• 
• 
• 
• 
• 
• 
• 
• 
• 
  

Among its many other functions, the skin plays an important role in the body's defenses. One to three percent of epidermal cells are Langerhans cells (LC), and LCs in the epidermis are among the first cells to encounter foreign antigens, including infectious organisms such as bacteria, viruses, and contact allergens. The antigen is ingested by the LC, which then migrates to neighboring lymph nodes, where it presents the antigen to a large number of T lymphocytes, thus triggering the immune response. The LC also secretes a number of different chemical substances

(cytokines), which aid in the immune reaction. Whatever the underlying etiology, Langerhans cell histiocytosis (LCH) appears to be due to an uncontrolled proliferation of LCs, and the damage to the various organs involved, including the skin, appears to be due to the various cytokines secreted. It is not surprising, therefore, that skin involvement is observed in up to 50% of children with Langerhans cell histiocytosis (LCH) and in about 10% of cases is reported as the only affected site (skin-only LCH)[1]. LCH can present at any age from birth to old age, and the skin is often the first site of involvement.

This "skin-only" manifestation of LCH is seen most commonly in the very young child, but in a recent series of 20 adult LCH patients described from the Hammersmith Hospital, two had LCH limited to the skin at presentation and during a five-year followup period [2]. Like children, however, adults may present with what appears to be skin-only LCH, which later progresses to involve other organs. This progression may occur rapidly or may be delayed. One adult in the Hammersmith series had scalp disease for four years before the disease progressed to involve the central nervous system.

Clinical Presentation

Cutaneous LCH is often the first manifestation of the disease, particularly in the infant, and these babies appear otherwise healthy.

The most common area of skin involved is the scalp, followed by the skin flexures, including the perineum, but any part of the skin can be affected, including the palms, soles, and nails. The appearance of skin LCH is very diverse with scaly papules, vesicles, nodules, eroded nodules, tumors, crested plaques, purple plaques, and purpuric nodules all being described [2]. Blue, nodular skin infiltrates in young babies have also been described [4] and must be distinguished from other causes of the "blueberry-muffin baby," such as congenital viral infections, congenital leukemia, neuroblastoma, and other malignancies of the neonate.

The most common presentation of skin LCH is with a scaly, erythematous, seborrhea-like eruption on the scalp, which is commonly misdiagnosed as seborrheic dermatitis or "cradle cap." Scalp LCH frequently becomes petechial, however. Both adults and children may present with scalp involvement which may be painful to the touch and is only occasionally itchy.

The most common skin flexures involved with LCH are the groin, the perianal area, behind the ears, the neck, the armpits, and the crease below the breasts in adult women [3]. Both perineal and scalp involvement is often misdiagnosed, and it is important for primary caregivers of young children to remember two maxims:

• A patient with seborrheic dermatitis that does not improve with therapy, or which continues to recur - think of LCH.
• A patient with diaper dermatitis that does not improve with therapy, or which continues to recur - think of LCH.

A recent example of this is a patient of the author, a physician's child, who was misdiagnosed with seborrheic dermatitis for nine months before the correct diagnosis of LCH was made. At diagnosis, a chest radiograph confirmed the presence of lung involvement.

Definitive diagnosis is made on skin biopsy, which demonstrates the presence of infiltration of skin by CD1a-positive Langerhans cells. Demonstration of Langerhans granules (Birbeck granules) within the cells on electron microscopy (EM) is helpful, and a portion of the biopsy should always be frozen for EM studies.

Natural History

The natural history of cutaneous LCH is very variable. Patients often present with disease limited to the skin, but even at presentation, the disease may involve other organs (such as bone), or the skin lesions may be part of multisystem, disseminated disease. Patients with skin-only disease may have spontaneous regression of their disease, or the disease may regress and then reactivate in the skin or with progression to other organs.

Hashimoto-Pritzker Disease

In 1973, Hashimoto and Pritzker described a pure cutaneous form of LCH, which occurs only in the neonate or young infant [5]. The characteristic features of this congenital, self-healing reticulosis were skin lesions in an otherwise well infant, a histopathology demonstrating a Langerhans cell infiltrate, and spontaneous involution of the skin lesions.

The pathology was said to be typical with histiocytic infiltration limited to the dermis and sparing of the epidermis and so-called "myelin-dense bodies" seen on electron microscopy. The implication was that physicians could distinguish a group of young patients with skin-only LCH, who would always spontaneously regress and present no further problem.

In one report of four cases of Hashimoto-Pritzker disease however, one child relapsed with skin disease and a second with bone disease at six months [6]. In another reported case series, several patients who presented with lesions limited to skin developed multi-organ disease within the first year from diagnosis [7]. Some of these apparently healthy babies progressed within weeks to widespread, disseminated disease.

It appears that distinction into Hashimoto-Pritzker type lesions and others is not warranted. There is clearly a need for careful followup of all skin LCH patients. The course of the disease cannot be reliably predicted from the clinical presentation or the histology of the lesions, and some of the infants may progress fairly rapidly to developing severe, life-threatening disease.

Treatment

Because of the varied natural history and the good prognosis in many of the cases, therapy should be given only for severely symptomatic disease. Surgical excision should be limited to small, isolated lesions and should not be performed for more widespread lesions. Mutilating surgery should not be done in view of the many other options available.

Local and systemic corticosteroids are often the first line of therapy tried. Such therapy is seldom effective in the long term, although it may be beneficial for short-term use, particularly in patients with spontaneously regressing disease.

Other local therapies which have been shown to be effective include phototherapy with psoralen and ultraviolet irradiation (PUVA) and topical nitrogen mustard [3,9]. Parenteral therapies include the use of oral trimethoprim sulfamethoxazole [10], chemotherapy with vinblastine and/or etoposide, nucleoside analogues such as cladribine (2-CdA), and immunomodulatory drugs such as cyclosporine.

If simple methods fail, the disease should be treated in conjunction with a dermatologist and oncologist familiar with therapy for LCH.

Conclusion

Primary caregivers should be able to recognize the skin manifestations of LCH and be aware of the natural history. Infants with cutaneous LCH need careful followup, and parents should not be falsely reassured. The diagnosis of skin-only LCH should only be made after several years of followup.

Bibliography

1. Willis B., Ablin, A., Weinberg, V., et al. "Disease Course and Late Sequelae of Langerhans Cell Histiocytosis: 25-Year Experience at the University of California, San Francisco." Journal of Clinical Oncology, vol. 14, 1996, p. 2073.
2. Chu, T., D'Angio, G., Favara, B., et al. "Histiocytosis Syndromes in Children." Lancet, vol. 1, 1987, pp. 208-209.
3. Munn, S., Chu, A. "Langerhans Cell Histiocytosis of the Skin." Hematology/Oncology Clinics of North America, vol. 12, 1998, pp. 269-286.
4. Enjolras, O., Leibowitch, M., Bonacini, F., et al. "Congenital Cutaneous Langerhans Histiocytosis. Apropos of Seven Cases." Ann. Dermatol. Venerol., vol. 119, 1992, pp. 111-117.
5. Hashimoto, K., Griffin, D., Kohsbaki, M. "Self-Healing Reticulohistiocytosis." Cancer, vol. 49, 1982, pp. 331-337.
6. Longaker, M., Frieden, I., Le Boit, P., et al. "Congenital Self-Healing Reticulocytosis: The Need for Long-term Followup." J. Am. Acad. Dermatol., vol. 31, 1994, pp. 910-916.
7. Easterly, N., Mauer, H., Gonzalez-Crussi, F. "A Seven-Year Experience at a Children's Hospital." J. Am. Acad. Dermatol., vol. 13, 1985, pp. 481-496.
8. Herman, L., Rothman, K., Harawi, S., et al. "Congenital Self-Healing Reticulohistiocytosis." Arch. Dermatol., vol. 126, 1990, pp. 210-212.
9. Sheehan, M., Atherton, D., Broadbent, V., Pritchard, J. "Topical Nitrogen Mustard: An Effective Treatment for Cutaneous Langerhans Cell Histiocytosis." J. Pediatr., vol. 119, 1991, pp. 317-321.
10. Tzortzatou-Stathopoulou, F., Zaidara, A., Mikraki, V., et al. "Effect of Trimethoprim Sulfamethoxazole in Langerhans Cell Histiocytosis: Preliminary Observations." Med. Pediatr. Oncol., vol. 25, 1995, pp. 74-78.