Mod Rheumatol (2012) 22:158162

DOI 10.1007/s10165-011-0487-7

CASE REPORT

Cytophagic histiocytic panniculitis with haemophagocytosis

in a patient with familial multiple lipomatosis and review
of the literature
Matthew Krilis Spiros Miyakis

Received: 1 April 2011 / Accepted: 2 June 2011 / Published online: 6 July 2011
Japan College of Rheumatology 2011

Abstract We report a patient with the extremely rare

familial multiple lipomatosis syndrome, who developed the
uncommon autoimmune disease cytophagic histiocytic
panniculitis, manifested as inflammation of preexisting
lipomas. Despite his initial critical condition and unsuccessful treatment with steroids, he responded to cyclosporin and remains well 15 years after diagnosis. In
contrast with most previous reports, our patient stays
dependent on cyclosporin; repeated attempts of discontinuing or substituting treatment were quickly followed by
relapse. Haemophagocytic panniculitis is considered as a
T-cell disorder, but its exact pathophysiological mechanism has not been clarified. Differential diagnosis of
cytophagic histiocytic panniculitis mainly includes malignant histiocytosis, subcutaneous panniculitis-like T-cell
lymphoma (SPTCL) and lupus erythematosus panniculitis
(lupus profundus). We discuss the main clinical features,

M. Krilis
Department of Medicine, Royal Prince Alfred Hospital,
University of Sydney, Sydney, Australia
S. Miyakis
Department of Microbiology and Infectious Disease,
St Vincents Hospital, University of New South Wales,
Sydney, Australia
M. Krilis (&)
Medical Training and Administration Unit,
Royal Prince Alfred Hospital, Missenden Road,
Camperdown, Sydney, NSW 2050, Australia
e-mail: matthewkrilis@gmail.com
Present Address:
S. Miyakis
3rd Department of Medicine, Aristotle University,
Papageorgiou Hospital, Thessaloniki, Greece

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diagnostic challenges and treatment issues of this usually

benign, but at times life-threatening autoimmune condition.
Keywords Cyclosporin
Familial lipomata

Haemophagocytosis
Histiocytic
Panniculitis

Introduction
Cytophagic histiocytic panniculitis (CHP) is a rare disease
consisting of subcutaneous fat inflammation with proliferation of histiocytes that phagocytize blood cells in the
subcutaneous fat, liver and bone marrow [1, 2]. The principal clinical features include high fever, malaise and
subcutaneous fat inflammation; hepatosplenomegaly, pancytopenia, liver failure and intravascular coagulation may
also occur [1]. CHP is often fatal; however, cases with a
protracted course have been reported [3]. Familial multiple
lipomatosis (FML) is an extremely rare, benign hereditary
condition in which several lipomas develop on the trunk
and limbs [4]. The cause of the disorder is not known, and
the mode of transmission may vary from one family to
another. We describe the first, to our knowledge, case of
CHP in a middle-aged man with inherited FML who
responded to treatment and was followed up for 15 years;
we also discuss the main features of CHP.

Case presentation
On May 1993, a 43 year-old Maori man presented with an
8-week history of malaise, fever with rigors, painful
abdominal-wall masses and 10 kg weight loss. His general
practitioner, after performing inconclusive investigations
(including blood and urine cultures) prescribed several

Mod Rheumatol (2012) 22:158162

courses of antibiotics without any effect. He had multiple

subcutaneous lipomata on his trunk and limbs since puberty. Prior to the presenting illness, all lipomata were
symptomless, never interfered with his daily activities and
their size had not changed. Several members of his large
family were affected by lipomas (Fig. 1). He was very
obese, with a body mass index (BMI) of 33, but did not
have diabetes, dyslipidemia or hypertension.
On admission, the patient was febrile (39.7C), and his
blood pressure was 100/70 mmHg and pulse rate 110/min.
A tender, indurated, hot and erythematous epigastric area
consisted of four confluent subcutaneous nodules with
slightly irregular borders on the midline, measuring
47 9 24, 37 9 21, 32 9 45 and 25 9 25 mm, respectively. Several other subcutaneous lipomata could be
identified on his back, flanks, lateral abdominal wall and
upper and lower limbs (sparing his face, neck and shoulders), their size varying from that of a small pea to that of
an egg; those on his flanks and back were tender on palpation. He had axillary, inguinal and cervical lymphadenopathy. His initial laboratory examinations revealed
pancytopenia (neutrophils 1,000 9 10-6/L with immature
forms and toxic granulosis, lymphocytes 400 9 10-6/L,
haemoglobin 92 g/L with orthochromia and normocytosis,
platelets 65 9 10-9/L), normal coagulation studies,
impaired liver-function alanine transaminase (ALT) 177 U/L,
gamma-glutamyltranspeptidase (GGT) 169 U/L, alkaline
phosphatase (ALP) 166 U/L, albumin 27 g/L) and
increased lactic dehydrogenase (LDH) (1,300 IU/L); bilirubin, reticulocytes and haptoglobin were normal. C-reactive protein and erythrocyte sedimentation rate were
4.8 mg/dl and 18 mm/1 h, respectively. Antinuclear antibodies, extractable nuclear antigens, antineutrophil cytoplasmic antibodies, complement and thyroid function
tests were normal; blood films for malaria, serology for Brucella, Legionella, Mycoplasma, Chlamydia, Leishmania,
Leptospira, EpsteinBarr virus (EBV), human T-cell
lymphocytotropic virus-1, human immunodeficiency virus
and hepatitis B and C virus were negative. Blood and urine
cultures were negative. The serum angiotensin-converting

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enzyme was 323 nm/ml/min. Protein electropherogram,

immunofixation and peripheral blood flow cytometry
revealed no abnormalities. A contrast computed tomography (CT) scan of the abdomen and pelvis showed
widespread anterior abdominal-wall induration without
drainable collection, splenomegaly (17 cm) and hepatomegaly (19 cm). Intravenously administered ampicillin,
flucloxacillin and metronidazole were initiated, but the
fever continued (up to 40C), and over the following days,
the patient developed shortness of breath, tachypnoea and
hypoxemia. A CT scan of his chest was normal, and a
ventilation/perfusion scan was of low probability for pulmonary embolism (PE), excluding its presence. A transesophageal echocardiogram was negative.
A bone marrow examination revealed reactive marrow
with an increased number of histiocytes showing prominent
haemophagocytic activity. There was no granuloma or
evidence of infiltration by monoclonal population. A
biopsy of the anterior abdominal wall mass showed lobular
panniculitis with fat necrosis; adipose tissue was diffusely
infiltrated by a mixed inflammatory infiltrate consisting
predominantly of lymphocytes and histologically mature
histiocytes. Those histiocytes (bean-bag cells) contained
numerous large forms and showed extensive erythrophagocytosis and leukophagocytosis, including phagocytosis of
apoptotic white-cell debris and platelets (Fig. 2). Immunohistochemistry revealed that most cells were T cells
(CD3 and UCHL1?). Alpha 1-antitrypsin (Alpha 1AT)
was positive in histiocytes, as was LN3 [human leukocyte
antigen (HLA)-DR] within some of the larger histiocytic
cells. Histiocytes stained weakly for lysozyme. No granulomata could be seen. Stains and cultures for mycobacteria
and fungi were negative.
In response to the biopsy result, prednisolone was started at a dose of 1 mg/kg per day. This had no significant
impact on the symptoms, and 10 days later, cyclosporin at
a total dose of 10 mg/kg per day was administered orally;
within 24 h, the patient was afebrile. His systemic symptoms and hematologic profile markedly improved over the
following week, and he was discharged, asymptomatic, on

Fig. 1 Pedigree of the patients

extended family with familial
multiple lipomatosis (FML);
*the described patient, affected
also by cytophagic histiocytic
panniculitis (CHP). Open circle
female without FML, filled
circle female with FML, open
square male without FML, filled
square male with FML

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Fig. 2 Histologic section of a subcutaneous nodule showing lobular

panniculitis with histiocytes phagocytosing mononuclear cells and
erythrocytes; filled arrow bean-bag cells (hematoxylin and eosin
9400)

oral prednisolone (0.5 mg/kg per day) and cyclosporin

(6 mg/kg per day in two divided doses). His full blood
count normalised, and on repeat CT scan, liver and spleen
size and the abdominal-wall induration were reduced. Both
his immunosuppressive medications were tapered, eventually to stop on October 1993.
The patient remained well without any treatment until
November 1997. Then, he was readmitted with febrile pancytopenia and transaminasaemia, weight loss and tenderness
in the lipomas of his abdominal wall and flanks. Relapse was
documented by abdominal subcutaneous fat biopsy, and the
histologic features of haemophagocytosis were less prominent, probably as a result of earlier presentation this time.
Cyclosporin was readministered, and the patient was again
afebrile within 24 h. Weaning off cyclosporin was attempted
several times (09/1998, 01/1999, 07/1999, 12/2000 and
10/2001), all quickly followed by relapses. The patient
remains asymptomatic, 15 years since disease onset, on
maintenance cyclosporin 0.5 mg/kg per day in two divided
doses. He has developed mild hypertension and microproteinuria, both controlled with perindopril. His creatinine
clearance has remained stable at 85 ml/min for the last
5 years. Glucose tolerance test and heart and kidney Doppler
ultrasound revealed no abnormalities. Serum levels of cyclosporin have been maintained between 100 and 200 ng/ml
throughout the course of treatment.

Discussion
We report a patient with FML who later developed CHP.
Both conditions are extremely uncommon and, to the best
of our knowledge, have never been described in the same

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Mod Rheumatol (2012) 22:158162

patient. FML is a rare benign syndrome of multiple subcutaneous lipomas [4]. Our patient had the typical clinical
features of the disorder: multiple asymptomatic lipomas on
trunk and limbs, sparing his face, neck and shoulders, at
puberty. Male predominance of the disorder is also in
agreement with the analysis of our patients pedigree.
Nevertheless, the exact mode of inheritance of the disorder
is not known; incomplete penetration, as well as multiple
gene involvement, has been postulated [4]. FML aetiology
is still unknown. Occasional coexistence of FML with
hyperlipidemia has been reported [5]; our patient had
repeatedly normal lipid profile despite his marked obesity
of genetic predisposition. No hypothesis on the immunologic basis of this disorder or any association with autoimmune conditions has been reported to date.
CHP is a very rare entity that combines lobular panniculitis with haemophagocytosis in liver, spleen and bone
marrow [1]. Histologically, the condition is characterised
by T-lymphocyte infiltration and mature activated histiocytes (bean-bag cells) phagocytosing blood cells and cellular debris. Several cytokines have been implicated in the
pathogenesis of macrophage activation, which results in the
haemophagocytic syndrome [6]. T lymphocytes in CHP are
stimulated to release macrophage-activating lymphokines
[2]. This is supported by the presence of abundant T lymphocytes in CHP infiltrates and the response of the disorder
to cyclosporine, which suppresses T-helper-cell function by
inhibiting lymphokine production; some lymphokines
(i.e. interferon-c and granulocyte-macrophage colonystimulating factor) exert macrophage-activating action [7].
Hemophagocytosis in organs at some distance from the
subcutaneous tissue also implies a serum circulating factor.
However, cytokines related to CHP have not yet been
identified. The triggering event that leads to T-lymphocytic
stimulation in CHP remains unknown; this also applies to
our case. The fact that our patient is dependent on cyclosporin for long-term remission, relapsing after weaning
attempts, implies continuing T-lymphocyte immune dysregulation as the basis of his disorder. Activation results in
alteration of histiocyte morphologic characteristics, which
acquire varying degrees of cytologic atypia. This process
also occurs in other forms of haemophagocytic syndrome,
which is mainly associated with infections (usually viral,
but also bacterial, fungal or parasitic); such patients usually
recover completely after eradication of the underlying
infection [8]. Hemophagocytosis occurring in the subcutaneous tissue distinguishes CHP, where fatal cases have been
described and complete recovery does not occur automatically. Interestingly, associations between infections and
CHP have not been reported; on the contrary, latent EBV
infection has been associated with both classic haemophagocytic syndrome and with haemophagocytosis associated with lymphoma [2].

Mod Rheumatol (2012) 22:158162

Three entities need to be excluded in CHP differential

diagnosis: malignant histiocytosis, subcutaneous panniculitis-like T-cell lymphoma (SPTL) and lupus erythematosus panniculitis (LEP), also termed lupus profundus.
Malignant true histiocytosis is an extremely rare malignancy of the macrophage lineage [9]. It may involve the
skin (causing subcutaneous nodules and ulcerations), usually together with other organs. It is rapidly progressing
and uniformly fatal. The morphologic appearance of
malignant histiocytes and appropriate immunohistochemical and cytogenetic studies confirm the histiocytic origin
and help distinguishing this entity from CHP [10]. LEP is
the rare involvement of subcutaneous fat occurring with
roughly equal frequency in the setting of discoid and systemic lupus erythematosus [11]. Female predominance,
prior diagnosis of lupus or concomitant systemic features
to suggest this disease usually suggest that the panniculitis
is due to LEP, but this may be especially problematic in the
rare cases in which involvement of the subcutaneous fat is
the only manifestation of lupus. Lymphocytic (rather than
histiocytic) infiltration with lymphocytes thatin contrast
with SPTL, stain negative for the MIB-1/Ki-67 monoclonal
antibody; presence of lymphoid follicles with reactive
germinal centres and clusters of B lymphocytes; eosinophilic fat necrosis; light microscopy with characteristics of
lupusand consistent involvement of the epidermis are
important histologic features to suggest LEP, as the presence of clonality and degree of lymphocytic atypia may
vary and cannot support the diagnosis [10, 11]. In LEP,
lesions resolve with hydroxychloroquine and/or steroids;
similar to CHP, recurrences occur following therapy cessation, but the course is not progressive. SPTL is classified
as a tumour confined to the subcutaneous fat and composed
of a/b or c/d CD8 cytotoxic lymphocytes [12]. The
minority of SPTL, which is associated with haemophagocytic syndrome, carries the poorer prognosis with usually
rapidly fatal course [12]. The histological distinction
between SPTL and CHP in those cases may be extremely
difficult and is based on malignant characteristics the T
cells may exert in SPTL, as well as on immunophenotypic
studies [2, 3]. Further diagnostic tests, such as EBV ribonucleic acid (RNA) (EBER1) in situ hybridization and
T-cell-receptor (TCR) gene rearrangement studies, have
been proposed in doubtful cases. However, they cannot
always differentiate between the two conditions with certainty: reports on EBV infection and/or clonality exist on
both benign and malignant cases [2, 3]. Some authors
propose that SPTL is the malignant counterpart of benign
panniculitis seen in CHP [2], whereas others suggest that
these conditions constitute the edges of a spectrum, with a
natural disease progression from CHP to SPTL [3]. In our
case, in situ hybridization for EBV was not performed, and
molecular genetic studies were not available at the time of

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the initial diagnosis; the latter was based on classic histologic and immunophenotypic features. Long-term remission on cyclosporin is in contrast with panniculitis in the
setting of SPTL, where cyclosporin is ineffective and a
short clinical course with early demise is the rule [3, 12].
Although initial diagnosis should nowadays be established
by appropriate molecular studies to optimise treatment
decisions, patients with CHP require close follow-up: cases
of initially unapparent lymphoma evolving several years
after CHP diagnosis have been reported [3, 13].
With the exemption of mild cases, corticosteroids seem
inadequate to control CHP, although some improvement of
clinical manifestations is expected [3]. Since 1990 the use of
combined cytotoxic agents such as cyclophosphamide,
doxorubicin, vincristine and prednisolone (CHOP) with or
without combination with cyclosporin has seen the mortality
rate decrease from 60% to approximately 24% [13], indicating that T-cell specific chemotherapy is optimal treatment
for patients with CHP. Complete remission in our case was
eventually achieved with the addition of cyclosporin.
Cyclosporin is the agent of choice in CHP not associated with
SPTL and the mortality rate is very high (70%) when this
agent is not used [14]. Cyclosporin has been associated with
side effects and fatal sepsis [2, 14]. When patients tolerate
cyclosporin, steroids can be discontinued and efforts should
be focused on adjusting cyclosporine to the minimal maintenance dose with close monitoring for side effects [7].
Long-term remission in our patient is maintained with a
cyclosporine dose of 0.5 mg/kg/day, which is lower than
most of those previously reported. There is one report of CHP
being responsive to azathioprine, followed by relapse after
discontinuation, as well as CHP cases that went into longterm remission with repeated courses of combination chemotherapy [15]. Given the proven efficacy of cyclosporin,
the use of combination chemotherapy should be reserved for
cases with evidence of SPTL [3].
A particularity of the described case is the patients
long-term remission and survival of 15 years despite his
initial presentation in critical condition. In the rare previous
reports of patients with CHP who have not experienced a
fatal outcome during long-term follow-up [3, 16], systemic
signs and symptoms were lacking, and cytophagia was not
evident in extracutaneous organs on disease onset; absence
of those features could be considered as predictive of mild
disease with a benign course.
To the best of our knowledge, this is the first description
of CHP manifesting as inflammation of already existing
subcutaneous nodules, the latter remaining asymptomatic
once CHP was controlled with cyclosporin. This association raises suspicion for a common immune dysregulation
underlying the pathogenesis of both conditions.
Conflict of interest

None.

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