CLINICAL ASPECTS OF LANGERHANS CELL HISTIOCYTOSIS

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The clinical manifestations of Langerhans cell histiocytosis (LCH) vary. The different patterns of clinical involvement have led to nosologic confusion as well as misunderstandings concerning the disease process itself (discussed in the article by Schmitz and Favara on p. 221 of this issue). Relatively recent efforts made to define the clinical and pathologic criteria needed for diagnosis have made it possible to accumulate and record coherent data.8, 11, 20, 22 This has allowed data on pathologic and clinical grounds to be compared. In particular, recent retrospective evaluations of large series of patients fitting such diagnostic criteria have improved our knowledge of the clinical manifestations of LCH, including isolated and less common ones.59, 64

The disease is most probably underdiagnosed; the bone lesions are either symptomless or, if presenting as painful lumps, ascribed frequently to trauma. Mild skin disease may be mistaken for seborrheic eczema. Thus, the true incidence of isolated bone lesion(s) or mild skin disease is not known. This is not true of the more aggressive, disseminated forms of the disease, which are brought readily to the attention of the specialist and, with modern techniques, soon diagnosed.

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ETIOLOGY

The nature of the disease is under continuing debate and the subject of extensive research. These aspects are discussed in the article by Willman and McClain on p. 407 of this issue, where issues such as those surrounding the demonstrable clonality of LCH cells are presented.

Here it is appropriate to ask whether LCH might be a genetic disease. Based on clinical observations and experience, most physicians reassure patients that LCH is not a familial disorder. This remains substantially true.

PATHOLOGY

The confidence levels for the diagnosis of LCH, which were recommended in 1987 by the Writing Group of the Histiocyte Society,11 are summarized in Table 1. These standards have been widely adopted. The benefits of accurate communication among physicians and of the comparison of results obtained by various treatment centers are self-evident.

CLASSIFICATION AND NOSOLOGY

The historical definitions of what is now termed LCH had one advantage: they emphasized the manifold clinical manifestations of the disease. Yet, even they covered only the more pronounced of the possible clinical patterns. It also had long been known that the number of sites involved is less important than the functional status of the affected organs. About 20 years ago Lahey38 proposed criteria for significant organ involvement and required objective evidence of a functional disorder in the

BONY SKELETON

Painful swelling is often the cause of consultation in patients with restricted LCH. The bones most frequently involved are the skull, the long bones, and the flat bones; hands and feet are rarely involved.19, 35, 40 The possible complications of an osteolytic lesion depend on the local situation; for instance, when the ear region is involved, the mastoid bone appearance may mimic mastoiditis; periorbital involvement may lead to proptosis; and vertebral LCH may produce bony collapse. In one

SKIN

Skin involvement is observed in more than one third of children with LCH. Frequently affected sites are the intertriginous zones (e.g., axillae) and the lumbosacral areas. The lesions may appear as reddish papules that progress and ulcerate, or depigmentate and heal (see figures in the article by Munn and Chu on p. 269 of this issue). Skin is reported as the only affected site in about 10% of cases, especially in male infants,53, 64, 65 and in such cases spontaneous regression is frequent

LYMPH NODES

Lymph nodes may be enlarged in a small number of LCH patients. It is found in fewer than 10% of children at presentation, and it may be part of disseminated disease or associated only with local disease affecting adjacent skin or bone. The cervical nodes are those most frequently involved, and their enlargement may be massive. In a few patients, lymph node LCH may be the harbinger of a more indolent but aggressive clinical picture, sometimes with recurrent bouts.

BONE MARROW

Pancytopenia is quite common in patients with disseminated disease, but in most cases massive infiltration by Langerhans cells may not be present, although marrow infiltration of some grade has been reported.59 In the LCH-I study, 18% of patients with multisystem disease had documented marrow infiltration, as compared with 33% with hematologic system involvement.37

LIVER

Hepatic enlargement is very common in patients with disseminated disease, but the cause is not completely clear. Systemic inflammatory hyperactivation including the reticuloendothelial system may account for the usually observed hyperplasia of von Kupffer cells. Langerhans cell infiltration may be histologically documented, and in some cases it could be the main cause of liver enlargement; in other cases, massive portal lymphadenomegaly may lead to cholestatic hepatomegaly.33 When persistent,

SPLEEN

An enlarged spleen is found in about 5% of patients at presentation,59 and in refractory disease, it may contribute to cytopenia. Although splenectomy is usually not indicated as part of LCH-directed therapy, in selected cases removal of the massively enlarged spleen may be indicated to reduce the need for blood transfusions. Rarely, the spleen may rupture, and this was the cause of death in an infant with LCH.7

LUNGS

Lung involvement in LCH is frequently observed in patients with multisystem disease, and it can cause respiratory distress with tachypnea, retraction, and persistent cough. Functional evaluation in such children has shown reduced lung or respiratory compliance.28 The radiologic picture consists of diffuse, interstitial infiltrations (Fig. 2). In such cases, invasive documentation of LCH involvement is not necessary. Isolated pulmonary involvement is more frequent in adults, but it has been

GASTROINTESTINAL TRACT

This is an unusual site of involvement in childhood LCH. Although some infants with disseminated disease may fail to thrive, intestinal malabsorption is not necessarily the cause. Vomiting, diarrhea, or protein-losing enteropathy are definitely rare. The diagnosis of gastrointestinal involvement in such cases must be supported not only by radiologic evidence of scattered stenotic areas, but also by intestinal biopsy.21, 57 Association of Crohn disease and small bowel LCH in an adult patient has

ENDOCRINE SYSTEM

Polyuria and polydipsia, sometimes as massive as up to 6 to 8 L of water intake daily, should be very suggestive of LCH in children. Once the central origin of the diabetes insipidus (DI) has been assessed, a thorough diagnostic work-up is needed for possible silent LCH localizations. DI may occur before9 or during additional manifestations of LCH.18 In most cases it occurs at a median time of 10 to 12 months after the disease onset, but the range extends to many years.6, 18, 44 DI develops

UNUSUAL SITES

The female genital tract can be involved by LCH. In one analysis of 42 cases, four patterns were suggested: (1) purely genital LCH; (2) genital presentation of multiorgan LCH; (3) oral or cutaneous LCH with genital LCH following; and (4) diabetes insipidus with subsequent genital and multiorgan LCH. Most of the reported patients were adults, and in all of the groups described a minority fell within the pediatric age range.3 A perirenal mass obstructing the ureter was observed in one child with

ASSOCIATED CONDITIONS

Eleven of 348 patients (3.5%) in the large French series had intercurrent diseases including unclassified neonatal encephalopathy, Hirschsprung disease, von Willebrand disease, myasthenia, unilateral multicystic renal dysplasia, posterior urethral valves, fibrous dysplasia, and intestinal fistulae.59 A child with Klinefelter syndrome developed progressive LCH that was controlled with allogeneic bone marrow transplantation.23

DIFFERENTIAL DIAGNOSIS

The diagnosis of LCH is not difficult if suspected. The clinical picture is suggestive in most cases; radiology usually demonstrates osteolytic lesions in patients with bone pain, and biopsy of skin lesions and enlarged lymph nodes can easily be performed to document LCH infiltration. This may provide abundant tissue to rule out “sinus histiocytosis with massive lymphadenopathy” (Rosai-Dorfman disease) (see article by Henter and colleagues on p. 417 of this issue), an alternative diagnosis.

PROGNOSIS

Untreated LCH can have a variable course. It can resolve spontaneously, or it can disseminate and compromise normal function of vital organs, with grave if not fatal consequences.50 In 1975 Lahey38 introduced the concept of organ dysfunction as a prognostic indicator based on his review of 83 patients treated with chemotherapy by the Children Cancer Study Group (CCSG). In 1981 the Southwest Oncology Group (SWOG) presented a retrospective report of 155 children,36 of which 59 had evidence of

ACKNOWLEDGMENT

The authors are grateful to Paola Fiori, MD (Pavia, Italy) for excellent radiologic collaboration and to Franco Cassinari for expert technical assistance.

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      LCH manifestation can be extremely variable in different patients and unfortunately due to its rarity we have few evidences on adult population, so that we still don't have a precise definition of clinical presentation and evolution of such disease in adults. As concerns endocrine system in our study population of adult pulmonary LCH patients DI reaches a prevalence of 50%, while antero-pituitary deficiencies (APD) affected about one third of the whole group and two third of the patients with DI, being a bit more frequent than that 30% of DI [50,51] and 20–24% of APD [14–17,19] already described in previous studies. It is important to stress that all antero-pituitary deficiencies in our patients were strongly associated to DI and temporally successive to its diagnosis.

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    Address reprint requests to Maurizio Aricò, MD, Associate Member, Department of Pediatrics, University of Pavia, IRCCS Policlinico San Matteo, 27100 Pavia, Italy

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