Generalized eruptive histiocytoma of childhood associated with rheumatic fever

ARTICLE

Generalized eruptive histiocytoma (GEH), first described by Winkelmann and Müller [1] in 1963, is a benign, non-Langerhans-cell (LC) and non-lipid histiocytosis, characterized by symmetrically distributed multiple papulonodules. The lesions involve the trunk, face, extremities and occasionnally the mucous membranes, and show spontaneous resolution towards brown macules or complete disappearance. The histological characteristic of the lesion is a monomorphous histiocytic proliferation without xanthomatous cells or multinucleated giant cells. Ultrastructural studies have revealed the presence of many dense bodies and the absence of Birbeck granules in the cytoplasm [2-6]. The first reported cases were seen in adults, but some pediatric cases have been subsequently reported [6-11].

We report herein a case of GEH in a child complicated with rheumatic fever.

Case report

A 5-year-old Japanese girl was referred to our department in July 1997 with a three-month history of multiple papulonodular eruption. The lesions had first appeared on the dorsal aspects of the feet and then increased in number during the next three weeks. She had been admitted to the pediatric department of another hospital because of high fever of unknown origin (FUO) up to 39š C for 10 days before the eruption was first noted.

On physical examination, brownish, small and shiny papules were seen on the dorsal aspect of the right hand, abdomen, and lower extremities (Fig. 1), but mucous membranes were spared. The skin lesions were asymptomatic, slightly elevated and firm to the touch. The total number of lesions was up to forty.

The pulse revealed a regular tachycardia (140/min), and a grade 2 pansystolic murmur was heard along the lower left sternal border. The echocardiogram showed grade 1 mitral regurgitation, trivial arterial regurgitation and high-echoic change of pericardia. X-ray examination of the chest and the skull did not reveal any abnormalities. Laboratory data were normal except for the increased white blood cell count (10,200 /mm³) and elevated levels of serum C-reactive protein, 6.2 mg/dl (normal range: < 0.2 mg/dl) and antistreptolysin O, 281 IU/ml (< 166 IU/ml). Rheumatoid factor and antinuclear antibodies were negative.

With the diagnosis of rheumatic fever, treatment with 25 mg of prednisolone and 1,400 mg of aspirin was started in November 1997. The fever remitted with an improvement of laboratory data, and in January 1998, the eruption began to regress spontaneously and completely disappeared within the next five weeks. During tapering off or after cessation of steroid therapy, there was no recurrence of the fever or the eruption.

Histopathological findings

The biopsy specimen taken from a lesion of the right foot showed a well-circumscribed cellular infiltrate in the upper and middle dermis (Fig. 2). The overlying epidermis was mildly acanthotic and rete ridges were flattened. The aggregating cells had abundant, poorly-limited, eosinophilic cytoplasm and round to oval nuclei with prominent nucleoli (Fig. 3). Some fibroblastic cells with hyperchromatic nuclei and small numbers of lymphocytic cells were intermingled, but eosinophils, foamy cells or multinucleated giant cells were absent. The histiocytic cells were periodic acid-schiff (PAS) negative. Sudan III stain of frozen sections showed no fat in the lesion. Immunohistochemical staining was performed using mouse monoclonal anti-CD1a, vimentin, CD68 and MAC387 antibodies and rabbit polyclonal anti-S-100 protein, lyzozyme and alpha1-antichymotrypsin (A1ACT) antibodies by means of avidin-biotin complex method. The histiocytic cells expressed vimentin, CD68, MAC387, A1ACT and lysozyme, but neither S-100 protein nor CD1a.

Electron microscopic findings

The infiltrate consisted mainly of large cells with an irregular contour and short villous processes (Fig. 4). The nuclei were polymorphous and deeply indented with peripherally condensed chromatin and large nucleoli. The cell cytoplasm contained a varied number of both smooth and rough-surfaced endoplasmic reticulum, free ribosomes, and mitochondria. Amorphous electron dense bodies, which were round to oval and lined with limiting membrane, were occasionally observed (Fig. 5). Some of these cells contained many lysosomal structures with areas of differing density, vesicles, remnants of mitochondria or concentric membranous materials. Neither Birbeck granules nor desmosomes was present.

Discussion

Our patient showed an asymptomatic and widespread papular eruption that was histologically composed of a collection of monomorphous histiocytic cells. Immunohistochemical study revealed that they were CD68, MAC387, A1ACT and lysozyme positive, but CD1a and S-100 protein negative. No Birbeck granule was observed on electron microscopy. These results indicate that the eruption is non-LC histiocytic origin.

Non-LC histiocytosis includes a spectrum of various disorders [12-14]. Among them, the most likely diagnosis of our patient was GEH of childhood. Reticulohistiocytoma cutis was ruled out because of the different distribution of the lesions (mostly on the upper half of the body), the age of onset (usually in the fourth to the sixth decade of life), negative PAS staining and the lack of characteristic giant cells with glassy cytoplasm. Papular xanthoma, xanthoma disseminatum (XD) and juvenile xanthogranuloma (JXG) were excluded in view of the color of lesions, the absence of foam cells and negative fat staining. On electron microscopic examination of our patient, there were some dense bodies and lysosomal structures in the cytoplasm of histiocytes. The presence of lysosomal structures suggests that they do have a phagocytic activity and can develop into more differentiated phenotype such as foam cells or multinucleated giant cells. Repiso et al. [10] reported a case of GEH showing evolution into XD. Winkelmann [15] demonstrated that the early lesion of JXG shows monomorphous histiocytic infiltration without foam cells and may resemble GEH. Perhaps GEH is the primitive form of other more differentiated non-LC histiocytoses rather than a distinct clinical entity.

To our knowledge, this is the first report of GEH complicated with rheumatic fever. On the other hand, some fibrohistiocytic proliferative diseases are occasionally associated with autoimmune disorders or altered immunity. Sjögren syndrome [16-18], systemic sclerosis [18], primary biliary cirrhosis [19] and dermatomyositis [20] were reported as autoimmune complications of multicentric reticulohistiocytosis. Several authors also described cases of multiple dermatofibromas associated with systemic lupus erythematosus [21, 22], myasthenia gravis [23], pemphigus vulgaris [24] or HIV infection [25]. Although a close onset of rheumatic fever and GEH in our patient may suggest a certain association between these two diseases, it is still unclear whether this is an incidental complication or not. Further collection of cases may be required to unravel the relationship between GEH and other diseases.

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