Pure red cell aplasia A preleukemic state

Case report

Pure red cell aplasia

A preleukemic state

Richard A. Savage, M.D.

Department of Laboratory Hematology and Blood Banking

Significant progress has recently been made in the characterization of the pre leukemic phase of acute nonlymphocyt ic leukemia (ANLL). In addit ion to the well-defined syndromes which have been f o u n d to precede ANLL, a n u m b e r of less well-defined and poorly unde r s tood pre-leukemic states have been described.1 T h e well-def ined syndromes associated with increased risk of A N L L include exposure to myelotoxic agents such as ch loramphenico l , 2 , 3 benzene , 4 , 5

phenylbutazone, 6 and arsenic;7 exposure to ion-izing radiat ion; 8 several chromosomal abnor -malities including Down's syndrome, 8 Kline-felter's syndrome, 9 and T u r n e r ' s syndrome; 1 0

Fanconi's congenital mar row hypoplasia;1 1

congenital agranulocytosis;12 idiopathic aplastic anemia;1 3 ataxia telangiectasia;14 and par-oxysmal noc turna l hemoglobinur ia . 1 5

T h e synd rome of acquired p u r e red cell apla-sia (PRCA) with or without an tecedent exposure to mar row toxins has only rarely been r e p o r t e d as a pre leukemic phase of ANLL. PRCA may be def ined as a normocytic , normochromic anemia without reticulocytes, but with normal leuko-cytes and platelets in the per iphera l blood; nor-mal marrow granulocytic and megakaryocytic elements with a virtual absence of erythroblast ic

267

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268 Cleveland Clinic Quar ter ly Vol. 43, No. 3

elements , and no evidence of extra-medullary hematopoiesis.1 6 T h e fol-lowing case illustrates idiopathic PRCA as a pre leukemic manifesta-tion of ANLL.

Case repor t

A 56 -yea r -o ld m a n was f o u n d to be

a n e m i c at a n o t h e r hosp i ta l i n D e c e m b e r

1970 f o l l o w i n g s u r g e r y f o r a r ena l ca lcu-

lus . A b o n e m a r r o w asp i rate was inter -

p re ted as s h o w i n g ap las ia . N o h i s to ry o f

e x p o s u r e to o r g a n i c t ox i n s , insect ic ides,

o r c h l o r a m p h e n i c o l c o u l d be el icited.

E m p i r i c trials o f p r e d n i s o n e a n d p y r i d o x -

ine fa i led to i m p r o v e the a n e m i a , a n d he

r e q u i r e d f r e q u e n t t r a n s f u s i o n s to m a i n -

ta in adequa te h e m o g l o b i n a n d h e m a t o -

crit. O n a d m i s s i o n to the C l e v e l a n d C l i n i c

H o s p i t a l he was obese a n d m i l d l y C u s h -

i n g o i d wi th n o r m a l b l o o d p r e s s u r e a n d

pu l se . N o abno rma l i t i e s were f o u n d o n

phys i ca l e x a m i n a t i o n ; the l iver a n d

sp leen were not e n l a r g e d to pa l pa t i on

a n d p e r c u s s i o n . In i t ia l h e m a t o l o g i c pa-

r amete r s we re h e m o g l o b i n , 5.3 g/dl; he-

matocr i t , 1 6 % ; ret icu locyte c o u n t , less

t h a n 0 . 1 % ; M C V , 87 fl; M C H , 31 p g ;

M C H C , 3 5 % ; W B C , 5200//d with a d i f -

ferent ia l c o u n t of 4 5 % s e g m e n t e d n e u t r o -

ph i l s , 3 3 % l y m p h o c y t e s , 9 % m o n o c y t e s ,

5 % metamye locy te s , a n d 4 % myelocytes ;

a n d 140,000 platelets/jul were p re sent . D i -

rect a n d i nd i r ec t a n t i g l o b u l i n tests we re

negat ive. S e r u m i r o n , i r o n - b i n d i n g ca-

pacity, a n d v i t a m i n B 1 2 levels were not

m e a s u r e d . B o n e m a r r o w asp i rate (Figs. 1 and 2) r evea led a n o r m o c e l l u l a r m a r r o w

with n o r m a l m e g a k a r y o c y t e s , a n M / E ra -

tio o f 32:1 with a g r a n u l o c y t i c p r e c u r s o r

d i f fe rent ia l c o u n t o f 1 0 % mye lob la s t s , 3 %

p r omye l o c y t e s , 9 % mye locy te s , 2 2 % m a -

ture n e u t r o p h i l s a n d b a n d s , a n d 5 1 %

l y m p h o c y t e s . A d i a g n o s i s o f P R C A was

m a d e . E x t e n s i v e s ea r ch f o r a t h y m o m a by

r o e n t g e n o g r a p h y was u n r e w a r d i n g . H e

rece ived t r a n s f u s i o n s at 3- to 5 -week in -

• 4 ' ¿ C T ! - S ^ . V l i i S R l F S S V " " * * V < * / „ • \ « 1

• m • - w w * > ifcs 4

?fc Fig . 1. Init ial b o n e m a r r o w a s p i r a t e s h o w i n g n o r m a l ce l lu lar i ty a n d n o r m a l m e g a k a r y o c y t e s (Wr igh t ' s s ta in , X64).



Winter 1976 Pure red cell aplasia 269

o y * * * <• ^

> ^ • • r il •

F i g . 2 . H i g h m a g n i f i c a t i o n o f init ial b o n e m a r r o w o r l y m p h o c y t e s ( W r i g h t ' s s t a i n , X400) .

terva l s ; th i s t h e r a p y m a i n t a i n e d h i s he -

m o g l o b i n level b e t w e e n 6 a n d 9 g/dl.

T h e r a p y w i th a z a t h i o p r i n e , p r e d n i s o n e ,

6 - m e r c a p t o p u r i n e , o x y m e t h o l o n e , a n d

d e x a m e t h a s o n e in v a r i o u s c o m b i n a t i o n s

f a i l ed to p r o d u c e re t i cu locy to s i s . D u r i n g

h i s c o u r s e t he m a j o r i t y o f re t i cu locy te

c o u n t s r e m a i n e d be l ow 0 . 1 % . E x c e p t f o r

s eve ra l e p i s o d e s o f h e r p e t i c s tomat i t i s

a n d febr i le n o n h e m o l y t i c t r a n s f u s i o n re -

a c t i on s w h i c h a p p e a r e d late i n h is c o u r s e ,

h e r e m a i n e d wel l . I n all h e r e c e i v e d 93

u n i t s o f w h o l e b l o o d , p a c k e d cel ls, a n d

l e u k o c y t e - p o o r p a c k e d cells i n a p e r i o d o f

23 m o n t h s .

T w e n t y - o n e m o n t h s a f te r h is init ial e x -

a m i n a t i o n b r o n c h i t i s d e v e l o p e d w h i c h

was t reated w i th a m p i c i l l i n . H i s p e r i p h -

e ra l s m e a r at th i s t ime s h o w e d the f o l l ow-

i n g va lue s : h e m o g l o b i n , 5.7 g/dl; h e m a t o -

cr i t , 1 7 % ; W B C , 1600/jLtl w i th 4 6 % seg -

m e n t e d n e u t r o p h i l s , 4 % b a n d s , 3 2 % l y m -

p h o c y t e s , a n d 1 5 % m o n o c y t e s ; a n d plate-

let c o u n t o f 80,000//¿I. H i s s y m p t o m s p e r -

a s p i r a t e . All cells p r e s e n t in field a r e g r a n u l o c y t e s

s i s ted de sp i t e ant ib io t i c t h e r a p y , a n d 1

m o n t h later h e was a d m i t t e d w i th f e ve r ,

s p l en i c p a i n , a n d c o u g h p r o d u c t i v e o f

ye l l ow s p u t u m . T h e s p l e e n was n o w pa l -

pab le 4 c m be l ow the left s ubco s t a l m a r -

g i n , a n d 5 c m h e p a t o m e g a l y h a d a p -

p e a r e d . A ches t f i l m r e v e a l e d atelectas is

o f the m i d d l e l obe o f t he r i g h t l u n g . E x -

a m i n a t i o n of t he p e r i p h e r a l b l o o d s m e a r

s h o w e d h e m o g l o b i n , 7.4 g/dl; h e m a t o c r i t ,

2 2 % ; W B C , 2200//iil w i t h 4 4 % s e g m e n t e d

n e u t r o p h i l s , 2 % b a n d s , 1 % b a s o p h i l s ,

2 6 % l y m p h o c y t e s , 1 0 % m o n o c y t e s , a n d

1 7 % blasts. Platelets w e r e r e p o r t e d as

m a r k e d l y d e c r e a s e d . B o n e m a r r o w a sp i -

rate was h y p o c e l l u l a r , b u t 1 3 % o f the

i den t i f i ab le cells w e r e b lasts . F i v e d a y s

later, the W B C was 6500//xl w i th a d i f f e r -

ent ia l c o u n t o f 2 0 % s e g m e n t e d n e u t r o -

ph i l s , 1 % b a n d s , 1 6 % l y m p h o c y t e s , 3 %

m o n o c y t e s , 2 % m e t a m y e l o c y t e s , 1 % m y e -

locytes, a n d 5 7 % b lasts . T h e pat ien t d i e d

that a f t e r n o o n af ter r e c e i v i n g t he first

d o s e o f c h e m o t h e r a p y .




Autopsy resul ts

Autopsy examinat ion revealed pul-monary consolidation in both lower lobes (combined weight 2000 g). Se-vere splenomegaly (weight 2590 g) with reddish-brown expansion of the red pulp and replacement of white pu lp was observed. Severe enlarge-ment of lymph nodes was present in all the regions examined . T h e bone marrow grossly was succulent and deep reddish-brown. The liver was enlarged (weight 3300 g) and on cut section showed whitish nodu la r ex-pansions of the portal areas. T h e pancreas was of normal weight but f i rmer than expected and dark tan to b rown.

Microscopic examinat ion of the lungs showed an infil trate of malig-nant cells involving alveoli and par-

enchyma. T h e cells resembled histio-cytes with agranu la r pink to light blue cytoplasm and folded nuclei with chromatic c lumping and occa-sional, p rominen t nucleoli (Fig. 3). ASD chloracetate esterase and Giemsa's staining failed to reveal spe-cific granules in the imma tu re cells. N u m e r o u s hyaline membranes were f o u n d along the alveolar septae, and hemosider in laden macrophages filled many alveoli. Neutrophi ls were absent f r o m the cell masses. Leu-kemic thrombi in small vessels with su r round ing infarct ion of lung tissue were present . Sections of spleen and lymph node (Fig. 4) showed exten-sive d i f fuse inf i l t rat ion, with the ma-lignant cells entirely obliterating the normal archi tecture . T h e spleen also contained foci of ex t ramedul la ry he-matopoiesis. T h e spleen and several

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F i g . 3 . M a l i g n a n t cells i n f i l t r a t i n g l u n g a t a u t o p s y . N o t e p l e o m o r p h i c nuc le i with p r o m i n e n t n u c l e o l i . Cel ls h a v e m o d e r a t e a m o u n t of a g r a n u l a r e o s i n o p h i l i c c y t o p l a s m ( h e m a t o x y l i n a n d eos in s t a i n , X400).



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F i g . 4 . Sec t ion f r o m a u t o p s y l y m p h n o d e s h o w i n g o b l i t e r a t i o n o f n o r m a l a r c h i t e c t u r e by i n f i l t r a t i n g m a l i g n a n t cells ( h e m a t o x y l i n a n d eos in s t a i n , X64) .

lymph nodes showed leukemic thrombi with infarct ion similar to those f o u n d in the lung . T h e malig-nant cells entirely replaced the mar-row (Fig. 5). T h e liver (Fig. 6) dis-played massive portal and periportal infiltration with malignant cells; ex-tensive n u m b e r s of Prussian blue positive iron granules were present in the K u p f f e r cells but not in the hepa-tocytes. I ron was also diffusely de-posited in pancreat ic islet and acinar cells, epithelial cells of the pancreatic ducts, and in macrophages . Micro-scopic infil tration of the malignant cells into kidneys, prostate , testis, thyroid, esophagus , and adrenals was also f o u n d .

Discuss ion

Several repor t s of PRCA as a pre-leukemic synd rome have been pub-

lished.1 , 1 7 - 2 2 In some of the case re-ports , insuff icient in format ion is pro-vided to decide whe ther these cases meet the criteria needed to make a diagnosis of PRCA. 1 , 20, 22 T h e case repor ted by Sout ter and Emerson1 9

does not fit the accepted defini t ion of PRCA, since the pat ient had a reticu-locytosis of 2.1% d u r i n g his course, and the degree of r ed cell aplasia in the marrow is not r e p o r t e d . Fur the r -more , the presence of imma tu re monocytoid cells in the marrow and per iphera l blood at the time of the initial diagnosis suggests that this pa-tient may already have had leukemia. The case repor ted by Mohler and Leavell17 was shown by marrow aspi-rate to represen t aplastic anemia ra ther than PRCA. T w o cases (14 and 15) r epor ted by Schmid et al21 (num-ber XX is the pat ient r epor ted by



Fig . 5. Sec t ion o f a u t o p s y b o n e m a r r o w s h o w i n g m a r r o w r e p l a c e m e n t by i n f i l t r a t i n g m a l i g n a n t cells

( h e m a t o x y l i n a n d eos in s ta in , X64).

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F ig . 6. S e g m e n t of l iver at a u t o p s y s h o w i n g e x p a n s i o n of po r t a l a r e a s d u e t o i n f i l t r a t e o f m a l i g n a n t cells. I n f i l t r a t i o n o f s i nuso id s a n d p e r i p o r t a l r e g i o n s is also p r e s e n t ( h e m a t o x y l i n a n d eosin s t a in ,

X64). 272




T a b l e . P R C A as a p r e l e u k e m i c s t a t e ; s u m m a r y of p r e v i o u s l y r e p o r t e d cases a n d p r e s e n t case

Age/sex Toxic exposure Duration of clinical course and type of leukemia

C a s e 142 ' 56 M N o n e 2 yr; t r a n s f o r m e d t o a c u t e l e u k e m i a

C a s e 1521 47 M P e n t a c h l o r o p h e n o l IV2 yr ; t r a n s f o r m e d to a c u t e l e u k e m i a

Case 1 8 65 F N o n e 5 m o ; t r a n s f o r m e d to a c u t e g r a n u l o c y t i c l e u k e m i a

P r e s e n t case 56 M N o n e 22 m o ; t r a n s f o r m e d to a c u t e m o n o c y t i c l e u k e m i a

Soutter and Emerson) appear to rep-resent t rue PRCA as illustrated by marrow differentials. T h e repor t by Rubenstein1 8 is a case of idiopathic PRCA terminat ing in acute leukemia.

T h e fou r cases accepted as PRCA terminat ing in acute leukemia are summarized in the Table. T h e aver-age age of the fou r patients was 56 years, and the durat ion of disease f r o m diagnosis to death was 17 months . In two cases, the leukemia was nonlymphocytic. In no patient was transient red cell aplasia a pre-leukemic manifestation, and no pa-tient had a thymoma. In one case, exposure to a toxic myelosuppressive agent was found to be a possible pre-disposing factor. Comparison with the Mayo Clinic study of preleuke-mia1 shows that the age and sex dis-tribution of the 32 patients with pre-leukemia that subsequently trans-fo rmed to acute leukemia were simi-lar to the age and sex distribution of the cases in the Table. T h e PRCA patients had a more rapidly progres-sive course (duration of disease 17 months for PRCA t ransforming to acute leukemia as compared to 47 months for all preleukemic mani-festations which t ransformed to acute leukemia). PRCA appears to be another member of the ill-defined g roup of hematologic syndromes termed preleukemia.

References

1. P i e r r e R V : P r e l e u k e m i c s t a t e s . S e m i n H e m a t o l 11: 7 3 - 9 2 , 1974.

2 . B r a n e r MJ , D a m e s h e k W: H y p o p l a s t i c a n e m i a a n d m y e l o b l a s t i c l e u k e m i a fo l low-i n g c h l o r a m p h e n i c o l t h e r a p y ; r e p o r t o f t h r e e cases . N E n g l J M e d 277: 1003-1005 , 1967.

3 . S e a m a n A J : S e q u e l s t o c h l o r a m p h e n i c o l ap fas t i c a n e m i a ; a c u t e l e u k e m i a a n d p a r -o x y s m a l n o c t u r n a l h e m o g l o b i n u r i a . N o r t h w e s t M e d 68: 8 3 1 - 8 3 4 , 1969.

4 . A k s o y M , D i n j o l K , E r d e m § , e t al: A c u t e l e u k e m i a d u e to c h r o n i c e x p o s u r e t o b e n -z e n e . A m J M e d 52: 160-166 , 1972.

5. O l d f e l t C O , K n u t s o n D: C h r o n i c b e n z e n e p o i s o n i n g . A c t a M e d S c a n d 130: S u p p l 206: 331 -342 , 1948.

6 . W o o d l i f f H J , D o u g a n L: A c u t e l e u k a e m i a a s soc ia t ed wi th p h e n y l b u t a z o n e t r e a t m e n t . B r M e d J 1: 7 4 4 - 7 4 6 , 1964.

7 . K j e l d s b e r g C R , W a r d H P : L e u k e m i a in a r s e n i c p o i s o n i n g . A n n I n t e r n M e d 77: 9 3 5 - 9 3 7 , 1972.

8 . R u n d l e s R W : Di scus s ion o f r a d i a t i o n ex-p o s u r e p r e d i s p o s i n g t o l e u k e m i a , in H e m -a t o l o g y . Wi l l i ams W J , e d . N e w Y o r k , M c G r a w - H i l l C o , 1972, p p 6 8 0 - 6 8 2 .

9 . M a m u n e s P , L a p i d u s P H , A b b o t t J A , e t al: A c u t e l e u k a e m i a a n d K l i n e f e l t e r ' s syn-d r o m e . L a n c e t 2: 2 6 - 2 7 , 1961.

10. W e r t l e c k i W, S h a p i r o J R : 45 , X O T u r n e r ' s s y n d r o m e a n d l e u k e m i a . L a n c e t 1: 7 8 9 -790, 1970.

11. Dos ik H , H s u L Y , T o d a r o G J , e t al: L e u -k e m i a in F a n c o n i ' s a n e m i a ; c y t o g e n e t i c a n d t u m o r v i r u s suscep t ib i l i ty s t u d i e s . B l o o d 36: 3 4 1 - 3 5 2 , 1970.

12. G i l m a n P A , J a c k s o n D P , G u i l d H G : C o n -g e n i t a l a g r a n u l o c y t o s i s ; p r o l o n g e d s u r -vival a n d t e r m i n a l a c u t e l e u k e m i a . B l o o d 36: 5 7 6 - 5 8 5 , 1970.




13. D e l a m o r e I W , G e a r y C G : Ap la s t i c a n a e -m i a , a c u t e mye lob la s t i c l e u k a e m i a , a n d o x y m e t h o l o n e . B r M e d J 2: 7 4 3 - 7 4 5 , 1971.

14. H e c h t F , K o l l e r R D , Rigas D A , e t a l : L e u -k a e m i a a n d l y m p h o c y t e s in a t a x i a - t e l a n -g i ec t a s i a . L a n c e t 2 : 1193, 1966.

15. H o l d e n D , L i c h t m a n H : P a r o x y s m a l n o c -t u r n a l h e m o g l o b i n u r i a wi th a c u t e l e u k e -m i a . B l o o d 33: 2 8 3 - 2 9 1 , 1969.

16. D i G i a c o m o J , F ü r s t S W , N i x o n D D : Pr i -m a r y a c q u i r e d r e d cell a p l a s i a in t h e a d u l t . J M t S ina i H o s p 33: 3 8 2 - 3 9 5 , 1966.

17. M ö h l e r D N , Leavel l BS: Aplas t ic a n e m i a — a n ana lys i s of 50 cases . A n n I n t e r n M e d 49: 3 2 6 - 3 6 2 , 1958.

18. R u b e n s t e i n M A : P u r e r e d cell ap l a s i a as a m a n i f e s t a t i o n o f l e u k e m i a . A b s t r a c t s o f t h e s i m u l t a n e o u s sess ions o f t h e X l l t h

C o n f e r e n c e o f t h e I n t e r n a t i o n a l Soc ie ty of H e m a t o l o g y , N e w Y o r k , 1968, p 27.

19. S o u t t e r L , E m e r s o n C P : Elec t ive t h y m e c -t o m y in t h e t r e a t m e n t of a r e g e n e r a t i v e a n e m i a a s s o c i a t e d wi th m o n o c y t i c l e u k e -m i a . A m J M e d 28: 6 0 9 - 6 1 4 , 1960.

20. B e r n a r d J , Levy J P , L o r t h o l a r y P: Les s t a d e s i n i t i a u x d e s l e u c e m i e s a i g ü e s h u -m a i n e s . P r o c 9 th C o n g r e s s o f t h e E u r o -p e a n Socie ty o f H e m a t o l o g y , L i s b o n , 1963. N e w Y o r k , K a r g e r , 1963, p p 9 7 1 - 9 8 2 .

21 . S c h m i d J R , Kiely J M , P e a s e G L , et al: A c q u i r e d p u r e r e d cell a g e n e s i s ; r e p o r t of 16 cases a n d r e v i e w o f t h e l i t e r a t u r e . A c t a H a e m a t o l 30: 2 5 5 - 2 7 0 , 1963.

22. H a v a r d C W H , Scot t R B : R e f r a c t o r y a n a e -m i a ; a d i s e a s e o r a s y n d r o m e ? L a n c e t X: 4 6 1 - 4 6 4 , 1963.



Pure red cell aplasia A preleukemic state

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