Chapter 148. Non-Langerhans Cell Histiocytosis

Non-Langerhans cell histiocytosis (NLCH), or class II histiocytosis, represents a broad group of different disorders characterized by the proliferation of histiocytes other than Langerhans cell (LC) (Table 148-1).

In some textbooks, these diseases are gathered under the term: macrophage/dermal dendritic cell disorders. In 2001, Zelger et al suggested a unifying approach to understand this disease group. They identified different types of macrophages in the prototype lesion, juvenile xanthogranuloma, and then used this morphology to subcategorize the diseases.

Clinicopathologic overlap makes it difficult to place some patients exactly into one defined entity, indicating a close relationship between these disorders. While many of these disorders may feature foamy cells, affected patients are normolipemic. In all instances, the etiology and pathogenesis are unknown.1

Most of these cells share the same immunophenotypes, but the resulting disorders differ in clinical presentation and course. Although all NLCH disorders are considered reactive with no clinical evidence of malignancy, some forms, as with class I histiocytosis (Langerhans cell histiocytosis or LCH), can be invasive and therefore they are not necessarily biologically benign. Patients have been described who have developed both LCH and an NLCH, particularly, juvenile xanthogranuloma (JXG).

These cases seem to demonstrate a relationship between LCH and NLCH.2 According to some authors the dendritic cell is the presumed cell of origin of both LCH and NLCH, leading to the shared categorization of these diseases as dendritic cell-related disorders and separated from macrophage-related proliferations such as sinus histiocytosis with massive lymphadenopathy (SHML), also known as Rosai–Dorfman disease. However, the coexistence of LCH and cutaneous SHML has also been reported, further complicating the complex relationships among histiocytic disorders. See Table 147-2 for a list of the recommended laboratory evaluations for a patient with LCH and Table 147-3 for a list of other investigations that should be carried out in LCH.

Several attempts have been made to classify NLCH, but none has been universally accepted.

Although impossible to perfectly correlate histologic features and immunophenotype with either clinical presentation or course of a single disease, one practical classification is infantile versus adult disease. Infantile forms with individual papulonodular lesions tend to be almost all cutaneous and self-healing [e.g., JXG, generalized eruptive histiocytosis (GEH), benign cephalic histiocytosis (BCH)], whereas the adult forms with coalescing plaque-like lesions tend often to be systemic and progressive/aggressive [e.g., Erdheim–Chester disease (ECD); necrobiotic xanthogranuloma (NXG); SHML]. Other rare forms including hereditary progressive mucinous histiocytosis are not discussed. An approach to the patient with NLCH is outlined in Fig. 148-1.

This chapter discusses only disorders of significance to the general dermatologist. Forms that are very rare (e.g., indeterminate cell histiocytosis) or that have been described in a single patient (e.g., fat-storing hamartoma of dermal dendrocytes) are not considered.

JXG accounts for 80%–90% of cases of NLCH. All of the other NLCHs are rare. The author has encountered almost 300 cases in the past 35 years. There is no sexual or racial predilection. JXG appears within the first year of life in approximately 80% of cases; in 20%–35% of cases, it is congenital. Approximately, 30 adult cases are reported in the literature. There is a slight male predominance among individuals with solitary JXG lesions and a strong male predominance among those with multiple cutaneous lesions. Papular xanthoma (PX), considered a variant of JXG, is a rare disorder; fewer than 20 cases have been described. The onset of PX in children is usually during the first year of life. The disease seems to be more frequent in males. GEH is rare, with approximately 40 cases described, of which 10 were in children. It may start at any age, with reports of onset ranging from 3 months to 58 years. BCH is also rare. Over the past 3 decades, approximately 30 cases have been described, with the same incidence in boys and girls. The age of onset is 5–34 months (mean, 13.5 months). Progressive nodular histiocytosis (PNH) is an exceptional form described in a few children and adults. Xanthoma disseminatum (XD) is rare (approximately 100 published cases) and affects males more frequently than females. The random nature of the disorder does not permit an exact evaluation of either familial involvement or morbidity. In approximately 60% of patients, onset is before age 25 years. ECD is also rare, and only about 60 cases have been described in 70 years. Multicentric reticulohistiocytosis (MRH) is an uncommon disorder but has been observed in more than 100 individuals reported up to 1990, with the purely cutaneous forms seen in more than 50 patients. Caucasians are affected in more than 85% of cases, and women are more frequently affected than men (female–male ratio of 3:1). In general, MRH affects adults 40 years of age, but the disease may appear during adolescence and rarely in childhood (pure cutaneous forms). NXG has been described in approximately 60 cases. The age of onset of NXG ranges from 17 to 85 years, and the disease shows no gender predilection. SHML is also a relatively rare disease; approximately 365 cases have been studied. The disease has a worldwide distribution with increased incidence in blacks from Africa and the West Indies. There is no gender predilection. Any age group may be affected, but 80% of cases occur in the first or second decade of life.

The pathogenesis of NLCH is unknown. Virus-induced local immune alternation in the transformation of the NLCH has been postulated since previous studies have suggested that the proliferation of histiocytes is a physiologically appropriate response to viral infection.3

MRH may represent an abnormal histiocytic reaction to different stimuli. In forms with solitary lesions, local trauma may play a role, whereas in diffuse forms, the association with internal malignancies and autoimmune diseases suggests an immunologic basis for the initiation of the reaction.

PNH is a progressive disease with no tendency to involute spontaneously. It is thought to entail proliferation of mature spindle-shaped cells and may represent an evolution of another form of NLCH. MRH may evolve from a less developed form of NLCH, such as GEH or adult JXG. It has also been suggested that urokinase released by the activated histiocytes may play a role in the extracellular matrix degradation leading to erosion of cartilage and adjacent bone. The origin and function of the pleomorphic cytoplasmic inclusions that are frequently present in the histiocytes forming the infiltrate in this disease are still debated. They may result from a peculiar kind of endocytosis or from the expression of an exocytosis phenomenon. These unique granules have already been described in several cases of reticulohistiocytosis, and if their presence is confirmed by subsequent observations, they could represent the ultrastructural marker.

The cause of NXG and its link to paraproteinemia are uncertain. It has been suggested that serum immunoglobulins complexed with lipid become deposited in the skin, eliciting a giant cell foreign-body reaction. Another hypothesis is that the paraproteinemia is the primary phenomenon, and a secondary proliferation of macrophages with receptors for the Fc portion of immunoglobulin G occurs. It has also been proposed that the paraprotein in NXG has functional features of a lipoprotein that may bind to lipoprotein receptors of histiocytes and induce granuloma formation. Mutations in SLC29A3, encoding an equilibrative nucleoside transporter (ENT3), have recently been shown to cause both familial histiocytosis syndrome (Faisalabad histiocytosis) and familial SHML.4

Clinical Findings

Cutaneous Lesions

JXG is a benign, self-healing disorder that is characterized by asymptomatic yellowish papulonodular lesions of the skin and other organs in the absence of a metabolic disorder. Lesions consist of an infiltrate of histiocytes with a progressively greater degree of lipidation. Two main clinical forms can be distinguished, a papular and a nodular form. In both the lesions are initially orange–red or red–brown but quickly turn yellowish. The papular form (Fig. 148-2) is characterized by numerous (up to 100) firm hemispheric lesions 2–5 mm in diameter. These lesions are irregularly scattered throughout the skin but are located mainly on the upper part of the body. PX is considered to be a form of JXG in which the lesions rapidly become xanthomatous. PX lesions range from 2 to 12 mm and show a generalized distribution with no tendency to merge into plaques. The nodular form (Fig. 148-3) is less frequent and occurs as one or a few lesions. Such nodules are generally round, 10–20 mm in diameter, and translucent, and might show telangiectases on their surface. The term giant juvenile xanthogranuloma is applied to lesions larger than 2 cm. Unusual clinical variants have been also reported. The mixed form is characterized by the simultaneous presence of both small and large nodules. The term juvenile xanthogranuloma en plaque defines a group of JXG lesions with a tendency to coalesce into a plaque as the only expression of the disease. In one study, 67% of 174 cases involved solitary papular lesions, and an additional 16% showed solitary nodular lesions. Multiple cutaneous lesions were noted in 7% of affected individuals, a solitary extracutaneous lesion in 5%, and multiple cutaneous and visceral-systemic lesions in an additional 5%.

Recently, two new variants have been described. The first was a case with skin lesions consisting of bluish papules and nodules (mimicking a “blueberry muffin baby”) located on the head, trunk, and proximal extremities. The second, “multiple lichenoid JXG,” was characterized by hundreds of discrete papules.5

Related Physical Findings

Ocular involvement is the most typical extracutaneous manifestation. It may precede or follow the cutaneous lesions. Approximately 0.4% of cases exhibit ocular manifestations, usually unilateral.6 Lesions may affect the orbit, iris, ciliary body, cornea, and episclera, and can result in spontaneous hyphema, glaucoma, and blindness. JXG of the uvea is a rare disease that usually responds to systemic steroids or low-dose radiotherapy; aggressive cases can be treated with chlorambucil.7 Therefore, the importance of ocular screening in patients with JXG, especially those with periocular lesions, should be emphasized. However, it is important to realize that the absence of skin lesions should not rule out JXG because skin lesions can often regress spontaneously.

An extremely rare extracutaneous manifestation of the papular variant is central nervous system (CNS) involvement. The nodular form of JXG may occasionally be related to systemic lesions of the lungs, bones, kidneys,8 pericardium, colon, ovaries, and testes. Juvenile chronic myelogenous leukemia (JMML) has been observed in association with this variant of JXG. Café-au-lait macules and JXGs occur together in 20% of individuals with papular JXGs and can be considered an excellent marker of neurofibromatosis type 1 (NF-1) (see Chapter 141) during the first years of life, even in the absence at that age of other reliable markers of NF-1. The occurrence of the triad of NF1, JXG, and JMML was first reported case in 1958, but is rare (approximately 20 cases in the literature). However, children with NF1 and JXG have a 20–30-fold higher risk for JMML than patients with NF1 without JXG.9

Laboratory Tests

No abnormalities in laboratory test results are usually found in JXG except in the very rare cases in which juvenile chronic myeloid leukemia is associated with JXG.

Histopathologic and Ultramicroscopic Findings

Biopsy sections of JXG lesions show a feature that is common to many NLCHs, i.e., a nonepidermotropic histiocytic infiltrate lacking Langerhans granules. Early lesions of JXG are characterized by a monomorphous, nonlipid-containing histiocytic infiltrate that occupies at least the upper half, and sometimes the entire thickness, of the dermis. Mature lesions (Fig. 148-4) contain foam cells, foreign-body giant cells, and Touton giant cells, mainly distributed in the superficial dermis and on the border of the infiltrate. Lymphocytes, eosinophils, and neutrophils are variably associated. Older lesions may show fibrosis. In mature lesions, fat stains yield positive results. The majority of JXG lesional biopsy sections stain positive for CD68/Ki-M1P and factor XIIIa but negative for CD1a and S100 protein. Recently, a 9-month-old boy was clinicopathologically diagnosed as S100-positive JXG. Longitudinal observation revealed that strong S100 reactivity disappeared in parallel with maturation of the lesions within 2 years after the initial diagnosis.10

Under the electron microscope, the histiocytes that characterize the early stage of the disease exhibit pleomorphic nuclei, are rich in pseudopods, and contain many elongated and irregular dense bodies. Clusters of comma-shaped bodies can occasionally be observed. In older lesions, there is a predominance of foam cells, the cytoplasm of which is completely filled with lipid vacuoles, cholesterol clefts, and myeloid bodies. Touton giant cells are extremely large and sometimes contain more than ten nuclei. Lipid material fills the periphery, whereas mitochondria and lysosomes predominate at the center.

The lesions of PX are composed almost entirely of foam cells and Touton giant cells. There is no evidence of a primitive histiocytic phase, and inflammatory cells are scarce or absent. Ultrastructurally, the cytoplasm is completely filled with lipid vacuoles without a limiting membrane, myeloid bodies, and lysosomal inclusions. Comma-shaped bodies are not found in these histiocytes.

Differential Diagnosis

The differential diagnosis of JXG is summarized in Box 148-1.

Complications

Eye involvement of a JXG lesion can cause severe secondary glaucoma. Lesions compatible with JXG have been described in many other organs as well, including oropharynx, lungs, spleen, liver, testes, heart, pericardium, gut, kidney, pancreas, lymph nodes, bone marrow, and even the CNS, and in rare cases can lead to death.11 Severe multisystemic JXG in infants is a life-threatening disorder, and thus treatment is often required.12 Patients may respond to multiagent chemotherapeutic regimens used to treat LCH.

Prognosis and Clinical Course

The cutaneous lesions of JXG tend to flatten with time. Each lesion evolves separately; thus, lesions at different stages of development may be seen in the same patient. Both cutaneous and visceral lesions disappear spontaneously, usually within 3–6 years. The patient's general health is not impaired, and physical and mental development is normal. Metabolic disturbances have not been identified. In the absence of associated conditions, prognosis is good. However, it is important to recognize that JXG may herald hematopoietic disorders in children and adults.13

Clinical Findings

The skin lesions of GEH consist of an asymptomatic eruption of round or oval papules that are firm, pink or dark red, and range in size from 3 to 10 mm (Fig. 148-5). These lesions appear in successive crops and are usually numerous (in the hundreds). In adults, the lesions are symmetrically distributed and may involve the mucous membranes, whereas in children the lesions are irregularly scattered over the entire body and the mucous membranes are spared.

BCH may evolve into GEH and therefore is now considered a limited form of the latter. BCH manifests as asymptomatic, slightly raised, round or oval, orange–red or red–brown lesions, 2–8 mm in diameter, that are initially localized on the upper part of the face, mainly around the eyelids, forehead, and cheeks (Fig. 148-6). Other lesions subsequently appear over the entire head, the auricles (particularly on the posterior side), the occipital region, and the neck. A few lesions may appear on the shoulders and arms. The number of early lesions varies considerably, from 2 to more than 100, and new ones continue to appear for many months. GEH and BCH do not, in general, show other features and do not lead to abnormalities in laboratory test results, or have known complications. However, diabetes insipidus has been reported in association with BCH from infiltration of the pituitary stalk, as has been described more commonly in LCH (see Chapter 147) and XD (see Section “Xanthoma Disseminatum”).

Histopathologic and Ultramicroscopic Findings

The lesions of GEH (Fig. 148-7) show a dense, monomorphous, nonxanthomatous histiocytic infiltrate in the papillary and midportion of the dermis, with a few lymphocytes. The histiocytes contain a nucleus with scanty chromatin and an abundant light, poorly limited cytoplasm. These cells are often arranged in nests around vessels. Older lesions in children may contain rare foam cells and few multinucleated giant cells with peripheral nuclei. By conventional microscopy, lesions of BCH cannot be distinguished from GEH lesions. In GEH, electron microscopy shows the tumor cells to contain a large number of dense and regularly laminated bodies, often clustered together. Occasionally, worm-like bodies are found. In BCH, many coated vesicles with a diameter ranging from 500–1500 nm are seen in all the histiocytes. Clusters of comma-shaped bodies are present in nearly one-fourth of the histiocytes. The comma-shaped bodies are formed by two electron-dense membranes of approximately 6 nm, separated by a light space of approximately 8 nm. Where the infiltrate is denser, desmosome-like junctions may be observed among the histiocytes.

Differential Diagnosis

The disorders from which GEH should be differentiated are listed in Box 148-2.

Prognosis and Clinical Course

In GEH, new crops of lesions may continue to appear for years. Slowly the disease subsides spontaneously without a trace or leaving anetoderma-like macules. Spontaneous regression of lesions occurs months to years after the onset of BCH. Regression of lesions starts characteristically where papules first appeared. The papules begin to flatten, and then, after a short period of hyperpigmentation, the lesions disappear without leaving scars.

Clinical Findings

PNH is a histiocytic disorder of skin and mucous membranes with a progressively deforming course. Cutaneous lesions consist of the eruption of hundreds of lesions of two different types: (1) superficial papules and (2) deep nodules. The most common lesions are yellow to orange papules, 2–10 mm in diameter that are randomly scattered over the body without localization in the flexural areas. These lesions may be present in the oral, laryngeal, and conjunctival mucosae. The deep lesions are dermal nodules ranging from 1 to 5 cm, with overlying telangiectasia, mainly located on the trunk. Café-au-lait spots, arthritis, and diabetes insipidus are absent. PNH has been described in a child with a hypothalamic tumor, probably histiocytic. Other patients with PNH have had hepatosplenomegaly, hypothyroidism, hypocholesterolemia, hyperuricemia, and chronic myeloid leukemia, or extensive involvement of pharynx and supraglottic larynx; the link between PNH and these other features is not clear.14

Histopathologic and Ultramicroscopic Findings

The histopathologic features of PNH are those of a xanthogranuloma with a predominance of storiform, spindle-shaped histiocytes that are positive for macrophage/dendritic cell line markers (CD68), and negative for CD1a and S100. Electron microscopic examination reveals histiocytes with a large indented nucleus.

Differential Diagnosis

The differential diagnosis for PNH is summarized in Box 148-3.

Prognosis and Clinical Course

In PNH, new lesions continue to develop during successive years with no sign of spontaneous involution. Despite the progressive nature of the lesions, patients remain in good health.

Clinical Findings

Cutaneous Lesions

XD is a rare, benign, normolipemic form of NLCH affecting the skin and mucous membranes. It is frequently associated with diabetes insipidus. The cutaneous manifestations consist of hundreds of papules that are red–brown at first and then become yellowish. They symmetrically involve the eyelids, trunk, face, and proximal extremities and, in flexures and folds, tend quickly to merge, forming soft plaques (Fig. 148-8). ECD is considered a variant of XD that has visceral manifestations and is progressive.

Related Physical Findings

In approximately 50% of cases of XD, xanthomatous lesions may also be observed on the mouth, pharynx, larynx, conjunctiva, and cornea. Symptoms of dyspnea and dysphagia are not uncommon. Vasopressin-sensitive transitory diabetes insipidus may be present, but polyuria and polydipsia are generally mild. Osteolytic lesions have been reported in only a few patients. XD may be associated with multiple myeloma, Waldenström macroglobulinemia, and monoclonal gammopathy. In ECD, the most common sign is chronic bone pain, usually mild and localized in the lower limbs. Extraosseous involvement can affect almost every organ, including the lungs, liver, kidney, heart, and CNS.

Laboratory Tests

A normal lipid profile is present in this disease, but slightly elevated levels of serum cholesterol or triglycerides have been found in a few cases. In some cases, multiple myeloma, Waldenström macroglobulinemia, and monoclonal gammopathy have been detected. When lesions affect the CNS, magnetic resonance imaging may show foci of abnormally high signal intensity. In ECD, radiographs show symmetric sclerosis typically affecting the long bones of the lower limbs with involvement of the diaphyseal and metaphyseal regions.

Histopathologic and Ultramicroscopic Findings

In the early stage of XD, biopsy specimens show a mixture of histiocytes, foam cells, and inflammatory cells; later, foam cells predominate and Touton giant cells are frequently present (Fig. 148-9). Siderosis is often observed. The proliferating cells resemble those of JXG ultrastructurally, but the plasma membranes of foam cells show many microvilli. Lesional skin sections in ECD show an infiltrate of lipid-laden histiocytes intermingled with Touton giant cells and eosinophils, surrounded by fibrosis.

Differential Diagnosis

The disorders from which XD should be differentiated are listed in Box 148-4.

Complications

In XD, organ involvement may lead to a variety of complications, particularly conjunctival inflammation and respiratory obstruction. Seizures, diabetes insipidus, and growth retardation have also been described. Chronic bone pain is the hallmark of ECD.

Prognosis and Clinical Course

Based on the evolution and prognosis of reported cases, three clinical variants of XD have been distinguished: (1) a self-healing form, (2) a persistent form, and (3) a progressive form (ECD). The persistent form is the most frequent one. Prognosis is usually good, but respiratory tract involvement may lead to dyspnea and dysphagia. Tracheotomy has been required in a few cases. In ECD, the prognosis is poor because of the high risk of visceral involvement, particularly pulmonary fibrosis.

Clinical Findings

Cutaneous Lesions

MRH is characterized by the association of a cutaneous and mucosal eruption with severe arthropathy and other visceral symptoms. The papulonodular lesions range in diameter from a few millimeters to 2 cm and are round, translucent, and yellow-rose or yellow-brown (Figs. 148-10 and 148-11). Grouping of lesions into plaques can give a cobblestone appearance, but lesions are generally scattered and isolated. They do not tend to ulcerate and are pruritic in about one-third of cases. These lesions preferentially affect the fingers (see Fig. 148-10), the palms and backs of the hands, the juxta-articular regions of the limbs, and the head (see Fig. 148-11). Small, scattered lesions may be found on the trunk. Periungual papules (see Fig. 148-10), arranged around the nail folds, resemble “coral beads” and have been noted in approximately 40% of cases. Severe involvement of the face may lead to a leonine facies. Xanthomatous lesions are found in 30% of cases. Periarticular nodules, resembling rheumatoid nodules, may occasionally be seen. Erythematous, photodistributed macules and papules have been observed in approximately 15% of cases and may be confused with dermatomyositis. Nail changes, including brittleness, longitudinal ridging, and atrophy, may occur. Almost 50% of affected patients have specific nodular lesions of the oral, nasal, and pharyngeal mucosae.

Two different subtypes without joint or visceral manifestations have been described: (1) solitary cutaneous reticulohistiocytosis (or reticulohistiocytoma cutis) and (2) diffuse cutaneous reticulohistiocytosis. Solitary cutaneous reticulohistiocytosis is characterized by a single firm, rapidly growing nodule varying in color from yellow-brown to dark red (Fig. 148-12). Its most common location is the head, but it may be found in almost any cutaneous site. It occurs without evidence of systemic involvement, and its onset may be preceded by trauma. Diffuse cutaneous reticulohistiocytosis is a purely cutaneous form characterized by the eruption of firm, smooth, asymptomatic papulonodular lesions, 3–10 mm in diameter, scattered diffusely over the skin. The color of early lesions is pinkish yellow, whereas older lesions show a red–brown color.

Related Physical Findings

In MRH, severe chronic diffuse polyarthritis with arthralgias is the initial sign of the disease in up to two-thirds of cases. The lesions symmetrically involve the hands (80% of cases), knees (70%), wrists (65%), and less frequently the shoulders, ankles, elbows, hips, feet, and spine. The osteoarticular lesions show a progressive destructive course for 6–8 years and then become stable. Involvement of the muscles (myositis, myotonia, and myoatrophy), cardiopulmonary system (pericarditis, cardiac insufficiency, pleuritis, pulmonary infiltration), eyes (exophthalmos, conjunctival infiltration), gastrointestinal system (gastric ulcer), thyroid gland (thyroid nodules), and submandibular salivary glands have occasionally been reported, but histologic documentation of involvement at these sites is rare. Fever, weight loss, and weakness can be present. The term familial histiocytic dermatoarthritis is used to indicate a particular form of MRH characterized by familial occurrence and typical ocular involvement (glaucoma, uveitis, and cataracts). Internal malignancy may be associated in 15%–27% of cases. Solid tumors such as bronchial, breast, gastric, and cervical carcinomas are most common. Lymphomas and myelodysplastic syndromes have been found less frequently, and malignant melanoma has been reported in three cases. Whether MRH can be interpreted as a true paraneoplastic disease is not clear. Whatever the nature of the association, the incidence of internal neoplasia is such that patients who come for treatment of MRH should be investigated for concomitant internal neoplasm. MRH has been described in association with autoimmune diseases, systemic vasculitis, tuberous sclerosis, sclerosing lesions of the leg, and tuberculosis.

Laboratory Tests

In MRH, elevated erythrocyte sedimentation rate and anemia have been observed in about half of patients and hypercholesterolemia in one-third of cases. An increase in immunoglobulin G and the presence of cryoglobulinemia and cold agglutinins have occasionally been reported. Rheumatoid factor is usually not detected. Radiographically, the joint lesions of MRH are characterized by bilateral, symmetrical, sharply circumscribed, and rapidly progressive erosions that spread from the margins to the joint surfaces, often with concomitant separation of the bone ends but without subchondral sclerosis.

Histopathology and Ultramicroscopic Findings

The histologic findings in MRH and its subtypes are identical. Histologically, the early lesions may be composed of histiocytes and lymphocytes, and therefore may be confused with other cutaneous histiocytoses. Older lesions show the presence of numerous large, mononucleated or multinucleated histiocytes with an abundance of eosinophilic, homogeneous cytoplasm containing fine granules that has a ground-glass appearance (Fig. 148-13). The number of giant cells may vary, and the diameter of these cells may reach 100 nm. The nuclei of the multinucleated cells may be arranged haphazardly or they may align along the periphery or cluster in the center. Plasma cells and eosinophils are sometimes present. Fragmentation and clumping of collagen and elastic fibers have been reported. At times, connective tissue and cell phagocytosis may be seen. Histochemically, the granular material in histiocytes and giant cells stains with periodic acid-Schiff after diastase digestion, Sudan black, and scarlet red, which indicates the presence of glycolipids and/or glycoproteins and neutral fat. Dermal proliferation of histiocytes with diffuse cytoplasmic granular cell changes has recently been described.15

Differential Diagnosis

The differential diagnosis for MRH is summarized in Box 148-5.

Complications

Complications occurring in MRH are mainly due to visceral involvement of the disease. Lesions in the upper airway may lead to dysphonia and/or dysphagia. Cardiopulmonary manifestations are more frequently reported and may also be fatal. In addition, bones and all the visceral organs may be affected, which leads to weight loss and pyrexia that complicate the potentially mutilating inflammatory polyarthritis.

Prognosis and Clinical Course

The purely cutaneous forms of reticulohistiocytosis may involute spontaneously. It is possible that the diffuse, purely cutaneous form is an early stage of MRH before the appearance of joint and visceral lesions. In MRH, the mucocutaneous course does not parallel the articular course. The mucocutaneous lesions have an unpredictable course and may remit spontaneously. In half of the patients, the osteoarticular manifestations become stable, whereas in the other half, they cause progressive destruction. The prognosis is favorable for cutaneous forms. The prognosis for MRH is related to the severity of the osteoarticular manifestations, the presence of visceral involvement, and underlying neoplasms if present.

To date, no treatment of MRH has been shown to be universally successful; the tendency to use multiple therapies as well as the natural relapsing and remitting nature of the condition makes interpretation of therapeutic response difficult. Recently, leflunomide was successful in one patient and therefore it can be considered a therapeutic option.16

Clinical Findings

Cutaneous Lesions

In NXG, early cutaneous lesions consist of indurated papulonodules varying in color from red–orange to violaceous or yellow and involving the dermis and subcutaneous tissue. These lesions slowly enlarge into plaques with well-demarcated edges, ranging in diameter from a few to 25 cm. There is central atrophy with telangiectasias or areas of ulceration (Fig. 148-14). Most cases are asymptomatic, but pain or a burning sensation may be noted. The lesions are usually multiple and involve, in order of frequency, the face, trunk, and extremities. The periorbital area is the site of predilection and is involved in 85% of cases. The oral mucosa is occasionally involved. Hepatosplenomegaly has been observed in approximately 20% of patients.

Related Physical Findings

NXG may be associated with myeloma, arthropathy, hypertension, neuropathy, neoplastic syndrome, primary biliary cirrhosis, and Graves disease.

Laboratory Tests

Ninety percent of patients with NXG have paraproteinemia (immunoglobulin G κ or λ light chains), especially in cases with associated myeloma. Cryoglobulinemia has been found in approximately 40% of cases. Other abnormal laboratory test results may include an elevated sedimentation rate, neutropenia, leukopenia, anemia, and decreased levels of CH50.

Histopathologic and Ultramicroscopic Findings

The histopathologic picture of NXG is characteristic and consists of a granulomatous infiltrate involving the whole dermis and subcutis composed of a mixture of lymphocytes, epithelioid cells, foam cells, and Touton giant cells. Areas of severe, clearly defined necrosis are sharply delineated from the surrounding granuloma. Typically, cholesterol crystals are located within the necrobiotic areas. Numerous, atypical, very large, bizarrely angulated, multinucleated giant cells may be seen adjacent to the areas of necrosis. Dense, well-defined lymphoid nodules, occasionally containing a germinal center, may be present in the dermis or subcutis. Touton cell panniculitis may involve the entire fat lobules. Occasionally, a granulomatous infiltrate may surround some vessels. Ultrastructurally, cells are rich in lipid droplets, cholesterol clefts, and myeloid bodies and are similar to those observed in JXG.

Differential Diagnosis

The disorders from which NXG should be differentiated are listed in Box 148-6.

Complications

In NXG, the periorbital involvement may lead to ocular complications such as lagophthalmos, conjunctivitis, keratitis, scleritis, uveitis, corneal ulceration, and even loss of ocular function. Nausea, vomiting, epistaxis, back pain, and Raynaud phenomenon have also been recorded.

Prognosis and Clinical Course

NXG has a chronic, often progressive course that is characterized by the appearance of new lesions and ulcerations. The prognosis in given cases is difficult to predict and depends on extracutaneous involvement and the presence of visceral tumors such as multiple myeloma.

Clinical Findings

Cutaneous Lesions

SHML is a benign, generally self-limited disease confined mainly to cervical lymph nodes. Cutaneous manifestations are observed in approximately 10% of patients and are polymorphic (Fig. 148-15). They may occur as yellowish macules and patches, reddish-brown papules, and plaques and nodules that may become eroded or ulcerated. In one patient, firm purple nodules and tumors as large as 10 cm in diameter were noted, but in most instances the lesions are much smaller, multiple, widespread, and asymptomatic. Periocular involvement of SHML can result in lobulated induration of the eyelids. Cutaneous lesions may be the initial manifestation and sole presenting feature of the disease. Massive bilateral cervical lymphadenopathy, usually painless, is the hallmark of the condition. Less commonly, axillary, mediastinal, inguinal, and preauricular lymph nodes may be affected.

Related Physical Findings

SHML is usually accompanied by fever. Extranodal disease occurs in approximately 25% of patients and may be the initial manifestation of the disorder. The extranodal noncutaneous sites most commonly affected are the eye, upper respiratory tract, liver, spleen, testes, skeleton, and nervous system. Involvement of the gastrointestinal tract is rare. An elderly woman with hematochezia was found to have SMLH of the rectum presenting as a rectal mass.

Laboratory Tests

SHML is usually accompanied by an elevated erythrocyte sedimentation rate, leukocytosis with neutrophilia, and polyclonal hypergammaglobulinemia. Less frequent findings include moderate anemia (60%), lymphopenia, elevated titers of Epstein–Barr virus, and, in one case, elevated Klebsiella antibody titers. Axial postcontrast computed tomography can highlight the lymphadenopathy.

Histopathologic and Ultramicroscopic Findings

Histopathologically, the skin lesions of SHML are characterized by a diffuse dermal infiltrate composed predominantly of histiocytes with large vesicular nuclei and abundant pale cytoplasm. Some histiocytes are foamy, multinucleated, or both. Histiocytes are sometimes aggregated in clusters resembling lymph node sinuses. Lymphocytes, plasma cells, and polymorphonuclear leukocytes, typically eosinophils, may be intermixed in the infiltrate. Emperipolesis (phagocytosis of leukocytes, especially lymphocytes) is a constant feature. In electron microscopic views, most of the histiocytes are rich in phagosomes and may contain clusters of comma-shaped bodies.

Differential Diagnosis

The differential diagnosis for SHML is summarized in Box 148-7.

Complications

The organs affected by primary extranodal SHML include: skin, soft tissue, nasal cavity and paranasal sinuses, eye (bilateral anterior granulomatous uveitis) and orbit, bone (leading to chronic ankle arthritis), CNS (mimicking neurofibromatosis, meningioma, pachymeningitis), and salivary glands. The digestive system is one of the least common sites of involvement by SHML, and only three pathologically confirmed cases of primary pancreatic SHML have been reported to date.17 Infections such as HIV and cytomegalovirus (CMV) can act synergistically in a myelosuppressive manner and provide the antigenic and inflammatory context for the development of fatal histiocytic complications.18

Prognosis and Clinical Course

In most patients, SHML has a benign course with spontaneous regression over a period of months to years. Usually the extranodal lesions regress first, whereas adenopathy may persist for years. A worse prognosis results mainly from the associated immunologic abnormalities.

Most forms of NLCH, such as JXG, do not require treatment because the disease is asymptomatic and self-healing. When treatment is necessary, as in XD, ECD, MRH, NXG, or SHML, therapy options are few and treatment is often unsuccessful.

Treatment of XD is usually not helpful. Vasopressin is necessary for the associated diabetes insipidus. Radiotherapy, cryotherapy, corticosteroids, and antiblastic chemotherapy have been attempted with palliative results in the more disfiguring forms.

Therapy for MRH has frequently been disappointing. Anti-inflammatory agents such as aspirin, indomethacin, and pyrazolones have shown little effect. Systemic corticosteroids may be effective on articular lesions, but only for a short period of time. Dexamethasone pulse therapy led to a dramatic response in one case. Azathioprine is of no benefit alone but in association with prednisolone may have a beneficial effect on both skin and joint lesions. Antimitotic agents (mainly cyclophosphamide and chlorambucil) have been reported to induce regression of lesions in only a few patients. Oral methotrexate seems to be the most effective. Etanercept has been used successfully to treat both cutaneous and articular symptoms. Generally, solitary cutaneous lesions are surgically excised.

In NXG, intermittent glucocorticoid treatment can induce a partial response. Low dosages of alkylating agents, such as chlorambucil or melphalan, may lead to remission of the paraproteinemia and skin lesions but do not prevent the evolution to multiple myeloma. Temporary remission of skin lesions has been obtained with radiation therapy and with plasmapheresis.

As a rule, because the vast majority of lesions of SHML heal spontaneously, no treatment is necessary. In rare instances, a space-occupying lesion will interfere with the function of an organ, and then treatment with systemic glucocorticoids or with various chemotherapeutic regimens might be useful.

At present, because the causes of all of the forms of NCLH are unknown, the possibility of preventing such diseases does not exist. As in LCH, future directions include complete genome hybridization and derivation of a gene expression profile.