Klinische Wochenschrift
Kiln. Wschr. 56, 17-30 (1978)
© Springer-Verlag 1978
Originalien Sea Blue Histioeytosis. A Clinical Cytologic and Nosographie Study on 23 Cases N. Quattrin, L. De Rosa, S. Quattrin Jr. and A. Cecio Department of Haematology and Social Centre for Leukemias, Cardarelli Hospital, Naples (Head: Prof. Nevio Quattrin), Italy
Meerblaue ttistozytose. Eine klinisch-zytologisehe und nosographische Studie an 23 Fiillen Zusammenfassung. An 23 Ffillen sowie Daten der Literatur (etwa 40 F~ille) untersuchen die Autoren die hauptsfichlichen klinischen, zytologischen und nosographischen Aspekte yon Krankheitszustfinden und Syndromen, die mit Sea-Blue Histiozytosis (SBH) einhergehen. Es mfissen 3 Krankheitsformen yon SBH unterschieden werden: hereditfire Erkrankungen; heredit~ir asymptomatische F o r m ; erworbene und asymptomatische Form. Vom klinischen Standpunkt ist um die Hfilfte weniger aller Ffille von SBH als hereditfir einzustufen. Sie bieten ein Syndrom, welches auf Splenomegalie und periodischer haemorrhagischer Diathese (infolge wechselnder Thrompozytopenie) basiert und nicht selten mit Hepatomegalie und Verfinderungen der Lungen oder des Nervensystems (h~ufig mit Beteiligung der Augen) einhergeht. Es gibt auBerdem eine zweite hereditfire Form von SBH, welche sehr selten ist und sich klinisch yon der ersten F o r m unterscheidet. Sie ist charakterisiert dutch einen Mangel yon Plasma-Lecithin-Chotesterin-Acetyltransferase. Die speziellen Eigenschaften des SBH-Syndroms werden besprochen aufgrund licht- und elektronenmikroskopischer sowie zytochemischer Untersuchungen, welche das polymorphe Aussehen dieser ,,verhungerten" Makrophagen betonen. Das in SBH-ZeIlen gespeicherte Material ist heterogen, und der enzymatische Defekt der h/iufigsten Form yon SBIt ist noch unbekannt. Der Befund von SBH-Zellen bei verschiedenen Bluterkrankungen hat eine analoge Bedeutung wie der Nachweis yon Gaucher-Zellen, die au!3erhalb der Gaucher'schen Krankheit gefunden werden. Die Existenz von 2 definierten Formen yon SBH kann heute nicht mehr bestritten werden. Offprint requests to: Prof, Dr. N. Quattrin (address see above)
Schliisselw6rter: Eine neue Glyko-Lipidose, die meerblaue Hystiocytose - Genotypische Formen - Erworbene Zust~nde - Ktinische Symptomatologie Zytologische Forschungen - Nosographische Bemerkungen - Identitfit der meerblauen Histiozytose. Summary. The authors examine the main clinical, cytologic and nosographic aspects of conditions and syndromes associated with SBH on the basis of the literature data (about 40 cases) and 23 personal ones. It is necessary to distinguish between three nosological conditions of SBH : hereditary disease, hereditary asymptomatic, acquired per se asymptomatic. From the clinical viewpoint less a half of all SBH cases are hereditary and present a syndrome based on splenomegaly0 periodic hemorrhagic diathesis (due to variable thrombocytopenia), not rarely associated with hepatomegaly and lung or nervous system changes (often eyes are involved). There is also a second SBH hereditary form, vary rare and clinically different from the former, determined by deficiency of plasma-lecitin-cholesterol acyltransferase. The peculiar features of SBH are discussed by means of optical, cytochemical, electron microscopical investigations which point out the polymorphous aspect of these " f a m i s h e d " macrophages. The material stored by SBH is heterogeneous and the enzymatic defect of the most frequent form still remains obscure. The presence of SBH in different haemopathies has an analogous significance as Gaucher's cells found outside Gaucher's disease. It is impossible today to deny the existence of two well-identified SBHS. Key words: A new glyco-lipidosis: the Sea-Blue Histiocytosis - Genotypical forms - Acquired Conditions - Clinical features - Cytological studies Nosographic discussion - Identity of S-B Histiocytosis.
18
N. Quattrin et aI.: Sea Blue Histiocytosis
The Sea-Blue Histiocytes (SBH) represent the last type of macrophages observed for the first time by Moeschlin in 1947 [32]. The knowledge of this singular thesaurocyte has gradually increased only in the last few years. The topic is very interesting but also strongly debated. In fact, there are still contrasting opinions on such points as the nature of the stored
material, the clinical symptomatology of a Sea-Blue Histiocytosis Syndrome (SBHS) and its nosologic identity, the pattern of genetic inheritance, the relation to other glyco-lipidoses. The aim of our study is to contribute to a better understanding of SBH and SBHS on the basis of our wide experience in this field of research.
Table 1. Five families with SBHS: clinical data
(first exam.)
Ang. (1970)
Serv. (1971)
Car. (1972)
RoL (1974)
Som. (1974)
megoJy
Hemorrhagic diathesis
[ Other symptoms I
+
e
very severe cure.co-mucous
S. S.
~ ~)
-9 ~-
severe anemia ~ severe cerebropathia
27
SO.
+++
~)
~
(~
58
M.
-
periodic cutaneous-mucous pinguicula on the
1 (Sled
d'
16
B.
. ++ +
+*
non severe periodic cutaneous-mucous
2(An.)
9
8
S.
+++
++
~
I(D.~N) 2(H.C.)
Q ~
40 23
M. So.
++ t
-
3(Ca.) 4(An.) 5(R~) 6(Pa.)
d' o ~
20 12 8 4
Sa SO. So. So.
-9~g ~
-e" ~e
~-
1 (Hi.) 2 (Ag.)
(:/' c#
6 35
So. E
+++ .9-
~ ~
recurrent cutaneous -e-
Cose
Sex
(yr,)
Relationo) megaly
I (Ros.)
~
14
S.
2 (C,io.) (*) 3 (Reg.)
9 9
9 16
1 (LUc.)
9
(*) 2 (Mad.)
-
Remarks improved by. splenectomy cured by Azathioprine osymptomatic -G
--
sometimes jaundice recovery by splenectomy milbry lung picture milicu'y lung picture
-~
~ carrier of rJ-Th hypochromicsideropeni( carrier of B-Th anemia with achyl.ia -~ carrier of 13-Th
~) ~
g-
(=) F. (Father), M. (Mother), B.(Brother), S(Sister), So. (Son) (*) Case not proved Normal or absent Table 2. Ten cases of acquired SBH: Clinical data Case (first exam.)
Sex
Age (yr)
Splenomegaly
Hepatomegaly
Hemorrhagic Diathesis
Other Symptoms
Disease
I.P.A.
9
35
G
G
-8
very severe
Ac. myeloblastic Leukemia
2. S.C.
~
40
0
0
severe cutaneousmucous
very severe anemia
Ac, promyelocytic basophilic Leukemia
3. F.P.
9
62
+++
+
O
4. B.A.
6'
76
+ +
O
O
cutaneous leukemides
Ac. myelo-monocytoide Leukemia
5. D.B.
d'
40
+ + +
mild
cxachexia
Blastic crisis by chr. myeloid Leukemia
6. S.F.
~
40
+++
O
O
Chr. myeloid leukemia
7. P.R,
$
4
8. M,C.
d
9. Z.B.
10. A.M.
+ +
Chr. myeloid Leukemia
4-
O
t)
O
Ac. myeloblastic Leukemia
60
++
+++
0
0
Chr. myeloid leukemia
~
11
t}
O
O
cutaneous and mucous
M. Werlhof
2
14
t~
0
bruising
0
M. Werlhof
N. Quattrin et al.: Sea Blue Histiocytosis
19
Material and Methods From April 1971 till March 1976, we observed 23 cases with SBH, 13 of which were genotypical and 10 of the acquired type. This represents the quite largest number of SBH cases gathered until now by a single medical group. Our genotypical cases came from 5 non-related families. One of these also carried /3-thalassemia. For all the patients we proceded to: (I) a careful investigation of their respective families, (2) a cytologic study by means of panoptical and cytochemicaI stains and, in certain cases, by electron microscopy. The main haematologic as well a s clinical features are reported in Tables 1-4.
SBH was found in the bone marrow of all patients. In one patient (Car. Stef.) it was also observed in the removed, very enlarged, spleen, and in the liver; in two others of acquired form (Z.B. and A.M. Table 3) only in the spleen. A complete enzymatic study was performed by Professor Van Hoof of Louvain on the hepatic tissue drawn from a patient (Car. Stef.) during a splenectomy. The results did not demonstrate a specific defect but only an increase of certain acid hydrolases with the meaning of a generic lysosomial disturbance. An investigation performed by Professor Durand of Genoa on the urine Iipides of all the six patients in the Rol. family did not show any positive features.
Table 3. Ten cases of acquired SBH : Main hematological data Case
Hb (g/dl)
RBC x 101z/1
WBC x 109/1
Platelets x 109/I
Myetobioptic finding 1. P.A.
4.5
1,3
5.6
30.0
Myeloblastic-promyelocytic proliferation with partial conservation of the megacarhyocytic system. Not rare scattered SBH (small vesicular in type).
2. S.C.
5.0
1.6
7.9
5.0
Diffuse proliferation of basophlilic promye!c~cytes with a lot of Auer's rods. Rare scattered SBH (granulous-macular in type).
3. F.P.
12.5
4.0
250.0
255.0
Metaplastic granulocytic proliferation. Scattered SBH (with large pachychromatic granula). Gaucher-like cells absent.
4. B.A.
10.0
3.0
18.0
90.0
Monocytoide and promyelocytic proliferation with partial conservation of the normal systems. Rare granulous gigantic SBH.
5. D.B.
10.0
3.1
63.0
33.0
Complete myeloblastic metaplasia. Numerous scattered SBH (also early forms).
6. S.F.
14.4
5.2
11.4
300.0
Complete granulous metaplasia, Rare SBH macular in type. Absence of Gaucher's cells.
7. P.R.
8.0
3.9
55.0
100.0
Myeloblastic diffuse infiltration. Some granulous SBH with gigantic granules are present.
8. M.C.
11.2
4.4
70.0
50.0
Metaplastic granulocytic proliferation. Some granulous SBH gigantic in type.
9. Z.B.
12.0
4.9
i0.8
5.0
10. A.M.
12.4
4.6
9.4
10.0
Smear of spleen by splenectomy Scattered, but not rare, large SBH sometimes phagocytising neutrophils. Nmnerous granulous SBH gigantic in type,
Table 4. Main semiophysicat features of SBH syndrome according to personal and from literature collected cases
a g e ( y r.) Max. Min. Average
Sex M. F.
Spleno- Hep~to- Hemorrhages a . t o . megaly megaty thrombocytopenia
23 Si[verstein and EUefson (1973)
60
3
26
11
12
22 (95°/o)
16 (70%)
? (30%)
3 (13 %)
36 Sawitsky etal. (1973)
83
1
21
~
-6-
30 (83°/°)
16 (44°/°)
very frequent
8 (22°/°)
13 our cases (1971-1974)
40
4
16
6
7
? (51°/°)
2 (15°/°)
4 (30°/°)
2 (15°/°)
42 all cases (known until 1974)
83
4,
31
20 22
28 (66°/o).
13 (31%)
17 (40°1o)
10 (23°/o)
Cases
Pulmonar changes
20
Results and Discussion
Clinical Symptomatology The literature reports 40 cases with SBH both genotypical and acquired [1-t 1, 14-23, 25-30, 32-34, 36-39, 41, 43-48, 50-53, 55-60]. With the addition of the present 23 cases, the total number is now about 60. This number, however, increases if we consider also the very recent investigations of Takahashi [53, 54] on a new form of ceroid-like granuloma of the gall bladder and the frequency of an associated SBH in chronic myeloid and acute granulous leukemias. The analysis of the physical symptomatology in our genetically determined SBH patients (Table 1) shows that only 7 out of 13 presented various pathological manifestations: large or moderate splenomegaly: 7 cases; haemorrhagic diathesis: 4 cases. In 4 of these patients both manifestations were present. Only 2 patients presented a moderate hepatomegaly in association with a large sptenomegaly. Other pathological features were tung miliary involvement (Fig. 1) in 2 siblings (Car. family), both spleno-hepatomegalic and one with sporadic jaundice attacks; pinguecola (mother of patient Luc. Serv.) ; association of heterozygous fl-thalassemia in 3 SBH carriers (Rol. family), one of them was also suffering from severe sideropenic hypochromic anemia with achytia. If our genotypical cases compared are with all
N. Quattrin et al. : Sea Blue Histiocytosis
of them mentioned in the literature (Table 4), we obtain concrete knowledge of the frequency, type and significance of the clinical manifestations associated with SBH. The average age of our patients is 16 years. The data from the literature as well as our own indicate that sex is not relevant. The most frequent symptom present in more than half of all the cases is splenomegaly (sometimes very remarkable). On this point our experience differs from that of Silverstein and Ellefson (1973) and Sawitsky et al. (1973) who affirm that almost all SBHS are characterized by sptenomegaty. We think that this discrepancy is due to the fact that t" ~,se authors had made their analysis on the basis of a selected group of case histories. Splenomegaly in SBHS may be responsible for hypersplenism (leuko-thrombocytopenia) of different degree. The second manifestation is haemorrhagic diathesis, at varying degree, but only exceptionally very severe as in one of our patients (Ang. Rosa). We can assume that this manifestation appears in about 40% of all the described cases. The pathogenesis of haemorrhagic diathesis is generally related to a thrombocytopenia of different degree. The association of splenomegaly with haemorrhagic diathesis represents the most frequent clinical picture; it is in fact associated with SBH in almost 40% of all the genotypical cases until now. Other important clinical manifestations are: lung
Fig. 1. Thorax radiography of pat. Car Stef. Miliary-like changes partially confluent chiefly in the low part of both lungs
N. Quattrin et al. : Sea Blue Histiocytosis
localization (Car. Faro.) which usually remains quite asymptomatic (Fig. 1). Analogous changes have been described in other 5 patients (Sawitsky et al., 1954; Cogan and Federman, 1964; Jones et al., 1970; Pardo-Evans, 1970; D6jardins, 1971). Its frequency may therefore be estimated at 20% in the genotypical cases. As for a clear hepatomegaly, its frequency in our case histories is only 15%; it is on the contrary about 50% if we consider all the cases so far described in the literature. The liver is not usually remarkably enlarged, but there are also some known SBHS cases associated with hepatic cirrhosis (Silverstein, 1964, 1970). Last, but not least in importance, appears the localisation of SBH in the nervous system. Besides the retinal macular involvement found by Cogan and Federman (1964), Winkler et al. (1969), Saidi et aI. (1970) and Wewalka (1950, 1970), severe peripheric as well as central progressive neuropathies have been reported (Levine et al., 1968; Saidi et al., 1970; Lake et al., 1971; Sawitsky et al., 1973; Btankenship et al., 1973). While we did not observe retinal localization in our 13 genotypical cases, we have to point out the severe congenital cerebropathy present in a sister (Regina, Fig. 8) of one of our patients (Ang. family). However, SBH could not be found in her bone marrow (Table 1), but the suspicion of a cerebral SBH involvement seemed to us to be founded. From the clinical viewpoint our analysis in general corresponds in conclusion with the data seen in the literature except for the minor frequency of hepatomegaly. In acquired SBH the symptomatology of the fundamental disease is invariably present. In these cases the presence of SBH is clinically silent (Tables 2 and 3).
21 Table 5. Five families with SBHS: Peripheral blood data Family
Ang.
5erw
Car.
RoL
Pat
RBC and Hb
WBC x 109t[
1
anaemia (+-t÷+)
Leucocytosis with Lymphopenia
3.000
2
e
~
250.000
3
~
e
220.000
1
~
2
~
1
-6.
3.200
90.000
2
9
6.000
250.000
1
4.000 (l.ymphopenia ,,~) ([ymphopenia,++)
4}
60.000 160.000
e
t80.OO0
2
anaemia (÷)
~
350.000
3 4
~ -6,
e O
200000 310.000
& G 4~
& O &
220000 250.000 230 000
-G O
4~ O
195.000 205D00
5 6 Father Sam.
P[atelets x 109/t
1 2
-6-:within normal range
symptomatology. In the acquired forms, however, they are generally scattered and much tess numerous than in the genotypical cases. The cytologic study of SBH must be performed by optical as well as by electron microscopical means. Despite the remarkable amount of research, however, certain features of these thesaurocytes still remain unclear.
Panoptical Stainings shows that the morphologic as6~tologic Findings
pect of SBH is polymorphous though all these cells possess several granules that are sea-blue or sea-green in colour. Our investigations have led us to distinguish
Peripheral Blood (Table 5). Few important changes occur in the genotypical cases. The most remarkable ones are thrombocytopenia (sometimes associated with leukopenia) and, in particular, lymphopenia which was observed in some of our cases. However, we can not agree, with Sawitsky et al. (1973) who affirm that thrombocytopenia is very frequent in SBHS. Only exceptionally is thrombocytopenia severe. In this case splenectomy is necessary. Anemia is not related to SBH. It is present in rare cases; namely in 2 of our patients.
Bone Marrow. This represents the elective site where SBH are observed. These cells are present in variable number not always corresponding with the clinical
Table
6. Differenttypes of SBH according to their stage
1- Early SBH and Sea Blue Hemohistioblas~ 2- Large or gigantic granulous SBH 3- Large or gigantic vesicular or lacunar SBH 4- Partially degranulated or emptied SBH 5- Foamy or spyder's web SBH 6- Spotted SBH
7- SBH with very strong and polymorphous phagocytosis
22
N. Quattrin et al. : Sea Blue Histiocytosis
Fig. 2. Spleen smear from splenectomy (pat. Car. Stef.) Generalized high birefringence of SBH ( x 200)
Fig, 3. The same of Figure 2. Ultraviolet autofluorescence. Moderate to strong positivity of some SBH
seven types of SBH as reported in Table 6. In general, all of these types are not present in the same individual. Sometimes, however, we were able to observe several stages of SBH development on a same slide, from the early histiocyte to the gigantic forms filled with sea-blue granules or in strong p o l y m o r p h o u s phagocytosis. This latter type is very characteristic because of the simultaneous phagocytosis of platelets, erythrocytes, erythroblasts, and leukocytes. F r o m this viewpoint it represents the most famished and polym o r p h o u s thesaurocyte known today.
On Dark Field. SBH show a very remarkable flat birefringence and appear like a narrow spider's web with polygonal features (Fig. 2). Autofluorescence Microscopy findings show some discrepancy. In these last few years, however, several authors (Sawitsky et al., 1973; Castoldi et al., 1974; Baumgartner and Bucher, 1975; Magrini et al., 1975) have pointed out the strong diffuse autoftuorescence of SBH. In general we can agree with this finding (Fig. 3).
N. Quattrin et al. : Sea Blue Histiocytosis
23
Fig. 4. Electron microscopy of removed spleen (pat. Car, Stef.) x 9.000. The SBH cytoplasm is filled with myelinic figures (lamellar bodies) and lipid little drops enveloped by a membrane
Table 7. Five families with SBHS: Bone marrow cytology Family-Pot,
[ Sea-blue
histiocytes
Other histi°cytesJPIosmacells[Histi°'Pl°'smal'" c e t t u b r i s t e t s l M ° ~ ¢" e u[s"
gas
i
Remarks
!
Ang
1 Sister
RoL
+ +
++
+
4~
-6-
Flaming plasmacells. S m a l l SBH Mocrophages with erythroblosts
2
id.
+
+
4)-
+
4}
++
3
id.
~
@
+
"0"
"8"
"8"
++
++
+++
++ +
-e-
+++
Serv. t Dough.
Car,
++
2 Mother
.
1 Brother
++++
. -8-
.
. 43-
.
-8-
. 4)
++
2 Sister
++++
-0-
-G
G
4}
+
] Mother
++
-6-
+ +
+ +
+
+÷
2 Dough. 3 Son
÷+ +
"8" +
+ + +
~O" 4}
+ -8-
4)÷+
4 Dough.
÷
-8-
++
-e'-
+
++
5
id.
++
-e-
+
+ +
-8-
+
6
id.
÷*
÷
+
$
-e-
+
Father Sam. 1 Son 2 Father
-8-
+ +
+
+
-8-
4)-
+++
-8-
÷
~
+
++
+
+
++
-G
+ +
++
-e- = n o r m o [ o r a b s e n t
4} M o c r o p h o g e s with e r y t h r o b t o s t s Flaming plosmacells She r e f u s e d m y e [ o b i o p s y (prob, c a r r i e r ) SBH with p o n - p h o g o c y t o s i s idem Moderate dyserythropoiesis idem
SBH p h o g o c y t i z i n g
ptate[ets
Dyserythropoiesis with mu[tinuctearity
H i s t i o c y t e s with n o n SB p h a g d c y t o s i s {} SBH with ptotelets p h o g o c y t o s i s
24
N. Quattrin et at. : Sea Blue Histiocytosis
Fig. 5. Same as Figure 3. Besides some myelinic figures and several vacuoles, two thrombocytes (Th.) and one erythrocyte (Er.) are visible in the SBH cytoplasm
Cytochemical Investigations were performed by the majority of authors who attended at SBHS. Among the numerous cytochemicat tests, the most differentially prominent are PAS and Sudan Black B. As a matter of fact SBH give a strongly positive reaction with these stainings. We agree with this behaviour. Some discrepancy results from an analysis of the data found in the literature regarding Sudan Black B since the positivity of this staining may depend also on the type of preparation. Other common stains (Toluidine-blue, Astra-btue, Perts, acide and alcatine phosphatase, AS-D chloracetate esterase, peroxidase, Feulgen) do but very rarely, give positive results:
UItrastructurat Investigations. Etectronmicroscopical studies have been performed till now only in a few cases of SBH (Kattlove et al., t970; Rywling et al., 1971; Jacobsen and Gjone, Magallon et al., 1973; Hopfner et al., 1974). Our results in this field generally agree with the data from the literature: SBH are characterized by a heterogeneous stored material. Their cytoplasm appears filled with vacuoles and a lot of round formations, various in size and sometimes confluent (Fig. 4, 5). Also are lamellar bodies (Revel et al., 1959; Ruska, 1963) frequent. Moreover, the cytoplasm contains erythrocytes, platelets and erythroblasts and sometimes leukocytes, too. The remarkable
N. Quattrin et al.: Sea Blue Histiocytosis
25
Fig. 6. Bone marrow aspirate of pat. Car. Stef. May-Grfinwald Giemsa stain ( x 1000). Typical reticulo-plasmacellular islet
heterogeneity of the ultrastructural picture of SBH agrees with their panoptical one.
Other Myelobioptic Findings. Table 7 reports certain cytologic findings that usually accompanied the presence of SBIt. They refer to a remarkable polymorphous hyperplasia and hyperactivity of almost all the reticulo-endothetial system. Prominent features of this were the presence of plasma cells, even flaming in type, and reticuloplasmacellular islets (Fig. 6), and the phagocytosis of erythroblasts by common histiocytes. The remarkable plaslnacellular hyperplasia might be related to a dysgammaglobulinemic picture which we observed in some of our cases. Eosinophilia was also frequent and sometimes a moderate mastocytosis as well. It should also be pointed out that this polymorphous R.-E. hyperplasia was present in a parent of the Rol. family who had no SBH. Splenic and tlepatic Findings. In one of our splenectomized patients (Car. Stef.) the spleen was entirely filled with SBH (Fig. 7) while the liver showed the same picture in the small granulomatous yellow formations scattered on its surface. In another splenectomized patient (Ang. Rosa) the spleen, instead of showing SBH, presented several areas of extramedullar myelopoiesis.
Enzymatic investigations Until now, we know of two genotypic SBHS, which are clinically and metabolically different, namely the usual form, studied here, and another one identified by Norum and Gjone (1967, 1972). This latter is determined by a deficiency of plasma lecithin cholesterol acyltransferase (Table 9). Important biochemical and pathophysiological investigations on this enzyme have been performed recently by Scherer (1974).
Genetic Features Thirteen of our twenty-three cases belong to the hereditary type of SBHS. The problem of SBHS genotypical pattern remains still open. Three categories should be considered, namely: hereditary forms, hereditary asymptomatic carriers, acquired conditions (Table 9). The genotypical patterns of the first two forms are still unclear. In our 5 families (Fig. 8--11) it seems that sometimes the SBH stigma is recessive and sometimes dominant in type. This uncertainty agrees with the data contained in the literature. Our Rol. family provided very interesting material because, for the first time, we were able to observe the association of SBH with/3-thalassemia in the same subjects. This combination can be explained by the richness of thalassemic (Quattrin and Ventruto, 1974)
26
N, Quattrin et al. : Sea Blue Histiocytosis
Fig. 7. Spleen smear (pat. Car, Stef.) x 800. Strong hyperptasia of SBH often degranulated Table 8. Sea-blue histiocyte-like cells
Type
Place
Disease
Cytoplasm
a) Blue CeLts
Bone Marrow
Chr. Myel. Leukemia
b) Transition-CelLs between Blue CeUs and Gaueher's Cells
Bone Marrow
idem
Gaucher's Celts with some blue-like inclusions
c) Foam Celts
Spleen
Cooley's D~,eo~e
Sea-Blue Histiocyte- Like
d) Lipid-laden Hisl,iocytes
Spleen
ldiop, thrombocytopenic purpura
Generic lipidic storage with phagocytosis of ptatetel,s PAS neg.
Phagocytizing granulocytes and their residual
a) Sundberg el" aL (1964), Dosik el, a1..(1973); b) Dosik et aL(1973); c) Bettrami et aL.(1973); d)Landing et al.. (1961), Dollberg et al.. (1965), Firkin et aL(1959), Rywtin et al.(1971).
and SBH stigmata in the same area. In fact, Campania today represents the region with the largest number of SBH cases in the world.
Therapy A valid therapy against SBH proliferation does not exist. Some cases, however, do not require any treat-
merit. Only complications should be treated. A m o n g these the most important is hemorragic thrombocytopenia due to hypersplenism. According to Sawitsky et al. (1973), six such patients have undergone splenectomy. I f we add Cazal's (1971) and Magrini's (1975) cases as well as our two patients, at least ten cases have been splenectomized up to now. This number represents about 25% of all SBHS now observed. We should also point out that in one of our splenec-
27
N. Quattrin et al. : Sea Blue Histiocytosis Table 9. Conditions and diseases with SBH Main symptoms
Place of the SBH
Condition or disease
Authors
Hereditary but asymptomatic
Bone marrow and/or spleen
none
Several authors
Acquired (per se asymptomatic)
Bone marrow and/or spleen
Ac. Myetobtastic Leukemia Ac. Basophilic Leukemia Ac. Myelo-monocytoide Leukemia Blastic Crisis of Chronic Myeloid Leukemia
Quattrin et al. Takahashi
Chronic Myeloses
Zach and Zach
Chronic Myetoid Leukemia
Hopfner et aI. Quattrin et al., Takahashi
Herrick's Disease
Kattlove et al.
Polycytemia and Myelomatosis
Sawitsky et al.
Hyperlipidemias
Imoto et al. Yamamoto et al.
Intestinal blastoma (?)
see in Silverstein and Ellefson
Myeloproliferative Syndromes
Karayatcin et al. Banmgartner and Bucher
M. Hodgkin
Baumgartner and Bucher
M. Werthof
Baumgartner and Bucher Quattrin et at.
Ceroid-like granulom of gallbladder
Takahashi
Spleno-(hepato)-megaly with purpura and/or thrombocytopenia
Bone marrow spleen, liver, lungs
Hereditary SBHS (the most common form)
Silverstein and Sawitsky Quattrin et al,
Hyper-dyslipidemia with absence of esterified cholesterol and lack of c~-lipoprotein proteinuria normocromic (hemolytic) anemia
Bone marrow spleen kidneys (foam cells)
Familial Plasma-Lecythin Cholesterol Acyltransferase Deficiency
Gjone and Norum
i
[]
I............Q "Regina. (16ys)
"Rosa,, (14ys)
"Giovanr~,, (9ys) (6ys)
(]~ Sea-blueHistiocytes in the Bone Marrow (~) Oligophrenia [ ] 0 Normal
Kiln. Wschr. 56, 17-30 (1978)
© Springer-Verlag 1978
Originalien Sea Blue Histioeytosis. A Clinical Cytologic and Nosographie Study on 23 Cases N. Quattrin, L. De Rosa, S. Quattrin Jr. and A. Cecio Department of Haematology and Social Centre for Leukemias, Cardarelli Hospital, Naples (Head: Prof. Nevio Quattrin), Italy
Meerblaue ttistozytose. Eine klinisch-zytologisehe und nosographische Studie an 23 Fiillen Zusammenfassung. An 23 Ffillen sowie Daten der Literatur (etwa 40 F~ille) untersuchen die Autoren die hauptsfichlichen klinischen, zytologischen und nosographischen Aspekte yon Krankheitszustfinden und Syndromen, die mit Sea-Blue Histiozytosis (SBH) einhergehen. Es mfissen 3 Krankheitsformen yon SBH unterschieden werden: hereditfire Erkrankungen; heredit~ir asymptomatische F o r m ; erworbene und asymptomatische Form. Vom klinischen Standpunkt ist um die Hfilfte weniger aller Ffille von SBH als hereditfir einzustufen. Sie bieten ein Syndrom, welches auf Splenomegalie und periodischer haemorrhagischer Diathese (infolge wechselnder Thrompozytopenie) basiert und nicht selten mit Hepatomegalie und Verfinderungen der Lungen oder des Nervensystems (h~ufig mit Beteiligung der Augen) einhergeht. Es gibt auBerdem eine zweite hereditfire Form von SBH, welche sehr selten ist und sich klinisch yon der ersten F o r m unterscheidet. Sie ist charakterisiert dutch einen Mangel yon Plasma-Lecithin-Chotesterin-Acetyltransferase. Die speziellen Eigenschaften des SBH-Syndroms werden besprochen aufgrund licht- und elektronenmikroskopischer sowie zytochemischer Untersuchungen, welche das polymorphe Aussehen dieser ,,verhungerten" Makrophagen betonen. Das in SBH-ZeIlen gespeicherte Material ist heterogen, und der enzymatische Defekt der h/iufigsten Form yon SBIt ist noch unbekannt. Der Befund von SBH-Zellen bei verschiedenen Bluterkrankungen hat eine analoge Bedeutung wie der Nachweis yon Gaucher-Zellen, die au!3erhalb der Gaucher'schen Krankheit gefunden werden. Die Existenz von 2 definierten Formen yon SBH kann heute nicht mehr bestritten werden. Offprint requests to: Prof, Dr. N. Quattrin (address see above)
Schliisselw6rter: Eine neue Glyko-Lipidose, die meerblaue Hystiocytose - Genotypische Formen - Erworbene Zust~nde - Ktinische Symptomatologie Zytologische Forschungen - Nosographische Bemerkungen - Identitfit der meerblauen Histiozytose. Summary. The authors examine the main clinical, cytologic and nosographic aspects of conditions and syndromes associated with SBH on the basis of the literature data (about 40 cases) and 23 personal ones. It is necessary to distinguish between three nosological conditions of SBH : hereditary disease, hereditary asymptomatic, acquired per se asymptomatic. From the clinical viewpoint less a half of all SBH cases are hereditary and present a syndrome based on splenomegaly0 periodic hemorrhagic diathesis (due to variable thrombocytopenia), not rarely associated with hepatomegaly and lung or nervous system changes (often eyes are involved). There is also a second SBH hereditary form, vary rare and clinically different from the former, determined by deficiency of plasma-lecitin-cholesterol acyltransferase. The peculiar features of SBH are discussed by means of optical, cytochemical, electron microscopical investigations which point out the polymorphous aspect of these " f a m i s h e d " macrophages. The material stored by SBH is heterogeneous and the enzymatic defect of the most frequent form still remains obscure. The presence of SBH in different haemopathies has an analogous significance as Gaucher's cells found outside Gaucher's disease. It is impossible today to deny the existence of two well-identified SBHS. Key words: A new glyco-lipidosis: the Sea-Blue Histiocytosis - Genotypical forms - Acquired Conditions - Clinical features - Cytological studies Nosographic discussion - Identity of S-B Histiocytosis.
18
N. Quattrin et aI.: Sea Blue Histiocytosis
The Sea-Blue Histiocytes (SBH) represent the last type of macrophages observed for the first time by Moeschlin in 1947 [32]. The knowledge of this singular thesaurocyte has gradually increased only in the last few years. The topic is very interesting but also strongly debated. In fact, there are still contrasting opinions on such points as the nature of the stored
material, the clinical symptomatology of a Sea-Blue Histiocytosis Syndrome (SBHS) and its nosologic identity, the pattern of genetic inheritance, the relation to other glyco-lipidoses. The aim of our study is to contribute to a better understanding of SBH and SBHS on the basis of our wide experience in this field of research.
Table 1. Five families with SBHS: clinical data
(first exam.)
Ang. (1970)
Serv. (1971)
Car. (1972)
RoL (1974)
Som. (1974)
megoJy
Hemorrhagic diathesis
[ Other symptoms I
+
e
very severe cure.co-mucous
S. S.
~ ~)
-9 ~-
severe anemia ~ severe cerebropathia
27
SO.
+++
~)
~
(~
58
M.
-
periodic cutaneous-mucous pinguicula on the
1 (Sled
d'
16
B.
. ++ +
+*
non severe periodic cutaneous-mucous
2(An.)
9
8
S.
+++
++
~
I(D.~N) 2(H.C.)
Q ~
40 23
M. So.
++ t
-
3(Ca.) 4(An.) 5(R~) 6(Pa.)
d' o ~
20 12 8 4
Sa SO. So. So.
-9~g ~
-e" ~e
~-
1 (Hi.) 2 (Ag.)
(:/' c#
6 35
So. E
+++ .9-
~ ~
recurrent cutaneous -e-
Cose
Sex
(yr,)
Relationo) megaly
I (Ros.)
~
14
S.
2 (C,io.) (*) 3 (Reg.)
9 9
9 16
1 (LUc.)
9
(*) 2 (Mad.)
-
Remarks improved by. splenectomy cured by Azathioprine osymptomatic -G
--
sometimes jaundice recovery by splenectomy milbry lung picture milicu'y lung picture
-~
~ carrier of rJ-Th hypochromicsideropeni( carrier of B-Th anemia with achyl.ia -~ carrier of 13-Th
~) ~
g-
(=) F. (Father), M. (Mother), B.(Brother), S(Sister), So. (Son) (*) Case not proved Normal or absent Table 2. Ten cases of acquired SBH: Clinical data Case (first exam.)
Sex
Age (yr)
Splenomegaly
Hepatomegaly
Hemorrhagic Diathesis
Other Symptoms
Disease
I.P.A.
9
35
G
G
-8
very severe
Ac. myeloblastic Leukemia
2. S.C.
~
40
0
0
severe cutaneousmucous
very severe anemia
Ac, promyelocytic basophilic Leukemia
3. F.P.
9
62
+++
+
O
4. B.A.
6'
76
+ +
O
O
cutaneous leukemides
Ac. myelo-monocytoide Leukemia
5. D.B.
d'
40
+ + +
mild
cxachexia
Blastic crisis by chr. myeloid Leukemia
6. S.F.
~
40
+++
O
O
Chr. myeloid leukemia
7. P.R,
$
4
8. M,C.
d
9. Z.B.
10. A.M.
+ +
Chr. myeloid Leukemia
4-
O
t)
O
Ac. myeloblastic Leukemia
60
++
+++
0
0
Chr. myeloid leukemia
~
11
t}
O
O
cutaneous and mucous
M. Werlhof
2
14
t~
0
bruising
0
M. Werlhof
N. Quattrin et al.: Sea Blue Histiocytosis
19
Material and Methods From April 1971 till March 1976, we observed 23 cases with SBH, 13 of which were genotypical and 10 of the acquired type. This represents the quite largest number of SBH cases gathered until now by a single medical group. Our genotypical cases came from 5 non-related families. One of these also carried /3-thalassemia. For all the patients we proceded to: (I) a careful investigation of their respective families, (2) a cytologic study by means of panoptical and cytochemicaI stains and, in certain cases, by electron microscopy. The main haematologic as well a s clinical features are reported in Tables 1-4.
SBH was found in the bone marrow of all patients. In one patient (Car. Stef.) it was also observed in the removed, very enlarged, spleen, and in the liver; in two others of acquired form (Z.B. and A.M. Table 3) only in the spleen. A complete enzymatic study was performed by Professor Van Hoof of Louvain on the hepatic tissue drawn from a patient (Car. Stef.) during a splenectomy. The results did not demonstrate a specific defect but only an increase of certain acid hydrolases with the meaning of a generic lysosomial disturbance. An investigation performed by Professor Durand of Genoa on the urine Iipides of all the six patients in the Rol. family did not show any positive features.
Table 3. Ten cases of acquired SBH : Main hematological data Case
Hb (g/dl)
RBC x 101z/1
WBC x 109/1
Platelets x 109/I
Myetobioptic finding 1. P.A.
4.5
1,3
5.6
30.0
Myeloblastic-promyelocytic proliferation with partial conservation of the megacarhyocytic system. Not rare scattered SBH (small vesicular in type).
2. S.C.
5.0
1.6
7.9
5.0
Diffuse proliferation of basophlilic promye!c~cytes with a lot of Auer's rods. Rare scattered SBH (granulous-macular in type).
3. F.P.
12.5
4.0
250.0
255.0
Metaplastic granulocytic proliferation. Scattered SBH (with large pachychromatic granula). Gaucher-like cells absent.
4. B.A.
10.0
3.0
18.0
90.0
Monocytoide and promyelocytic proliferation with partial conservation of the normal systems. Rare granulous gigantic SBH.
5. D.B.
10.0
3.1
63.0
33.0
Complete myeloblastic metaplasia. Numerous scattered SBH (also early forms).
6. S.F.
14.4
5.2
11.4
300.0
Complete granulous metaplasia, Rare SBH macular in type. Absence of Gaucher's cells.
7. P.R.
8.0
3.9
55.0
100.0
Myeloblastic diffuse infiltration. Some granulous SBH with gigantic granules are present.
8. M.C.
11.2
4.4
70.0
50.0
Metaplastic granulocytic proliferation. Some granulous SBH gigantic in type.
9. Z.B.
12.0
4.9
i0.8
5.0
10. A.M.
12.4
4.6
9.4
10.0
Smear of spleen by splenectomy Scattered, but not rare, large SBH sometimes phagocytising neutrophils. Nmnerous granulous SBH gigantic in type,
Table 4. Main semiophysicat features of SBH syndrome according to personal and from literature collected cases
a g e ( y r.) Max. Min. Average
Sex M. F.
Spleno- Hep~to- Hemorrhages a . t o . megaly megaty thrombocytopenia
23 Si[verstein and EUefson (1973)
60
3
26
11
12
22 (95°/o)
16 (70%)
? (30%)
3 (13 %)
36 Sawitsky etal. (1973)
83
1
21
~
-6-
30 (83°/°)
16 (44°/°)
very frequent
8 (22°/°)
13 our cases (1971-1974)
40
4
16
6
7
? (51°/°)
2 (15°/°)
4 (30°/°)
2 (15°/°)
42 all cases (known until 1974)
83
4,
31
20 22
28 (66°/o).
13 (31%)
17 (40°1o)
10 (23°/o)
Cases
Pulmonar changes
20
Results and Discussion
Clinical Symptomatology The literature reports 40 cases with SBH both genotypical and acquired [1-t 1, 14-23, 25-30, 32-34, 36-39, 41, 43-48, 50-53, 55-60]. With the addition of the present 23 cases, the total number is now about 60. This number, however, increases if we consider also the very recent investigations of Takahashi [53, 54] on a new form of ceroid-like granuloma of the gall bladder and the frequency of an associated SBH in chronic myeloid and acute granulous leukemias. The analysis of the physical symptomatology in our genetically determined SBH patients (Table 1) shows that only 7 out of 13 presented various pathological manifestations: large or moderate splenomegaly: 7 cases; haemorrhagic diathesis: 4 cases. In 4 of these patients both manifestations were present. Only 2 patients presented a moderate hepatomegaly in association with a large sptenomegaly. Other pathological features were tung miliary involvement (Fig. 1) in 2 siblings (Car. family), both spleno-hepatomegalic and one with sporadic jaundice attacks; pinguecola (mother of patient Luc. Serv.) ; association of heterozygous fl-thalassemia in 3 SBH carriers (Rol. family), one of them was also suffering from severe sideropenic hypochromic anemia with achytia. If our genotypical cases compared are with all
N. Quattrin et al. : Sea Blue Histiocytosis
of them mentioned in the literature (Table 4), we obtain concrete knowledge of the frequency, type and significance of the clinical manifestations associated with SBH. The average age of our patients is 16 years. The data from the literature as well as our own indicate that sex is not relevant. The most frequent symptom present in more than half of all the cases is splenomegaly (sometimes very remarkable). On this point our experience differs from that of Silverstein and Ellefson (1973) and Sawitsky et al. (1973) who affirm that almost all SBHS are characterized by sptenomegaty. We think that this discrepancy is due to the fact that t" ~,se authors had made their analysis on the basis of a selected group of case histories. Splenomegaly in SBHS may be responsible for hypersplenism (leuko-thrombocytopenia) of different degree. The second manifestation is haemorrhagic diathesis, at varying degree, but only exceptionally very severe as in one of our patients (Ang. Rosa). We can assume that this manifestation appears in about 40% of all the described cases. The pathogenesis of haemorrhagic diathesis is generally related to a thrombocytopenia of different degree. The association of splenomegaly with haemorrhagic diathesis represents the most frequent clinical picture; it is in fact associated with SBH in almost 40% of all the genotypical cases until now. Other important clinical manifestations are: lung
Fig. 1. Thorax radiography of pat. Car Stef. Miliary-like changes partially confluent chiefly in the low part of both lungs
N. Quattrin et al. : Sea Blue Histiocytosis
localization (Car. Faro.) which usually remains quite asymptomatic (Fig. 1). Analogous changes have been described in other 5 patients (Sawitsky et al., 1954; Cogan and Federman, 1964; Jones et al., 1970; Pardo-Evans, 1970; D6jardins, 1971). Its frequency may therefore be estimated at 20% in the genotypical cases. As for a clear hepatomegaly, its frequency in our case histories is only 15%; it is on the contrary about 50% if we consider all the cases so far described in the literature. The liver is not usually remarkably enlarged, but there are also some known SBHS cases associated with hepatic cirrhosis (Silverstein, 1964, 1970). Last, but not least in importance, appears the localisation of SBH in the nervous system. Besides the retinal macular involvement found by Cogan and Federman (1964), Winkler et al. (1969), Saidi et aI. (1970) and Wewalka (1950, 1970), severe peripheric as well as central progressive neuropathies have been reported (Levine et al., 1968; Saidi et al., 1970; Lake et al., 1971; Sawitsky et al., 1973; Btankenship et al., 1973). While we did not observe retinal localization in our 13 genotypical cases, we have to point out the severe congenital cerebropathy present in a sister (Regina, Fig. 8) of one of our patients (Ang. family). However, SBH could not be found in her bone marrow (Table 1), but the suspicion of a cerebral SBH involvement seemed to us to be founded. From the clinical viewpoint our analysis in general corresponds in conclusion with the data seen in the literature except for the minor frequency of hepatomegaly. In acquired SBH the symptomatology of the fundamental disease is invariably present. In these cases the presence of SBH is clinically silent (Tables 2 and 3).
21 Table 5. Five families with SBHS: Peripheral blood data Family
Ang.
5erw
Car.
RoL
Pat
RBC and Hb
WBC x 109t[
1
anaemia (+-t÷+)
Leucocytosis with Lymphopenia
3.000
2
e
~
250.000
3
~
e
220.000
1
~
2
~
1
-6.
3.200
90.000
2
9
6.000
250.000
1
4.000 (l.ymphopenia ,,~) ([ymphopenia,++)
4}
60.000 160.000
e
t80.OO0
2
anaemia (÷)
~
350.000
3 4
~ -6,
e O
200000 310.000
& G 4~
& O &
220000 250.000 230 000
-G O
4~ O
195.000 205D00
5 6 Father Sam.
P[atelets x 109/t
1 2
-6-:within normal range
symptomatology. In the acquired forms, however, they are generally scattered and much tess numerous than in the genotypical cases. The cytologic study of SBH must be performed by optical as well as by electron microscopical means. Despite the remarkable amount of research, however, certain features of these thesaurocytes still remain unclear.
Panoptical Stainings shows that the morphologic as6~tologic Findings
pect of SBH is polymorphous though all these cells possess several granules that are sea-blue or sea-green in colour. Our investigations have led us to distinguish
Peripheral Blood (Table 5). Few important changes occur in the genotypical cases. The most remarkable ones are thrombocytopenia (sometimes associated with leukopenia) and, in particular, lymphopenia which was observed in some of our cases. However, we can not agree, with Sawitsky et al. (1973) who affirm that thrombocytopenia is very frequent in SBHS. Only exceptionally is thrombocytopenia severe. In this case splenectomy is necessary. Anemia is not related to SBH. It is present in rare cases; namely in 2 of our patients.
Bone Marrow. This represents the elective site where SBH are observed. These cells are present in variable number not always corresponding with the clinical
Table
6. Differenttypes of SBH according to their stage
1- Early SBH and Sea Blue Hemohistioblas~ 2- Large or gigantic granulous SBH 3- Large or gigantic vesicular or lacunar SBH 4- Partially degranulated or emptied SBH 5- Foamy or spyder's web SBH 6- Spotted SBH
7- SBH with very strong and polymorphous phagocytosis
22
N. Quattrin et al. : Sea Blue Histiocytosis
Fig. 2. Spleen smear from splenectomy (pat. Car. Stef.) Generalized high birefringence of SBH ( x 200)
Fig, 3. The same of Figure 2. Ultraviolet autofluorescence. Moderate to strong positivity of some SBH
seven types of SBH as reported in Table 6. In general, all of these types are not present in the same individual. Sometimes, however, we were able to observe several stages of SBH development on a same slide, from the early histiocyte to the gigantic forms filled with sea-blue granules or in strong p o l y m o r p h o u s phagocytosis. This latter type is very characteristic because of the simultaneous phagocytosis of platelets, erythrocytes, erythroblasts, and leukocytes. F r o m this viewpoint it represents the most famished and polym o r p h o u s thesaurocyte known today.
On Dark Field. SBH show a very remarkable flat birefringence and appear like a narrow spider's web with polygonal features (Fig. 2). Autofluorescence Microscopy findings show some discrepancy. In these last few years, however, several authors (Sawitsky et al., 1973; Castoldi et al., 1974; Baumgartner and Bucher, 1975; Magrini et al., 1975) have pointed out the strong diffuse autoftuorescence of SBH. In general we can agree with this finding (Fig. 3).
N. Quattrin et al. : Sea Blue Histiocytosis
23
Fig. 4. Electron microscopy of removed spleen (pat. Car, Stef.) x 9.000. The SBH cytoplasm is filled with myelinic figures (lamellar bodies) and lipid little drops enveloped by a membrane
Table 7. Five families with SBHS: Bone marrow cytology Family-Pot,
[ Sea-blue
histiocytes
Other histi°cytesJPIosmacells[Histi°'Pl°'smal'" c e t t u b r i s t e t s l M ° ~ ¢" e u[s"
gas
i
Remarks
!
Ang
1 Sister
RoL
+ +
++
+
4~
-6-
Flaming plasmacells. S m a l l SBH Mocrophages with erythroblosts
2
id.
+
+
4)-
+
4}
++
3
id.
~
@
+
"0"
"8"
"8"
++
++
+++
++ +
-e-
+++
Serv. t Dough.
Car,
++
2 Mother
.
1 Brother
++++
. -8-
.
. 43-
.
-8-
. 4)
++
2 Sister
++++
-0-
-G
G
4}
+
] Mother
++
-6-
+ +
+ +
+
+÷
2 Dough. 3 Son
÷+ +
"8" +
+ + +
~O" 4}
+ -8-
4)÷+
4 Dough.
÷
-8-
++
-e'-
+
++
5
id.
++
-e-
+
+ +
-8-
+
6
id.
÷*
÷
+
$
-e-
+
Father Sam. 1 Son 2 Father
-8-
+ +
+
+
-8-
4)-
+++
-8-
÷
~
+
++
+
+
++
-G
+ +
++
-e- = n o r m o [ o r a b s e n t
4} M o c r o p h o g e s with e r y t h r o b t o s t s Flaming plosmacells She r e f u s e d m y e [ o b i o p s y (prob, c a r r i e r ) SBH with p o n - p h o g o c y t o s i s idem Moderate dyserythropoiesis idem
SBH p h o g o c y t i z i n g
ptate[ets
Dyserythropoiesis with mu[tinuctearity
H i s t i o c y t e s with n o n SB p h a g d c y t o s i s {} SBH with ptotelets p h o g o c y t o s i s
24
N. Quattrin et at. : Sea Blue Histiocytosis
Fig. 5. Same as Figure 3. Besides some myelinic figures and several vacuoles, two thrombocytes (Th.) and one erythrocyte (Er.) are visible in the SBH cytoplasm
Cytochemical Investigations were performed by the majority of authors who attended at SBHS. Among the numerous cytochemicat tests, the most differentially prominent are PAS and Sudan Black B. As a matter of fact SBH give a strongly positive reaction with these stainings. We agree with this behaviour. Some discrepancy results from an analysis of the data found in the literature regarding Sudan Black B since the positivity of this staining may depend also on the type of preparation. Other common stains (Toluidine-blue, Astra-btue, Perts, acide and alcatine phosphatase, AS-D chloracetate esterase, peroxidase, Feulgen) do but very rarely, give positive results:
UItrastructurat Investigations. Etectronmicroscopical studies have been performed till now only in a few cases of SBH (Kattlove et al., t970; Rywling et al., 1971; Jacobsen and Gjone, Magallon et al., 1973; Hopfner et al., 1974). Our results in this field generally agree with the data from the literature: SBH are characterized by a heterogeneous stored material. Their cytoplasm appears filled with vacuoles and a lot of round formations, various in size and sometimes confluent (Fig. 4, 5). Also are lamellar bodies (Revel et al., 1959; Ruska, 1963) frequent. Moreover, the cytoplasm contains erythrocytes, platelets and erythroblasts and sometimes leukocytes, too. The remarkable
N. Quattrin et al.: Sea Blue Histiocytosis
25
Fig. 6. Bone marrow aspirate of pat. Car. Stef. May-Grfinwald Giemsa stain ( x 1000). Typical reticulo-plasmacellular islet
heterogeneity of the ultrastructural picture of SBH agrees with their panoptical one.
Other Myelobioptic Findings. Table 7 reports certain cytologic findings that usually accompanied the presence of SBIt. They refer to a remarkable polymorphous hyperplasia and hyperactivity of almost all the reticulo-endothetial system. Prominent features of this were the presence of plasma cells, even flaming in type, and reticuloplasmacellular islets (Fig. 6), and the phagocytosis of erythroblasts by common histiocytes. The remarkable plaslnacellular hyperplasia might be related to a dysgammaglobulinemic picture which we observed in some of our cases. Eosinophilia was also frequent and sometimes a moderate mastocytosis as well. It should also be pointed out that this polymorphous R.-E. hyperplasia was present in a parent of the Rol. family who had no SBH. Splenic and tlepatic Findings. In one of our splenectomized patients (Car. Stef.) the spleen was entirely filled with SBH (Fig. 7) while the liver showed the same picture in the small granulomatous yellow formations scattered on its surface. In another splenectomized patient (Ang. Rosa) the spleen, instead of showing SBH, presented several areas of extramedullar myelopoiesis.
Enzymatic investigations Until now, we know of two genotypic SBHS, which are clinically and metabolically different, namely the usual form, studied here, and another one identified by Norum and Gjone (1967, 1972). This latter is determined by a deficiency of plasma lecithin cholesterol acyltransferase (Table 9). Important biochemical and pathophysiological investigations on this enzyme have been performed recently by Scherer (1974).
Genetic Features Thirteen of our twenty-three cases belong to the hereditary type of SBHS. The problem of SBHS genotypical pattern remains still open. Three categories should be considered, namely: hereditary forms, hereditary asymptomatic carriers, acquired conditions (Table 9). The genotypical patterns of the first two forms are still unclear. In our 5 families (Fig. 8--11) it seems that sometimes the SBH stigma is recessive and sometimes dominant in type. This uncertainty agrees with the data contained in the literature. Our Rol. family provided very interesting material because, for the first time, we were able to observe the association of SBH with/3-thalassemia in the same subjects. This combination can be explained by the richness of thalassemic (Quattrin and Ventruto, 1974)
26
N, Quattrin et al. : Sea Blue Histiocytosis
Fig. 7. Spleen smear (pat. Car, Stef.) x 800. Strong hyperptasia of SBH often degranulated Table 8. Sea-blue histiocyte-like cells
Type
Place
Disease
Cytoplasm
a) Blue CeLts
Bone Marrow
Chr. Myel. Leukemia
b) Transition-CelLs between Blue CeUs and Gaueher's Cells
Bone Marrow
idem
Gaucher's Celts with some blue-like inclusions
c) Foam Celts
Spleen
Cooley's D~,eo~e
Sea-Blue Histiocyte- Like
d) Lipid-laden Hisl,iocytes
Spleen
ldiop, thrombocytopenic purpura
Generic lipidic storage with phagocytosis of ptatetel,s PAS neg.
Phagocytizing granulocytes and their residual
a) Sundberg el" aL (1964), Dosik el, a1..(1973); b) Dosik et aL(1973); c) Bettrami et aL.(1973); d)Landing et al.. (1961), Dollberg et al.. (1965), Firkin et aL(1959), Rywtin et al.(1971).
and SBH stigmata in the same area. In fact, Campania today represents the region with the largest number of SBH cases in the world.
Therapy A valid therapy against SBH proliferation does not exist. Some cases, however, do not require any treat-
merit. Only complications should be treated. A m o n g these the most important is hemorragic thrombocytopenia due to hypersplenism. According to Sawitsky et al. (1973), six such patients have undergone splenectomy. I f we add Cazal's (1971) and Magrini's (1975) cases as well as our two patients, at least ten cases have been splenectomized up to now. This number represents about 25% of all SBHS now observed. We should also point out that in one of our splenec-
27
N. Quattrin et al. : Sea Blue Histiocytosis Table 9. Conditions and diseases with SBH Main symptoms
Place of the SBH
Condition or disease
Authors
Hereditary but asymptomatic
Bone marrow and/or spleen
none
Several authors
Acquired (per se asymptomatic)
Bone marrow and/or spleen
Ac. Myetobtastic Leukemia Ac. Basophilic Leukemia Ac. Myelo-monocytoide Leukemia Blastic Crisis of Chronic Myeloid Leukemia
Quattrin et al. Takahashi
Chronic Myeloses
Zach and Zach
Chronic Myetoid Leukemia
Hopfner et aI. Quattrin et al., Takahashi
Herrick's Disease
Kattlove et al.
Polycytemia and Myelomatosis
Sawitsky et al.
Hyperlipidemias
Imoto et al. Yamamoto et al.
Intestinal blastoma (?)
see in Silverstein and Ellefson
Myeloproliferative Syndromes
Karayatcin et al. Banmgartner and Bucher
M. Hodgkin
Baumgartner and Bucher
M. Werthof
Baumgartner and Bucher Quattrin et at.
Ceroid-like granulom of gallbladder
Takahashi
Spleno-(hepato)-megaly with purpura and/or thrombocytopenia
Bone marrow spleen, liver, lungs
Hereditary SBHS (the most common form)
Silverstein and Sawitsky Quattrin et al,
Hyper-dyslipidemia with absence of esterified cholesterol and lack of c~-lipoprotein proteinuria normocromic (hemolytic) anemia
Bone marrow spleen kidneys (foam cells)
Familial Plasma-Lecythin Cholesterol Acyltransferase Deficiency
Gjone and Norum
i
[]
I............Q "Regina. (16ys)
"Rosa,, (14ys)
"Giovanr~,, (9ys) (6ys)
(]~ Sea-blueHistiocytes in the Bone Marrow (~) Oligophrenia [ ] 0 Normal
