NOSOLOGY AND PATHOLOGY OF LANGERHANS CELL HISTIOCYTOSIS

LANGERHANS CELL HISTIOCYTOSIS

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NOSOLOGY AND PATHOLOGY OF LANGERHANS CELL HISTIOCYTOSIS Laura Schmitz, MD, and Blaise E. Favara, MD

INTRODUCTION AND NOSOLOGY

Langerhans cell histiocytosis (LCH) is a rare disorder in which lesions contain cells with features similar to the Langerhans cell (LC) of the epidermis. Synonyms of Langerhans cell histiocytosis include the following: Histiocytosis X Eosinophilic granuloma Hand-Schuller-Christian disease Letterer-Siwe disease Langerhans cell granulomatosis Langerhans cell (eosinophilic) granulomatosis Type I1 histiocytosis Hashimoto-Pritzker disease Selt-healing histiocytosis Pure cutaneous histiocytosis Non-lipid reticuloendotheliosis The term histiocytes refers to two groups of immune cells: (1)macrophages, the cardinal antigen-processing cells; and (2) dendritic cells, the primary antigenpresenting cells, each of which contributes to an immunocytologic continuum?O Dendritic cells are most relevant to LCH and to its differential diagnosis and This work was funded, in part, by the Histiocytosis Association of America.

From North Pathology Associates, North Memorial Medical Center, Robbinsdale, Minnesota (LS); the Department of Pathology, University of Minnesota, Minneapolis, Minnesota (LS);the Department of Pathology, University of Utah, Salt Lake City, Utah (BEF); and the National Institutes of Health, Rocky Mountain Laboratories, Hamilton, Montana (BEF) HEMATOLOGY/ONCOLOGY CLINICS OF NORTH AMERICA VOLUME 12 NUMBER 2 * APRIL 1998

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include indeterminate cells, LCs, interdigitating dendritic cells, and dermal dendrocytes (the lesional cells of juvenile xanthogranuloma, the disorder most often confused with LCH).". in Follicular dendritic cells, although important, are not generally germane. Histiocytes, excluding follicular dendritic cells, are derived from bone marrow and develop their characteristic phenotype under the influence of cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor-a, interleukin (IL)-3, and IL-4.", lo3 It is unclear whether dendritic cells arise from a lineage-specific bone marrow precursor cell or from a less specific immune cell influenced by a local paracrine cytokine effect, or both. Although the various histiocytes are conveniently identified by name, it is important to remember that a single cell may manifest different phenotypes under different circumstances. A serviceable schema of the ontogeny of histiocytes is shown in Figure 1 . Recent nosology of the histiocytic disorders places LCH in the category of dendritic cell-related diseases of varied biologic behavior together with juvenile xanthogranuloma and histiocytomas, as shown in Table 1. Although there are rare malignancies featuring cells with the 1.C phenotype, malignant LCH is not recognized. The extraordinarily rare malignant disorders are referred to as d e w d ri t ic cell-rela f e d / I is t iocy t ic sa rcomas, La ngrrlia t is cell type..w This treatise describes normal epidermal Langerhans cells, the basic lesion in LCH, histologic patterns in different sites, diagnostic methods, results of special studies, and current theories on pathogenesis. THE EPIDERMAL LANGERHANS CELL

Normal Langerhans cells reside primarily in the epidermis, in the orobuccal and vaginal epithelia, and in the lungs. They represent 1%)to 2% of all epidermal

Figure 1. Ontogeny of histiocytes depicting relationships between the various types of cells.

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Table 1. CLASSIFICATION OF HlSTIOCYTlC DISORDERS DISORDERS OF VARIED BIOLOGICAL BEHAVIOR

Dendritic cell-related disorders Langerhans cell histiocytosis Secondary dendritic cell processes Juvenile xanthogranuloma and related disorders Solitary histiocytomas of various dendritic cell phenotypes Macrophage-related disorders Hemophagocytic syndromes Primary hemophagocytic lymphohistiocytosis (Familial and sporadic; commonly elicited by viral infections) Secondary hemophagocytic syndromes Infection-associated Malignancy-associated Other Rosai-Dotfman disease (sinus histiocytosis with massive lymphadenopathy) Solitary histiocytoma with macrophage phenotype Others, including multicentric reticulohistiocytosis (often arthritis-associated)and generalized eruptive histiocytoma MALIGNANT DISORDERS

Monocyte-related malignant disorders Leukemias (FAB and revised FAB classifications) Extramedullary monocytic tumor or sarcoma (monocytic counterpart of granulocytic sarcoma) Dendritic cell-related histiocytic sarcoma (localized or disseminated) Specify phenotype; follicular dendritic cell, interdigitating dendritic cell, etc. Macrophage-related histiocytic sarcoma (localized or disseminated) cells and play a critical role in cutaneous immunosurveillance. After antigen contact, the Langerhans cells migrate through the dermal lymphatics to regional lymph nodes, most likely to present antigen to paracortical T cells, after which they presumably become interdigitating dendritic cells. Indeterminate cells, believed to be precursors of LCs, express similar surface antigens but lack LC granules, and veiled cells, which are found in the afferent lymphatics, may represent LCs in transit.17,36 Shared features of these cells suggest that they are a cohort of dendritic cells or, more likely, a cytologic continuum. With hematoxylin and eosin (H&E) stains, normal Langerhans cells are approximately 12 micrometers in diameter with moderate amounts of homogeneous pink cytoplasm. The nucleus is usually folded, indented, or lobulated with an irregular granular chromatin pattern and one to three small nucleoli. CDla and S l O O staining of normal skin highlights the dendritic processes of resident Langerhans cells. Table 2 shows the comparative phenotypes of pathologic and normal Langerhans cells and that of other relevant histiocytes. Co-expression of S l O O neuroprotein and CDla antigen is highly characteristic of LCs, and the presence of Birbeck or LC granules is specific. The monoclonal antibody 010 detects the CDla antigen in paraffin-embedded tissue,@ and its value in the diagnosis of LCH has been c ~ n f i r m e d . ~ ~ HISTOPATHOLOGY OF THE BASIC LESION

The histopathology of LCH is generally uniform regardless of the clinical severity, but it is influenced to some degree by the site of the lesion and more

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Table 2. PRACTICAL MARKERS OF HISTIOCYTES'

CD1a s-100

Factor XlllaS FascinS

CD 68 LC granules

+ + -

-

+

+ +

-

-

+ + -

-

-

-

?

+ +

-

-

+

-

+ + + -

-

-t -

+-

'This group of immunohistochemicalstudies, all of which can be done on paraffin processed tissue with commercially available antibodies (with the exception of fascin), and the use of electron microscopy will help identify all but the most puzzling histiocytic disorder. tMay be positive under certain conditions of activation $.Needs further study LC = Langerhans cell: IC = indeterminate cell, IDC = interdigitating dendritic cell; PLC = pathologic Langerhans cell; DD = dermal dendrocyte; M = macrophage

so by the age of the lesion.l0,15, 33, *08 The basic lesion of LCH is formed by collections of pathologic Langerhans cells (PLC),indeterminate cells, interdigitating cells, and macrophages accompanied by T lymphocytes with variable numbers of multinucleated giant histiocytes and eosinophils. Granulocytes and plasma cells, when present, are considered to be reactants (Fig. 2). The hallmark of the lesion is the PLC, which is cytologically benign and resembles the normal Langerhans cell described previously, but it is not morphologically dendritic. For the definitive diagnosis of LCH, the lesion must display the characteristic morphology, and some of the lesional histiocytes must be proven to have the phenotype shown in Table 2. Special studies to demonstrate the presence of LC

Figure 2. This typical lesion of Langerhans cell histiocytosis (LCH) in lymph node features PLC, T lymphocytes, and, in this example, reactive neutrophils (hematoxylin-eosin stain, original magnification x 400).

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granules by electron microscopy or the expression of the CDla antigen on the cell surface are necessary for a definitive diagnosis of LCH.= The minimal level of diagnostic confidence derives from finding the characteristic histology of LCH without marker studies; S l O O positivity further supports the diagnosis. The availability of the 0 1 0 antibody makes it feasible to derive a definitive diagnosis on essentially all specimens in which LCH is included in the differential diagnosis (Fig. 3). Although LC granules specifically identify the LC phenotype, histiocytes with LC granules are occasionally found in other disorders such as dermatopathic lymphadenitisffiand benign hyperplastic lymph nodes.= LCH lesions are initially cellular with a predominance of histiocytes. Older lesions, particularly those of bone, may defy diagnosis in that they exhibit a paucicellular and fibrotic appearance with only small numbers of macrophages, some of which are xanthomatous. Rare PLCs or their absence makes the diagnosis difficult or impossible. The number of mitotic figures in LCH lesions varies from 0 to 23 per 10 high-power Proliferative indices of 3% to 48% have been observed, with the largest indices noted in lymph node lesions, suggesting that LCH is locally proliferative and not solely the product of migrating PLCs to lesional sites.3,43,99 Histiocytes seem to be the only cycling cells. Excluding one study in which strong positive staining for proliferating cell nuclear antigen (PCNA) was correlated with a more aggressive clhical course, histopathology, including cytologi97 cal atypia, mitotic activity, and proliferative indices, is not progn~stic.~~, 50, LCH is a monoclonal proliferation of CDla-positive histiocytes. Self-limited solitary lytic lesions of bone, the frequently fatal disseminated multisystem disease, and the intermediate form of disease with multisystem involvement and a chronic course are all Clonality is, therefore, not prognostic in LCH. Monoclonal proliferation of hemopoietic cells usually connotes neoplasia, but the significance of monoclonality in LCH remains unclear. Cytogenetic

Figure 3. Histiocytes in an LCH skin lesion stain intensely for CDla. Note the absence of dendrites and the presence of lobulated nuclei in lesional cells (010 antibody, peroxidase, anti-peroxidase stain, original magnification x 1000).

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studies usually fail because lesional cells do not propagate in culture, and direct preparations have not been rewarding in spite of the high proliferative rates in some lesions. Comparative genomic hybridization failed to provide evidence of somatic mutation in one study of a small number of LCH lesions.4z SECONDARY DENDRlTlC CELL PROCESSES It has become apparent that not all lesions that feature dendritic cells, including Langerhans cells, fit into the spectrum of LCH. Aggregates of dendritic cells, most often Langerhans cells, are encountered in association with Hodgkin's disease and less often with other lymphomas and tumors of the lung and thyr~id.~, 9, 26, 34, 83 When the lesional cells feature the Langerhans cell phenotype, distinction from LCH requires clinical correlation. In lesions associated with lung tumors, it appears that locally produced cytokines foster the induction of the Langerhans cell phenotype in local cells.'* These secondary dendritic cell processes usually involute as the primary disease is controlled. This topic is considered in greater detail elsewhere in this compendium. HISTOPATHOLOGYOF THE SPECIFIC ORGANS The basic lesion described previously is seen in various sites involved in LCH, although lesions of brain and lymph node may show different patterns and cellular phenotypes. Only special features related to location are noted subsequently.

Bone Osseous lesions are present in most cases of LCH, either in isolation or as part of multisystem disease. There is a predilection for hematopoietically active medullary sites, the skull being most frequently involved. Other common locations are the femur, pelvis, tibia, scapula, jaw, humerus, vertebrae, and ribs, but the small bones of the hands and feet are rarely involved.I0,"O Radiographs show a well-defined lytic lesion with or without sclerotic margins.'", 79, Because early lesions are often painful, biopsies are usually performed during this phase of the disease. Typically, there are osteoclast-like multinucleated giant histiocytes with bone destruction, necrosis (occasionally extensive), hemorrhage, and eosinophilic abscesses. The presence of plasma cells casts doubt on the diagnosis of LCH or suggests secondary infection of an LCH bone lesion. Older lesions show fibrosis and xanthomatous change.", 61, 71, ll0 The differential diagnosis of LCH of bone includes bacterial and fungal osteomyelitis, Rosai-Dorfman disease, lymphoma, and cat scratch disease. Skin Cutaneous involvement is present in more than 80% of patients with disseminated disease and in 30% of patients with less extensive multisystem dis48,69,7a, 91,113 Skin of the head ease?] Isolated cutaneous involvement also and neck region, trunk, groin, and extremities are common sites of involvement with a diversity of clinical appearances: seborrhea-like papular scaling eruptions,

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petechial and purpuric lesions, papular xanthoma-like lesions, bronzing of the skin, and mucocutaneous ulcers.3o,91 In spite of the various clinical appearances, the histopathology of cutaneous LCH is uniform.'", 20, 48, 50, 56, 70, 99, 113 Diffuse band-like or multifocal nodular aggregates of PLCs in the papillary dermis are accompanied by violation of the epidermal-dermal interface and occasionally epidermal ulceration. Intraepiderma1 microabscesses and bullae are only occasionally seen?, 56 Orientation of histiocytes around adnexal structures, usually hair follicles, is common, and PLCs sometimes extend into the deep dermis.50The histiocytes are mixed with variable numbers of T lymphocytes and eosinophils. Neutrophils, plasma cells, and mast cells are rarely present. Multinucleated giant histiocytes are uncommon. Eosinophilic abscesses and extravasated red blood cells have been reported.2O The term congenital self-healing reticulohistiocytosis, first used by Hashimoto and PritzkeP9 in 1973, applies to an unusual nodular form of cutaneous LCH that affects young infants. Lesions involve the deep dermis, spare the epidermis, and are composed of nodular aggregates of histiocytes, which may be multinuclear. Lesional cells contain LC granules, confirming the relationship with LCH, but the granules are fewer in number than in the typical lesion of cutaneous LCH. S l O O staining in these cells is variable. The lesions regress spontaneously over several weeks to months.49,59

Lymph Nodes and Spleen

Lymphadenopathy may be the sole manifestation of LCH, it may occur in multisystem disease, or it may be a focal process associated with neighboring bone or skin disease.35Patients are usually afebrile and present with localized Cervical nodes are most often involved followed by inguinal, axillary, mediastinal, and retroperitoneal sites.82Five histologic patterns are recognized: (1) most commonly the sinusoidal pattern, (2) a limited sinusoidal pattern, (3) epithelioid granulomas, and effacement that may be (4) partial or (5) complete (Figs. 4 to 8). Lesions are composed of PLCs and related dendritic cells, macrophages, multinucleated giant histiocytes, T lymphocytes, and eosinophils. Proliferative fractions vary from 2.6% to 48%. In some specimens eosinophils abound and surround central areas of necrosis.%,39, 95, Extensive coagulation necrosis surrounded by sheets of PLCs may be strikingE2Lesional histiocytes occasionally penetrate the nodal capsule and surrounding tissue with resultant capsular expansion and fibrosis. Intralymphatic collections of PLCs are often seen in vessels outside of the nodal capsule. In older lesions xanthomatous histiocytes, fibroblasts, and proliferating capillaries remain, whereas CDla-positive histiocytes and eosinophils are only rarely identified. Two unusual patterns of nodal histology have been reported. The first is epithelioid granulomas composed of histiocytes, with the LC phenotype reported only in nodes from abdominal sites.% The other is total lymph node effacement by predominately unmarked histiocytoid cells with a high proliferative index and rarely an aneuploid DNA ploidy profile. This latter type has been associated with a poor prognosis, but few cases have been reported.%Different histologic patterns of disease in separate sites in the same patient may be seen in cases with these unusual histologic presentations. The presence of some lesions with typical histology of LCH in cases with these unusual patterns of nodal disease facilitates the diagnosis of LCH.

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Figure 4. When multinucleated giant histiocytes in LCH lesions in the lymph node are derived from CD1a + cells, the nuclei tend to be irregular (hematoxylin-eosinstain, original magnification x 100).

Figure 5. Some multinucleated giant histiocytes in LCH lesions in the lymph node are huge, and, as shown here, demonstrate striking leukocytophagocytosis. The round-to-oval nuclei suggest that this cell derived from macrophages, although one nucleus is irregular-perhaps it belonged to a PLC phagocytized by this cell (hematoxylin-eosin stain, original magnification x 100).

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Figure 6. lntralymphatic collections of PLC are not uncommon in vessels just outside of the nodal capsule (hematoxylin-eosin stain, original magnification x 400).

Flgure 7. light collections of PLC form epithelioid granulomas in this node from the mesentery of a child with multisystem LCH. Lesions of bone and skin showed no granulomas, but more typical histology (hematoxylin-eosin stain, original magnification X 400).

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Figure 8. Hemophagocytosis by PLC is uncommon, but often is striking in nodes with total effacement. Such cells are CD1a + (hematoxylin-eosin stain, original magnification x 100).

Splenic involvement in LCH mimics that of lymph nodes, but there are fewer multinucleated cells and LC granules are rarely seen.l0,33

Lung

Pulmonary involvement in LCH may be isolated or integral to widespread multisystem disease. Isolated pulmonary LCH has unique clinical features as a disease primarily affecting young adult smokers presenting with diffuse bilateral Io5 Primary pulinterstitial reticulonodular infiltrates on chest roentgenogram.lY* monary LCH in children is rare, but it has pathologic features similar to that described in The classic pulmonary lesions are stellate, focal, 0.4 to 13 mm (average, 2.5 mm) nodular infiltrates separated by areas of normal lung.52Eosinophils, neutrophils, and macrophages are present in most specimens and may be numer0us.'05 Giant cells, lymphocytes, and plasma cells are variable.ly Eighty percent of cases undergo central cavitation or cyst formation, but central necrosis is u n c o ~ ~ u n o nThe . ' ~ ~lesions center on bronchioles and in early stages may involve bronchiolar which eventually enlarge to form cellular nodules (Figs. 9 and 10). As lesions age, a central fibroblastic proliferation progressively forms the classic stellate n0du1e.I~Lesions in different phases of development are seen in the same biopsy specimen. Concomitant invasion of small arteries and veins by PLCs and/or inflammatory cells may be present.lo5 Patients with progressive disease show confluence of focal scars and a honeycomb pattern indistinguishable from idiopathic interstitial fibrosis. The adjacent lung tissue may show an accumulation of macrophages in alveoli mimicking desquamative interstitial pneumonitis or discrete foci of organizing connective tissue in the lumen of distal airways and alveoli, at times resembling

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Flgure 9. Bronchioles are the epicenter of LCH involvement in the lung (hematoxylin-eosin stain, original magnification x 400).

Figure 10. A higher power view of the same bronchiole involved by LCH shown in Figure 9 reveals the irregular nuclei of the PLC (hematoxylin-eosin stain, original magnification

x 100).

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bronchiolitis obliterans with organizing pneumonia.1o5Alveolar lining cell hypertrophy and hyperplasia are frequent findings. Caution must be used in interpreting electron microscopy and immunoperoxidase studies for S-100 and CDla in lung specimens. The finding of Langerhans cells in normal bronchiolar mucosa and most types of non-neoplastic lung disease as secondary dendritic cell proliferations reduces the specificity of these findings. LCH is distinguished from secondary dendritic cell lung processes by the presence of large, focal aggregates of lesional cells. In one study, nonneoplastic lung disorders generally had less than 35 S-100+ cells per 10 high power fields as compared with greater than 75 in cases of LCH.Io7 Transbronchial biopsies are diagnostic of LCH in only 16% to 40% of cases sampled.5z,Io5 Compared with patients with other lung diseases, patients with LCH have a greater number of macrophages in transbronchial specimens, but equivalent numbers of eosinophils, neutrophils, and S-100 + histiocytes. Staining with S l O O was therefore not helpful in distinguishing LCH from other lung processes. Evaluation of bronchial lavage fluids (BAL) with immunophenotyping has shown increased numbers of CDla-positive histiocytes in all patients with pulmonary LCH. LCH patients had 1.8% to 25% (mean, 5.29% 5 1.14%)positive cells in BAL fluids as compared with less than 1% in most patients with other lung diseases; however, a small number of patients without LCH also had increased CDla-positive cells, with a degree of overlap that precluded clear separation between these two groups of patients.l6In general, patients with LCH have greater than 3% CDla-positive cells in BAL Because lesions of LCH are focal and usually peripherally located, transbronchial biopsy is not the diagnostic method of choice. BAL specimens likewise have limited diagnostic use, and pathologic confirmation of LCH by open lung biopsy is preferred. Increased expression of the p chain of platelet-derived growth factor and enhanced expression of the monocyte colony-stimulating factor (M-CSF) gene and of the c-fms gene that encodes the M-CSF receptor have been reported in one patient with LCH lung disease. Gene expression was reduced to normal levels after treatment.6 Liver

Hepatomegaly is present in one third to one half of children with disseminated LCH, but actual involvement by LCH is less frequent.10*3z,68 Liver disease in adults is less common.1o4Hepatomegaly can occur without signs of hepatic dysfunction or may be accompanied by jaundice, portal hypertension, and abnormal liver function tests. Three histologic abnormalities are found in liver biopsies: (1)triaditis; (2) activation of von Kupffer cells; and (3) LCH lesion^.^^,^^ Triaditis denotes enlarged portal areas featuring a polymorphous inflammatory process composed of small, medium, and large lymphocytes, and small numbers of neutrophils, eosinophils, macrophages, and plasma cells; PLCs are absent. Similar inflammatory lesions involving hepatic parenchyma can accompany triaditis?', 32,51, 68 The prominence of enlarged von Kupffer cells has been interpreted as evidence of activation. Less frequently, typical LCH lesions are present with a preferential portal distribution, but concomitant or isolated acinar LCH lesions are also seen. Triaditis and inflammatory lesions may accompany nodular LCH lesions. Because of the focal nature of hepatic lesions, they often escape needle biopsy. Steatosis, when present, is nonspecific and cholestasis is unusual.5l.68 Cholangitis, bile duct proliferation, and bile duct destruction have been described in association with triaditi~.~~, 51, 92 Bile duct damage leads to

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portal fibrosis or biliary cirrhosis, resulting in a clinicopathologic picture in adults resembling sclerosing cholangitis. LC granules are only rarely found in liver lesions.

Thymus In disseminated LCH, the thymus can be large or small depending on the balance between involution and the pathologic process. Thymic disease in LCH takes the form of focal or diffuse involvement or generalized changes unrelated to histiocytic involvement. Tumoral disease is rarely restricted to the thymus. In local involvement destructive aggregates of PLCs undergo subsequent cystic degeneration within an otherwise normal-appearing gland. Diffuse involvement results in the loss of corticomedullary demarcation and damage to Hassall's corpuscles, which involute or mineralize. Necrosis, hemorrhage, and xanthomatous change with dystrophic calcification and cystic degeneration precede eventual fibrosis. PLCs can be distinguished from the CDla-positive thymocytes on the basis of size and morphology?,lo,33, Autopsy studies revealed three types of secondary thymic alterations: (1) One pattern resembles congenital thymic dysplasia with loss of corticomedullary demarcation and Hassall's corpuscles as lobules are replaced by fibrovascular and reticular tissue devoid of small lymphocytes. (2) The most frequent histology, termed dysmorphic thymic changes, has dysplastic features as noted earlier, but with smaller lobules containing clefts or pseudocysts filled with vacuolated or hemosiderin-laden macrophages and giant cells. (3) The third alteration was that of nonspecific thymic involution with marked depletion of corticolymphoid cells, but with preservation of Hassall's corpuscles and medulla.@

Bone Marrow

LCs are not normal constituents of the bone marrow, although other S-100positive dendritic cells are present in small numbers.33Peripheral blood findings in patients with LCH are nonspecific. Cytopenias occur in the most severe forms of disease, but myelophthisis is not the cause. Bone marrow aspirate smears are often nondiagnostic because focal lesions may be missed and PLCs in air-dried films with Wright staining are not distinctive. When present in bone marrow smears, PLCs occur as single cells or in groups at the smear The nucleus is oval or elongated, but nuclear folding and grooving may not be prominent. The nuclear chromatin is delicately clumped with a well-defined nuclear membrane and inconspicuous nucleoli. The cytoplasm is lightly basophdic and occasionally contains scattered, coarse azurophilic granules or rarely hemosiderin and lipid droplets.8,33, 73 In trephine biopsy sections, lesions are focal (Fig. ll),with some composed primarily of PLCs, whereas others are polymorphous, also containing neutrophils, eosinophils, lymphocytes, multinucleated cells, and rarely eosinophilic abscesses. Focal fibrosis may occur. Xanthomatous changes evolve with time in treated and untreated cases.8,33 When the histology is equivocal, stains for S-100 proteins are not helpful, but the CDla stain is valuable.

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Figure 11. Bone marrow involvement in LCH is usually focal and, as shown here, actively proliferative as suggested by two mitotic figures in this field (hematoxylin-eosin stain, original magnification x 400).

Central Nervous System (CNS)

Neurologic dysfunction occurs in 1%to 4% of patients with LCH, with the pituitary-hypothalamic axis, hypothalamus, and the cerebellum being sites most commonly involved.41,62Disease confined to the CNS is rare and most common in the frontal and temporal 10bes.I~. 54, *, The neuroradiology and clinical aspects of CNS disease in LCH are detailed in the article by Grois et a1 on p 287 of this issue. The histopathology of CNS lesions is rarely similar to that in other sites.41,89,96 Lesions associated with type Ia, Ib, IIa, and IIb magnetic resonance (MR) images as defined by Grois et a1 in this issue, often show histology uncharacteristic of LCH. In well-defined MR images, perivascular demyelination and edema are present, with small numbers of histiocytes around vessels or rarely in areas of reactive astrogliosis. Phenotypically, these are usually ordinary histiocytes lacking CDla and S-100 antigens and LC granules; less often PLCs are present. In the cerebellum, these changes may be associated with loss of Purkinje cells and Bergman’s gliosis. Fields of exuberant reactive gliosis without histiocytes are another histologic pattern that may be seen, most often associated with poorly defined MR imaging lesions94 (Fig. 12). These CNS lesions, unlike those of characteristic LCH, contain T lymphocytes and plasma cells but eosinophils are absent. Astrogliosis may be closely associated with histiocytic lesions or remote from them when it is accompanied by perivascular collections of T lymphocytes. This dichotomy of lesions may be so striking as to suggest different processes. Type I11 images reflect lesions of the meninges and choroid plexus that tend to be fibroxanthomas. Although foamy macrophages predominate in such lesions, some fields show collections of histiocytes without cytoplasmic vacuolation. These cells are S-100 and CDla negative, and LC granules are usually absent (Figs. 13 to 15). Presumed older lesions are dominated by large xanthoma-

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Figure 12. A polymorphous perivascular collection of T lymphocytes and histiocytes is shown in this biopsy from a child with LCH and la lesions of the cerebellum (hematoxylineosin stain, original magnification x 400).

Figure 13. This type 111 lesion presented with seizures in a child with long-standing LCH. Bilateral masses of the choroid plexus of the lateral ventricles were biopsied. The fibroxanthomatous lesion was devoid of CDla+ cells and no Langerhans cell granules were found. Entrapped ependyma is shown in the upper right corner (hematoxylin-eosin stain, original magnification x 400).

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Figure 14. Some areas of type 111 lesions are dominated by xathomatous cells as shown here in one area of the lesion described in Figure 13 (hematoxylin-eosin stain, original magnification x 400).

Figure 15. Some type 111 lesions show areas that have the appearance of juvenile xanthogranuloma as in this left temporal meningeal mass in an 11 year old who had LCH from 3 years of age (hematoxylin-eosin stain, original magnification x 400).

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tous histiocytes and collagen. The histology of these extraparenchymal masses may mimic that of juvenile xanthogranuloma, but the histiocytes are factor XIIIa negative. Biopsies of type IV lesions show the characteristic histology of LCH but with plasma cells. Histiocytes are S-100 and CDla positive and contain LC granules. Multinucleated giant histiocytes may be present. Gastrointestinal Tract

Gastrointestinal involvement is unusual in LCH, but it can occur in generalized disease or as an extraordinary primary process. Tumoral lesions have been reported, most in the stomach. Lesions of stomach, small bowel, and large bowel are associated with vomiting, diarrhea, and protein-losing enteropathyZ,53, 85, lo2 In the gastrointestinaltract the characteristic LCH lesion occupies the lamina propria and submucosa, with glandular and mucosal atrophy and possible erosion (Fig. 16). Villus atrophy may be present. Eosinophils aggregated about areas of necrosis are occasionally seen. Involvement of the muscularis propria and subserosal connective tissue is unusual.s5,Io2 FINE-NEEDLE ASPIRATION (FNA) OF LANGERHANS CELL HlSTlOCYTOSlS

Several studies have demonstrated the feasibility of diagnosing LCH by FNA.*,28, 66,106 Cytologic specimens are cellular and composed of large numbers of benign-appearing CDla-positive histiocytes that only occasionally cluster. The PLCs are polygonal, with abundant clear blue (Diff-Quick and Geimsa stained)

Figure 16. Pathologic Langerhans cells are distributed in the lamina propria of the colon in this infant with multisystem LCH. A mucosal crypt is seen in the right upper corner (hematoxylin-eosin stain, original magnification x 400).

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or eosinophilic (H&E stained) cytoplasm with irregular borders, surrounding oval or indented nuclei with fine homogeneous chromatin, and indistinct nucleoli. A nuclear groove or crease is usually present, but this can be rare or absentIo6(Fig. 17). The PLCs are usually nonphagocytic, but they rarely show cytoplasmic aggregates of hemosiderin or other phagocytized material. In some cases, the cells show prominent dendritic process?! Variable numbers of eosinophils, neutrophils, lymphocytes, and macrophages provide background. Normal macrophages can be distinguished from PLCs by the lack of nuclear grooves or clefts and vacuolated cytoplasm with or without phagocytic material. Giant cells resembling foreign body giant cells except for nuclear grooves and indentations may be frequent depending on the site of the lesion?,63,1ffi Mitotic figures are sparse. Electron microscopy and immunocytochemistry are essential adjuncts to diagnostic FNA in LCH.2*z8 The proportion of PLCs varies. In one study, LCH was subdivided into three categories based on the numbers of PLCs in FNA specimens? In the PLCpredominant type, large numbers of PLCs formed loose sheets or clusters with rare inflammatory cells. Large numbers of eosinophils are mixed with only a few PLCs in the eosinophilic-predominant pattern, whereas the macrophagepredominant pattern had abundant foamy macrophages with few PLCs. Because of the occasional coexistence of secondary dendritic cell processes and malignancies, caution should be used in diagnosing LCH by cytology alone.3,9,26* 83 Aspiration cytology is best used to establish the extent of disease or recurrence.ffi ELECTRON MICROSCOPY OF LCH

LCs and PLCs have general features of histiocytes by electron microscopy, including abundant cytoplasm and irregular plasma membranes, but with nuclei

Figure 17. The irregular nuclei of these PLC identify them in this fine-needle aspiration biopsy of an enlarged lymph node in a child known to have bone and skin lesions of LCH (Wright’s stain, original magnification x 1000).

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that tend to be irregularly shaped or lobated. The one distinctive feature is the presence of the Langerhans cell or Birbeck gran~le.2~8 45, 76, 98 The granules are rod- or racquet-shaped cytoplasmic structures 200 to 400 nanometers in length with a constant width of 33 nanometers. They have a zipper-like appearance with a central striated line and a double outer sheath.76These structures are pathognomonic for LCs or PLCs. The number of cells in LCH lesions with granules varies from 2% to 69%. Granules are more easily detected in early lesions76and are rare in lesions of the liver, spleen, or gastrointestinal tract. The sensitivity of detecting granules is slightly decreased when formalin-fixed, paraffin-embedded material is used. Granules in the nucleus of PLCs may be a specific marker for the pathologic h i s t i ~ c y t e(Fig. ~ ~ 18). Tubuloreticular structures, cylindric confronting cisternae, and curvilinear membranous formations are ultrastructural stigmata of the influence of cytokines, and they have been found in PLCs, lymphocytes, and endothelial cells in LCH lesionsz7, (Fig. 19). The function and origin of the LC granule is unknown, although in-vitro induction of the LC phenotype, including the LC granule, suggests that cytokines play a SPECIAL STUDIES IN LCH

DNA Ploidy Profiles

DNA ploidy studies performed on archival paraffin-embedded tissue from LCH patients with localized and disseminated forms of the disease generally show a diploid population.M,74, 87, 93 S-phase fractions have not been studied in detail. Only four cases of LCH with aneuploid cell populations been reported, too few to judge prognostic relevance.34,s7 The case of a 76-year-old man with a

Figure 18. The intranuclear Langerhans cell granules (open arrow) and more numerous granules in the cytoplasm (solid arrow) of this PLC are an unusual finding (original magnification x 21,600; Courtesy of Dr Gary Mierau, Denver, Colorado).

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Figure 19. A tubuloreticularinclusion is shown in this PLC (original magnification x 44,000; Courtesy of Dr Gary Mierau, Denver, Colorado).

generalized nodular eruption, constitutional symptoms, and no signs of internal involvement appears to have been one of histiocytic sarcoma rather than LCH.38

Cytokines

Histiocytes, including LCs, produce cytokines that may be self-regulating.116 Histiocytes with the Langerhans cell phenotype can be generated in vitro from CD34-positive stem cells after synergistic application of GM-CSF and TNF-a. Additionally, monocytes, subjected to GM-CSF in culture, express the CDla antigen.”, 12, Recent evidence suggests that aberrant or uncontrolled cytokine production plays a role in the reactive histiocytic disorders.37The results of studies of serum levels of cytokines and lesional cytokine profiles in LCH, reviewed elsewhere in this issue, together with ultrastructural evidence of a “cytokine effect” in LCH lesions imply a prominent role for these mediators in the pathogenesis of disease.” 58,

Adhesion Molecules

Leukocyte adhesion molecules influence adhesion and migration of leukocytes and play a role in antigen presentation by dendritic cells to T cells. It has been shown that PLCs abnormally express a T-cell adhesion molecule, CD2, the receptor for leukocyte function antigen-3 (CD58). They also express the adhesion-related antigens, CD54 (ICAM-1) and CD58, that are usually present on normal LCs only after activation. These alterations could play a role in abnormal migration of PLCS.~~

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PATHOPHYSIOLOGY

Aberrations of cellular immunity have been postulated as underlying the pathogenesis of LCH. Immune abnormalities resulting in unchecked proliferation of PLCs after exposure to a virus or some other stimulus have been suggested. Findings suggestive of immune dysfunction, including abnormal immunoglobulin levels, mitogen responses, and T-suppressor cell levels, have been noted inconsi~tently.~~ That LCH might be a pathologic response to virus(es) with or without an immunologic abnormality remains a possibility. A virus could theoretically activate histiocytes and also impair immune regulation by disabling suppressor T cells, resulting in an amplified and uncontrolled response to the primary infection. With one exception, studies in search of viral pathogen72, Overall, results suggest that immunologic esis have been unre~arding.6~. dysfunction and/or viral infection do not play a basic role in LCH. Recent studies establishing LCH as a monoclonal proliferative disease have provided strong evidence that it is a neoplastic disorder.’l2, Monoclonal histiocytes were, however, detected in all forms of LCH, raising the question of clinical significance. Data on multiple and recurrent lesions in the same patient and the clonality of normal LCs are needed. In one limited study, enhanced expression of the oncogenes c-myc and H-ras was detected in mononuclear cells and multinucleated cells in two cases of LCH using in situ hybridization, suggesting oncogene activation may also contribute to pathogenesis.’ An animal model of LCH and methods for establishing cell lines from lesions are needed to enhance research efforts. The histiocytic disorder that affects the Bernese mountain dog seems to be a reasonable model of this

SUMMARY

The pathology of LCH is continuing to be defined and diagnostic features clarified as unprecedented research is done. Although the etiology of LCH remains unknown, new information on cytokines, viruses, immunologic dysfunction, cell surface antigen expression, and clonality in the disease are providing essential pieces of the puzzle. References 1. Abdelalif OMA, Chandler FW, Pantazis CG, McGuire BS Enhanced expression of the c-myc and H-ras oncogenes in Letterer-Siwe disease. A sequential study using colorimetric in situ hybridization. Arch Pathol Lab Med 11431254-1260,1990 2. Akhtar M, Ashraf MA, Bakry M, et al: Fine-needle aspiration biopsy of Langerhans histiocytosis (histiocytosis-X).Cytopathology 9:527-533, 1993 3. Almanaseer IY, Kosova L, Pellettiere E V Composite lymphoma with immunoblastic features and Langerhans cell granulomatosis (histiocytosis X). Am J Clin Pathol 85111-114, 1986 4. Altman J, Winkelmann RK: Xanthomatous cutaneous lesions or histiocytosis X. Arch Dermatol87:74, 1963 5. Auerswald U, Barth J, Magnussen H Value of CD-1-positive cells in bronchoalveolar lavage fluid for the diagnosis of pulmonary histiocytosis X. Lung 169:305-309, 1991 6. Barth J, Kreipe H, Radzun HJ, et al: Increased expression of growth factor genes for macrophages and fibroblasts in bronchoalveolar lavage cells of a patient with pulmonary histiocytosis X. Thorax 462335838, 1991

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