Hemophagocytic Syndrome in Patients with Unexplained Cytopenia: Report of 15 Cases / Açıklanamayan Sitopenili Olgularda Hemofagositik Sendrom: 15 Olgu Sunumu

Abstract Objective: To investigate the frequency of hemophagocytic syndrome in a series of patients with otherwise unexplained cytopenia. Material and Method: In this cross-sectional, single-centre study, bone marrow specimens (n=288) were obtained from the patients with unexplained cytopenia. Th e diagnosis of hemophagocytic syndrome was made according to universally accepted criteria. Characteristics of the patients, as well as the clinical and laboratory findings were reported. Results: Fift een cases (5.2%) fulfilled the hemophagocytic syndrome criteria, including 8 males (53.3%) and 7 females (46.7%) with a mean age of 39.7±20.7 (range: 14-72) years at the time of diagnosis. Th e main clinical and laboratory findings were cytopenia (100%), fever (73.3%), hyperferritinemia (66.7%), elevated erythrocyte sedimentation rate (60%), hypertriglyceridemia (60%), organomegaly (53.3%), elevated liver enzymes (53.3%), lymphadenopathy (26.7%), neurological symptoms (20%), and skin rash (13.3%). Two patients (13.3%) died before a diagnosis was made. Conclusion: Our findings indicate that the hemophagocytic syndrome is not a rare pathologic condition in patients with otherwise unexplained cytopenia. Without treatment, the mortality rate may be high. ÖZ Amaç: Başka nedenlerle acıklanamayan sitopenisi olan bir dizi hastada hemofagositik sendrom sıklığını araştırmaktır. Gereç ve Yöntem: Bu kesitsel ve tek merkezli calışmada başka nedenlerle acıklanamayan sitopenisi olan 228 hastanın (n=228) kemik iliği biopsileri değerlendirilmiştir. Hemofagositik sendrom tanısı genelde kabul gormuş kriterlerle konmuştur. Hastaların ozellikleri ve klinik/laboratuvar bulguları kaydedilmiştir. Bulgular: Sekizi (%53,3) erkek ve 7’si kadın (%46,7) olmak uzere ortalama yaşları 14-72 arasında değişen (39,7±20,7) 15 olgunun tanı anında hemofagositik sendrom kriterlerini taşıdığı saptanmıştır. Temel klinik ve laboratuvar bulgular sitopeni (%100), ateş (%73,3), hiperferritinemi (%66,7), yuksek eritrosit sedimentasyon hızı (%60), hipertrigliseridemi (%60), organomegali (%53,3), yukselmiş karaciğer enzimleri (%53,3), lenfadenopati (%26,7), norolojik belirtiler (%20) ve deri dokuntuleridir (%13,3). İki hasta (%13,3) tanıdan once kaybedilmiştir. Sonuç: Bulgularımız, başka nedenlerle acıklanmayan sitopenisi olan hastalarda hemofagositik sendromun ender rastlanan bir patolojik durum olmadığına işaret etmektedir. Tedavi yapılmazsa mortalite yuksek olabilir.


INTRODUCTION
Hemophagocytic lymphohistiocytosis or hemophagocytic syndrome (HPS) is an uncommon hematologic disorder typically characterized by the activation of macrophages/ histiocytes with notable hemophagocytosis in the bone marrow and other reticuloendothelial systems (1).
Secondary HPS is believed to be associated with various conditions such as malignancies, autoimmune diseases, certain drugs, hematopoietic stem cell or organ transplantations, and infections (Epstein-Barr virus in particular) (3,4).
Th e clinical and laboratory fi ndings in patients with HPS are summarized in Table II.
Th e major fi ndings in the microscopic examination of the bone marrow specimens obtained from the patients with HPS were megaloblastic anemia (n=2), chronic granulomatous disease (n=1), and bone marrow sea-blue histiocyte syndrome (n=1).
Although HPS is usually regarded as a rare condition, to the best of our knowledge, there is not suffi cient relevant data available in the literature except for a limited number of case reports (5)(6)(7)(8).
Th is lack of data is even more signifi cant when it is born in mind that the prognosis of the patients with HPS is not very good, particularly when left untreated. It is shown that early recognition and aggressive treatment of HPS may change a uniformly fatal disease to one with a 55% rate of survival (9).
As cytopenia is a key fi nding in the cases with HPS (10), the main objective of this study was to examine a series of patients with otherwise unexplained cytopenia in terms of the frequency of HPS.

MATERIAL and METHODS
In this cross-sectional study, 1388 consecutive specimens from the bone marrow obtained by biopsy/aspiration were evaluated in a referral teaching hematology-oncology centre from April 2007 through April 2010.
Th is study was performed according to the principles of the World Medical Association Declaration of Helsinki. Informed consent was obtained from all participants.
Two hundred eighty eight specimens (20.7%) belonged to patients with otherwise unexplained cytopenia aft er thorough clinical and paraclinical investigations.
HPS was diagnosed based on the criteria reported by Henter et al. (10), summarized in Table I. All the specimens were examined by a skilled pathologist with over 20 years experience by light microscopy under proper magnifi cation aft er appropriate preparation and staining (hematoxylin and eosin staining protocol for paraffi n embedded biopsy specimens, Giemsa's stainin g protocol for touch smear and aspiration specimen, ( Figure  1).
Th e patients' characteristics, as well as clinical and laboratory fi ndings were recorded.
Statistical analysis was performed using SPSS Soft ware version 15.0 (Chicago, USA). Th e results were expressed as mean ± standard deviation or frequency (%).

RESULTS
Fift een patients out of 288 cases with unspecifi c cytopenia were reported to be eff ected with HPS ( Figure 2).
Two patients (13.3%) died before the diagnosis of HPS was made. Th e remaining patients were discharged aft er appropriate management.

DISCUSSION
Th is series showed that almost 5% of the patients with otherwise unexplained progressive cytopenia suff er from HPS. Although the cytopenia is a key fi nding in patients with HPS, to our knowledge there is no report about the real frequency of this condition among patients with unexplained cytopenia.
In a series by Fukaya et al., 1014 inhospital patients with systemic autoimmune diseases were evaluated as to the presence of HPS. Finally, 30 patients (2.3%) fulfi lled the HPS criteria (11).
Th e male to female ratio was 1.1 in our study. Th is fi nding is in line with the previous reports indicating that there is no obvious gender preponderance in cases with HPS (12,13).
Th e mean age of the patients was 39.7±20.7 (range: 14-72) years in the present study, with the most common age group 20-29 years. In another study by Ishii et al., the age distribution showed a peak of autoimmune disease-and infection-associated HPS in children, while familial type and lymphoma-associated HPS occurred almost exclusively in infants and the elderly, respectively (14). Th us, it seems that the age of the patients is a key determiner of the type of HPS.
It should be noted that the possible underlying causes of HPS were not investigated in our study, because it was not part of our objectives. However, the cases with primary HPS were apparently not included because there was another referral centre specialized in pediatric hematologic/oncologic disorders in the region which did not participate in the present study. Further multicenter studies are possibly indicated in this regard to have more defi nite conclusions drawn.
Th e main clinical and laboratory fi ndings of the studied patients with HPS were cytopenia, fever, hyperferritinemia, elevated erythrocyte sedimentation rate (ESR), hypertriglyceridemia, organomegaly, deranged (raised) liver enzymes, lymphadenopathy, neurological symptoms, and rash in a decreasing order of frequency. All these fi ndings are in conformity with previous reports (12,15) except for elevated ESR, indicating a role of infl ammatory   process in some of the patients. Th is needs to be clarifi ed in further studies.
Before HPS was confi rmed and an appropriate therapy started, two patients (13.3%) with HPS died in our series. On the other hand, all the remaining 13 patients were discharged aft er receiving suffi cient treatment. Hence, it may be concluded that fi rst, HPS carries a signifi cant mortality rate if left untreated; and second, HPS is still a great challenge to be timely diagnosed (16,17).
In summary, although HPS is generally considered as a rare entity, the current study showed that this may not be quite accurate at least among patients with otherwise unexplained cytopenia. Likewise, the patients with HPS are possibly a high risk group for early mortality if left untreated (18). As a consequence, it seems wise for all patients with unexplained cytopenia to undergo a thorough examination for possible presence of HPS.
To the best of our knowledge, this is the fi rst study that deals with the association between unexplained cytopenia and HPS. Due to the heterogeneity of the disease, particularly in terms of its characteristics (14), as well as the race and ethnicity of the patients (9), further controlled investigations may be warranted to have the issue elucidated.