Bjornsson Spontaneous Necrosis

8/11/2019 Bjornsson Spontaneous Necrosis

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Virchows Archiv A Pathol Anat (1993) 423:195-199

Virchows rchiv

Pathological natomy

and H istopathology

9 Springer-Verlag 1993

r o g n o s t i c s i g n i fi c a n c e o f s p o n t a n e o u s t u m o u r n e c r o si s

i n o s t e o s a r c o m a

J o h a n n e s B j ~ r n s s o n 1 C a r r i e Y . I n w a r d s 1 L e s t e r E . W o l d 1 F r a n k l i n H . S i m

2

W i l l ia m F . T a y l o r 3

1 Division of Pathology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, USA

2 Department of Orthopedics, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, USA

3 Section of Biostatistics, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, USA

Received March 9, 1993 / Received after revision June 3, 1993 / Accepted June 8, 1993

A b s t r a c t .

Preoperative chemotherapy is an integral part

of the management of osteosarcoma, and the extent o f

tumour necrosis found at operation is an important

prognostic variable. Knowledge about spontaneous, pre-

therapy necrosis is difficult to obtain but provides im-

portant quantitative information about the necrotic ef-

fect of chemotherapy. Using three different methods,

we studied spontaneous tumour necrosis in 20 localized

intramedullary osteosarcomas of the distal femur diag-

nosed between 1963 and 1972. All patients received sur-

gical treatment only. All six patients with spontaneous

necrosis involving more than 20% of tumour died. Five

of 14 patients with necrosis amounting to less than 20%

were qong-t erm, disease-free survivor s. The extent of ne-

crosis was independent of tumour size. Two semiquanti-

tative methods of evaluation were easily applied and

reproducible. Spontaneous necrosis in untreated osteo-

sarcomas occurs frequently; extensive necrosis ma y indi-

cate a rapid clinical course. Tumour necrosis can be

quantified reliably in clinical work.

K e y w o r d s :

Chemothe rapy - M orpho metr y - Necrosis

Osteosarcoma - Prognosis

sponse of the tumour to preoperative chemotherapy

(Ku mp an et al. 1986; Pan et al. 1990). The unde rlyi ng

assumption is that untreated primary osteosarcoma is,

to a great extent, c ompo sed o f viable tum our cells. In

malignant tumours in general, the relative volume of

spontaneous necrosis is considered to be an expression

of a given tumour's growth rate and thus its biological

aggressiveness. A highly necrotic osteosarcoma would

be expected to spread earlier, i ndependent of other clini-

copathological variables, than a largely viable tumour.

Knowledge about the extent o f pretreatment necrosis

in a given tumour would influence the appraisal of the

effects of chemotherapy. Data on prechemotherapy ne-

crosis can clearly be obtained only by indirect means,

not by a thorough histopathological evaluation in any

way comparable to the work-up of resection specimens.

We studied 20 preoperatively untreated high-grade

intramedullary osteosarcomas of the distal femur seen

at the Mayo Clinic between 1963 and 1972 in order

to map the extent of spontaneous necrosis and analyse

the relationship between the extent of necrosis and clini-

cal outcome. We compared methods for the evaluation

of tumour necrosis.

I n t r o d u c t i o n

Tumour necrosis resulting from preoperative chemother-

apy is a recognized prognostic determinant in osteosar-

coma. A statistically significant relationship exists be-

tween the extent of postchemotherapy necrosis, mea-

sured in percentage of necrotic tumour mass, and post-

operative survival (Ray mon d etal. 1987; Rosen et al.

1979). Sequential angiography and magnetic resonance

imaging before and during preoperative chemotherapy,

by providing a record of changes in neoplastic angiogen-

esis, have proved useful, if indirect, measures of the re-

Correspondence to

J. Bj6rnsson, Mayo Clinic, 200 First Street

SW, Rochester, MN 55905, USA

M a t e r ia l s a n d m e t h o d s

Twenty patients with high-grade intramedullary osteosarcoma lo-

calized to the distal femur at the time of diagnosis were included

in the study. Their ages ranged from 10 to 51 years (mean 16 years).

No patient received preoperative or postoperative radiation or che-

motherapy. With the exception of sections taken at the time of

initial

diagnosis, the entire tumour tissue from all patients was

preserved in formalin and available for analysis.

The gross specimens were processed as follows: a 3 mm slice

of the entire specimen parallel to the initial plane of sectioning

was obtained with a band saw, every attempt being made to include

the largest diameter of tumour as well as the greater of the two

minor axes. This slice was placed in a transparent plastic envelope

and photocopied. This photocopy was used as a template to iden-

tify the location of each section of tumour submitted for routine

tissue processing. Between seven and 20 (mean 13) slides stained

with haematoxylin and eosin were made from each tumour.


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Dur ing microscopic rev iew, a reas o f v iab le and nonviab le tu -

mour were ou t l ined wi th a mark ing pen on the g lass s l ide , the

s l ide was photographed , and the p r in t was en la rged th ree fo ld .

T h r e e m e t h o d s o f e v a l u a t io n w e r e u se d . M e t h o d 1 u s e d a n X Y -

p l o t t e r ( H I - P A D D i g i ti z e r; H o u s t o n I n s t r u m e n t s , A u s t i n , T ex . ) a n d

a n I B M P C - X T m i c r o c o m p u t e r t o e v a l u a t e a n d c a l c u l a t e a r e a s

o f v ia b l e a n d n e c r o t i c t u m o u r o n e a c h p h o t o g r a p h . I n m e t h o d 2 ,

a s te reo log ica l a ssessment o f v iab le and necro t ic a reas was ob ta ined

by p lac ing a g r id over the en la rged pr in t s and us ing po in t count ing

wi th a manua l haemato logy ce l l counte r . In method 3 , mic roscopi -

ca l e s t imate o f the re la t ive a rea o f necros i s on each s l ide was made ,

wi thout the a id o f o ther t echn iques . The resu l t s o f methods 1 and

2 were expressed as pe rcen tages , by a rea, o f necro t ic tumour . The

microscop ic es t ima t ion of necros i s (meth od 3) was expressed in

two ways : as g rades o f necros i s , s l igh t ly modi f ied f rom o ther au-

thors (Rosen e t a l . 1979; Sa lze r -Kun tsch ik e t a l . 1983a , b )

grade 1, l it t l e o r no necros i s ; g rade 2A, l ess than 50% necros i s

b y a r e a : g r a d e 2 B , 5 0 - 9 5 % n e c r o s is ; g r a d e 3 , m o r e t h a n 9 5 % ;

grade 4 , no v iab le tu rnout iden t i f i ed - and as a compos i te pe rcen t -

age . Met hod 3 was app l ied a t the t ime of mic roscopic rev iew and

wi thout knowledge of the resu l t s f rom the o ther two methods .

Necros i s was d ef ined as the absence o f v iab le tum our ce ll s .

Loss o f v iab i l i ty denoted the fa i lu re o f tumou r ce l l nuc le i to t ake

up the haematoxyl in s ta in . Thus def ined , necros i s may be repre -

sen ted by eos inophi l i c coagula t ive necros i s o f the tumour (F ig . 1 ) .

H a e m o r r h a g i c n e c r os i s ( F ig . 2 ) c o n s t i tu t e d a n o t h e r p a t t e r n o f v i a-

b i l i ty loss. A th i rd pa t te rn showed prese r va t ion of a rch i tec tu re ,

inc lud ing tumo ur ce l l boundar ie s . Here , cy top lasm and , in pa r t i cu-

la r , nuc le i were d i sce rned as eos inophi l i c s i lhoue t tes o r gh os t s .

Mere smudging or d i s to r t ion of nuc le i (F ig . 3 ) d id no t cons t i tu te

necros i s . The tumours were s taged accord ing to the Musculoske le -

ta l Tumor Soc ie ty (Enneking 1988) . Fo l low-up in format ion was

obta in ed f rom the pa t ien t s ' May o Cl in ic char t s . F ig . 2 . Haem orrha g ic necros i s. Viab le tum our ce l ls in lower ha l f

o f p h o t o m i c r o g r a p h . ( H a e m a t o x y l i n a n d e o si n , 2 5 0 )

Fig 1 . Coagula t ive necros i s in h igh-grade os teosarcoma. Necro t ic

t u m o u r s u r r o u n d i n g a b o n y t r a b e c u l a . ( H a e m a t o x y l i n a n d e o s i n ,

x 250)

Fig . 3 . Viab le tumour . Ind is t inc t and d i s to r ted tu mou r ce l l nuc le i

w i t h s m u d g e d c h r o m a t i n . A n i d e n t i c a l h is t o l og i c a l a p p e a r a n c e m a y

resu l t f rom chemotherapy . (Haematoxyl in and eos in , x 250)


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T a b l e 1. Clinical and pa tholog ical characteristics of 20 patien ts with osteosarcoma of the distal femur

197

Patien t Age Tumour Osteo- Stage b Follow (months)~ Necrosis (%)

no. (years/sex) size sarcoma up

(cm) type

Digitizing Point Microscopic

pad counti ng estimate

Necrosis grade

(microscopic

estimate) d

10/M 11 O liB DOD 28 < 2A

2 20/F 12 O IIB DOD 17 36 33 22 2A

3 11/M 6 O IIA DOD 9 38 39 31 2A

4 13/F 8.5 O IIB NED 122 2 2 2 2A

5 14/F 8.5 O IIA DOD 11 2 2 2 2A

6 11/M 12 O IIB NED 150 5 5 10 2A

7 16/M 10 T liB DOD 11 12 12 10 2A

8 16/F 6.5 O IIA NED 117 1 1 < 1 2A

9 17/F 10 O IIB DOD 6 42 41 18 2A

10 14/M 8 F IIB DOD 7 13 12 11 2A

11 17/F 10.5 C IIB NED 183 0 0 0 1

12 12/M 8 O IIB DOD 8 69 67 41 2B

13 14/F 9 O IIB DOD 5 0 0 0 1

14 16/M 9 O IIB DOD 6 3 2 < 11 2A

15 11/F 16 O IIB NED 159 19 19 1 2A

16 18/M 8 O IIB DOD 45 2 2 1 2A

17 51/F 8 O IIB DOD 44 25 21 10 2A

18 15/M 14.5 T IIB DOD 6 49 50 62 2B

19 10/F 11 C IIB DOD 17 0 0 0 1

20 10/M 8.5 O IIB DOD 14 3 3 0 1

No patient received chemotherapy or radiation

C, Chondroblastic;F, fibroblastic;O, osteoblas tic; T, telangiectatic

b Stage IIA, Localized high-grade tumour without cortical break-

thro ugh; stage IIB, localized high-grade tumour with cortical

breakthrough

0 DOD, Died of osteosarcoma; NED, no evidence of disease

a Grade I, Little or no necrosis; grade 2A, necrosis < 50%; grade

2B, 50 95% ; grade 3, >95% ; grade 4, no viable tumour

.ffl

ffl

o

o

e

o~

70

60 / ~

50 --

, o - . / /

30 -- 9 /

10

0 I I I I I I I

10 20 30 40 50 60 70

necrosis

Fig. 4. Necrosis (%) in osteosarcoma tissue measured by method 1

(digitizing pad), y-axis, and method 2 (point counting), x-axis, r =

0.998, P


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198

0

o

cE

70

60

5O

4 0

I

3O

2 0 - -

1 0 - -

0

0

i i i . T : : . _ , ; i i i

2 4 6 8 10 12 14 16 18

T um or d iame t e r cm

Fig. 6. Necrosis (%) in osteosarcoma issue measured by method 1

(digitizing pad), y-axis, and tumor size, x-axis, r=0.12, P>0.05

1 0 0

8 0

o . 6 O

d

>

4 0

2 0

_

~

w

I

0 10

< 2 0 n e c r o s i s (n = 1 4 )

> 2 0 n e c r o s i s ( n = 6 )

L J J l v ~

2 0 3 0 4 0 5 0

M o n t h s a f t e r t r e a t m e n t

Fig. 7. Percentage alive by time (months) after treatment for pa-

tients with 20% necrosis. Rank-sum

test, P = 0.07

ease 6-44months (mean 15months) postdiagnosis.

Fourteen patients had less than 20% necrosis in their

tumours (range 0 19%; mean 4%). Nine of these 14 pa-

tients (64%) died of disease 5 45m ont hs (mean

16 months) postdiagnosis. The remaining five living pa-

tients had a mean observation period of 146 mont hs

(range 117 183 months) . The overall difference in sur-

vival (Fig. 7) was marked: at 2 years, 17% of the high-

necrosis and 50% of the low-necrosis patients were alive.

Statistical testing by the rank-sum test, however, resulted

in a P value of only 0.07.

i s c u s s i o n

Postchemotherapy necrosis in conventional high-grade

osteosarcomas is an important prognosticator of biolog-

ical behaviour. The extent o f postchemotherapy necrosis

in a surgically removed primary tumour is considered

to be indicative of a particular patient's responsiveness

to a particular chemotherapeutic regimen (Rosen et al.

1982, 1984). Raymond and colleagues (1987) found that,

of several contribut ing clinicopathological determinants,

tissue necrosis was the single most significant predictor

of prognosis in a given patient. This interdependence

of necrosis in the primary tumour and prognosis appears

to hold true even if metastases show less necrosis than,

or a cellular composition different from, the primary

tumour (Nachman et al. 1987; Roessner et al. 1984).

Little attention has been paid to the presence, extent,

and biological significance of spontaneous, pretreatment

necrosis in osteosarcomas. A positive correlation be-

tween spontaneous necrosis and survival would tend to

diminish the favourable prognostic impact of postche-

motherapy necrosis, thus weakening the arguments in

favour of presurgical chemotherapy. However, if sponta-

neous necrosis adversely affected the prognosis, then

that would strengthen the arguments in support of pre-

operative chemotherapy, indicating that chemotherapy

not only overcomes the unfavourable effect of necrosis

but also possesses an additional definitive therapeutic

effect. This is what we found in this study.

Three recent histopatho logical studies have addressed

spontaneous necrosis in osteosarcoma. Misdorp and col-

leagues (1988) analysed 44 patients with osteosarcomas

of various bones. Their findings in untreated patients

differed from ours in that only 12 out of 22 untreated

patients (55%) had less than 50% necrosis, a figure sig-

nificantly lower than ours, even if their methodology

was somewhat different. Their study, however, differed

from ours because half of their patients had tumours

in sites other than the distal femur. Von Hochstetter

(1990) investigated 15 high-grade and low-grade osteo-

sarcomas of various bones and reported results compa-

rable to ours, including the observation that the extent

of necrosis was independent o f tumour size. Springfield

and co-workers (1991) reported their findings of sponta-

neous necrosis in 76 osteosarcomas of various sites. They

included all histological subtypes and grades except the

telangiectatic variety. Almost half (45%) of the lesions

did not show evidence of spontaneous necrosis, a mark-

edly higher proportion of non-necrotic tumours than

we and the two other studies found. Variations in sub-

types, sites, and grades of their tumours probably ac-

count for this difference. Sixty-two of their patients re-

ceived postoperative chemotherapy. Thus, none o f these

three studies specifically addressed the biological signifi-

cance of spontaneous necrosis.

Our results indicate that spontaneous necrosis in

high-grade osteosarcomas portends a rapid clinical

course. By selecting a group of patients with tumours

of the distal femur only and by including only those

with con ven tiona l osteosarcomas in the Dahlin classi-

fication (Dahlin and Unni 1986) in stages IIA and IIB

(Enneking 1988), we tried to exclude as many confound-

ing variables as possible. The fact that tumour diameter

did not correlate with extent of necrosis indicates that

necrosis operates as an independent variable in progno-

sis. The biological predictive value of necrosis, irrespec-

tive of tumour size, also holds true for sarcomas of soft

tissue (Costa et al. 1984). Detailed histopathological ex-


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a m i n a t i o n o f t u m o u r s b e f o r e c h e m o t h e r a p y i s i m p o s s i -

b l e. E v e n i f t h e h i s t o l o g i c a l a p p e a r a n c e s i n p r e- a n d

p o s t c h e m o t h e r a p y t u m o u r s d if fe r s o m e w h a t M i s d o r p

1 9 8 6 ; P i c c i e t a l . 1 9 8 5; R a y m o n d e t a l . 1 98 7 ) , th e s e d i f -

f e r en c e s a r e n o n s p e c i f i c a n d p e r m i t n o r e l i a b le q u a n t i f i-

c a t i o n o f , o r d i s c r i m i n a t i o n b e t w e e n , t h e t w o t y p e s o f

n e c r o s is , e v en b y e x p e r i e n c e d b o n e p a t h o l o g i s t s F i g . 3).

O t h e r , a n d i n d i r e c t , m o d a l i t i e s , i n c l u d i n g a n g i o g r a p h y

C a r r a s c o e t al . 1 9 8 7; K u m p a n e t a l. 1 98 6 ) a n d m a g n e t i c

r e s o n a n c e i m a g i n g P a n e t a l . 1 9 9 0 ; S a n c h e z e t a l . 1 9 9 0 ),

a r e n e e d e d .

T h e r e w a s g o o d g e n e r a l a g r e e m e n t b e t w e e n o u r t w o

s e m i q u a n t i t a t i v e a n d r e p r o d u c i b l e m e t h o d s o f m a p p i n g

n e c r o s is . E i t h e r p o i n t c o u n t i n g o r d ig i t a l p a d m e t h o d o -

l o g y is w el l su i t e d t o p a t h o l o g i c a l s t u d y . I t a p p e a r s t h a t

t h e t h i r d a p p r o a c h , a s i m p l e h i s t o l o g i c a l e s t i m a t e o f t h e

r e l a t i v e a r e a o f n e c r o s i s , i s le s s re l i a b l e , e v e n a t a n i n s t i -

t u t i o n w i t h c o n s i d e r a b l e e x p e r i e n c e in t h e d i a g n o s i s a n d

t r e a t m e n t o f m a l i g n a n t b o n e t u m o u r s .

W e c o n c l u d e t h a t s p o n t a n e o u s n e c r o si s in i n t r am e -

d u l l a r y h i g h - g r a d e o s t e o s a r c o m a s o c c u r s f r e q u e n t l y , i s

i n d e p e n d e n t o f t u m o u r s iz e, a n d i s s i g n i f ic a n t l y l es s e x -

t e n s i v e t h a n n e c r o s i s f o u n d i n t u m o u r s s u b j e c t e d t o p re -

o p e r a t i v e c h e m o t h e r a p y . O s t e o s a r c o m a s w i t h s ig n i fi c a nt

s p o n t a n e o u s t u m o u r n e c ro s is m a y b e e x p e c te d to g r o w

f a s t e r a n d d i s s e m i n a t e s o o n e r t h a n o s t e o s a r c o m a s w i t h

s m a l l a r e a s o f s p o n t a n e o u s t u m o u r n e c ro s is . S p o n t a n e -

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