Leukemic reticuloendotheliosis. A clinicopathologic study with review of the literature

REVIEW

Leukemic Reticuloendotheliosis.

A Clinicopathologic

Study with Review of the Literature

ISA0

KATAYAMA,

HARVEY

M.D.

E. FINKEL, M.D

Boston. Massachusetts

From the Departments of Pathology and Medicine, Boston University Medical Center, Boston, Massachusetts; and Department of Pathology, St. Vincent Hospital, Worcester, Massachusetts, and the Greater Lawrence Community Cancer Program, Lawrence, Massachusetts. Requests for reprints should be addressed to Dr. I. Katayama, Department of Pathology, St. Vincent Hospital, 25 Winthrop Street, Worcester, Massachusetts 01610. Manuscript accepted October 4, 1973.

The salient clinical and pathologic features of leukemic reticuloendotheliosis are evaluated in our 13 patients and in 98 patients described in the literature. Leukemic reticuloendotheliosis affects mainly male adults whose chief clinical manifestations are related to pancytopenia and splenomegaly. Splenomegaly is nearly constant and frequently massive, whereas lymphadenopathy is infrequent and skin involvement rare. Characteristic pathologic changes are present in the bone marrow, spleen and liver. Splenectomy often leads to remission; chemotherapy is not beneficial in most cases and is probably to be discouraged. The entity deserves recognition because the optimal clinical management is different from that of other forms of leukemia and lymphoma. Bouroncle, Wiseman and Doan published in 1958 [l] a classic paper on leukemic reticuloendotheliosis in which 26 patients with a strikingly uniform disease picture were described. Subsequently, two additional series of leukemic reticuloendotheliosis were reported under the terms “reticulum cell leukemia” and “hairy cell [2,3]. Some workers, however, made a diagnosis of leukemia” leukemic reticuloendotheliosis in patients who, in our view, probably had other hematologic malignancies [4-81. Confusion in semantics and lack of pathologic criteria have hampered a wider recognition of leukemic reticuloendotheliosis as a distinct clinicopathologic entity. In the past 3 years, we studied 13 patients with leukemic reticuloendotheliosis. In general, the diagnosis in our patients was made earlier than in most reported series, partly due to the utilization of the sensitive histochemical test for the demonstration of tartrateresistant acid phosphatase activity in tumor cells of those suspected of having the disease [ 9-1 I]. Our purpose here is to report the clinical, hematologic and pathologic findings in these 13 patients and to review the literature for acceptable cases of leukemic reticuloendotheliosis, and thus to try to define the clinicopathologic features of leukemic reticuloendotheliosis. MATERIALS

AND METHODS

was comprised of 13 patients, most of whom were referred to us from neighboring hospitals. The diagnosis of leukemic reticuloendo-

Our series

theliosis was based on the demonstration of the pathognomonic neOPlaStic lymphoid reticulum cell in blood or bone marrow 1121 which is hereafter referred to as “LRE cell.” The patients were examined, clinical records reviewed, follow-up data obtained, and hematologic and histopathologic

materials reviewed.

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LEUKEMIC RETICULOENDOTHELIOSIS-KATAYAMA.

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The surgical specimens (11 spleens, 7 bone marrow biopsy specimens, 4 lymph nodes and 6 liver biopsy specimens) and autopsy material (Cases 2 and 7) were fixed in formalin, embedded in paraffin and cut at 8 p. Sections were stained with hematoxylin and eosin, Gomori’s reticulum or Masson’s trichrome stains. The tartrate-resistant acid phosphatase reaction was performed on at least one specimen from each patient (method in reference [IS]). Specimens (most biopsy specimens mentioned plus 2 bone marrow aspirates, 5 peripheral blood buffy coats and autopsy material) were also fixed in glutaraldehyde, embedded in Epon, cut at 1 to 2 p and stained with toluidine blue for light microscopy [ 141. We reviewed the reports of other investigators with particular reference to the descriptions of their case records regarding clinical, hematologic and pathologic findings. Cases were accepted as leukemic reticuloendotheliosis primarily on the basis of adequate morphologic descriptions of the diagnostic LRE cells, although in the cases thus selected from the literature clinical and pathologic features were remarkably homogeneous. CLINICAL PICTURE OF OUR 13 PATIENTS (TABLE I). The patients

in our series were predominantly

middle-

aged and included 10 men and 3 women. Four sought medical attention for unrelated problems, leading to the discovery of asymptomatic splenomegaly or abnormal blood counts. In three additional patients, the symptoms were minimal. Presenting symptoms of anemia or thrombocytopenia related to hypersplenism occurred in six and four patients, respectively. Massive splenomegaly probably produced symptoms in two patients, a sense of abdominal fullness in one and a left inguinal hernia in the other. Infections were present at the time of presentation in four patients; disseminated aspergillosis in one, a rectal fistula in another, a draining pilonidal cyst and superficial herpes simplex in a third, and superficial herpes simplex in a fourth. Aside from the signs of the complications just described, abnormal physical findings were virtually limited to splenomegaly which was massive in seven patients and moderate in five. Notable by its absence was lymphadenopathy. Significant laboratory findings not listed in Table I included tartrate-resistant acid phosphatase isoenzyme 5 [ 91 in all patients, abnormal platelet function in the seven patients appropriately tested, markedly increased leukocyte alkaline phosphatase in three, an accelerated erythrocyte sedimentation rate in five, normal karyotypes in four and folate deficiency in one. There was no particular abnormality of serum proteins. Treatment consisted of chemotherapy only (Cases 4 and 7), splenectomy only (Cases 8, 9, 11 and 12) chemotherapy and splenectomy (Cases 1, 3, 5, IO and 13) and splenic radiation, chemotherapy and splenectomy (Cases 2 and 6). In cases with combined therapies, chemotherapy preceded splenecto-

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my in three (Cases 2, 6, and 13), splenectomy preceded chemotherapy in three (Cases 3, 5 and lo), and chemotherapy was given before and after splenectomy in one (Case 1). Chemotherapy and/or splenic radiation were administered to some patients (Cases 2, 3, 5 and 13) because of initial misdiagnosis, e.g., lymphosarcoma for Case 3 in 1954, which was later revised to leukemic reticuloendotheliosis. In more recent cases the patients were treated only by splenectomy. Improvement occurred after splenectomy in 9 of 11 patients in whom this operation was performed. The two who did not show improvement died 5 (Case 1) and 9 months (Case 10) after splenectomy. No long-term benefit resulted from chemotherapy in the nine patients who received it, except for a temporary improvement in one (Case 4). Of the total 13 patients, 4 patients were dead at the time of study and 1 patient was being considered for splenectomy because of continuing transfusion requirement. The remaining eight patients were in symptomatic remission as long as 19 years (Case 3). Apparently remission followed splenectomy in all eight cases. CLINICAL PICTURE OF 98 PREVIOUSLY CASES (TABLE II)

REPORTED

There were 79 males and 14 females (sex was not described in 5 patients), with a male to female ratio of approximately 6 to 1. Age of the patients ranged from 30 to 83 years, with an average of 53 years. Physical examination revealed splenomegaly, hepatomegaly and lymphadenopathy, respectively, in 90 (92 per cent), 31 (31 per cent) and 24 (24 per cent) patients. Hematologically, most patients showed pancytopenia. In 63 patients from the three largest series combined [l-3], 50 patients were anemic, 37 leukopenic and 59 thrombocytopenic. Thus the incidence and degree of cytopenia were highest in platelets and lowest in leukocytes. The white cell count actually varied considerably: of 92 patients with documented white cell counts, 55 had counts below 5,000/mm3, 28 between 5,000 and 15,000/mm3 and 9 over 15,000/mm3. The four highest counts recorded were 38,000 [2], 43,100 [3], 127,000 [15] and 134,000/mm3 [ 11. The ratio of LRE cells in the differential cell count varied between 0 to 99 per cent at different times for a given patient as well as among the different patients. Of 85 patients with known follow-up, 49 had died and 36 were still alive. Of the 49 deaths, 17 occurred in less than a year, 23 between 1 and 5 years and 9 after 5 years with 5 deaths occurring more than 13 years after onset [ l-3,15]. Of the 27 documented causes of death, 17 were related to infection and 3 resulted from massive hemorrhage. Transition from leukemic reticuloendotheliosis to other forms of leu-

42,M

32,F

56,M

2

3

4

Case and No. Sex _.._____ 1 47,M

Age (yr>

TABLE I

Congestive heart failure due to anemia

Massive splenomegaly found after child birth

Fatigue, abdominal fullness

Anorexia, weight loss, sweats, chills

Presenting Symptoms

Pallor, wide mediastinum by x-ray

AA

LSA

Massive spleno-

megaly, perioral herpes simplex

CLL

LRE

Massive splenomegaly

Splenomegaly, hepatomegaly

Initial Diagnosis* (%)

12 0.2

9.0 (0.8)

28

(0.8)

(40)

(37)

1.4

28

2.6 (1.7)

mm3) 34 (48)

(%)

Neutrophils

48

3.0 (7.0)

2-28 (9.8)

1.4

18 (40)

40 (25)

46

? (40)

47 (75)

35 (37)

(%)

30

87 (197)

51 (250)

122 (150)

mm‘)

Plater lets LRE Cells (i< 10X:

~_~~ ~______

(Z)(E)

(%)

White Blood Cells (x lo”/

Blood Counts Before Splenectomy (After Splenectomy)

Reticutoencbthetiosis

Packed Cell ReticUIOVolume cytes

with Leukemic

Initial Physical FIndings

Data on Our 13 Patients

Dry (40)

Dry?, nearly complete replacement by LRE cells

(82)

(80)

Bone Marrow (% replaced by LRE cell)

.

3,380

3,450

975

(8)

Weight of Spleen

Vincristine, steroids, androgen

Chlorambucil

Steroids, splenic radiation

Chlorambucil, vincristine, steroids

Specific Therapy

Chemotherapy resulted in transient benefit and several complications; severe anemia requires transfusions:

Since splenectomy patient has remained well except for one episode of pneumonia with hemolysis and one of almost complete marrow suppression by chlorambucil

After 5 years well being postsplenectomy, patient became anemic and required transfusion; serum hepatitis developed and patient died of liver failure

Systemic symptoms and abnormal blood counts continued despite therapy; died with disseminated aspergillosis and LRE

Course

Alive (13 mo)

Alive (210 mo)

Dead (126 mo)

Dead (13 mo)

Follow-up (survival)

Weakness

41,M

8

Fatigue, dyspnea, perineal pain, diarrhea

-

40,M

Splenomegaly discovered during physical examination

7

54, M

6

Fatigue, dyspnea, ankle edema, bruising, epistaxis

LSA

LRE

Splenomegaly, ecchymoses, rectal fistula

LRE

RCS

Splenomegaly, pallor, herpes simplex on nose, pilonidal sinus

Massive splenomegaly

Massive splenomegaly

Initial Physical Findings

Initial Diagnosis’ 2.8 (0.8)

1.7 (5.6)

mm3)

White Blood Cells (xlOt/

,::,

19

1.2 (0.8)

2.5

(16’::)

3.5

(Z)(Z) (ii)

13 (43)

(%)

Packed Cell RetieVoluloume cytes (%)

Reticuloendotheliosis

(3)

16

12

(36)

83

40

79 (22)

19

60 (40)

(%)

LRE Cells

(54)

24 (42)

(%)

Neutrophils

Blood Counts Before Splenectomy (After Splenectomy)

Data on Our 13 Patients with Leukemic

Presenting Symptoms

-~

38,F

5

Age (yr) Case and No. Sex

TABLE I (cont’d)

(120)

25

33

(211)

16

23 (465)

mm,‘)

Platelets (xlOa/

Dry, nearly complete replacement by LRE cells

Nearly complete replacement by LRE cells

(65)

Dry nearly complete replacement by LRE cells

Bone Marrow (% replaced by LRE cell)

520

topsy)

1,110 (au-

1,175

2,920

(g)

Weight of Spleen

Pneumonia, urinary tract infection and sepsis developed; splenectomy resulted in improvement; active and working since None

Alive (15 mo)

(2 mo)

Dead

Therapy was of no substantial benefit, but might have intensified leukopenia; died of pulmonary aspergillosis Vincristine, steroids

mo)

Alive (96

Initial therapy with steroids and splenic radiation was of no help; purpura developed; splenectomy relieved symptoms and patient has remained well since Steroids, splenic radiation

Vincristine, cyclophosphamide, steroids

Alive (78 mo)

Course Pancytopenia improved after splenectomy; mild mediastinal and cervical lymphadenopathy was unresponsive to chemotherapy; patient has remained well

Specific Therapy

Follow-up (survival)

.z a $ P

F 2 2

m

6 3 m 2

2

LEUKEMIC RETlCULOENDOTHELlOSlS-KATAYAMA.

FINKEL

0

z

I

!a 'a I

3

ID

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119

et al.

Trubowitz et al. 1971 (211 Ghadially, Skinnider 1972 [40]

VI

[201 Skarin et al. 1971

.

10.5-11.5 ..,

73,F

9.4

8.0 11.9 7.1 11.3 7.0 Anemic (11/12 patients)

Anemic (19/25 patients)

9.9 ...

10.5 9.6 10.5 10.0 10.0 8.0 (average)

5.1 5.0

Anemic (20/26 patients)

(g/100 m f)

0.2-0.5

11.0-13.0

1.9

12.4

6.0 2.3 0.9 1.6 5.1 1.1-43.1

Leukopenic (15/25 patients)

3.6

2.9 2.6 127.0 7.8 7.1 4.7 1.3 4.2 2.5 (average)

3.2-18.8

Leukopenic (15/26 patients)

White Blood Cells

.

Described

51.0

...

..

70.0

Thrombocytopenic (22125 patients) 30.0 60.0 67.0 60.0 60.0-120.0 Thrombocytopenic (11/12 patients) 80.0

.

97.0 53.0 62.0 120.0 48.0 8.0 (average)

. ...

. .

Thrombocytopenic (26/26 patients)

Platelets

Blood Counts (X 10”/mms)

Reticuloendotheliosis

Hemoglobin

55,M

47,M

Padilla,

Soloff 1971

(12M)

64,M 41,M 55,M 35,M 47,M 37-78

[31

Plenderleith

1970

1 4

Rubin et al. 1969 [41] Berg, Brandt 1970

[171

25

(421 Lee et al. 1969 [2]

34-83 (21M,4F)

48,M 51,M

1161

Schrek, Donnelly 1966 [18] Boiron et al. 1968

Yam et al. 1968 (231 Beachey et al. 1969

31-76 (21M,5F)

83,M 54,M 52,M 55,F 55,F 42,F 68,M 46,M 30-64 (lOM,lF)

1 1

26

Age (yr) and Sex

Rabinowitz, Schrek 1962 (651 Matsui 1963 (151 James, Goodwin 1964 [19]

IQ1

Mitus et al. 1961

Bouroncle 1958 [II

No. of Patients

Data on 98 Patients with Leukemic

Reference

TABLE II

+

+

+

+

patients)

+ + + + + + v/12

+ (21125 patients)

+ +

+ + + + + + + + + (1001 patients)

+ (5/5 patients)

+ (25/26 patients)

.

-

patients)

+ (S/12

+

-

l/2 patients)

+ (about

+ ...

+ + (3/11 patients)

.. .. ... .. ... (11/U patients)

alive

dead (24 mo)

. . +

(12 mo)

alive (32 mo)

mo) alive (24 mo)

mo) 7 dead (l-156

9 alive (< 12-204 mo), 16 dead (<12-180 mo) dead (36 mo) alive (3 mo) alive (8 mo) alive (12 mo) alive (36 mo) 5 alive (12-156

. .

..

,,.

+

.. .. ... . . . ..

...

... +

~(ll/ll patients)

... .

500-3.800 (6 spleens)

(g)

Weight of Spleen

3,300

2,900

900 600-1,690 (4 spleens)

2,000 870

1,100-l, 600 (6 spleens)

dead (3 mo) dead (8 mo) dead (156 mo) 2,450 alive (72 mo) alive (48 mo) alive (36 mo) alive (24 mo) alive (16 mo) 750 1 alive (36 mo) 5 dead (6-45 mo) 5 lost (660 mo) 2,940

...

... ... . ...

9 alive (<12-84 mol), 16 dead (i 12-190 mo), I lost (?)

Follow-up (survival)

+ (3/26 patients)

Skin Involvement

-

-

-

+ (5/12 patients)

... -

patients)

+ (9125

...

-

...

-

...

... + +

+ (9/26 patients)

Lymphadenopathy

+ (5126 patients)

Splenomegaly Hepatomegaly

in the Literature

6

LEUKEMIC AETlCULOENDOTHELlOSlS-KATAYAMA,

kemia or lymphoma was not recorded except for one instance in which reticulum cell sarcoma developed [ 121. The survival time in the 36 survivors terminally ranged from 3 months to 17 years, with 3 patients surviving over 13 years [2,3]. The modes of treatment included blood transfusion, radioactive phosphorus-32, steroids, alkylating agents, vinca alkaloids and splenectomy. Long-term or temporary improvement followed splenic radiation [ 16- 191, vincristine [ 2,191, cyclophosphamide [ 201, [ 16,171 and splenectomy [ 16,18,2 l-231. steroids Because of possible spontaneous remission in some cases [2], as well as the extreme variability in the severity of disease among the patients, it is difficult to evaluate the relative merits of different therapies, and probably more studies are necessary for the final analysis. However, in recent reviews on this subject, splenectomy rather than chemotherapy is recommended for hypersplenism [3,11]. Data on many other cases reported in the literature were not included in Table II because sufficient cytologic descriptions of the leukemic cells were lacking. However, the clinical and pathologic features in many of them were highly suggestive of leukemic reticuloendotheliosis [24-3 11. Although diagnosed as leukemic reticuloendotheliosis by the investigators, some patients were so young [4-6,32,33], the course of disease so acutely fatal [8,34] or so atypical in other clinical or histochemical aspects [7,35371 that the diagnosis of leukemic reticuloendotheliosis would seem to be most unlikely. PATHOLOGY OF LEUKEMIC RETICULOENDOTHELIOSIS LRE

Cells.

(Inset, Figure

In Romanovsky stained preparations l), LRE cells were of medium size, usu-

ally measuring to be eccentric was markedly

FINKEL

10 to 18 p in diameter. Nuclei tended in location. The nuclear configuration variable ranging from the most fre-

quently observed oval form to dumbbell, horseshoe and clover-leaf shapes. The nuclear membrane was heavy and distinct, and the chromatin pattern was more open than in mature lymphocytes and less so than in blast forms. Nucleolar features were variable, being prominent in about half of the LRE cells but quite inconspicuous in others. The cell border was characteristically serrated in all LRE cells, with the pathognomonic long cytoplasmic villi recognizable in occasional cells. In the cytoplasm of some of the LRE cells, azurophilic granules were present; and, in addition, intracytoplasmic inclusions [38] were demonstrated occasionally in preparations from a few patients. Phase contrast microscopy readily revealed the pathognomonic lace-like projections and also numerous mitochondria [ 121. Histologic sections (Figure 2) showed LRE cells with cytology essentially similar to that in Romanovsky stained preparations. Electron microscopy (Figure 1) demonstrated multiple mitochondria, lamellate ergastoplasm, Golgi apparatus, centrioles, numerous vesicles (lysosomes), ribosome-lamella complexes and cytoplasmic villi measuring up to 4 p in length [39]. Spleen. The weight of our 11 splenectomy specimens ranged from 335 to 4,000 g, with 4 spleens weighing more than 2,000 g. The weight of the 24 spleens detailed in Table II ranged from 500 to 3,800 g, with 12 spleens (50 per cent) weighing more than 2,000 g. Healed or recent infarcts were frequently observed: otherwise the cut surface was homogeneously dark red and meaty. Definite tumor nodules were not seen. Microscopic examination disclosed diffuse proliferation of LRE cells (Figure 3). Conges-

Figure 1. An LRE cell with long cy-toplasmic villi and multiple ribosome-lamella complexes (arrows). Electron micrograph; original magnification X 10,000, reduced by 12 per cent. Inset, an LRE cell. Wright-Giemsa stain; original magnification X 1,300O reduced by 12 per cent. From Katayama et al. 1391, reproduced by permission of the American Journal of Pathology.

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Figure 2. Epoxy section from huffy coat of peripheral blood (Case 11). All nucleated cells in this field are LRE cells, which are characterized by variable nuclear configuration, occasional prominent nucleoli, and hairy cytoplasmic borders. Toluidine blue stain; original magnification X 1,400, reduced by 25 per cent.

Figure 3. Section- of spleen (Case ii) shows diffuse infiltration with LRE cells. The normal architecture is hardly recognizable except for an attenuated trabecula. Hematoxylin and eosin stain; original magnification X 73, reduced by 25 per cent.

Figure 4. Epoxy section of spleen (Case 1) shows LRE cells, erythrocytes and a few histiocytes with phagocytized debris in the cytoplasm (arrows). Toluidine blue stain; original magnification X 800, reduced by 25 per cent.

Figure 5. Section of bone marrow (Case 4). In otherwise normal marrow, there is a focus of LRE cell infiltration which is indicated between large and small arrows. The same lesion is marked likewise by two arrows in Figures 6 and 7. Hematoxylin and eosin stain; original magnification X 140, reduced by 25 per cent.

tion was marked, and focal hemorrhage was frequent. The Malpighian follicles were atrophic or absent. The trabeculas were slender and sparse, and E >me were infiltrated by LRE cells. The sinusoids \rl .re difficult to recognize, as they were masked by the heavy infiltration of LRE cells. Study of epoxy embedded sections (Figure 4) revealed phagocytic histiocytes scattered among LRE cells. These histiocytes differed cytologically from LRE cells, and the possibility of their being altered LRE cells during active phagocytosis could be excluded by morphologic criteria. Erythrophagocytosis by LRE cells was not observed. Of particular importance was the rarity of mitoses and the lack of cytologic atypicality, points also stressed by other investigators [ 16,171, al-

though mitoses were relatively frequent in one instance (Case 8). Most investigators [2,3,15, 18,21,40] did not elaborate on the splenic histopathology beyond noting leukemic infiltration. Some workers made a diagnosis of lymphosarcoma or equivalent descriptions [ 1,17,19,22]. Malpighian follicles were generally atrophic [ 1,231; hypertrophy of Malpighian follicles would probably favor an alternative diagnosis of lymphosarcoma. Extramedullary hematopoiesis may be present [2,17] or absent [ 161. Bone Marrow. The bone marrow was always infiltrated by LRE cells. In the early stage (Figures 5 and 6) there was only an occasional area of LRE cell infiltration surrounded by normal marrow. The early small focus of LRE cell infiltration was made evident

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LEUKEMIC RETICULOENDOTHELIOSIS-KATAYAMA, FINKEL

Figure 6. A magnified view of the same section as Figure 5 shows presence of LRE cells mixed with lymphocytic infiltration. Hematoxylin and eosin stain; original magnification X 550, reduced by 25 per cent.

Figure 6. Section of bone marrow (Case 9) with more advanced involvement than in Figures 5, 6 and 7. Almost all nucleated cells here are LRE cells, which are loosely packed and show no mitoses. A persisting megakaryocyte is visible in one corner. Hematoxylin and eosin stain; original magnification X 880, reduced by 25 per cent.

with reticulum stain, which revealed an increase of fine reticular meshwork (Figure 7). In the more advanced stages (Figure 8), the bone marrow was extensively replaced by proliferating LRE cells. The cells were usually less densely packed than in infiltrates in lymphosarcoma or chronic lymphatic leukemia. Mitosis of LRE cells was rare. Many authors [i-3,16,18,40,41] emphasized the importance of bone marrow biopsy as opposed to aspiration since, after repeated unsuccessful or hypocellular aspiration, the biopsy usually revealed a hypercellular marrow with numerous LRE cells and dense reticulin fibrosis. Liver. The liver was often slightly to moderately enlarged. No circumscribed tumor was seen at the time

The same field shown in Figures 5 and 6 reveals increase of reticulin fibers in the area of LRE cell infiltration. Gomori’s reticulum stain; original magnification X 3 70, reduced by 25 per cent.

Figure 7.

of splenectomy. At autopsy, however, nodular areas of leukemic infiltration were present, ranging in diameter from 0.3 to 2.5 cm in Case 2, and up to 0.2 cm in Case 7. On microscopic examinations of the liver biopsy specimen isolated cells or clusters of LRE cells were present diffusely in the sinusoids and portal tracts, and occasional foci of densely packed LRE cells were noted in the dilated space of Disse. In the later stage as observed at autopsy, nests of LRE cells invaded the hepatic parenchyma and were grossly recognizable as circumscribed tumor. Both portal and sinusoidal infiltration by LRE cells were described [ 1,3,22], but circumscribed tumor had not been previously recorded. Lymph Nodes. No lymph node biopsy as such was performed in our series. All the perisplenic lymph nodes obtained from the splenectomy specimens (Cases 1, 5, 10 and 13) were of normal size, but they showed leukemic infiltration ranging from focal aggregation of LRE cells to almost complete obliteration of normal architecture, thus simulating lymphosarcoma very closely. Of the two autopsies, enlargement of para-aortic lymph nodes up to 3 by 1.5 by 0.5 cm with leukemic infiltration was found in Case 2 and no enlargement of lymph nodes was found in Case 7. A biopsy diagnosis of lymphosarcoma or an equivalent description (complete loss of normal architecture) was made by some workers [ 1,201, whereas only minimal lymph node enlargement was noted at autopsy by others [ 15,401. Skin. None of the patients in our series had skin manifestations, and skin biopsy was not performed. In only 5 of 98 previously reported cases were skin lesions documented. In two instances the presence of LRE cells in the skin lesions was proved by phase microscopy [20,42]. In the remaining three cases skin lesions were described as being infiltrative [ 11. July 1974

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DIFFERENTIAL DIAGNOSIS Malignant Lymphoma. The fact that a pathologic diagnosis of lymphosarcoma or reticulum cell sarcoma was made on biopsies from patients with LRE [ 19,20,22] is more indicative of the pathologist’s unfamiliarity with the entity than of diagnostic difficulties. In contrast to other lymphomas, leukemic reticuloendotheliosis as a rule shows very little mitotic activity, cytologic atypia, necrosis or phagocytosis. Furthermore, in the spleen and lymph nodes the basic architecture remains unaltered until very late, despite heavy LRE cell infiltration. In the bone marrow, cellular infiltrates are often less densely packed than in lymphosarcoma or chronic lymphocytic leukemia. Histiocytic Medullary Reticulosis (Malignant Histiocytosis). This is a rapidly fatal disease, with death occurring within 6 months after onset in most patients. The clinical picture is characterized by profound systemic symptoms including fever, wasting and jaundice. Generalized lymphadenopathy and hepatosplenomegaly are present. Histopathologic studies reveal diffuse proliferation of morphologically atypical histiocytes with prominent erythrophagocytosis and frequent mitosis in the lymph nodes, liver, spleen and bone marrow [43,44]. Areas of necrosis, hemorrhage and fibrin deposition are present [45]. Abnormal histiocytes may circulate in the blood [43,46]. By contrast, leukemic reticuloendotheliosis is a chronic disease with insidious onset and vague symptoms. The patients are often able to perform their normal functions. Lymphadenopathy is uncommon. Microscopic studies rarely show erythrophagocytosis, mitosis or necrosis. histiocytosis,” Under the heading of “malignant Rappaport [47] included both histiocytic medullary reticulosis and leukemic reticuloendotheliosis, and he described a wide spectrum of possible histopathologic alterations in order to accommodate several heterologous disorders. Hence, the four cases of malignant histiocytosis reported by Liao et al. [48] were neither typical histiocytic medullary reticulosis nor by any means typical leukemic reticuloendotheliosis. On the contrary, two cases considered to be histiocytic medullary reticulosis by Scamps et al. [27] were instead suggestive of leukemic reticuloendotheliosis. Schilling’s Monocytic Leukemia (Histiocytic Leukemia). The classic Schilling type of monocytic leukemia can be readily distinguished from leukemic reticuloendotheliosis by its fulminating course, overtly leukemic blood picture, and the cytologic characteristics of the abnormal cells [49,50]. In contrast, chronic monocytic leukemia, a rare and poorly defined variant of Schilling’s leukemia, may simulate leukemic reticuloendotheliosis very closely; both diseases are characterized by a chronic course, leuko-

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penia, anemia, minimal lymphadenopathy and moderate to marked splenomegaly [49,51,52]. Differential diagnosis, therefore, rests on identification of the abnormal cells in the blood or bone marrow. A negative muramidase [ 171 and positive tartrate-resistant acid phosphatase reaction [ 1 l] may help in excluding monocytic leukemia. Reticulum Cell Sarcoma Terminating in Acute Leukemia. Leukemic transformation is a relatively rare complication in the course of reticulum cell sarcoma. It occurred in 6 of 113 [53] and 2 of 40 cases [54] of reticulum cell sarcoma. Leukemic reticulum cell sarcoma and leukemic reticuloendotheliosis can be differentiated not only by the clinical picture, but also by the pathologic mononuclear cells present in the blood. In a tabulation of cases from the literature, Lowenbraun et al. [55] excluded two of six cases in Zeffren’s series [53] with an interpretation that they represented leukemic reticuloendotheliosis, but in our view the two cases were indeed leukemic reticulum cell sarcoma and not leukemic reticuloendotheliosis. A few workers [7,56] have Sbzary’s Syndrome. postulated that Sezary’s syndrome is no more than a clinical variant of leukemic reticuloendotheliosis. The presence of reticuloendothelial cells in the blood, involvement of skin and lymph nodes, and the chronic course were the basis for this hypothesis. However, involvement of the bone marrow is exceptional in Sezary’s syndrome [57] and constant in leukemic reticuloendotheliosis, whereas involvement of skin and lymph node is constant in Sezary’s syndrome and uncommon in leukemic reticuloendotheliosis. Moreover, Sezary cells and LRE cells are distinctively different cytologically. COMMENTS We have reviewed the literature and have been able to find 98 well documented cases of leukemic reticuloendotheliosis. To these, 13 cases of our own are added. It is clear that leukemic reticuloendotheliosis is a distinct clinicopathologic entity to be distinguished from other lymphomas and leukemias. The pathognomonic LRE cell is characterized by the hairy appearance and tartrate-resistant acid phosphatase activity. The role of the LRE cell in the diagnosis of leukemic reticuloendotheliosis appears analogous to that of Reed-Sternberg cells in Hodgkin’s disease in that the cell is essential for diagnosis but a proper clinicopathologic background is also necessary [ 581. The clinical picture is so characteristic that the disease can be suspected on this basis alone. The pathologic features are likewise very characteristic, and the diagnosis can be ascertained by histopathologic observation. The term “leukemic reticuloendotheliosis” was

LEUKEMIC RETICULOENDOTHELIOSIS-KATAYAMA. FINKEL

first coined

in 1923

by Ewald

[59]

when

he de-

scribed a case of acute leukemia. This case was later interpreted by many reviewers [49,50,60] to be an example of Schilling’s monocytic leukemia. Subsequently the term became synonymous with Schilling’s monocytic leukemia [61,62] until 1958, when Bouroncle and her associates [l] published their classic paper on leukemic reticuloendotheliosis in which they defined the disease as we understand it today. Since then most investigators have used the term leukemic reticuloendotheliosis in the same context as Bouroncle et al. After Schrek et al. [ 181 introduced the term “hairy cell” for the spectacular appearance of the LRE cell under the phase microscope, leukemic reticuloendotheliosis gained wider recognition [ 631, and a few workers started to call it “hairy cell leukemia” [3,40]. However, in the opinion of Trubowitz et al. [21], with which we concur, it seems practical to adhere to the term “leukemic reticuloendotheliosis,” for most students of the disease prefer it. Moreover, the recent literature does not use leukemic reticuloendotheliosis as a synonym for Schilling’s leukemia, and, above all, a new name [41] would merely add to the semantic confusion. The histogenesis of the LRE cell is controversial. Arguments have been made for both lymphocyte and reticulum cell origin of LRE cells on the basis of functional [ 18,4 11, histochemical [ 12,231 and ultrastructural [40,64] studies. We suspect that the bone marrow plays a major role in producing the LRE cells,

and that the spleen and liver play a secondary role of filtering the cells from the circulating blood and storing them. This hypothesis is based on the observations of early multicentric involvement of the bone marrow, and retention of the normal architecture of the spleen until later stages of the disease, despite massive infiltration by LRE cells. There is relatively little involvement of lymph nodes. Thus, although the question of the site of origin of the LRE cells cannot be considered to be settled, it seems to us that the bone marrow has first claim. Based on this assumption one might wish to add leukemic reticuloendotheliosis to the already established group of myeloproliferative disorders. In this regard, the abnormalities of platelet function and leukocyte alkaline phosphatase are particularly intriguing. ACKNOWLEDGMENT We are indebted to Drs. L. T. Yam and L. Weintraub for their generous collaboration during the progress of this study and to Drs. W. J. Mitus, T. Shirahama and R. A. DeLellis for reviewing the manuscript. We are grateful to Drs. W. H. Crosby, I-l. Fanger, D. Fitzpatrick, A. Gagnon, J. Grassi, J. Hiebel, P. H. Levine, J. Lipkind, W. Murray, R. S. Schwartz, E. Sharp, M. Tavassoli, R. Wenk, P. Wheat and L. Wolsky for allowing us to study their patients and providing us with follow-up data. We thank Mr. Gerald Ribicki for photography and Mrs. Evelyn Teague for secretarial assistance.

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