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Cutaneous Manifestations of Hemophagocytic Lymphohistiocytosis
Dean S. Morrell, MD;
Marie A. Pepping, MD;
J. Paul Scott, MD;
Nancy B. Esterly, MD;
Beth A. Drolet, MD
Arch Dermatol. 2002;138:1208-1212.
ABSTRACT
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Background Hemophagocytic lymphohistiocytosis is a rare, rapidly progressive, and
potentially fatal disorder of activated histiocytes. The initial clinical
presentation commonly includes fever, hepatosplenomegaly, and pancytopenia.
Skin eruptions are described in up to 65% of patients. Information regarding
the morphological features, configuration, and distribution of these eruptions
is lacking and is typically reported as nonspecific and "maculopapular." The
aim of this report is to better delineate the cutaneous manifestations of
the disorder to assist in differentiating the process from other systemic
diseases.
Observation A case report of a neonate with hemophagocytic lymphohistiocytosis with
generalized purpuric macules is described. The clinical features of 5 other
patients with hemophagocytic lymphohistiocytosis at Children's Hospital of
Wisconsin, Milwaukee, are summarized. Clinical images of 1 additional neonatal
patient with hemophagocytic lymphohistiocytosis are presented as well. These
observations demonstrate the varied cutaneous manifestations of hemophagocytic
lymphohistiocytosis: erythroderma, generalized purpuric macules and papules,
and morbilliform eruptions.
Conclusion Awareness of cutaneous involvement can assist in the initial diagnosis
of hemophagocytic lymphohistiocytosis and potentially signify recurrences.
INTRODUCTION
HEMOPHAGOCYTIC lymphohistiocytosis is a rare, rapidly progressive, and
potentially fatal disorder of activated histiocytes. The initial clinical
presentation commonly includes fever, hepatosplenomegaly, and pancytopenia.
In 1991, the International Histiocyte Society established diagnostic guidelines
for hemophagocytic lymphohistiocytosis to embrace both primary and secondary
hemophagocytic lymphohistiocytosis.1 Cutaneous
eruptions have been reported to occur in 6% to 65% of cases.2-3
Descriptions of the morphological features, configuration, and distribution
of these eruptions are lacking and are typically reported as nonspecific "transient,
maculopapular rashes."2-3 It is
important to differentiate the eruption from other systemic processes including
myofibromatosis, extramedullary hematopoiesis, Langerhans cell histiocytosis,
and leukemia cutis. We present the case of a neonate with prominent skin manifestations
of hemophagocytic lymphohistiocytosis and summarize the clinical features
of 5 additional patients with hemophagocytic lymphohistiocytosis at our pediatric
institution. To further illustrate the cutaneous features of these disorders,
we include clinical images of 1 of 3 neonatal cases seen by 2 of us (J.P.S.
and N.B.E.) at another institution.
REPORT OF A CASE
A term female infant was born to unrelated parents at a local community
hospital. Prenatal laboratory studies were unremarkable. At birth, petechiae,
hepatosplenomegaly, and thrombocytopenia (38 x 103/µL)
were noted. Investigations for bacterial and viral causes were initiated and
2 platelet transfusions were administered prior to discharge on day of life
7.
Because of prominent skin findings on day of life 8, the dermatology
department was consulted. Although more pronounced on her face, scalp, and
upper chest, a generalized petechial and purpuric macular eruption involved
most of her skin except the palms and soles (Figure 1A and B). Mucous membranes were not involved. No nodules,
papules, erosions, or epidermal changes were noted. Hepatosplenomegaly was
present at 1 cm below the costal margin. Laboratory evaluation revealed the
following values: white blood cell count, 7.3 x 103/µL;
hemoglobin, 10.8 g/dL; platelets, 112 x 103/µL; aspartate
aminotransferase, 71 U/L; alanine aminotransferase, 124 U/L; and lactate dehydrogenase,
1727 U/L. A peripheral blood smear reviewed by one of us (J.P.S.) demonstrated
no blast forms. A skin biopsy specimen was obtained and demonstrated an interstitial
and perivascular mixed infiltrate. Immunohistochemical staining revealed a
CD3-positive lymphocyte population. Special stains with CD1a and toluidine
blue were negative.
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Figure 1. Neonate with generalized purpuric
macules involving the face (A) and torso (B). Note the suggestion of hepatomegaly
in A.
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At follow-up 1 week later, the initial cutaneous eruption had faded
to a dusky, nonblanching reticulated pattern. Multiple fine petechiae were
present. Liver and spleen were now both enlarged to 3 cm below the costal
margin. Laboratory evaluation revealed continued deterioration with the following
values: platelets, 12 x 103/µL; aspartate aminotransferase,
744 U/L; and alanine aminotransferase, 317 U/L. The patient was admitted to
our hematology/oncology service.
During hospitalization, an extensive investigation for viral infections,
including Epstein-Barr virus, was negative. Head imaging, ophthalmological,
and auditory examinations failed to demonstrate findings typical of congenital
viral infections. Maternal antiplatelet antibodies were absent. An abdominal
ultrasound revealed hepatosplenomegaly, but no expansive vascular lesion within
the liver to account for the cytopenias. Thrombocytopenia reached a nadir
of 1 x 103/µL despite multiple platelet transfusions
and intravenous immunoglobulin. Triglyceride levels increased from 172 mg/dL
(1.94 mmol/L) at admission to 797 mg/dL (9.01 mmol/L) on day of life 27. Hypofibrinogenemia
was present. Bone marrow aspirate and biopsy on day of life 17 revealed a
hypercellular marrow with abundant megakaryocytes, but no interstitial histiocytes
or phagocytic activity. A specimen obtained by open liver biopsy on day of
life 22 revealed extensive erythrophagocytosis by benign-appearing histiocytes
(Figure 2). Epstein-Barr viral stains
demonstrated nuclear staining in more than 80% of hepatocytes and 20% of bile
duct epithelial cells.
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Figure 2. Giemsa-stained liver biopsy specimen
demonstrating erythrophagocytosis (black arrow) and phagocytosis of a lymphocyte
(white arrow) (hematoxylin-eosin, original magnification x 40).
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The patient was started on treatment with dexamethasone followed by
induction chemotherapy with etoposide. A gradual normalization of hepatic
transaminases, triglycerides, and platelet counts occurred. All skin manifestations
resolved. At 3 months of age, the patient was observed to have a recurrence
of purpuric macules at her bilateral temples and temporal scalp. At this time,
triglyceride levels were elevated to 1269 mg/dL (14.3 mmol/L). Hepatic enzymes,
platelet counts, and blood cell counts remained normal. At 10 months of age,
the patient is well with no evidence of recurrence.
COMMENT
Hemophagocytic lymphohistiocytosis was first described by Farquhar and
Claireaux4 in 1952 as hereditary medullary
reticulosis. Thorough descriptions of the clinical features of hemophagocytic
lymphohistiocytosis are presented in reviews by Janka,2
Henter et al,3 Favara,5
and Imashuku et al.6 Previously, a distinction
between primary or familial hemophagocytic lymphohistiocytosis and secondary
or infection-associated hemophagocytic syndrome was made because immunosuppressed
adults with renal transplant were observed to develop a hemophagocytic syndrome
in response to viral infections.7 As attempts
to distinguish primary and secondary hemophagocytic lymphohistiocytosis in
children have been inconclusive, a unifying diagnosis of hemophagocytic lymphohistiocytosis
is appropriate.1 In fact, viral infections
may initiate the disease process in familial hemophagocytic lymphohistiocytosis.
In hemophagocytic lymphohistiocytosis, there is uncontrolled activation
or lack of down-regulation of the cellular immune system causing a generalized
proliferation of benign-appearing histiocytes. Previous reports have described
hemophagocytic lymphohistiocytosis as a hypercytokinemia or macrophage activation
syndrome. This reactive disorder lacks the typical cells of Langerhans cell
histiocytosis, but involves the widespread infiltration of lymphocytes and
macrophages into the liver, spleen, lymph nodes, and central nervous system.
Although not consistently present, viral infections and impaired natural killer
activity have been reported in cases of hemophagocytic lymphohistiocytosis.
Linkage analysis indicates genetic heterogeneity with linkage of some individuals
to multiple gene loci. Defects in the perforin gene have been recognized in
approximately 20% of unrelated patients with familial hemophagocytical lymphohistiocytosis.8-9 Perforin-based mechanisms appear to
be important in the control of activated immune activity.
In 1991, the International Histiocyte Society established diagnostic
guidelines in an effort to facilitate early diagnosis and management.1 According to the guidelines, the diagnosis of hemophagocytic
lymphohistiocytosis requires the features noted in Table 1. Strong supportive evidence for the diagnosis of hemophagocytic
lymphohistiocytosis includes cerebral spinal fluid pleocytosis, histopathological
evidence of chronic persistent hepatitis, and low natural killer cell activity.
"Skin rash" is considered to be a potential abnormal finding in hemophagocytic
lymphohistiocytosis.1 Atypical presentations
have been reported; failure to demonstrate all diagnostic criteria does not
preclude the diagnosis of hemophagocytic lymphohistiocytosis. As in our patient,
fever is a less prominent feature in neonatal cases.
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Table 1. Diagnostic Criteria of Hemophagocytic Lymphohistiocytosis
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A computerized review of all patient diagnoses at Children's Hospital
of Wisconsin between 1990 and 2000 revealed 5 additional patients with hemophagocytic
lymphohistiocytosis. The details of their clinical features are summarized
in Table 2 and Table 3. Our patient (patient 1) had cutaneous involvement at presentation
while 2 other patients developed a hemophagocytic lymphohistiocytosis–associated
eruption within 2 months of presentation (patients 2 and 3). Skin biopsy specimens
revealed epidermal spongiosis, necrotic keratinocytes, and sparse exocytosis.
Perivascular lymphohistiocytic infiltrates and extravasated red blood cells
were located in the dermis. No evidence of erythrophagocytosis was present
in the skin biopsy specimens. Two of the 3 surviving patients received bone
marrow transplantation 1 (patient 5) and 5 (patient 4) years ago, while 3
patients died secondary to disseminated candidiasis (patients 2 and 3) and
bacterial sepsis (patient 6).
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Table 2. Age, Clinical, and Laboratory Features of Patients With Hemophagocytic
Lymphohistiocytosis at Children's Hospital of Wisconsin, 1990-2000*
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Table 3. Pathological, Treatment, and Cutaneous Features of Patients
With Hemophagocytic Lymphohistiocytosis at Children's Hospital of Wisconsin,
1990-2000*
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A review of the literature reveals approximately 30 cases with reference
to cutaneous manifestations.2-3
Janka2 reports skin changes early in the disease
in 6% of 108 cases of familial hemophagocytic lymphohistiocytosis. In another
retrospective chart review of 32 cases with familial hemophagocytic lymphohistiocytosis,
43% were cited to have skin involvement early in the disease (<10 days)
and 65% to have skin lesions at some time during the disease.3
The discrepancy between these reports may reflect the review of hospital charts
in the latter study in which it was assumed that all skin involvement was
related to the underlying disease. The Familial Hemophagocytic Lymphohistiocytosis
Registry cites "skin rash" in 24% of patients.10
Cutaneous involvement was present in 3 of the 6 patients with hemophagocytic
lymphohistiocytosis at our institution.
In the majority of cases with cutaneous involvement, a transient generalized
maculopapular eruption is reported. Our patient (patient 1) had extensive
petechial and purpuric macules at presentation similar to cases of neonatal
purpura secondary to congenital viral infections. Similar primary lesions
limited to an acral distribution in a neonate were seen in patient 3. Although
not a neonate, patient 2 demonstrated a generalized, purpuric, and papular
eruption.
In addition to hemorrhagic and purpuric macules, there are other types
of cutaneous lesions in hemophagocytic lymphohistiocytosis. We (J.P.S. and
N.B.E.) have observed 3 additional cases of hemophagocytic lymphohistiocytosis
in the neonatal period with prominent cutaneous manifestations. Unfortunately,
the medical records of these patients were unavailable; therefore, the details
of their cases are not included in Table
2 and Table 3. One neonate
demonstrated generalized purpuric macules similar to patients 1 and 3 (Figure 3). Another neonate with generalized
erythroderma and edema presented much like the erythrodermic "sunburnt" integument
described by Farquhar and Claireaux.4 A less
distinctive morbilliform erythema can also be prominent on skin examination
of these patients.
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Figure 3. Neonate with generalized purpuric
macules.
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The cutaneous manifestations are not specific to hemophagocytic lymphohistiocytosis.
The generalized distribution reveals an underlying systemic process. Skin
biopsy findings are not diagnostic and rarely demonstrate hemophagocytosis.
Favara5 describes typical histological features
to include a lymphohistiocytic perivascular infiltrate in the reticular dermis,
without evidence of epidermal changes or vasculitis.5
Extravagated erythrocytes account for purpuric lesions. Although some cases
present much like neonatal purpura of infectious origin, skin biopsies fail
to demonstrate extramedullary hematopoiesis.
Differential diagnosis includes myofibromatosis, extramedullary hematopoiesis,
Langerhans cell histiocytosis, and leukemia cutis. Although clinical and pathological
features of hemophagocytic lymphohistiocytosis are nonspecific, it is important
to histologically rule out other systemic diseases.
The pathological and cutaneous findings are consistent with the current
understanding of the pathophysiology of hemophagocytosis lymphohistiocytosis.
Activated lymphocytes produce hypercytokinemia involving interleukin 211 and interferon  ,12
causing massive activation of histiocytes and secretion of additional cytokines.
Loss or deficiency of potential immune regulatory mechanisms (ie, perforin
gene defects) in the setting of hypercytokinemia allows activated lymphocytes
and histiocytes to uncontrollably infiltrate organ systems, including skin.
The actual initiator of the process may be variable. Multiple cases
(including our patient) demonstrate evidence of preceding Epstein-Barr virus
infection,3 while reports suggest additional
infectious etiologies including cytomegalovirus, adenovirus, and parvovirus.7, 11 As in the proliferative phases of
Chediak-Higashi, Griscelli, and X-linked lymphoproliferative (Duncan disease)
syndromes, stimulated T-lymphocytes create a chemokine environment that activates
mononuclear phagocytes that lack features of Langerhans cell and malignant
histiocytoses. Some cases of hemophagocytic lymphohistiocytosis actually share
the same germline mutations in SH2D1A seen in X-linked lymphoproliferative
disease.13 The clinical picture of hemophagocytic
lymphohistiocytosis probably represents a phenotypic expression of several
different defects in homeostasis of immune activation.
Erythrophagocytosis in hemophagocytic lymphohistiocytosis is commonly
present in lymphoid tissues (liver, spleen, and bone marrow), but rarely evident
in skin biopy specimens. Phagocytic activity in liver, spleen, and marrow
biopsy specimens is not universally present, however. Only one third of initial
bone marrow biopsy specimens demonstrate hemophagocytosis.5
Infiltrating histiocytes acquire a phagocytic character with disease progression.
The mechanisms that control cellular interactions (cytokines and cell markers)
may account for the transition from nonphagocytic to hemophagocytic activity.
Cutaneous histiocytes in hemophagocytic lymphohistiocytosis may lack specific
markers or cellular interactions that allow for hemophagocytosis. Alternatively,
as skin biopsies are routinely performed early in the process, it is possible
that cutaneous erythrophagocytosis may actually occur more frequently than
reported.
Historically, hemophagocytic lymphohistiocytosis has been a diagnosis
made at autopsy. Bleeding, infection, and progressive cerebral damage are
the usual causes of death. Hemophagocytic lymphohistiocytosis can be an elusive
diagnosis prior to available pathological evidence of hemophagocytosis. As
is evident in our patients (Table 2),
failure to find hemophagocytosis on the initial bone marrow aspirate warrants
serial bone marrow aspirates and/or histopathological evaluation of other
organs (liver, lymph nodes, or spleen). It is important to diagnose the condition
early in the course, as chemotherapy14-15
and bone marrow transplantation16 have improved
survival rates. Five-year survival outcomes with chemotherapy and autologous
bone marrow transplantation are 10% to 44% and 66%, respectively.6, 10
Prominent cutaneous manifestations can accompany underlying hemophagocytic
lymphohistiocytosis in the form of purpuric, macular, papular, erythrodermic,
or morbilliform eruptions. The reappearance of cutaneous manifestations in
a patient treated with chemotherapy may herald a recurrence of hemophagocytic
lymphohistiocytosis. Although clinical features are nonspecific, awareness
of the various types of cutaneous presentations can assist in the initial
diagnosis. Skin biopsies can assist in differentiating hemophagocytic lymphohistiocytosis
from other systemic and potentially malignant diseases.
AUTHOR INFORMATION
Accepted for publication January 15, 2002.
Corresponding author and reprints: Dean S. Morrell, MD, University
of North Carolina, Department of Dermatology, 3100 Thurston-Bowles CB#7287,
Chapel Hill, NC 27514 (e-mail: morrell{at}med.unc.edu).
From the Department of Dermatology (Drs Morrell, Pepping, Esterly,
and Drolet), and the Division of Pediatric Hematology and Oncology (Dr Scott),
Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee,
Wis.
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