently

described

a

case

of

PEComa

of

the

urachal

cyst

composed

of

pleomorphic

cells

and

containing

necrosis

and

a

high

mitotic

activity

In

this

case

they

also

found

a

peculiar

aspect

that

they

named

pecosis

remote

from

the

tumor

there

were

isolated

capillaries

surrounded

by

a

single

layer

of

clear

cells

Uterus

The

first

case

of

PEC

tumor

of

the

uterus

was

reported

by

Pea

et

al.

-LSB-

-RSB-

it

was

a

polypoid

neoplasm

involving

the

endometrium

which

showed

morphological

features

overlapping

those

of

the

CCST

of

the

lung

-LRB-

Fig.

-RRB-

Fig.

PEComa

composed

of

epithelioid

cells

with

a

clear

cytoplasm

and

well-defined

cell

borders

H&E

Vang

and

Kempson

-LSB-

-RSB-

described

eight

cases

of

uterine

PEC

tumor

-LRB-

PEComa

-RRB-

They

distinguished

a

morphologic

spectrum

of

neoplasms

varying

from

tumors

with

a

tongue-like

growth

pattern

composed

of

sheets

of

clear

epithelioid

cells

which

they

called

group

A

to

circumscribed

tumors

composed

of

hyalinized

stroma

and

neoplastic

cells

focally

positive

for

and

extensively

immunoreactive

for

actin

and

desmin

which

they

refer

to

as

group

B

In

two

of

these

eight

cases

pelvic

lymph

nodes

contained

lymphangiomyomatosis

Lesions

considered

to

be

uterine

involvement

of

lymphangioleiomyomatosis

are

usually

asymptomatic

and

some

of

them

correspond

to

an

incidental

finding

in

patients

with

TSC

PEComas

of

the

uterus

have

usually

shown

benign

behaviour

but

tumors

of

them

associated

with

TSC

were

aggressive

-LSB-

-RSB-

In

two

of

six

uterine

PEComas

described

by

Folpe

et

al.

-LSB-

-RSB-

patients

have

metastases

and

one

of

six

patients

died

of

PEComa

Fadare

et

al.

-LSB-

-RSB-

described

a

case

of

uterine

PEComa

in

a

patient

with

TSC

in

which

there

was

intra-abdominal

PEComatosis

surgeon

found

small

foci

of

epithelioid

cells

in

the

lamina

propria

of

the

small

intestine

myometrium

and

ovarian

hilum

Ovary

vulva

and

vagina

A

tumor

with

a

strong

and

diffuse

expression

morphologically

corresponding

to

an

epithelioid

angiomyolipoma

has

been

reported

in

the

ovary

-LSB-

-RSB-

Tazelaar

et

al.

-LSB-

-RSB-

reported

a

case

described

as

primary

extrapulmonary

clear-cell

sugar

tumor

of

the

vulva

Finally

cases

of

vaginal

PEComa

have

also

been

described

-LSB-

-RSB-

Lung

PEComas

of

the

lung

include

lymphangioleiomyomatosis

and

clear-cell

sugar

tumor

Lymphangioleiomyomatosis

-LRB-

LAM

-RRB-

-LRB-

Fig.

-RRB-

is

a

rare

and

progressive

disease

that

affects

the

lungs

of

women

usually

in

premenopausal

age

occasionally

it

can

be

extrapulmonary

-LRB-

as

described

above

-RRB-

It

consists

of

a

nodular

often

widespread

and

bilateral

interstitial

proliferation

of

actin

and

desmin-positive

smooth

muscle

cells

which

can

vary

from

small

spindle-shaped

cells

to

large

epithelioid

cells

usually

arranged

around

thin-walled

branching

vascular

channels

this

proliferation

is

associated

with

dilated

lymphatics

and

cystic

changes

-LSB-

-RSB-

Fig.

lymphangioleiomyomatosis

composed

of

epithelioid

cells

arranged

around

a

vascular

channel

H&E

LAM

is

usually

sporadic

patients

with

TSC

are

frequently

afflicted

In

many

cases

of

LAM

there

is

a

slow

progression

to

pulmonary

failure

and

the

only

therapy

is

lung

transplantation

In

no-transplanted

patient

there

is

a

median

survival

of

years

-LSB-

-RSB-

CCST

-LRB-

Fig.

-RRB-

was

originally

described

in

the

lung

-LSB-

-RSB-

It

is

a

rare

and

benign

neoplasm

composed

of

a

uniform

population

of

round-to-polygonal

epithelioid

cells

with

a

clear

or

eosinophilic

cytoplasm

and

well-defined

cell

borders

Tumor

cells

are

surrounded

by

prominent

and

thin-walled

vascular

channels

CCST

has

a

nested

or

alveolar

appearance

We

have

also

observed

adipocytic

cells

in

a

few

cases

of

CCST

-LSB-

-RSB-

Tumor

cells

are

positive

for

-LRB-

Fig.

-RRB-

-LSB-

-RSB-

Fig.

clear-cell

sugar

tumor

composed

of

epithelioid

cells

with

a

clear

cytoplasm

and

well-defined

cell

borders

A

prominent

and

vascular

channel

is

present

H&E

clear-cell

sugar

tumor

immunoreactivity

in

tumor

cells

Pulmonary

CCST

is

rarely

associated

with

TSC

-LSB-

-RSB-

in

the

vast

majority

of

cases

it

is

a

sporadic

lesion

Pancreas

PEComa

of

the

pancreas

was

reported

for

the

first

time

in

by

Zamboni

et

al.

-LSB-

-RSB-

It

was

actually

the

first

time

that

the

very

term

PEC

was

introduced

-LRB-

Fig.

-RRB-

Fig.

clear-cell

sugar

tumor

this

tumor

has

overlapping

features

of

the

clear-cell

sugar

tumor

of

the

lung

epithelioid

cells

with

a

clear

cytoplasm

and

with

a

nested

or

appearance

H&E

The

paper

reported

a

tumor

with

overlapping

features

of

the

benign

clear-cell

sugar

tumor

of

the

lung

This

finding

was

in

our

opinion

consistent

with

the

hypothesis

that

similar

tumors

could

possibly

arise

in

many

if

not

all

locations

Thus

the

term

PEComa

was

introduced

to

include

all

similar

lesions

arising

outside

the

lung

At

the

time

we

believed

this

to

be

a

unique

case

However

in

the

following

years

we

have

observed

other

two

cases

of

PEComa

of

the

pancreas

with

overlapping

morphological

phenotypical

and

clinical

features

Thus

while

still

a

very

rare

disease

of

the

pancreas

PEComa

is

not

an

extraordinary

finding

in

this

location

The

clinical

aspects

of

PEComa

of

the

pancreas

are

interesting

because

they

are

discovered

incidentally

during

echography

of

the

abdomen

and

then

investigated

usually

with

cyto-aspiration

The

observation

of

clear

epithelioid

cells

can

understandably

lead

to

the

wrong

diagnosis

of

clear-cell

carcinoma

of

the

pancreas

and

thus

lead

to

duodenocephalopancreasectomy

A

primary

angiomyolipoma

of

the

pancreas

has

also

been

described

It

was

a

cephalopancreatic

nodule

in

a

non-TSC

woman

-LSB-

-RSB-

Liver

Apart

from

kidney

liver

is

the

most

likely

organ

involved

by

angiomyolipoma

-LRB-

Fig.

-RRB-

either

classic

or

epithelioid

-LSB-

-RSB-

Frequently

hepatic

AML

shows

a

prominent

component

of

large

epithelioid

cells

-LSB-

-RSB-

There

has

also

been

described

a

case

of

CCST

of

the

common

bile

duct

-LSB-

-RSB-

Fig.

angiomyolipoma

solid

component

made

of

large

epithelioid

cells

H&E

Other

sites

Lymphangioleiomyomatosis

has

also

been

reported

in

extrapulmonary

sites

including

mediastinal

and

retroperitoneal

lymph

nodes

soft

tissue

of

the

mesentery

and

the

renal

sinus

as

previously

described

Usually

extrapulmonary

LAM

presents

as

a

localized

well-circumscribed

mass

called

lymphangiomyoma

-LSB-

-RSB-

Apart

from

kidney

and

liver

classic

or

even

epithelioid

angiomyolipoma

can

occur

in

different

visceral

and

somatic

sites

as

gastrointestinal

tract

pelvis

-LSB-

-RSB-

nasal

cavity

-LSB-

-RSB-

soft

tissues

-LSB-

-RSB-

retroperitoneum

-LSB-

-RSB-

bone

-LSB-

-RSB-

and

orbit

-LSB-

-RSB-

Clear-cell

sugar

tumor

has

been

described

in

a

variety

of

extrapulmonary

sites

apart

from

uterus

and

pancreas

skin

-LSB-

-RSB-

soft

tissues

-LSB-

-RSB-

breast

-LSB-

-RSB-

skull

base

-LSB-

-RSB-

gastrointestinal

tract

-LSB-

-RSB-

inter-atrial

cardiac

septum

-LSB-

-RSB-

and

oral

mucosa

-LSB-

-RSB-

Clear-cell

myomelanocytic

tumour

of

the

falciform

ligament/ligamentum

teres

-LRB-

CCMMT

-RRB-

is

a

PEComa

showing

predominantly

spindled

cell

morphology

It

has

been

first

described

in

by

Folpe

et

al.

-LSB-

-RSB-

who

presented

seven

cases

of

PEComa

arising

in

the

abdomen

All

patients

but

one

were

women

ranging

from

to

years

of

age

These

neoplasms

were

composed

of

spindle

cells

arranged

in

fascicles

and

nests

positive

for

and

in

three

cases

also

for

Melan-A

microophtalmia

transcription

factor

-LRB-

Mitf

-RRB-

and

actin

Also

in

these

cases

premelanosomes

were

ultrastructurally

detected

At

follow-up

in

one

patient

presumed

lung

metastasis

developed

CCMMT

has

also

been

described

in

thigh

-LSB-

-RSB-

and

in

the

skin

-LSB-

-RSB-

PEComa

the

future

PEComas

are

a

group

of

ubiquitous

neoplasms

sharing

morphological

immunohistochemical

ultrastructural

and

genetic

distinctive

features

There

are

some

open

questions

about

PEComas

the

histogenesis

and

the

normal/physiological

counterpart

of

PEC

the

definition

of

epithelioid

AML

and

the

identification

of

the

histological

criteria

of

malignancy

The

histogenesis

and

the

normal/physiological

counterpart

of

PEC

are

unknown

but

some

hypotheses

have

been

proposed

One

hypothesis

is

that

PEC

derives

from

undifferentiated

cells

of

the

neural

crest

that

can

express

dual

smooth

muscle

and

melanocytic

phenotype

a

second

hypothesis

is

that

PEC

has

a

myoblastic

smooth

muscle

origin

with

a

molecular

alteration

that

brings

to

expression

of

melanogenesis

and

melanocytic

markers

-LSB-

-RSB-

a

third

hypothesis

is

that

PEC

has

a

pericytic

origin

As

regards

PEComa

's

histogenesis

the

involvement

of

TSC

pathway

in

these

neoplasms

can

suggest

some

possibilities

it

has

been

previously

proposed

that

B-raf

activity

in

cells

lacking

may

play

a

role

in

cell

differentiation

-LSB-

-RSB-

Moreover

TSC

pathway

regulates

negatively

Wnt/beta-catenin

pathway

-LSB-

-RSB-

and

beta-catenin

regulates

transcription

of

genes

involved

in

cell

proliferation

and

differentiation

Nevertheless

more

cases

should

be

analysed

to

better

understand

PEC

origin

and

PEComa

's

histogenesis

The

second

issue

regarding

PEComas

is

which

cases

should

be

classified

as

epithelioid

AML

particularly

in

the

kidney

and

liver

where

AML

occurs

with

higher

frequency

We

defined

epithelioid

AML

as

a

neoplasm

composed

of

purely

epithelioid

cells

with

melanogenesis

markers

immunoreactivity

arranged

in

sheets

without

adipocytes

and

abnormal

blood

vessels

However

in

otherwise

classic

AML

areas

of

epithelioid

cells

can

be

observed

raising

the

question

how

much

they

should

be

represented

to

call

a

tumor

epithelioid

angiomyolipoma

The

collection

of

such

cases

and

a

consensus

meeting

could

be

useful

tools

to

answer

to

this

problem

Malignant

PEComa

can

be

a

very

aggressive

disease

leading

to

multiple

metastases

and

death

as

expected

with

a

high-grade

sarcoma

-LSB-

-RSB-

A

few

malignant

PEComas

metastasised

after

several

years

-LRB-

years

-RRB-

-LSB-

-RSB-

-LRB-

Table

-RRB-

Table

cases

of

malignant

PEComas

in

literatureReferenceDiagnosisSiteSex/ageOutcomeCommentsSale

and

Kulander

-LSB-

-RSB-

CCSTLungn.a

n.a.AWD

at

yearsHepatic

metastases

at

yearsFerry

et

al.

-LSB-

-RSB-

Epithelioid

at

months

Al-Saleem

et

al.

-LSB-

-RSB-

Epithelioid

at

months

Pea

et

al.

-LSB-

-RSB-

Epithelioid

at

yearPelvic

and

hepatic

metastasesPea

et

al.

-LSB-

-RSB-

Epithelioid

at

monthsPulmonary

and

hepatic

metastasesChristiano

et

al.

-LSB-

-RSB-

Epithelioid

at

months

L'Hostis

et

al.

-LSB-

-RSB-

Epithelioid

at

years

Folpe

et

al.

-LSB-

-RSB-

PEComaLigamentum

teres

falciform

at

yearRadiographically

suspected

lung

metastasis

at

monthsMartignoni

et

al.

-LSB-

-RSB-

Epithelioid

at

yearsLocal

recurrence

at

years

pulmonary

pelvic

and

abdominal

metastases

at

yearsBonetti

et

al.

-LSB-

-RSB-

at

monthsOvarian

mass

at

presentationBonetti

et

al.

-LSB-

-RSB-

at

monthsAggressive

local

recurrence

at

month

lung

and

bone

metastases

at

monthsBonetti

et

al.

-LSB-

-RSB-

PEComaTerminal

ileum

and

at

monthsHepatic

metastasisCibas

et

al.

-LSB-

-RSB-

Epithelioid

at

months

Saito

et

al.

-LSB-

-RSB-

at

yearRetroperitoneal

recurrence

at

monthsYamamoto

et

al.

-LSB-

-RSB-

Epithelioid

with

spinal

lung

and

lymph

node

metastases

-LRB-

autopsy

case

-RRB-

Dimmler

et

al.

-LSB-

-RSB-

at

yearsLung

metastasesGreene

et

al.

-LSB-

-RSB-

PEComaUterus

and

pelvic

side

at

several

monthsPelvic

and

mesenteric

recurrence

at

yearsLau

et

al.

-LSB-

-RSB-

Epithelioid

at

yearsLiver

metastases

at

years

thymus

and

lung

metastases

at

yearsLeclerc

et

al.

-LSB-

-RSB-

Epithelioid

node

metastasesLin

et

al.

-LSB-

-RSB-

Epithelioid

AMLKidneyn.a

and

lymph

node

metastasesOng

et

al.

-LSB-

-RSB-

Epithelioid

metastasesPan

et

al.

-LSB-

-RSB-

at

yearsSubmitted

to

adjuvant

chemotherapy

lung

metastases

at

yearsTakahashi

et

al.

-LSB-

-RSB-

Epithelioid

at

monthsSubmitted

to

adjuvant

chemotherapy

pulmonary

metastasesTakahashi

et

al.

-LSB-

-RSB-

Epithelioid

at

monthsSplenic

and

retroperitoneal

metastases

at

years

hepatic

metastases

at

monthsYanai

et

al.

-LSB-

-RSB-

at

monthsPelvic

wall

recurrence/local

metastases

at

months

ovarian

metastases

at

monthsDarai

et

al.

-LSB-

-RSB-

Epithelioid

AMLUrachF/n

a.AWDLymph

node

metastasesHarris

et

al.

-LSB-

-RSB-

PEComaSoft

tissue

near

at

monthsInguinal

lymph

node

and

lung

metastases

at

monthsLehman

-LSB-

-RSB-

PEComaSkull

at

monthsParaspinal

and

lung

metastasis

at

weeksBosincu

et

al.

-LSB-

-RSB-

at

yearPelvic

recurrence

at

monthsEvert

et

al.

-LSB-

-RSB-

PEComaRectovaginal

metastases

at

presentationFolpe

et

al.

-LSB-

-RSB-

at

monthsRe-excision

and

submitted

to

adjuvant

radiotherapyFolpe

et

al.

-LSB-

-RSB-

at

monthsRe-excision

and

submitted

to

adjuvant

radiotherapyFolpe

et

al.

-LSB-

-RSB-

PEComaBroad

at

monthsRe-excisedFolpe

et

al.

-LSB-

-RSB-

PEComaFalciform

at

monthsRe-excisedFolpe

et

al.

-LSB-

-RSB-

at

yearsSubmitted

to

adjuvant

radio

and

chemotherapy

lung

and

bone

metastasesFolpe

et

al.

-LSB-

-RSB-

PEComaPelvic

soft

at

monthsLocal

recurrenceFolpe

et

al.

-LSB-

-RSB-

at

monthsExtensive

intra-abdominal

recurrence/local

metastasesFolpe

et

al.

-LSB-

-RSB-

at

monthsSubmitted

to

adjuvant

chemotherapy

liver

and

lung

metastases

at

monthsFolpe

et

al.

-LSB-

-RSB-

at

monthsSubmitted

to

adjuvant

chemotherapy

extensive

intra-abdominal

recurrence

and

liver

metastases

at

monthsFolpe

et

al.

-LSB-

-RSB-

at

monthsSubmitted

to

adjuvant

chemotherapy

lung

metastases

at

months

and

liver

metastases

at

monthsSvec

and

Velenska

-LSB-

-RSB-

Epithelioid

at

monthsRecurrence

at

monthsYu

et

al.

-LSB-

-RSB-

Epithelioid

at

monthsLymph

node

metastases

submitted

to

adjuvant

chemotherapyAgaimy

and

Wünsch

-LSB-

-RSB-

at

monthsAbdomino-pelvic

recurrenceKim

et

al.

-LSB-

-RSB-

CCMTBroad

at

yearIliac

fossa

recurrenceMai

and

Belanger

-LSB-

-RSB-

at

yearPulmonary

and

brain

metastasesMai

and

Belanger

-LSB-

-RSB-

at

yearPulmonary

metastasesMai

and

Belanger

-LSB-

-RSB-

at

yearsLymph

node

metastasesParfitt

et

al.

-LSB-

-RSB-

at

yearsHepatic

recurrence

and

pulmonary

pancreatic

and

muscular

metastases

at

years

bladder

metastases

at

yearsParfitt

et

al.

-LSB-

-RSB-

PEComaLung/Adrenal

metastases

at

several

mothsYamamoto

et

al.

-LSB-

-RSB-

at

monthsPeritoneal

dissemination

at

monthsGupta

et

al.

-LSB-

-RSB-

Epithelioid

at

yearHepatic

and

rib

metastasesHuang

et

al.

-LSB-

-RSB-

Epithelioid

at

months

Park

et

al.

-LSB-

-RSB-

Epithelioid

at

monthsHepatic

and

peritoneal

metastasesPark

et

al.

-LSB-

-RSB-

Epithelioid

at

monthsHepatic

and

lymph

node

metastasesWeinreb

et

al.

-LSB-

-RSB-

and

lung

metastasesANED

Alive

not

evidence

of

disease

AWD

alive

with

disease

DOC

dead

of

other

causes

DOD

dead

of

disease

n.a.

not

available

Recently

Folpe

et

al.

-LSB-

-RSB-

reported

cases

of

PEComas

of

soft

tissue

and

gynaecologic

origin

proposing

criteria

for

the

classification

of

these

tumors

as

benign

of

uncertain

malignant

potential

and

malignant

In

this

study

they

observed

a

significant

association

between

tumor

size

cm

infiltrative

growth

pattern

high

nuclear

grade

necrosis

and

mitotic

activity

HPF

and

subsequent

aggressive

clinical

behaviour

of

PEComas

We

think

that

this

approach

is

the

best

available

at

the

moment

While

more

cases

with

long

follow-up

are

needed

to

verify

the

effectiveness

of

this

prognostic

classification

we

believe

that

all

cases

of

PEComa

should

be

classified

according

to

the

criteria

proposed

by

Folpe

et

al.

Another

future

challenge

regarding

PEComas

is

their

management

Surgery

seems

to

be

the

only

approach

for

aggressive

cases

as

chemio

and

radiotherapy

has

not

shown

significant

results

However

this

derives

from

anecdotical

cases

as

no

therapeutic

trial

has

so

far

been

implemented

There

are

obvious

difficulties

to

perform

a

therapeutic

trial

mainly

due

to

the

rarity

of

the

disease

An

international

cooperative

study

is

needed

to

address

this

problem

A

very

different

problem

is

posed

by

lymphangioleyomyomatosis

In

fact

lymphangioleyomyomatosis

is

composed

of

a

population

of

cells

with

no

atypia

Mitotic

activity

is

virtually

absent

or

extremely

low

In

spite

of

this

the

disease

usually

progresses

inexorably

towards

lung-function

impairment

Recently

Kenerson

et

al.

-LSB-

-RSB-

demonstrated

inactivation

and

m-TOR

hyperactivation

in

non-TSC

AMLs

and

in

extrarenal

PEComas

using

immunohistochemistry

and

Western

blot

analysis

In

particular

m-TOR

hyperactivation

can

be

studied

in

such

lesions

using

immunohistochemical

detection

of

As

we

have

previously

mentioned

is

a

protein

kinase

activated

by

m-TOR

Immunohistochemical

reaction

for

can

stain

both

which

gives

a

cytoplasmic

signal

-LRB-

Fig.

-RRB-

and

a

second

isoform

of

kinase

which

is

also

activated

by

m-TOR

and

which

gives

a

nuclear

signal

Fig.

angiomyolipoma

cytoplasmic

signal

in

immunohistochemical

reaction

for

Rapamycin

is

a

specific

inhibitor

of

m-TOR

-LSB-

-RSB-

which

is

approved

by

the

US

Food

and

Drug

Administration

for

immunosuppression

therapy

after

renal

transplant

-LSB-

-RSB-

and

it

has

recently

been

approved

also

for

therapy

of

renal

cell

carcinomas

and

acute

myeloid

leukemia

-LSB-

-RSB-

Preclinical

studies

in

animal

models

of

TSC

have

shown

significant

in

vivo

response

to

rapamycin

-LSB-

-RSB-

As

regards

LAM

an

innovative

therapeutic

trial

is

under

way

Rapamycin

seems

to

block

signaling

through

the

Akt

cell

growth

and

survival

pathway

-LRB-

for

up-to-date

information

see

-RRB-

A

similar

trial

has

already

shown

a

positive

effect

on

renal

AML

and

we

can

hope

to

see

the

same

effect

on

LAM

If

this

will

be

the

case

this

could

provide

the

rationale

for

the

use

of

the

same

drug

in

other

lesions

composed

of

PECs

O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O B O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

pecoma
pec
angiomyolipoma
lymphangioleiomyomatosis
sugar tumor
tsc
mtor
rapamycin