Leukemia Research 22 (1998) 893 – 898

Hemophagocytic syndrome associated with hematological

neoplasias
Abraham Majluf-Cruz *, Rosa Sosa-Camas, Oscar Pérez-Ramı́rez,
Alejandro Rosas-Cabral, Florencia Vargas-Vorackova, Juan Labardini-Méndez
Department of Hematology, Instituto Nacional de la Nutrición Sal6ador Zubirán, México City, México

Received 15 December 1997; accepted 30 March 1998

Abstract

Hemophagocytic syndrome (HPS) is a reactive process that complicates several diseases including hematological neoplasias
(HN). It has been suggested that HPS may be a negative prognosis factor for neoplastic diseases. In this retrospective analysis,
13 cases with HPS associated to HN were compared with two age, sex, diagnosis, disease stage and treatment matched controls
in order to determine the impact of this syndrome on the survival. Cases with HPS were adult patients with a male:female ratio
of 1:1 and their clinical picture was characterized by fever, lymphadenopathy, hepatosplenomegaly, and pancytopenia. Median
survival since HN diagnosis was 7 and 48 months for the HPS and control groups, respectively (P= 0.0001). In ten patients who
died, median survival after HPS presentation was 1 month. These results suggest that the presence of HPS is a negative prognosis
factor in patients with HN. Due to its high mortality rate, an individualized, early, and intensive chemotherapeutic regimen may
be required for HN complicated with this syndrome. © 1998 Elsevier Science Ltd. All rights reserved.

Keywords: Hemophagocytosis; Hematological neoplasia; Hemophagocytic syndrome; Lymphoproliferative diseases

1. Introduction For a long time, patients with hemophagocytosis

In 1939 Scott and Roob-Smith [1] described a clinical
entity characterized by fever, wasting, generalized
lymphadenopathy, hepatosplenomegaly and pancytope-
nia. Histopathologically, histiocytes were found phago-
cytosing blood cells. This syndrome was called
histiocytic medullary reticulosis and later, malignant
histiocytosis (MH). Initially, MH was considered a
primary disease [2], but later it was associated with
other neoplastic illnesses [3 – 5].
Abbre6iations: MH, malignant histiocytosis; VAHS, virus-associ-
ated hemophagocytic syndrome; HPS, hemophagocytic syndrome;
HN, hematological neoplasias; PC, platelet count; PMNs, neu-
trophils; Fg, fibrinogen; AP, alkaline phosphatase; LDH, lactic dehy-
drogenase; WBC, white blood cell counts; PTT, partial
thromboplastin time; PT, prothrombin time; CMV, citomegalovirus;
EBV, Epstein-Barr virus; HV, herpes virus; HBsAg, hepatitis B
surface antigen.
* Corresponding author. Present address: Apartado Postal 12-1100,
Mexico 12, Mexico City, Mexico. Tel.: +52 5 6053369; fax: +52 5
6390069.
were considered carriers of MH. However, neither
pathological findings were always the same, nor was it
possible to adequately define the level of histiocytic
malignancy. Moreover, occasionally, clinical evolution
was not fatal. In 1979, Risdall et al. [6], analyzed 19
patients with viral diseases, a clinical picture suggestive
of MH, and mature histiocytes showing an intense
hemophagocytosis. Because all these changes disap-
peared with the improvement of the viral disease, the
illness was called virus-associated hemophagocytic syn-
drome (VAHS).
Today, classified as primary (hemophagocytic
lymphohystiocytosis) or secondary (associated with a
primary benign or neoplastic disease) [7], the term
hemophagocytic syndrome (HPS) describes a clinical
entity characterized by fever, severe constitutional
symptoms, lymph node enlargement, hep-
atosplenomegaly, and hemophagocytosis in the bone
marrow, spleen or lymph nodes [8]. Skin rash and
pulmonary infiltrates may be present but pancytopenia
is the most frequent finding. Sometimes, HPS is accom-
panied with positive direct Coomb’s test, antinuclear

0145-2126/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.

PII: S0145-2126(98)00083-6
894 A. Majluf-Cruz et al. / Leukemia Research 22 (1998) 893–898
antibodies, disseminated intravascular coagulation or
hypogammaglobulinemia [9 – 11]. The clinical course
depends on the resolution of the primary disease. In
those patients who survive the acute phase of HPS,
improvement begins within 8 weeks, and relapses have
not been documented [9,10]. Sometimes, however, the
evolution of patients with this disorder is worse, result-
ing in highly variable mortality rate during the acute
phase[9].
Based upon a classification of histiocytic abnormali-
ties [12], secondary HPS is considered an entity associ-
ated either to infectious process [13 – 17], autoimmune
disease [18], drugs [19], congenital or acquired im-
munodeficiency [20], myelodysplastic syndrome [21], or
neoplastic illness, including hematological neoplasias
(HN). Based on clinical observations, it has been pro-
posed that HPS could represent a worse prognosis
factor for patients with neoplasia, however, there is no
evidence about its true prognostic value in oncological
diseases.
The aim of this study was to analyze the clinical,
histological, and laboratory characteristics of HPS as-
sociated to HN and to determine the impact of this
syndrome on the clinical outcome of the patients.
2. Patients and methods
The clinical records of 1836 patients with HN (acute
and chronic leukemia, lymphoma, Hodgkin’s disease,
and multiple myeloma) seen in the last 20 years at our
hospital were reviewed. We included those patients with
hemophagocytosis of one, two or three cell lines by
mature histiocytes in the presence of a normocellular or
hypercellular bone marrow, and who fulfilled the crite-
ria for the primary hemophagocytic syndromes [7]:
fever ] 38.5°C for 7 or more days, splenomegaly,
bicytopenia or pancytopenia (HbB10g/dl, platelet
count (PC)B100× 109/l, neutrophils (PMNs)B1×
109/l), and low fibrinogen (Fg) level. At the time of
HPS diagnosis the following data were recorded, age,
sex, presence of other illnesses (including infectious
diseases), constitutional symptoms, hepatomegaly, and
lymphadenopathy as well as, diagnosis, stage, phase
(first treatment or relapse), treatment and follow-up of
the HN. Also, we recorded the results of liver enzymes
(alkaline phosphatase (AP) and lactic dehydrogenase
(LDH)), white blood cell counts (WBC), coagulation
assays (partial thromboplastin time (PTT) and
prothrombin time (PT)), Coomb’s test, antinuclear anti-
bodies, and the hystopathological findings in the bone
marrow, spleen, liver, and lymph nodes. Finally, in
order to determine the presence of simultaneous infec-
tious diseases as the cause of HPS, we recorded the
available data about nasopharyngeal, blood, and urine
cultures as well as the results from serological tests for
viral infections: cytomegalovirus (CMV), Epstein Barr
virus (EBV, IgG anti-EBV nuclear antigen, and/or IgM
anti-EBV viral capside antigen), herpes virus (HV),
hepatitis A and the hepatitis B surface antigen
(HBsAg).
The histopathological classification of the cases was
made based on the International Working Formulation
for lymphoma, the FAB Classification for acute and
chronic leukemia, and the Rye Conference Classifica-
tion for Hodgkin’s disease.
Follow-up since HPS diagnosis was evaluated in
terms of time to last visit and survival status. For those
patients who died, the cause of death was recorded; for
those who were alive, bone marrow aspirates were
re-reviewed for hemophagocytosis. Furthermore, we
performed a histological review of the biopsies available
from each patient in order to confirm the original
hematologic diagnosis and the presence of hemophago-
cytosis. To undertake survival comparisons, two pa-
tients with HN but without HPS (controls) were
matched to each HPS case by age at HN diagnosis, sex,
HN diagnosis, clinical stage and phase of the disease,
and treatment. If treatment was not the same, controls
with a treatment of similar effectiveness were chosen.
Results were summarized in terms of medians and
ranges. To analyze the differences between the groups
we used a X 2-test and a Two-Sample Wilcoxon Rank-
Sum test. Based on HN evolution time, Kaplan-Meier
survival curves were plotted and differences between
the curves were analyzed by means of the log-rank test.
We performed a Cox regression analysis in order to
determine which variables affected the survival. Differ-
ences were statistically significant when PB 0.05.
3. Results
We found 29 cases with hemophagocytosis in the
bone marrow during the last 15 years of the study
period, but only 13 fulfilled the criteria for HPS. The
general characteristics and evolution of the group with
HPS are summarized in Table 1. All were adult subjects
with a median age of 56 years and a male:female ratio
of 1:1. Duration of symptoms before admission was few
days to 4 weeks, and none of them responded to broad
spectrum antibiotics although three patients had evi-
dence of bacterial disease at the time of HPS presenta-
tion (positive blood cultures for P. aeruginosa, E. coli,
S. pneumoniae). Clinical and laboratory data of the
entire group are shown in Table 2. Seven patients had
a Coomb’s test but it was positive in only one patient.
Antinuclear antibodies tests were performed in five
patients and were negative in all of them. Serological
tests for viral infections were performed in 11 patients,
and in four the screening was completely negative. A
total of three patients had a positive anti-EBV IgG test
 A. Majluf-Cruz et al. / Leukemia Research 22 (1998) 893–898 895

Table 1
General characteristics and evolution of patients with hemophagocytic syndrome

n Age (years) Sex HN Clinical stagea HN Cause of death

Follow-up (months)b Survival (months)c

1 30 M HDNS III-B 2 1 HN
2 56 F HDMC II-A 6 1 Sepsis
3 79 M LCL II-B 1 1 HN
4 73 F LCL II-B 5 1 PT
5 48 M HDMC IV-B 3 3 HN
6 68 F HDNS III-A 6 1 HN
7 83 F SNCL II-B 4 1 HN
8 83 M CLL I 20 24
9 53 F HDMC IV-B 12 12
10 39 M HDMC II-B 6 2 Sepsis
11 18 M HDLC III-B 1 56
12 56 F CLL III 2 1 HN
13 44 M HDMC IV-B 8 2 HN

a
at the initial diagnosis of HN or at relapse, according to the staging systems described in Section 2.
b
since HN diagnosis to HPS presentation.
c
After HPS presentation
PT, pulmonary thrombosis; HDNS, Hodgkin’s disease. nodular sclerosis; HDMC, mixed cellularity; LCL, large cell lymphoma; CLL, chronic
lymphocytic leukemia; SNCL, small non-cleaved cell lymphoma; HDLD, lymphocyte depletion.

(cases 3, 8, and 13). One patient (case 4), was HV+ ,
another one was CMV + (case 1), and 2 were HB-
sAg + (cases 2 and 10).
None case with HPS was diagnosed as having MH
and all were associated with active HN. In cases 3 and
11, HPS was found simultaneously with the HN while
cases 9 and 13 had relapsed after an initial remission of
the HN. The remaining patients were under their first
treatment for the HN when HPS appeared. For each
case, the histopathological review confirmed the initial
HN diagnosis. The immunophenotypic characterization
of lymphomas showed a B-cell lymphoma in patients 3
and 7 and a T-cell phenotype in case 4. Case 8, a
chronic lymphocytic leukemia, also had a B-cell pheno-
type as the flow cytometry analysis demonstrated. Bone
marrow aspirates showed hypercellularity in nine cases
and normal cellularity in four. Essentially, all cell lines
were well conserved without evidence of dyspoietic
changes. Hemophagocytosis in the bone marrow biop-
sies was found in only eight cases and it was present in
lymph node and/or spleen biopsies in only seven cases.
A total of three patients had a long-term survival
(cases 8, 9 and 11). They achieved a complete remission
of the HN without subsequent evidence of hemophago-
cytosis in the bone marrow, lymph nodes and/or spleen.
Both HPS and control groups were comparable in
terms of age at HN diagnosis, sex, HN diagnosis,
clinical stage, and phase of the disease. However, cases
and their respective controls were significantly different
in terms of WBC (P = 0.004), PC (P= 0.0002), AP
(P =0.0007) and presence of hepatomegaly (P = 0.001).
A total of 23 non-HPS controls received the same HN
treatment as the HPS cases to whom they were
matched. Among the eight HPS cases with Hodgkin’s
disease, seven received MOPP (Nitrogen mustard, vin-
cristine, procarbazine, and prednisone) and one re-
ceived ChlVPP (Chlorambucil, vinblastine,
procarbazine and prednisone). Patients with lymphoma
received CHOP (Cyclophosphamide, doxorubicin, vin-
cristine, and prednisone), and those with chronic
lymphocytic leukemia received chlorambucil (0.25 mg/
kg per day per 4 days) and prednisone (60 mg/m2 per
day per 4 days) each 4 weeks. One control patient with
Hodgkin’s disease was treated with ChlVPP while his
HPS counterpart received MOPP while two other con-
trol patients with lymphoma received CHOP-
Bleomycin. All chemotherapeutic regimens were
administered at currently accepted doses.
Fig. 1, shows the survival curves for both cases and
controls. Median survival was 7 and 48 months for the
HPS and control groups, respectively (P= 0.0001). Be-
side the presence of HPS, only the differences in Hb,
which were almost different between cases and controls
(P= 0.06), significantly affected the survival for both
groups (P= 0.015).
4. Discussion
Histiocyte abnormalities encompass a broad scope of
clinical syndromes, from benign (spontaneous remis-
sion) to lethal [22]. Hemophagocytosis is a reactive
histiocytic abnormality not always associated with full-
blown HPS. In this review, only 45% of cases with
hemophagocytosis developed HPS. Hemophagocytosis
is likely due to cytokines produced in excess by neo-
896 A. Majluf-Cruz et al. / Leukemia Research 22 (1998) 893–898

Table 2
Clinical and laboratory data at diagnosis of HPS

n F/LN H/S Hb/PC (g/d, ×109/l) WBC/PMNs (×109/l) PT/PTT (s) LDH/AP (IU) Coomb’s test Fg (mg/dl)

1 +/+ +/+ 6.8/6 4.0/0.5 15/36 296/247 105

2 −/+ +/+ 8.9/116 10.0/1.0 18/36 398/425 90
3 +/+ +/+ 10.4/101 4.7/0.8 18/46 540/61 ND ND
4 +/+ +/+ 6.8/45 3.1/0.2 15/37 409/158 + B50
5 +/+ +/+ 8.9/119 2.7/1.4 13/27 342/198 − B50
6 +/− −/− 9.4/25 2.0/0.5 19/45 221/485 105
7 −/+ +/− 8.2/200 6.5/0.8 26/39 291/842 ND 75
8 +/+ +/+ 13.3/150 9.4/1.4 14/36 315/195 130
9 +/+ +/− 14.7/139 2.5/0.1 19/41 255/162 ND 110
10 +/+ +/+ 7.8/5 11.9/3.2 10/32 243/115 210
11 +/+ +/+ 7.3/25 1.2/0.3 13/34 746/298 ND ND
12 +/+ +/+ 4.2/12 0.8/0.1 16/42 556/328 100
13 +/+ +/+ 5.4/16 2.4/1.1 17/56 256/525 ND

F, fever; LN, lymph node enlargement; H, hepatomegaly; S, splenomegaly; ND, not done; IU, international units.

plastic T-cells (T-cell lymphomas), or immunologically
dysregulated T-cells (VAHS or HPS) [23 – 26]. In the
last two entities, cytotoxic T-cells may be activated to
combat infected or neoplastic cells producing histio-
cyte-activating cytokines [9,27]. Then, a cascade of bio-
logical and pathological events may be triggered
resulting in full-blown HPS [28 – 30]. Therefore, it seems
that, depending upon its presence and intensity,
hemophagocytosis could have a role in determining the
clinical presentation of the primary disease; from clini-
cally silent events to fulminant evolutions.
We used the criteria of the Histiocyte Society in
order to diagnose HPS [7]. Although these guidelines
were designed for the primary HPS, they are applied to
clinical settings with a similar picture (secondary HPS).
Our cases had an aggressive picture characterized by
fast evolution, fever, and great malaise resembling pa-
tients previously reported with HPS early in the course
of HN [25,31]. Because our hospital is an adult-care
facility, the patients were middle-age or older contrast-
Fig. 1. Kaplan – Meier survival curves of patients with hematological
neoplasia and hemophagocytic syndrome (HPS) and controls (non-
HPS).
ing with previous studies reporting mostly pediatric
populations. Therefore, our frequency of HN-related
HPS may be under-estimated. HPS diagnosis was com-
pleted with the expected clinical and laboraratory ab-
normalities. Thrombocytopenia was a common finding
likely worsened by a coagulopathy supported by abnor-
mal Fg levels and coagulation tests. The high AP and
LDH levels support liver impairment.
We consider that our patients had a secondary HPS
because of the benign morphological findings of the
macrophages (low nucleus:cytoplasm ratio, absence of
nucleoli, abundant cytoplasm, relatively condensed nu-
clear chromatin, and active hemophagocytosis) [9,32],
and the evidence of HN. For a long time, MH was
classified as a distinct clinical entity, however, today is
considered as a manifestation of the broad spectrum of
the HPS, an uncontrolled hemophagocytic phe-
nomenon leading to a clinical over-expression of the
HPS. Reassessment of cases initially diagnosed as hav-
ing MH has revealed that most of them were indeed
lymphoid neoplasms of T-cell lineage or HPS [31,33].
Moreover, T-cell lymphoma with hemophagocytosis
mimicking MH is difficult to distinguish from benign
HPS clinically and pathologically [33], a fact leading to
propose that previous HPS reports may include cases of
unrecognized T-cell lymphoma. Although challenged by
the ubiquitous nature of EBV, a strong relation among
EBV infection, HPS, and T-cell lymphomas has been
found [30]. In T-cell lymphomas, it seems that EBV
permits an uncontrolled production and release of cy-
tokines by neoplastic T-cells or inflammatory cells al-
lowing the HPS, a phenomenon similar to that
observed in EBV-associated Hodgkin’s disease [34]. The
role of EBV in HPS associated with T-cell lymphomas
is unquestionable, however, HPS complicating other
neoplasias has been reported without evidence of simul-
taneous infection [35–39]. Although we can not discard
any contribution of EBV, our results suggest that this
 A. Majluf-Cruz et al. / Leukemia Research 22 (1998) 893–898
virus is not an absolute requirement for HPS associated
with non-T cell HN since our cases with chronic EBV
infection had a B-cell phenotype.
Although this is a retrospective study with only 13
patients, the matching of cases and controls allows us
to consider some facts regarding the HN-related HPS.
According to the survival analysis HPS seems to be a
lethal finding and a negative prognosis factor for HN.
Comparing HPS cases and controls, median survival
since HN diagnosis was very different; 7 versus 48
months, respectively, a fact due to a 1-month median
survival after HPS for those patients who died. For
example, according to the Rai Clinical Staging System
[40], the expected survival for case 12 (19 months) was
dramatically shortened. Our results agree with previous
studies reporting extremely poor outcomes when HPS
was present [24,25].
HPS reflects a hyper-reactive state likely induced by
the neoplastic activity and its consequent low immune
regulation and vigilance (the greater the activity, the
greater the immunodeficiency). Furthermore, aging is a
contributory cause of immune down-regulation. To-
gether, these factors may allow self-unrecognition and
hemophagocytosis. Thus, the short survival in the HPS
group could be explained on the bases of a higher
HN-associated immunosuppression. Some reports sug-
gest that early treatment may have a beneficial effect on
the survival. Using conventional chemotherapy for
MH, Sonnevald et al found 57% response rate and
median duration of remission of 38 months [41] and
another group reported a median duration of remission
\ 30 months [42]. Our patients received standard
chemotherapy but the response rate was extremely
poor, a fact likely due to the difference in age. In the
two above-mentioned reports, median age was 28 and
29 years respectively, contrasting with 56 years in this
study. In old patients, HPS may represent an excessive
neoplastic activity requiring aggressive treatment, how-
ever, these patients have a poor tolerance to high
chemotherapy doses. Although prospective studies are
required, we feel that HN complicated with HPS might
require prompt, individualized, and intensive
chemotherapy regimen. This therapy would allow to
promptly decrease the T-cell factors inducing the reac-
tive process. The current experience is too small to
suggest any specific therapy.
This attempt to evaluate the prognostic value of
HN-related HPS suggests that this association is a rare
event and strongly suggests that represents a negative
prognosis factor. Survival is short despite therapy but if
this is successful, HPS disappears and the survival rate
returns to that expected. It is likely that early and
intensive chemotherapy regimens may be useful but
still, the best treatment for HPS complicating HN
should be addressed in prospective studies.
897
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