LANGERHANS CELL HISTIOCYTOSIS
Langerhans cell
histiocytosis (LCH) is a rare disorder caused by the proliferation of
Langerhans cells in various tissues. Historically, the disease was categorized
based on the grouping of symptoms and organs affected, with names such as
Letterer-Siwe disease and Hand- Schüller-Christian disease. Over the last
decade, the classification of LCH has been standardized. The new classification
does not remove the eponyms that have been used for years but rather
categorizes the LCH into subgroups based on prognosis and amount of involvement.
These histiocytoses are a heterogeneous group of diseases that may affect both
the skin and various internal organs. The main pathological finding is the
accumulation of pathological Langerhans cells within the affected tissue. The
diagnosis is made on clinical, histological, laboratory, and radiographic findings.
The newer classification of LCH is based on the number of organ systems
involved. It includes the subtypes of restricted single-system LCH, extensive
multisystem LCH, and single-system pulmonary LCH. The extensive multisystem
form of LCH can be further divided into those cases with and without organ
dysfunction. Prognosis and therapy depend on the organ systems involved and the
number of systems implicated. Optimal therapy has yet to be determined.
Clinical
Findings: LCH is a very rare condition that affects approximately 8 of every
1,000,000 people. There is a 2:1 male-to-female predilection, and all races are
affected equally. Usually, the condition is first noticed in childhood, but
adult-onset disease does occur. LCH isolated to the skin has one of the best
prognoses of all of the forms of LCH. Most cases of LCH manifest first in the
skin, even before the development of systemic findings; therefore, all patients
with cutaneous LCH should be routinely screened for systemic diseases.
In infants,
the typical presenting skin findings are those of a persistent papulosquamous
eruption on the scalp that resembles cradle cap. On closer inspection, small
petechiae are observed. These petechiae are very characteristic for LCH and can
be easily overlooked. The scalp form is often misdiagnosed as seborrheic
dermatitis early in infancy, and frequently it is not until the child is 3 to 6
months old and the rash has persisted that the diagnosis of LCH is entertained.
The other common presentation in children is that of persistent diaper
dermatitis. The rash has a unique predisposition to affect the groin folds and
can be quite inflammatory and resistant to typical therapy for irritant contact
dermatitis or diaper rash. The groin rash appears as red to yellowish-orange
papules that coalesce into plaques. Ulcerations and erosions are common.
Superinfection with bacteria often leads to an odor. Both of these forms are
almost always considered to be another diagnosis before LCH is considered and a
skin biopsy is done to prove the diagnosis. Other skin findings that can be
observed by the astute clinician are adenopathy, ear inflammation and drainage
from the external ear, and soft tissue swelling. The soft tissue swelling is
seen only in those patients with underlying bony disorders. Gingival
hypertrophy may also be seen, but it is often subtle. Infants may also have
premature eruption of their teeth, which is most commonly noticed by the still
breast-feeding mother.
Twenty
percent of patients do not exhibit any cutaneous signs of disease and present
solely with varying systemic
complaints. The most common extracutaneous form of LCH, formerly designated
eosinophilic granuloma, is now called single-system unifocal bone disease.
Children present with a painless to slightly tender soft tissue swelling
overlying the bony area of involvement, most commonly the calvarium. Palpation
of the swelling reveals the fluctuant nature of the soft tissue distention, and
in some cases the defect in the underlying bone can be felt. Plain radiographs
can help delineate the extent of
disease. If one area of bony involvement is found, a skeletal survey should be
performed to evaluate for other silent bony lesions, which can occur in up to
15% of cases. The involved bone has a radiolucent appearance that is sharply
demarcated from the surrounding bone. Bony involvement has been described to
occur in almost every bone in the body. Most cases are inconsequential, but if
the involvement affects a critical portion of the spine, the possibility of weakening of the joint
and potential fracture could have life-threatening implications. The term
“floating teeth” has been used to describe the finding of radiolucent aspects
of the mandible that give the appearance that the teeth are floating without
the support of the under- lying bone.
LCH can be a
life-threatening, progressive disease. The lymphatic system, lungs,
hypothalamus, and pituitary are commonly involved. Lymphadenopathy in the
region of skin or bony involvement is usually seen. Biopsies of lymph nodes can
show involvement with Langerhans cells or dermatopathic changes.
Lung
involvement is almost always a component of multisystem disease. Radiographs
may be normal or may show cystic spaces or a nonspecific interstitial infiltrate.
Pulmonary function testing may reveal a decrease in diffusion capacity and a
decrease in forced expiratory volume. Lung abnormalities are very frequently
seen in adults with LCH.
The
pituitary stalk can also be affected in this disease. The eponym Hans-Schüller-Christian
disease describes those patients with LCH who have the constellation of
diabetes insipidus, lytic bony lesions, and exophthalmos. The involvement of
the pituitary stalk leads to the diabetes insipidus. The lack of antidiuretic
hormone causes the excretion of large amounts of dilute urine and increased
thirst. The skull is the bony region most commonly involved.
Letterer-Siwe
disease is
the name given to the constellation of symptoms that include severe skin
involvement, hepatosplenomegaly, anemia, and leukopenia. These patients have
early onset of disease in infancy and have a poor prognosis because of the
aggressiveness and extent of the disease load.
The
diagnosis and prognosis of LCH depend on the number of organ systems involved
and the extent of disease. Treatment likewise depends on these factors, and a
multidisciplinary approach should be taken.
Pathogenesis:
The
exact etiology is unknown, and there is considerable ongoing research to
determine whether this is a clonal malignant process or a reactive process. The
Langerhans cells that are present within the areas of involvement have a
different morphology from their normal counterparts. The affected Langerhans
cells are round, without dendritic processes, and have been found to express
different cell surface markers. The initiating factor or factors for these findings
are as yet only theoretical. No gene defect has been described.
Histology:
Histological
findings from the skin and other involved tissues are only slightly different.
The main pathology is found within the sheets of abnormal-appearing Langerhans
cells. On microscopic evaluation, the cells have kidney bean–shaped nucleus and
show varying amounts of epidermotropism. Immunohistochemical staining shows
CD1a, S100 and CD207 positivity. On electron microscopy, the characteristic
tennis racket–shaped Birbeck granules are seen.
Treatment:
Therapy
is determined by the extent and location of disease state. Mild, localized
cutaneous single-system disease may be observed and watched carefully for the
development of systemic involvement. Supportive care is given with topical anti-inflammatory agents and
antiinfectives to help treat and prevent possible infections, especially
infections of the groin region in infants. A small percentage of patients
experience spontaneous remission. Single bony lesions may also remit
spontaneously.
Bony lesions
have been treated with resection of the involved tissue, with curettage of the
region, and with systemic steroid therapy. The use of steroids has been
associated with recurrences after the drug is stopped.
Multisystem
disease is treated in myriad manners, depending on the burden of disease, the
systemic involvement, and the patient’s symptoms. The disease can be difficult
to treat, and systemic chemotherapies are the mainstay of treatment.
Vinblastine or etoposide based regimens are most
commonly used as first-line therapy. Some refractory disease has been treated
with ablative chemotherapy and subsequent bone marrow transplantation.
