Distinguishing

benign

notochordal

cell

tumors

from

vertebral

chordoma

Objective

The

objective

was

to

characterize

imaging

findings

of

benign

notochordal

cell

tumors

-LRB-

BNCTs

-RRB-

Introduction

The

giant

notochordal

rest

and

notochordal

hamartoma

are

terms

that

have

been

used

to

describe

a

benign

notochordal

cell

tumor

-LRB-

BNCT

-RRB-

that

may

be

mistaken

for

a

chordoma

-LSB-

-RSB-

This

recently

discovered

intraosseous

benign

lesion

of

notochordal

cell

origin

may

be

a

potential

precursor

of

chordoma

-LSB-

-RSB-

but

based

on

the

few

cases

with

long-term

follow-up

-LRB-

those

previously

published

and

our

present

series

-RRB-

has

clinically

grown

to

become

a

chordoma

The

anatomical

predilection

is

identical

to

that

of

chordoma

The

most

common

locations

are

the

sacro-coccygeal

region

and

the

base

of

the

skull

followed

by

cervical

and

lumbar

vertebrae

Most

tumors

are

usually

small

and

asymptomatic

and

are

often

found

at

autopsy

The

occasional

lesion

may

become

large

and

can

be

detected

on

advanced

imaging

Our

working

group

collected

cases

of

BNCT

that

were

detected

on

imaging

We

report

on

their

management

outcomes

and

histology

Five

patients

underwent

surgical

management

based

on

a

misdiagnosis

of

chordoma

and

failure

to

recognize

the

entity

of

BNCT

This

paper

focuses

on

the

clinical

radiological

and

histological

features

of

these

cases

which

get

overtreated

when

misdiagnosed

Materials

and

methods

The

data

came

from

patients

with

BNCTs

that

were

found

clinically

Clinical

records

included

patient

sex

age

presenting

symptoms

and

anatomic

site

involved

All

formalin-fixed

specimens

were

decalcified

with

formic

acid

solution

and

then

routinely

processed

for

hematoxylin-eosin

and

periodic

acid

Schiff

-LRB-

PAS

-RRB-

staining

For

immunohistochemical

study

paraffin-embedded

specimens

were

cut

into

to

sections

and

then

mounted

on

glass

slides

coated

with

The

sections

were

stained

by

the

streptavidin-biotin-peroxidase

method

-LRB-

Nichirei

Tokyo

Japan

-RRB-

The

antibodies

used

are

listed

in

Table

Microwave

antigen

retrieval

was

carried

out

prior

to

immunostaining

with

vimentin

CAM

and

cytokeratin

-LRB-

CK

-RRB-

To

determine

the

specificity

of

immunostaining

we

included

known

positive

and

negative

tissues

as

controls

Table

used

in

the

studyAntibodiesSourceClonalityDilutionEpithelial

membrane

antigenDAKO

Cytomation

Glostrup

-LRB-

-RRB-

DAKO

Cytomation

Glostrup

-LRB-

-RRB-

Becton

Dickinson

San

Jose

CA

Cytomation

Glostrup

Cytomation

Glostrup

proteinNichirei

Tokyo

monoclonal

P

polyclonal

Results

Table

summarizes

ages

symptoms

treatment

and

outcomes

of

the

patients

with

BNCTs

that

were

found

clinically

-LRB-

Figs.

-RRB-

Two

lesions

were

documented

as

possible

vertebral

osteonecrosis

without

collapse

however

recent

histological

re-evaluation

indicated

BNCTs

-LSB-

-RSB-

The

other

cases

were

originally

diagnosed

as

chordoma

histologically

The

patient

group

consisted

of

men

and

women

ranging

in

age

from

to

years

-LRB-

mean

years

-RRB-

One

patient

was

found

to

have

two

lesions

at

different

sites

evident

in

the

fifth

lumbar

vertebra

and

the

second

sacral

vertebra

-LRB-

Fig.

-RRB-

The

latter

was

not

examined

microscopically

A

small

lesion

was

found

incidentally

in

another

patient

in

the

far

distal

coccyx

and

was

resected

Of

the

lesions

were

in

the

cervical

vertebra

each

in

the

lumbar

vertebra

and

sacrum

and

in

the

coccyx

The

most

common

symptom

was

pain

in

patients

however

patient

complained

of

pain

radiating

to

the

fingers

and

numbness

that

possibly

was

caused

by

known

ossification

of

the

posterior

longitudinal

ligament

-LRB-

OPLL

-RRB-

at

the

sixth

to

seventh

cervical

vertebrae

Another

patient

was

found

to

have

cervical

OPLL

on

radiographs

The

pain

was

usually

indolent

except

for

that

caused

by

OPLL

Lesions

were

found

incidentally

in

patients

on

MR

images

when

they

were

examined

for

unrelated

symptoms

due

to

traffic

accidents

A

needle

or

open

biopsy

was

done

for

lesions

Four

lesions

were

diagnosed

as

chordoma

and

as

osteonecrosis

The

remaining

lesions

were

clinically

diagnosed

as

osteonecrosis

and

an

intraosseous

benign

condition

respectively

The

patients

whose

lesions

were

diagnosed

as

osteonecrosis

and

chordoma

respectively

underwent

curettage

Three

patients

underwent

vertebrectomy

after

the

diagnosis

of

chordoma

One

patient

underwent

wide

resection

following

a

preceding

curettage

One

patient

who

did

not

undergo

a

surgical

procedure

was

followed

because

the

diagnosis

of

osteonecrosis

was

made

at

biopsy

Another

patient

did

not

undergo

any

surgical

management

in

spite

of

the

histological

diagnosis

of

chordoma

at

biopsy

and

was

followed

because

the

clinician

doubted

the

histological

diagnosis

of

chordoma

based

on

unusual

radiological

findings

for

chordoma

The

prognosis

of

all

patients

but

was

excellent

Four

patients

who

underwent

surgical

management

were

well

without

recurrent

or

metastatic

disease

for

follow-up

periods

between

and

months

-LRB-

mean

months

-RRB-

Two

patients

who

did

not

undergo

surgery

were

alive

without

progressive

disease

as

judged

by

imaging

for

months

and

months

after

biopsy

respectively

-LRB-

Fig.

-RRB-

One

patient

who

underwent

vertebrectomy

died

of

hemostasis

after

surgery

because

she

would

not

accept

a

blood

transfusion

on

religious

grounds

Table

of

benign

notochordal

cell

tumors

found

clinicallyPatientAge

-LRB-

years

-RRB-

GenderLocationSymptomsTreatmentOriginal

diagnosisFollow-up

back

painVertebrectomy

following

biopsy

and

curettageChordomaAlive

with

no

evidence

of

disease

and

pain

of

the

fingers

bilaterally

probably

due

to

OPLL

at

following

biopsyChordomaAlive

with

no

evidence

of

disease

pain

shoulder

stiffnessBiopsyChordomaAlive

with

no

progressive

disease

accident

injury

-LRB-

incidentally

found

on

MRI

-RRB-

CurettageOsteonecrosisAlive

with

no

evidence

of

disease

upper

back

pain

OPLL

focalNeedle

biopsyOsteonecrosisAlive

with

no

progressive

disease

Cox

-LRB-

microscopic

-RRB-

Buttock

painWide

resection

following

curettageChordomaAlive

with

no

evidence

of

disease

accident

injury

-LRB-

incidentally

found

on

MRI

-RRB-

Vertebrectomy

following

biopsy

at

of

postoperative

complicationsL

lumbar

vertebra

C

cervical

vertebra

S

sacrum

Cox

coccyx

OPLL

ossification

of

posterior

longitudinal

ligamentFig

man

who

complained

of

low

back

pain

-LRB-

patient

-RRB-

a

Lateral

radiograph

of

the

lumbar

spine

reveals

vague

sclerosis

in

the

fourth

lumbar

vertebra

b

Axial

computed

tomography

-LRB-

CT

-RRB-

scan

of

the

fourth

lumbar

vertebra

demonstrates

significant

sclerosis

in

the

center

of

the

body

partly

extending

to

the

cortex

c

Sagittal

spin

echo

magnetic

resonance

-LRB-

MR

-RRB-

image

reveals

a

large

intraosseous

lesion

with

low

signal

intensity

The

normal

bone

marrow

signal

is

preserved

in

the

anterior

and

posterior

portions

of

the

body

d

Sagittal

MR

image

shows

slightly

bright

signal

intensity

intermingled

with

intermediate

signal

e

Sagittal

gadolinium-DTPA-enhanced

MR

image

does

not

demonstrate

any

enhancement

No

soft

tissue

mass

is

recognizedFig

woman

who

was

examined

for

ossification

of

the

posterior

longitudinal

ligament

at

the

sixth

to

seventh

cervical

vertebrae

-LRB-

patient

-RRB-

A

lesion

was

found

incidentally

a

Lateral

radiograph

reveals

faint

or

vague

osteosclerosis

in

the

cervical

vertebral

body

The

physiological

lordosis

of

the

cervical

spine

is

decreased

b

Axial

CT

scan

reveals

diffuse

sclerosis

within

the

vertebral

body

c

Sagittal

spin

echo

MR

image

reveals

low

signal

intensity

in

almost

the

entire

marrow

space

of

the

sixth

cervical

vertebra

d

Sagittal

MR

image

reveals

intensely

high

signal

replacing

the

entire

marrow

space

No

soft

tissue

mass

is

evidentFig

woman

who

was

found

to

have

two

separate

abnormalities

in

the

lower

spine

during

an

imaging

study

for

a

traffic

accident

-LRB-

patient

-RRB-

a

Lateral

radiograph

of

the

lumbar

spine

and

sacrum

reveals

intense

sclerosis

of

the

entire

fifth

lumbar

vertebral

body

and

mild

sclerosis

in

the

cephalad

portion

of

the

sacrum

b

Sagittal

MR

image

reveals

homogeneous

low

signal

intensity

in

both

the

fifth

lumbar

and

second

sacral

vertebraeFig

man

who

complained

of

mild

upper

back

pain

-LRB-

patient

-RRB-

a

Sagittal

MR

image

reveals

an

intraosseous

lesion

with

high

signal

intensity

in

the

fifth

cervical

vertebra

at

initial

presentation

b

Sagittal

MR

image

demonstrates

no

progressive

disease

months

after

needle

biopsy

No

extraosseous

tumor

extension

or

enlargement

is

recognized

Imaging

findings

Clinical

images

reviewed

included

conventional

radiographs

-LRB-

n

-RRB-

bone

scintigrams

-LRB-

n

-RRB-

CT

scan

-LRB-

n

-RRB-

and

MR

imaging

-LRB-

n

-RRB-

Conventional

radiographs

revealed

ill-defined

vague

sclerosis

within

the

vertebral

body

in

lesions

-LRB-

Figs.

-RRB-

and

diffuse

prominent

sclerosis

presenting

as

ivory

vertebra

in

-LRB-

Fig.

-RRB-

The

remaining

lesions

were

not

identified

on

radiographs

In

all

lesions

involving

the

cervical

spine

physiological

lordosis

was

decreased

Bone

scintigrams

did

not

reveal

any

abnormal

uptake

All

lesions

were

sclerotic

on

CT.

One

was

mildly

sclerotic

in

the

center

of

the

vertebral

body

The

others

were

moderately

to

markedly

sclerotic

-LRB-

Figs.

-RRB-

Among

them

lesions

that

were

located

in

the

central

part

of

the

vertebral

body

extended

partly

to

the

cortex

Another

lesion

had

diffuse

sclerosis

replacing

the

entire

bone

marrow

space

No

cortical

disruption

or

bone

destruction

was

evident

in

any

of

the

lesions

MR

images

revealed

an

intraosseous

lesion

with

homogeneous

low

signal

intensity

-LRB-

Figs.

-RRB-

MR

images

revealed

homogeneous

intermediate

to

bright

signal

intensity

Gadolinium-DTPA-enhanced

MR

images

were

available

for

lesions

and

did

not

show

any

significantly

increased

intensity

-LRB-

Fig.

-RRB-

Three

lesions

occupied

the

entire

marrow

space

and

the

other

lesions

were

surrounded

by

residual

bone

marrow

tissue

No

extraosseous

disease

was

demonstrated

Histological

findings

Eight

lesions

were

histologically

examined

All

lesions

were

located

within

the

vertebral

bodies

The

lesions

were

unencapsulated

and

composed

of

solid

sheets

of

adipocyte-like

vacuolated

chordoid

cells

mixed

with

eosinophilic

less

vacuolated

cells

of

various

degrees

-LRB-

Fig.

-RRB-

The

adipocyte-like

cells

had

clear

cytoplasm

and

eccentrically

or

centrally

located

round

or

polygonal

nuclei

-LRB-

Fig.

-RRB-

Some

tumor

cells

were

multi-vacuolated

and

their

nuclei

were

mildly

polymorphic

or

hyperchromatic

-LRB-

Fig.

-RRB-

No

mitotic

figures

were

recognized

in

any

of

the

lesions

No

myxoid

background

was

evident

In

some

cases

cystic

spaces

were

found

in

the

lesions

that

contained

eosinophilic

colloid-like

material

The

lesions

lacked

any

apparent

vascular

network

Islands

of

hematopoietic

bone

marrow

were

seen

within

the

lesions

The

entrapped

bone

trabeculae

were

sclerotic

because

of

appositional

or

reactive

new

bone

formation

-LRB-

Fig.

b

-RRB-

PAS

staining

demonstrated

intracytoplasmic

glycogen

granules

In

all

lesions

examined

immunohistochemically

the

tumor

cells

stained

intensely

positive

for

vimentin

protein

EMA

and

-LRB-

Fig.

e

-RRB-

The

appearance

in

each

of

the

cases

was

consistent

with

benign

notochordal

cell

tumor

-LSB-

-RSB-

There

were

no

features

to

support

the

diagnosis

of

chordoma

Patient

was

presented

at

the

Members

Meeting

of

the

International

Skeletal

Society

in

Fig.

of

benign

notochordal

cell

tumors

a

Low

power

magnification

-LRB-

patient

-RRB-

reveals

solid

sheets

of

adipocyte-like

vacuolated

cells

The

affected

bone

trabeculae

are

sclerotic

Some

islands

of

non-neoplastic

hematopoietic

bone

marrow

are

seen

in

the

lesion

-LRB-

hematoxylin-eosin

-LSB-

HE

-RSB-

stain

-RRB-

b

Higher

power

magnification

-LRB-

patient

-RRB-

reveals

a

solid

sheet

of

vacuolated

tumor

cells

of

various

sizes

The

nuclei

are

oval

and

appear

bland

-LRB-

HE

stain

-RRB-

c

Some

tumor

cells

-LRB-

patient

-RRB-

are

multivacuolated

and

centrally

located

nuclei

are

mildly

polymorphic

They

are

reminiscent

of

lipoblasts

-LRB-

HE

stain

-RRB-

d

Biopsy

specimen

-LRB-

patient

-RRB-

reveals

sheets

of

vacuolated

cells

with

pyknotic

nuclei

between

bone

trabeculae

The

tumor

cells

may

be

mistaken

for

degenerative

fatty

marrow

-LRB-

HE

stain

-RRB-

e

The

tumor

cells

-LRB-

patient

-RRB-

stain

immunohistochemically

positive

for

cytokeratin

-LRB-

-RRB-

indicating

notochordal

cell

origin

-LRB-

SAB

immunohistochemical

stain

-RRB-

Discussion

Six

lesions

consistent

with

BNCT

have

been

documented

previously

by

others

-LSB-

-RSB-

Darby

and

coauthors

-LSB-

-RSB-

first

described

a

case

in

which

was

surgically

excised

A

man

who

complained

of

a

history

of

persistent

low

back

pain

was

found

to

have

an

intraosseous

lesion

replacing

almost

the

entire

fifth

lumbar

vertebra

Radiographs

and

scintigraphy

appeared

normal

The

lesion

was

well

visualized

by

MRI

but

showed

only

mild

sclerosis

on

a

CT

scan

Histological

findings

were

identical

to

those

of

our

cases

presented

here

They

were

not

typical

for

chordoma

however

the

authors

suspected

that

the

lesion

might

be

an

intraosseous

chordoma

rather

than

a

giant

notochordal

rest

Mirra

and

Brien

-LSB-

-RSB-

reported

cases

under

the

name

of

giant

notochordal

hamartoma

of

intraosseous

origin

A

woman

complained

of

low

back

pain

after

falling

down

the

stairs

and

was

found

to

have

an

intraosseous

lesion

involving

almost

the

entire

sixth

thoracic

vertebral

body

on

MRI

The

other

case

was

a

man

who

had

suffered

from

intermittent

stiffness

and

mild

pain

in

the

neck

MR

images

demonstrated

an

intraosseous

lesion

involving

about

of

the

fifth

cervical

vertebral

body

Neither

of

the

lesions

was

visible

on

radiographs

CT

scans

revealed

osteosclerosis

in

the

center

of

the

affected

vertebral

bodies

The

lesions

showed

low

signal

intensity

on

MR

images

and

intermediate

to

high

signal

intensity

on

images

and

no

extraosseous

disease

No

abnormal

uptake

was

detected

on

bone

scintigrams

in

either

case

The

patients

did

not

undergo

a

surgical

procedure

after

the

biopsies

The

follow-up

examinations

after

years

and

months

respectively

demonstrated

no

progressive

disease

and

indicated

their

benign

nature

Kyriakos

et

al.

-LSB-

-RSB-

reported

a

case

that

involved

the

fourth

lumbar

vertebra

An

boy

with

Tourette

's

syndrome

had

a

history

of

repeated

low

back

pain

after

a

playground

injury

Radiographs

CT

scan

and

single

photon

emission

computed

tomographic

bone

scan

-LRB-

SPECT

-RRB-

were

normal

MRI

revealed

an

intraosseous

lesion

with

low

and

high

signal

intensities

within

the

fourth

lumbar

vertebral

body

Cell

block

material

obtained

by

a

fine

needle

aspiration

biopsy

led

to

the

diagnosis

of

chordoma

and

the

patient

underwent

vertebrectomy

On

subsequent

evaluation

they

concluded

that

the

lesion

was

likely

a

giant

notochordal

rest

rather

than

chordoma

The

most

recently

documented

case

reported

by

Chauvel

et

al.

-LSB-

-RSB-

was

an

intraosseous

lesion

in

the

fifth

lumbar

vertebral

body

The

patient

was

a

woman

who

had

complained

of

low

back

pain

for

years

Radiographs

and

bone

scan

were

normal

however

CT

scan

revealed

fine

sclerosis

in

the

vertebra

MRI

demonstrated

an

intraosseous

lesion

with

homogenous

low

signal

on

image

and

high

on

image

The

patient

underwent

vertebrectomy

because

the

lesion

was

histologically

diagnosed

as

a

chordoma

on

biopsy

The

histological

features

from

the

vertebra

were

similar

to

those

of

previously

documented

cases

reported

by

Darby

et

al.

-LSB-

-RSB-

Mirra

and

Brien

-LSB-

-RSB-

and

Kyriakos

et

al.

-LSB-

-RSB-

A

further

case

was

illustrated

in

the

textbook

by

Dorfman

and

Czerniak

-LSB-

-RSB-

The

lesion

entirely

occupied

the

third

lumbar

vertebra

Recent

studies

have

discovered

unique

benign

notochordal

cell

lesions

within

axial

bone

that

may

be

precursors

of

chordoma

-LSB-

-RSB-

The

new

term

benign

notochordal

cell

tumor

was

proposed

for

these

lesions

-LSB-

-RSB-

Careful

autopsy

examination

can

identify

the

lesions

in

approximately

of

adult

cadavers

-LSB-

-RSB-

They

are

usually

tiny

or

small

and

found

most

frequently

in

both

ends

of

the

axial

skeleton

followed

by

the

mobile

spine

Their

histological

features

are

different

from

those

of

classic

chordoma

or

notochordal

vestiges

in

fetal

intervertebral

disks

-LRB-

Table

-RRB-

BNCTs

are

characterized

histologically

by

intraosseous

sheets

of

adipocyte-like

vacuolated

chordoid

cells

intermingled

with

less

vacuolated

eosinophilic

cells

of

various

degrees

The

lesions

were

not

lobulated

Some

colloid-like

material

containing

cystic

spaces

are

seen

in

the

lesions

however

the

lesions

lack

any

myxoid

background

The

nuclei

are

usually

bland

but

sometimes

appear

mildly

atypical

No

mitotic

figures

are

recognized

The

affected

bone

trabeculae

are

sclerotic

because

of

appositional

or

reactive

new

bone

formation

These

histological

features

are

completely

identical

to

those

of

the

lesions

reported

by

Darby

et

al.

-LSB-

-RSB-

Mirra

and

Brien

-LSB-

-RSB-

Kyriakos

et

al.

-LSB-

-RSB-

Chauvel

et

al.

-LSB-

-RSB-

and

Dorfman

and

Czerniak

-LSB-

-RSB-

These

reported

cases

are

considered

by

us

to

represent

BNCTs

that

grew

and

replaced

almost

the

entire

vertebrae

Table

and

microscopic

features

of

benign

notochordal

cell

tumorsEvaluation

method

FeaturesRadiograph

-LRB-

n

-RRB-

Vague

sclerosis

-LRB-

n

-RRB-

Marked

sclerosis

-LRB-

n

-RRB-

Invisible

-LRB-

n

-RRB-

Bone

scintigram

-LRB-

n

-RRB-

No

abnormal

uptake

-LRB-

n

-RRB-

CT

scan

-LRB-

n

-RRB-

Osteosclerosis

in

vertebral

body

-LRB-

n

-RRB-

No

bone

destruction

or

cortical

disruption

-LRB-

n

-RRB-

MRI

-LRB-

n

-RRB-

-LRB-

n

-RRB-

low

signal

-LRB-

n

-RRB-

intermediate

high

signal

intensityGd-DTPA

-LRB-

n

-RRB-

no

enhancementNo

invasive

soft

tissue

mass

-LRB-

n

-RRB-

Histology

-LRB-

n

-RRB-

Solid

sheets

of

adipocyte-like

vacuolated

cells

combined

with

less

vacuolated

eosinophilic

cells

of

various

degreesRound

or

polygonal

pyknotic

nuclei

occasionally

with

polymorphismNo

lobular

configurationNo

extracellular

myxoid

matrixSome

cystic

spaces

containing

eosinophilic

colloid-like

materialNo

mitotic

figuresPoor

vascular

networkEntrapped

islands

of

hematopoietic

bone

marrowSclerotic

bone

trabeculae

affectedPositive

immunostaining

for

vimentin

cytokeratin

-LRB-

-RRB-

EMA

and

proteinCT

computed

tomography

MR

magnetic

resonance

WI

weighted

image

Gd

gadolinium

CK

cytokeratin

EMa

epithelial

membrane

antigen

Benign

notochordal

cell

tumors

are

usually

asymptomatic

or

indolent

Most

lesions

are

overlooked

even

at

autopsy

because

of

their

anatomical

location

or

size

Only

one

such

lesion

had

been

documented

with

a

name

of

ecchordosis

physaliphora

vertebralis

in

-LSB-

-RSB-

Enlarged

BNCTs

may

be

detected

on

CT

or

MR

images

or

rarely

by

conventional

radiography

The

imaging

findings

of

our

cases

are

somewhat

variable

but

distinctive

in

the

absence

of

trabecular

destruction

on

CT

or

of

a

soft

tissue

mass

on

either

CT

or

MR

images

-LRB-

Table

-RRB-

Gadolinium

enhancement

was

absent

in

the

patients

in

whom

it

was

administered

Radiographs

may

reveal

ill-defined

vague

sclerosis

in

the

vertebral

body

and

occasionally

show

diffuse

sclerosis

presenting

as

an

ivory

vertebra

-LRB-

Fig.

-RRB-

Often

the

lesions

are

invisible

on

radiographs

CT

scans

may

reveal

unequivocal

sclerosis

which

is

much

more

obvious

than

on

radiographs

No

bone

destruction

or

cortical

disruption

is

recognized

MR

images

reveal

relatively

well-demarcated

intraosseous

lesions

with

homogeneous

low

signal

intensity

MR

images

show

homogeneous

high

signal

intensity

Gadolinium-DTPA

enhanced

MR

images

do

not

show

enhancement

Bone

scintigraphy

did

not

show

any

abnormal

uptake

Diagnosis

of

the

cases

presented

was

based

upon

biopsy

or

preoperative

imaging

the

diagnosis

was

chordoma

in

cases

and

osteonecrosis

in

Hence

patients

underwent

vertebrectomy

wide

resection

or

curettage

All

patients

but

are

well

without

recurrent

or

metastatic

disease

Two

patients

who

underwent

only

biopsy

had

no

progressive

disease

as

judged

by

radiography

CT

or

MR

images

for

months

and

months

respectively

As

described

by

Mirra

and

Brien

the

follow-up

information

was

consistent

with

the

benign

nature

of

the

tumors

The

terminology

of

the

lesions

is

controversial

Dorfman

and

Czerniak

-LSB-

-RSB-

Kyriakos

et

al.

-LSB-

-RSB-

and

Chauvel

and

coauthors

-LSB-

-RSB-

used

the

term

giant

notochordal

rest

Mirra

and

Brien

-LSB-

-RSB-

proposed

the

term

giant

notochordal

hamartoma

of

intraosseous

origin

In

addition

the

International

Skeletal

Society

has

used

the

term

benign

chordoma

on

the

brochure

of

the

Pathology

Refresher

Course

since

However

we

prefer

the

term

BNCT

to

the

others

BNCTs

show

histological

and

immunohistochemical

features

that

are

different

from

those

of

notochordal

vestiges

in

fetal

intervertebral

disks

BNCTs

lack

any

myxoid

background

and

show

positive

immunoreactivity

for

cytokeratin

although

notochordal

vestiges

in

the

fetal

intervertebral

disks

are

associated

with

myxoid

matrix

and

are

negative

for

cytokeratin

Notochordal

vestiges

are

often

found

in

the

intervertebral

disks

of

neonates

and

finally

disappear

by

the

age

of

to

years

In

our

personal

autopsy

experience

we

have

never

seen

any

notochordal

tissue

in

the

vertebral

bodies

in

fetuses

and

babies

who

had

notochordal

vestiges

in

their

intervertebral

disks

In

contrast

BNCTs

are

found

in

of

the

axial

skeleton

dissected

from

adult

cadavers

Therefore

BNCTs

are

considered

to

develop

after

birth

The

term

of

hamartoma

is

not

proper

for

the

lesions

as

mentioned

by

Kyriakos

et

al.

-LSB-

-RSB-

and

one

of

the

present

authors

-LSB-

-RSB-

The

term

of

benign

chordoma

is

oxymoronic

because

chordoma

has

been

used

to

describe

a

malignant

notochordal

cell

tumor

-LSB-

-RSB-

In

clinically

identified

BNCTs

including

our

cases

and

those

reported

by

others

tumors

were

found

in

the

lumbar

spine

in

the

cervical

spine

in

the

sacrum

and

each

in

the

thoracic

spine

and

coccyx

This

anatomical

distribution

is

different

from

that

found

at

autopsy

-LSB-

-RSB-

We

believe

the

reason

for

this

discrepancy

is

that

the

cervical

and

lumbar

regions

often

are

examined

with

MRI

for

neck

pain

and

low

back

pain

Lesions

in

the

sacrum

and

coccyx

may

be

overlooked

because

they

are

less

frequently

imaged

The

most

important

disease

that

should

be

distinguished

from

BNCT

is

chordoma

Microscopically

chordoma

is

composed

of

cords

or

strands

of

atypical

chordoid

cells

with

a

myxoid

matrix

of

various

degrees

-LSB-

-RSB-

Chordomas

are

associated

with

a

large

soft

tissue

component

However

differential

diagnosis

may

be

difficult

because

cellular

atypia

of

BNCT

and

chordoma

may

overlap

They

also

share

the

same

immunohistochemical

profile

-LSB-

-RSB-

Imaging

is

critical

in

separating

the

benign

lesion

from

the

chordoma

Chordomas

are

osteolytic

tumors

In

contrast

BNCTs

may

show

osteosclerotic

reaction

and

do

not

exhibit

osteolytic

change

Chordomas

are

not

intracompartmental

lesions

and

are

associated

with

a

soft

tissue

mass

In

those

cases

with

histological

overlap

with

our

present

understanding

of

these

diseases

we

would

suggest

that

the

absence

of

a

soft

tissue

mass

should

favor

a

BNCT

and

the

presence

of

a

soft

tissue

mass

should

indicate

a

chordoma

Biopsy

specimens

of

BNCTs

may

be

easily

mistaken

for

fatty

marrow

because

of

their

morphological

similarity

to

that

tissue

Indeed

lesions

among

our

cases

were

overlooked

as

normal

fat

marrow

on

biopsy

sections

Careful

observation

can

distinguish

BNCTs

from

fatty

marrow

Furthermore

immunohistochemical

study

can

help

to

distinguish

BNCTs

from

fatty

marrow

BNCTs

stain

positive

for

epithelial

markers

whereas

fat

cells

do

not

-LRB-

Fig.

-RRB-

Differential

diagnosis

also

includes

metastatic

carcinoma

particularly

originating

from

clear

cell

carcinoma

of

the

kidney

Metastatic

clear

cell

carcinoma

usually

is

osteolytic

on

radiographs

and

CT

scans

Gadolinium-DTPA

enhanced

MR

images

have

increased

signal

intensity

Histologically

clear

cell

carcinoma

has

an

alveolar

pattern

and

vascular

fibrous

septa

Clear

cell

carcinoma

rarely

exhibits

positive

immunoreaction

for

protein

-LSB-

-RSB-

Large

BNCTs

may

be

found

during

routine

clinical

examination

They

may

have

the

potential

of

malignant

transformation

to

chordoma

however

the

transformation

as

we

know

from

the

collected

cases

is

a

rare

happening

-LSB-

-RSB-

We

however

are

not

aware

of

any

cases

of

what

we

term

BNCT

growing

beyond

the

confines

of

bone

and

displaying

features

of

chordoma

and

therefore

they

should

be

managed

as

benign

lesions

and

carefully

followed

by

thin

section

CT

and

MRI

for

signs

of

extraosseous

disease

More

extensive

follow-up

by

cross-sectional

imaging

over

a

long

period

of

time

would

be

required

before

firmly

determining

the

biological

behavior

of

BNCTs

BNCTs

do

not

require

any

surgical

management

until

they

undergo

malignant

transformation

BNCTs

should

be

recognized

by

radiologists

pathologists

and

orthopedic

surgeons

to

prevent

unnecessary

radical

surgery

and

carefully

followed

by

advanced

imaging

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 I O B I O O O O O O O O O B I I I 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 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 O O O O O O O O O O O O O O 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 O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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 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 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 O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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 O O O O O O O O O O O O O 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 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 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 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 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 O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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 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 O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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 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 O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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 I I 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 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 B O O O O O O O O O O O O O B O O O O B I 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 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 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 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 B I 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 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 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 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 B I I 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 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 O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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 O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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 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 B I 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 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 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 B 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 O 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 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 B O O O O O O O O O O O O O O O O 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Low intense physical exercise in normobaric hypoxia leads to more weight loss in obese people than low intense physical exercise in normobaric sham hypoxia Training in mild to moderate hypoxia -LRB- 14 -- 17 % O2 in breathing air -RRB- and extended resting in moderate hypoxia -LRB- 9 -- 13 % O2 -RRB- have been shown to have effects in animals and humans on lipid and glucose metabolism , appetite loss , and , in part , on body weight . The causality for these effects is not yet known in detail , and the available data in humans from high-altitude and low-pressure chamber studies are scarce . New technical developments by German companies in the production of artificial climates with normobaric hypoxic conditions in larger rooms at reasonable energy costs allow now to perform hypoxia weight loss studies in obese humans with stable experimental conditions and protocols with a sham hypoxia control . Thirty-two obese people were recruited for a mild intense training study in normobaric hypoxia -LRB- 15 vol . % O2 -RRB- and normoxia/sham hypoxia -LRB- 20.1 vol . % O2 -RRB- . Twenty of these -LSB- mean age 47.6 years , mean body mass index -LRB- BMI -RRB- 33.1 , 16 m , 4 f -RRB- were willing to follow up on an 8-week , three times per week , 90-min low intense physical exercise in their individual fat burning mode , which has been determined by an exercise testing with spiro-ergometry upfront . The subjects were evenly randomized into a hypoxia and sham hypoxia group . The difference of the two groups in weight loss and changes in HBa1C values were analyzed before and after the training period . No nutritional diet was applied . Subjects in the hypoxia group in mean lost significantly more weight than in the sham hypoxia group -LRB- Δ1 .14 kg vs Δ0 .03 kg ; p = 0.026 -RRB- . This resulted in a tendency to reduce the BMI more in the hypoxia group -LRB- p = 0.326 -RRB- . In the mean , there was no HbA1C exceeding normal values -LRB- mean 5.67 and 5.47 % -RRB- , and the HbA1C stayed basically unchanged after the 8-week training . Mild physical exercise three times per week for 90 min in normobaric hypoxia for 8 weeks led to significantly greater weight loss in obese persons than the exercise in sham hypoxia in this , to our knowledge , first sham hypoxia controlled study . Introduction High altitude exposure which cause hypoxaemia has various serious effects on the human body . Those effects are studied by physiologists since the nineteenth century , and science has shed light on a lot of physiological and pathophysiological body reactions -LSB- 1 -RSB- . Weight loss in high altitude under hypoxic climate conditions is one of those effects in which the causes remain still unclear , and it is not known if it is dose/altitude-dependent and affects everybody or only certain individuals -LSB- 3 -- 5 -RSB- . The detection of the hypoxia-induced factor-alpha 1 -LRB- HIF-α1 -RRB- and the chain reaction on mediators that this factor starts have prompted some speculations and investigations on various nutritional signals . One of the nutritional signals that seem to be triggered by HIF is the peptide hormone leptin -LSB- 6 -- 9 -RSB- . This could lead to the direction that the human lipid metabolism is affected by hypoxia and that hypoxia causes signals to reduce food intake and also changes in fat mobilization and fat uptake to the body -LSB- 10 -RSB- . Because the societies in first and second world countries struggle with an increased body weight , pathological fat levels , and the increasing number of individuals with metabolic syndrome in their populations , the urge for various inexpensive treatment forms including a lifestyle change has risen . The idea is coming up whether training or stay at moderate altitude or simulated altitude could enhance weight loss and improvement of fat and sugar metabolism because of the known effects of hypoxia on weight loss . Several open trial field studies with low numbers of individuals have been carried out so far , but they do not have controls -LSB- 11 -- 13 -RSB- . In the AMAS 2000 study , patients with metabolic syndrome have trained and stayed for 3 weeks at 1,700 m altitude or within a control group at sea level . In this randomized controlled study , significant improvements in fat metabolism and regarding weight loss have been found for the patients at altitude compared to patients at sea level -LSB- 14 -RSB- . The construction design of our facility with normobaric hypoxic climate rooms allows pretending hypoxic conditions without actually running the rooms in hypoxic climate -LRB- sham hypoxia -RRB- and to perform a single blind randomized controlled weight loss study in simulated altitude . Our aim was to perform a physical exercise weight loss study in obese subjects under moderate hypoxia -LRB- 15 vol . % O2 -RRB- and to compare the effects on body weight and fat metabolism to a control group training on the same level in sham hypoxic conditions . Materials and methods Site Our facility for simulated altitude in the renovated Kurmittelhaus der Moderne in Bad Reichenhall in southeast Bavaria has three rooms -LRB- 90 , 37 , and 25 m2 -RRB- in which a hypoxic climate at normobaric conditions can be produced up to an simulated altitude of 6,000 m -LRB- approximately 7 vol . % O2 ; see Fig. 1 -RRB- . Fig. 1The 90 m2 hypoxia training room with exercise devicesThe rooms are two well-equipped training facilities and one sleeping and rest room with a full bath . To reach a hypoxic climate , the air in the room is flushed with nitrogen , and the volume percent of oxygen is reduced to the determined level . To control the climate , oxygen and carbon dioxide are constantly controlled . The data are transmitted to a computer , and the computer controls via specialized software the electronic climate unit and the inflow of nitrogen and fresh air through the air condition -LRB- software by Low Oxygen Systems , Berlin-Buch , Germany ; hardware by Atlas Copco , Walter Bau and Siemens and Fujitsu-Siemens , all Germany -RRB- . The nitrogen is produced via a filtration system that eliminates oxygen from pressurized air . Because of the constant air flow , there is a low noise level from the air condition in the room . The level of simulated altitude is usually displaced in the rooms . To keep subjects uninformed about the oxygen level in the room while the air condition was running at all times , this display was covered during the study times and made invisible to the subjects . Subjects Thirty-two healthy subjects -LRB- 22 men , 10 women -RRB- with a minimum age of 16 years and a minimum body mass index -LRB- BMI -RRB- of 27 were asked to participate in an 8-week trial with three times 90-min moderate physical exercise . Estimation of sample size was calculated to reach a statistical significance for a change in BMI of one point . Acquisition of subjects was done by local radio announcement and personal contact . Subjects did not receive any kind of reimbursement for participation . All subjects were asked to continue with their normal diet/nutrition which they had before the study.Twenty subjects were finally willing to perform the whole 8-week training period and gave written consent . Subjects were randomly allocated to the hypoxia training and the sham hypoxia training group . Subjects were not told to which group they were allocated . Antropometric data of the subjects in the two groups are shown in Figs. 2 and 3 . Both groups were comparable in terms of age and sex . Fig. 2Mean age -LRB- SD -RRB- , weight , and body mass index -LRB- BMI -RRB- of the subjects who finished the trial in the hypoxia groupFig . 3Mean Age , weight , and BMI of the subjects who finished the trial in the sham hypoxia groupIn all 20 subjects , spiro-ergometry was performed to determine the max O2 consumption -LRB- ml kg − 1 min − 1 -RRB- at exercise and the training level for the study set at the heart frequency value at 60 % of the max O2 -LRB- ml kg − 1 min − 1 -RRB- . In all subjects , an echocardiography was performed for safety reasons to exclude subjects with heart insufficiency levels NYHA 2 -- 4 . Study parameters Primary study parameter was bodyweight -LRB- kg -RRB- before and after the trial . Secondary study parameters were : BMI and the laboratory parameters -LRB- serum and EDTA blood sample -RRB- ; HbAC1 , cholesterol , high - and low-density lipoproteins and triglycerides . Other exercise and blood parameters were not part of this trial but are available on request for reviewers from the laboratory and exercise test data sheets.Blood samples were drawn at the beginning and end of the 8-week trial ; bodyweight and height were measured via a regular medical weight scale . Training period Subjects performed exercise at a heart rate level which corresponded to 60 % of the heart rate level at their individual max O2 -LRB- ml kg − 1 min − 1 -RRB- on three different training -LRB- stepper , treadmill , and bicycle ergometer -RRB- devices for 90 min on 3 days per week , 8 weeks , either in normobaric hypoxia -LRB- 15 vol . % O2 , equivalent to 2,500-m altitude -RRB- or in normobaric normoxia -LRB- 20 vol . % O2 , equivalent to 450-m altitude -RRB- . For safety reasons , SaO2 was controlled regularly during the training via pulseoximeter -LRB- Konica Minolta , Japan -RRB- in all subjects , and the subjects were asked for the main symptoms of acute altitude sickness -LRB- headache , nausea , and training untypical weakness in the legs -RRB- . Pulse oximetry was blinded to subjects . Training was under constant control of medical personnel . Statistical analysis The differences between the two groups were analyzed via Student 's t test , statistical significance determined as p < 0.05 -LRB- statistical software used : Excel , Microsoft , Redwood , WA , USA -RRB- . Data are presented as descriptive data , and values are given as mean values . Ethics and informed consent The study protocol was approved by the ethical committee of the Paris Lodron University Salzburg . All subjects gave written informed consent to participate in the study . Subjects under 18 were finally excluded ; therefore , written consent by the parents was not necessary . Results All 20 subjects who were included in the training sessions finished the study without problems . No adverse side effects were reported by the subjects , including no signs of acute mountain sickness in those who exercised in 15.2 vol . % oxygen level . The average heart rate at 60 % O2max for all subjects was 118/min . Subjects kept this heart frequency level stable during exercise -LRB- ± 3/min -RRB- . This meant that because of the slightly increased heart frequency at rest in hypoxia , the hypoxia group exercised at a lower wattage . Because of the neutral smell of the air-conditioned air , subjects could not tell if they are in hypoxia or sham hypoxia . More than 50 % of the subjects guessed wrongly as to which group they belong . Weight loss : The hypoxia group lost 1.14 kg in mean ; the sham hypoxia group lost no bodyweight at all -LRB- p = 0.02 , see Figs. 4 and 5 -RRB- . This led to a non-statistical significant tendency in the hypoxia group to reduce the BMI more than the sham hypoxia group -LRB- p = 0.33 -RRB- . The number of subjects had been too low to reach statistical significance . Fig. 4Mean -LRB- SD -RRB- weight loss after 7 weeks in the hypoxia group vs the sham hypoxia groupFig . 5Weight reduction or increase in the single subjects -LRB- matched pairs by age -RRB- of the hypoxia vs sham hypoxia group -LRB- y-axis = kg , x-axis = number of subject -RRB- . Weight loss occurred in six subjects of the hypoxia group and in four of the sham hypoxia group , weight increase in two of the hypoxia group and four of the sham hypoxia group , weight stayed unchanged in two subjects of hypoxia -LRB- four and eight -RRB- and two of the sham hypoxia group -LRB- eight and nine -RRB- Lipid levels and HbA1C : None of the differences in lipid levels reached statistical significance . However , the hypoxia group showed little non-statistical significant tendencies to lose more cholesterol -LRB- − 10.7 mg/ml vs 6.0 mg/ml ; p = 0.68 -RRB- , triglycerides , and low-density lipoproteins than the sham hypoxia group , but less high-density lipoproteins -LRB- Figs. 6 and 7 -RRB- . Fig. 6Mean -LRB- SD -RRB- reduction and increase in triglycerides values of the hypoxia vs sham hypoxia groupFig . 7Mean -LRB- SD -RRB- reduction in high-density lipoproteins -LRB- HDL -RRB- in the hypoxia vs sham hypoxia group The healthy subjects of both groups were not diabetics . They had HbA1C levels on the edge but still in normal values -LRB- mean 5.67 and 5.47 % -RRB- , and those levels did not change after the training period of 8 weeks . Discussion The here presented study on fat metabolism and weight loss in mild to moderate hypoxia is , to our knowledge , the first one with a sham hypoxia control protocol . We could show that obese subjects did lose significantly more weight during an 8-week training period with three times per week 90-min low intense exercise when this exercise took place in 15 vol . % O2 hypoxia than in normal air at 450-m altitude -LRB- 20 vol . % O2 -RRB- . We could also show that there have been non-statistical differences in fat metabolism or at least in serum levels of lipoproteins and triglycerides between the hypoxia training and the sham hypoxia training group . There are , due to the nature of the study and above that , several limitations , which have to be addressed . The number of subjects is not big enough to show a reduction in BMI , and power analysis shows that we would need about 32 subjects to have a significant BMI reduction . We wanted to get more subjects into the study , but the reduction of subjects to a limited number due to time restrictions and willingness is a common problem in weight loss protocols with obese people . The difference in weight loss in mean with 1.14 kg seems , for 8 weeks of training , not really a lot . However , several subjects did significantly lose more weight in the hypoxia group , and the mean bodyweight loss is not due to natural swings in weight change . This also happened although the hypoxia group trained at a slightly lower wattage due to a slightly increased heart frequency in hypoxia . We can not fully exclude that the normoxia group decreased body fat and increased muscle mass due to the slightly higher level of muscle load , but it seems unlikely with this very low intense training . Because we did not put our subjects on a stringent diet , there might have been the chance that some individuals did eat more than normally and some less . Keeping the subjects on their routine food seemed to us the natural choice of being uninfluenced in the weight change by a special nutritional diet . The other point is that weight loss in hypoxia might be caused by reduced food intake , and that was a part of the study . To let the subjects reduce their food intake , you have to have them on a longer leash . This is especially true if leptin and hypothalamic signals come into play and might let subjects be less hungry , respectively , less hungry for fat . To achieve more accuracy , the only chance would be to exactly control the nutrition of all subjects already before the study and during the training period . To do this , subjects have to be under full supervision all the time . This is an almost impossible achievement in ambulatory care or with independent volunteers . Our findings are consistent with previous studies which have shown that low intense training in moderate hypoxia leads to weight loss -LSB- 11 -- 14 -RSB- . The protocol with a sham hypoxia control group , which did not lose weight with the same amount of exercise , strengthens this hypothesis . A definite reason why this weight loss occurs is still not known . Several investigations could prove that the body reduces fat as a substrate for energy production due to the higher use of oxygen necessary in fat burning -LSB- 2 , 13 -RSB- , but this is still controversially discussed -LSB- 14 -RSB- . One of the reasons for a controversial discussion is that so far , nobody did observe subjects on a longer term -LSB- 14 -RSB- . Most studies have dealt with exercise in hypoxia for hours or a maximum of a few days , not for 2 months as we did . In our investigation , the subjects in hypoxia had reduced their triglycerides , their cholesterol , and their low-density lipoproteins and kept their high-density lipoproteins stable , whereas the subjects in normoxia did not do so . However , none of the effects reached statistical significance . Due to the actual literature , this can be explained by several possible causes : Either the fat mobilization is reduced due to hypoxia over time and so the serum levels of lipids are lower at the point of measurement or the increased catecholamine levels during hypoxia lead to reduced lipolysis and a depot of intracellular fat -LSB- 16 , 17 -RSB- . Most likely , it seems that increased leptin levels lead to a reduced fat intake via food , and that is the reason why triglyceride levels decrease -LSB- 6 , 10 -RSB- . The answer is still open , and more research is needed to clarify this . Other mediators besides catecholamines , like insulin like growth factor , might influence both fat and carbohydrate metabolism in hypoxia -LSB- 15 -RSB- . In conclusion , there is more and more evidence that even mild moderate hypoxia in comfortable simulated altitude , if combined with exercise , leads to weight loss . Weight loss regimes with exercise and diets or just exercise could be combined with normobaric hypoxia in the future . Future investigations should include whether the stay in moderate hypoxia alone without exercise increases the weight loss and if such a regimen would still be safe .

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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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 O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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 O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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 O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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 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 O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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normobaric hypoxia
weight loss
physical exercise