Hemophagocytic Lymphohistiocytosis can Mimic the Superior Vena Cava Syndrome

Article (PDF Available)inJournal of Pediatric Hematology/Oncology 34(4):e152-4 · March 2012with61 Reads
DOI: 10.1097/MPH.0b013e3182422a20 · Source: PubMed
We report a case of a 3-year-old boy with hemophagocytic lymphohistiocytosis (HLH), with enlarged cervical lymph nodes causing internal jugular vein compression, who initially presented a condition similar to the superior vena cava syndrome. Laboratory data along with neck node and bone marrow biopsies confirmed the HLH. Genetic analysis revealed the patient to be compound heterozygous for 2 variations of the perforin gene, c.1620 A>G and c.562C>G. This case featuring a rare initial manifestation of HLH that has not been previously reported, points to the necessity of considering this disease when symptoms similar to superior vena cava syndrome are encountered.
Hemophagocytic Lymphohistiocytosis can Mimic the
Superior Vena Cava Syndrome
Meerim Park, MD,* Jae-Wook Choi, MD,
Hyeon Jin Park, MD,* Hee Jin Kim, MD,
Meong Hi Son, MD,* Jong-Hyung Yoon, MD,* Su-Jin Kim, MD,* Won Seo Park, MD,
and Byung-Kiu Park, MD*
Summary: We report a case of a 3-year-old boy with hemophago-
cytic lymphohistiocytosis (HLH), with enlarged cervical lymph
nodes causing internal jugular vein compression, who initially
presented a condition similar to the superior vena cava syndrome.
Laboratory data along with neck node and bone marrow biopsies
confirmed the HLH. Genetic analysis revealed the patient to be
compound heterozygous for 2 variations of the perforin gene,
c.1620 A>G and c.562C> G. This case featuring a rare initial
manifestation of HLH that has not been previously reported,
points to the necessity of considering this disease when symptoms
similar to superior vena cava syndrome are encountered.
Key Words: HLH, SVCS, cervical lymph node
(J Pediatr Hematol Oncol 2012;34:e152–e154)
Hemophagocytic lymphohistiocytosis (HLH), a reactive
disorder of the monomacrophage-histiocyte lineage, resulting
in uncontrolled phagocytosis of normal hematopoietic cells,
most frequently presents with fever, hepatosplenomegaly,
and cytopenia.
Generalized lymphadenopathy is found in
about 42% of the childhood cases of HLH, but prominent
cervical lymph node enlargement is rare.
Here, we report a
case of a 3-year-old boy with HLH, who initially presented
with a condition superficially similar to superior vena cava
syndrome (SVCS), which was related to internal jugular vein
(IJV) compression due to cervical lymph node enlargement
and soft tissue swelling. To our knowledge, this is the first
such case reported in the literature.
A 3-year-old boy who was previously healthy presented with
persistent fever for more than 7 days, dyspnea and swelling of the
neck and upper chest. Physical examination at the time of admis-
sion revealed multiple enlarged cervical lymph nodes, the largest
measuring about 3 cm in diameter, along with abdominal dis-
tension with hepatosplenomegaly.
Complete blood cell counts showed hemoglobin (8.4 g/dL),
white blood cell count (29,370/mL; 72% neutrophils, 23% lympho-
cytes), and a platelet count of 60,000/mm.
Laboratory inves-
tigations revealed aspartate aminotransferase (90 IU/L), alanine
aminotransferase (79 IU/L), C-reactive protein (4.4 mg/dL), and
lactate dehydrogenase (516 U/L). The patient showed increased
fasting triglyceride (133 mg/dL) and ferritin (1426 ng/dL), and de-
creased fibrinogen (85 mg/dL). Natural killer (NK) cell activity was
normal. Neck computed tomography scan revealed multiple lymph
node enlargement, at levels II, III, IV, and V and in the left supra-
clavicular area, along with external compression of the left IJV by
adjacent, enlarged lymph nodes. In addition, interruption of venous
flow in the left IJV was detected by Doppler sonography. Chest and
abdomen computed tomography showed bilateral pulmonary in-
filtrates with pleural effusion, hepatosplenomegaly, and enlarged
para-aortic lymph nodes in the retroperitoneum. Echocardiography
demonstrated no abnormality. The patient showed progressive res-
piratory distress, requiring intubation and ventilatory support after a
few hours. Furthermore, like SVCS, edema of the scalp, face, and
neck, subsequently progressed, complicated by systemic fluid re-
tention and tissue edema which exacerbated the IJV compression in
a vicious cycle (Fig. 1). On the basis of laboratory and clinical
findings pointing to a likely diagnosis of lymphoma and HLH, with
or without combined infection, intravenous dexamethasone and
broad-spectrum antibiotics were commenced and subsequently fever
disappeared. However, swelling of the neck, scalp, and face,
along with cervical lymph node enlargement, did not significantly
Cervical lymph node biopsy performed at the time of ad-
mission revealed diffuse proliferation of histiocytes positive for
CD68 with a Ki-67 rate of 20% (Fig. 2). Bone marrow biopsy
showed normocellular marrow with proliferation of many histio-
cytes and hemophagocytosis featuring cells positive for CD38
(Fig. 3). Cytomegalovirus and Epstein-Barr virus surveys and trans-
tracheal aspiration culture for virus isolation were all negative, as
were blood and bone marrow cultures for bacteria and fungi. There
was no evidence of any underlying immunodeficiency. Based on
international diagnostic criteria for HLH,
a diagnosis of HLH was
made and HLH-2004 chemotherapy, comprising etoposide, cyclo-
sporine, and dexamethasone, was started. Neurologic investigations,
including brain magnetic resonance imaging and cerebrospinal fluid
examination, did not reveal any abnormalities. The patient gradually
showed clinical improvement. Tissue swelling, and respiratory dis-
tress had completely disappeared by 10 days after initiation of
chemotherapy. Genetic analysis identified compound heterozygous
perforin gene (PRF1) alterations, c.562C>G and c.1620 A>G. The
mother was heterozygous for the c.562C>G variant and the father
was heterozygous for the c.1620 A>G, whereas analysis of DNA
from the patient’s brother showed no mutation. Flow cytometric
analysis was used to establish patterns of perforin staining in NK
cells and CD8
T cells from the patient. The patient showed a little
different perforin staining pattern from the control patient in NK
cells, however, the perforin positivity was not decreased markedly
(Fig. 4).
After 8 weeks of chemotherapy, signs and symptoms of HLH
had resolved completely and we stopped chemotherapy. The pa-
tient has remained well, with outpatient follow-up for 9 months.
Received for publication April 22, 2011; accepted August 16, 2011.
From the *Center for Pediatric Oncology; yDepartment of Pathology,
National Cancer Center, Goyang; wDepartment of Pediatrics, Seoul
National University Hospital, Seoul National University College of
Medicine; and zDepartment of Laboratory Medicine and Genetics,
Samsung Medical Center, Sungkyunkwan University School of
Medicine, Seoul, Korea.
Supported by the Korea Healthcare Technology R&D Project
(A080588), Ministry for Health and Welfare, Republic of Korea.
The authors declare no conflict of interest.
Reprints: Hyeon Jin Park, Pediatric Oncology Center, National Cancer
Center, Ilsandong-gu, Goyang-si, Gyeonggi-do 410-769, Korea
(e-mail: hjpark@ncc.re.kr).
2012 by Lippincott Williams & Wilkins
www.jpho-online.com J Pediatr Hematol Oncol
Volume 34, Number 4, May 2012
This case demonstrated a rare initial manifestation of
HLH that has not been previously reported. The patient
initially showed symptoms and signs similar to SVCS, as-
sociated with IJV compression by enlarged cervical lymph
nodes. The majority of massive lymphadenopathy includes
Kikuchi disease (histiocytic necrotizing lymphadenitis),
Castleman disease, viral lymphadenitis (Epstein-Barr virus
and human immunodeficiency virus), Rosai-Dorfman
disease, and lymphoma.
Although lymphadenitis is one
of the clinical features of HLH, such a prominent cervical
lymph node enlargement compressing a large vein has been
rarely reported. There have been a few cases showing
prominent cervical lymph nodes in HLH, but all of them
were finally diagnosed as complicated by Kikuchi disease.
However, the pathologic findings of our patient differed
from those of Kikuchi disease because neutrophils and
necrosis were lacking.
SVCS is a clinical manifestation of different diseases
leading to obstruction of large central veins, including the
subclavian, the brachiocephalic, and the vena cava, usually
resulting from compression by malignancies or thymoma
and/or mediastinal lymphadenopathy.
It is therefore
marked by the signs and symptoms of venous congestion
including prominent venous patterns over the neck, chest,
and upper extremities, and facial edema, orbital suffusion,
plethora, and symptoms of cerebral edema on rare occa-
However, as exemplified by the present case, IJV
compression can also cause similar symptoms and signs. In
IJV compression, furthermore, the cerebral blood flow can
be significantly reduced and cause increase in total venous
resistance and elevation in both pressure and volume of the
cerebrospinal fluid.
In our patient, although IJV compression was initially
caused by adjacent, enlarged cervical lymph nodes, it was
worsened by tissue edema complicated by fluid retention,
resulting in marked swelling of the face, scalp, and neck in a
vicious cycle. HLH is a potentially fatal hyperinflammatory
syndrome, and associated vascular complications can lead
to rapid deterioration, with systemic fluid retention unless
appropriate management is initiated. Therefore, recog-
nition of potential associations between HLH and vascular
compression, such as demonstrated by our case for the IJV,
due to enlarged lymph nodes is necessary.
Broadly, HLH can be classified according to the under-
lying etiology into either primary (genetic) or secondary (ac-
quired), although in practice this distinction is often difficult.
Disease-causing mutations have been identified in the genes
encoding PRF1, syntaxin-11 (STX11), Munc18-2 (STXBP2),
and Munc13-4 (UNC13D).
Genetic analysis showed our
patient to be compound heterozygous for 2 variants of the
PRF1 gene, c.562C>G and c.1620 A>G, each inherited
from 1 of the parents. Although the c.1620 A>G is not listed
FIGURE 1. External features of the patient. Note face, scalp, and
neck edema, similar to that found with the superior vena cava
FIGURE 2. Cervical lymph node biopsy showing diffuse pro-
liferation of histiocytes (hematoxylin-eosin, 400).
FIGURE 3. Bone marrow aspiration showing pronounced he-
mophagocytosis (Wright-Giemsa, 400).
J Pediatr Hematol Oncol
Volume 34, Number 4, May 2012 HLH Mimicking of SVCS
2012 Lippincott Williams & Wilkins www.jpho-online.com
in the SNP databases, it has been reported in HLH patients
and is lacking in normal individuals.
However, the patient
did not show definite abnormality in perforin staining result,
which made it difficult to draw a conclusion. Considering
primary HLH usually has a poor prognosis unless treated by
hematopoietic stem cell transplantation, the patient’s courses
with prolonged survival without any morbidity after only 8
weeks of chemotherapy implies acquired HLH rather than
primary. Therefore, it is difficult to make a conclusion as
to whether the HLH in this patient was primary or secondary
in nature. The variations identified clearly warrant further
In conclusion, we described a rare initial manifestation
mimicking SVCS in HLH, which we believe to be the first such
case reported. When obscure cervical lesions presenting with
conditions similar to SVCS are encountered, the possibility of
HLH presenting with IJV compression should be considered.
The authors thank our patient and his family for facili-
tating this study.
1. Janka GE. Familial and acquired hemophagocytic lymphohis-
tiocytosis. Eur J Pediatr. 2007;166:95–109.
2. Henter JI, Elinder G, Soder O, et al. Incidence in Sweden and
clinical features of familial hemophagocytic lymphohistiocy-
tosis. Acta Paediatr Scand. 1991;80:428–435.
3. Henter JI, Horne A, Arico M, et al. HLH-2004: diagnostic and
therapeutic guidelines for hemophagocytic lymphohistiocyto-
sis. Pediatr Blood Cancer. 2007;48:124–131.
4. Varoczy L, Illes A, Gergely L, et al. Uncommon lymphade-
nopathies of immunopathogenesis can be misinterpreted as
malignant diseases. Rheumatol Int. 2007;27:753–757.
5. Krishnan C, Warnke RA, Arber DA, et al. PD-1 expression in
T-cell lymphomas and reactive lymphoid entities: potential
overlap in staining patterns between lymphoma and viral
lymphadenitis. Am J Surg Pathol. 2010;34:178–189.
6. Lee HY, Huang YC, Lin TY, et al. Primary Epstein-Barr virus
infection associated with Kikuchi’s disease and hemophago-
cytic lymphohistiocytosis: a case report and review of the
literature. J Microbiol Immunol Infect. 2010;43:253–257.
7. Kampitak T. Fatal Kikuchi-Fujimoto disease associated with
SLE and hemophagocytic syndrome: a case report. Clin
Rheumatol. 2008;27:1073–1075.
8. Yellin A, Rosen A, Reichert N, et al. Superior vena cava
syndrome. The myth—the facts. Am Rev Respir Dis. 1990;141:
9. Janin Y, Becker J, Wise L, et al. Superior vena cava syndrome
in childhood and adolescence: a review of the literature and
report of three cases. J Pediatr Surg. 1982;17:290–295.
10. Issa PY, Brihi ER, Janin Y, et al. Superior vena cava syndrome
in childhood: report of ten cases and review of the literature.
Pediatrics. 1983;71:337–341.
11. Bosnjak R, Kordas M. Circulatory effects of internal jugular
vein compression: a computer simulation study. Med Biol Eng
Comput. 2002;40:423–431.
12. Gupta S, Weitzman S. Primary and secondary hemophagocytic
lymphohistiocytosis: clinical features, pathogenesis and ther-
apy. Expert Rev Clin Immunol. 2010;6:137–154.
13. Zur Stadt U, Beutel K, Kolberg S, et al. Mutation spectrum in
children with primary hemophagocytic lymphohistiocytosis:
molecular and functional analyses of PRF1, UNC13D, STX11,
and RAB27A. Hum Mutat. 2006;27:62–68.
14. Lu G, Xie ZD, Shen KL, et al. Mutations in the perforin gene
in children with hemophagocytic lymphohistiocytosis. Chin
Med J (Engl). 2009;122:2851–2855.
FIGURE 4. The perforin staining pattern (A) in a healthy control and (B) in the patient. NK indicates natural killer.
Park et al J Pediatr Hematol Oncol
Volume 34, Number 4, May 2012
2012 Lippincott Williams & Wilkins
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