Unusual Variants of Non-Langerhans Cell Histiocytoses

REVIEWS

Unusual variants of non-Langerhans cell histiocytoses

Ruggero Caputo, MD,a Angelo Valerio Marzano, MD,a Emanuela Passoni, MD,a and Emilio Berti, MDb Milan, Italy

Histiocytic syndromes represent a large, heterogeneous group of diseases resulting from proliferation of histiocytes. In addition to the classic variants, the subset of non-Langerhans cell histiocytoses comprises rare entities that have more recently been described. These last include both forms that affect only the skin or the skin and mucous membranes, and usually show a benign clinical behavior, and forms involving also internal organs, which may follow an aggressive course. The goal of this review is to outline the clinical, histologic, and ultrastructural features and the course, prognosis, and management of these unusual histiocytic syndromes. ( J Am Acad Dermatol 2007;57:1031-45.)

istiocytic syndromes represent a large, puzzling group of diseases resulting from Abbreviations used: proliferation of cells called histiocytes.1 BCH: benign cephalic histiocytosis H ECD: Erdheim-Chester disease The term ‘‘histiocyte’’ includes cells of both the GEH: generalized eruptive histiocytosis monocyte-macrophage series and the Langerhans HPMH: hereditary progressive mucinous cell (LC) series, both antigen-processing and anti- histiocytosis 1 IC: indeterminate cell gen-presenting cells deriving from CD34 progeni- ICH: indeterminate cell histiocytosis tor cells in the bone marrow. JXG: juvenile xanthogranuloma In 1987, the Histiocyte Society proposed a classi- LC: Langerhans cell LCH: Langerhans cell histiocytoses ﬁcation of histiocytic syndromes based on 3 classes: MR: multicentric reticulohistiocytosis (1) class I, corresponding to LC histiocytoses (LCH); PNH: progressive nodular histiocytosis (2) class II, encompassing the histiocytoses of mon- PX: papular xanthoma onuclear phagocytes other than LC (non-LCH); and SBH: sea-blue histiocyte 2 SBHS: sea-blue histiocytic syndrome (3) class III, comprising the malignant histiocytoses. XD: xanthoma disseminatum In addition to the classic variants listed in Table I, the group of non-LCH includes unusual or extremely rare disorders that have more recently been de- forms affecting only the skin or the skin and mucous scribed (Table II). Indeed, among the latter, indeter- membranes, such as hereditary progressive muci- minate cell (IC) histiocytosis (ICH) is a disease in nous histiocytosis (HPMH) and progressive nodular which the predominant cells have the characteristics histiocytosis (PNH), and forms involving also inter- of both LC and macrophages3 and whose actual nal organs, such as ErdheimeChester disease (ECD) existence as a separate entity is still debated.4 More- and sea-blue histiocytic (SBH) syndrome (SBHS). over, this heterogeneous group comprises both The former usually have a benign clinical behavior, whereas the latter may follow a progressive course. Thus, the purpose of this review is to schemati- From the Institute of Dermatological Sciences, University of cally outline the clinical, histologic, and ultrastruc- MilaneFondazione IRCCS Ospedale Maggiore Policlinico, tural ﬁndings and the course, prognosis and a Mangiagalli e Regina Elena ; and Department of Clinical and management of these uncommon histiocytic syn- Preventive Medicine, University of Milano-Bicocca.b Funding sources: None. dromes on the basis of both our personal experience Conflicts of interest: None declared. and an accurate review of the literature. The clinical Reprint requests: Angelo Valerio Marzano, MD, Institute of Derma- characteristics, course, and management of these tological Sciences, Via Pace 9e20122, Milano, Italy. E-mail: francesca. unusual variants of non-LCH are summarized in [email protected]. Table III, whereas their histopathologic, immuno- Published online May 10, 2007. 0190-9622/$32.00 histochemical, and ultrastructural features are indi- ª 2007 by the American Academy of Dermatology, Inc. cated in Table IV. Markers and antibodies used for doi:10.1016/j.jaad.2007.03.014 immunohistochemistry are listed in Table V.

1031 1032 Caputo et al JAM ACAD DERMATOL DECEMBER 2007

Table I. Classic forms of non-Langerhans cell Table II. Unusual variants of non-Langerhans cell histiocytosis, abbreviations used histiocytosis, abbreviations used

GEH, generalized eruptive histiocytosis ICH, indeterminate cell histiocytosis BCH, benign cephalic histiocytosis PNH, progressive nodular histiocytosis JXG, juvenile xanthogranuloma HPMH, hereditary progressive mucinous histiocytosis PX, papular xanthoma ECD, Erdheim-Chester disease XD, xanthoma disseminatum SBHS, sea-blue histiocytic syndrome NX, necrobiotic xanthogranuloma SHML, sinus histiocytosis with massive lymphadenopathy MR, multicentric reticulohistiocytosis lymphocytes to mite antigens.27,28 On the other hand, the development of generalized eruptive ICH at the site of already healed pityriasis rosea has also INDETERMINATE CELL HISTIOCYTOSIS been described, further suggesting that ICH may Definition occur as a lymphohistiocytic reaction to various In 1985, Wood et al5 first described as ICH an antigens.9 However, in our view, such cases should unusual, distinctive variant of cutaneous histiocytosis be regarded as distinct from classic ICH. whose cardinal features, distinguishing it from LCH, Mucous membranes are always spared. Usually, were: (1) lack, on ultrastructural study, of Birbeck there is no visceral involvement and the patients are granules; (2) absence, on histology, of epidermotro- in good general health. pism; and (3) lack of extracutaneous involvement. Furthermore, advances in the immunophenotypic Laboratory findings characterization of histiocytic dendritic cells and Routine laboratory tests and radiographic investi- macrophages subsequently led to the demonstration gations usually show nonabnormalities. that the IC expressed both LC and monocyte/macrophage markers, ie, S-100/CD1 and CD68/CD14, re- Histopathologic, immunohistochemical, spectively.6 Various hypotheses have been proposed and ultrastructural findings on the origin of IC, ie, whether IC are immature Light-microscopic evaluation reveals an infiltra- precursors of LC, LC are precursors of IC, or both are tion of histiocytic cells in the whole dermis and independent types of dendritic cells.7 sometimes within the epidermis. The proliferating cells show an abundant, pale eosinophilic cytoplasm Age of onset and incidence and large, irregularly folded or twisted nuclei. A few ICH affects predominantly adults, showing no mitotic figures and multinucleated giant cells may sex- or age-specific predilection, although about one be observed. Clusters of lymphocytes are admixed third of the cases so far reported in the literature are (Fig 2). pediatric.4,8-15 Immunohistochemically, the proliferating cells Since the original description of Wood et al,5 only are KP1 (CD68)1, S-1001, CD1a1, and factor e about 20 cases of ICH had been reported, until a XIIIa .5,16,18,20,24 In summary, these cells display recent study on a large collection that included 18 similar histologic and antigenic features to LC. Ultra- patients with ICH.4 structurally, however, they differ in that Birbeck granules are absent.12,18,20,24 Clinical findings Two clinical subtypes seem to predominate: Course and prognosis a solitary nodular form11-14,16 (Fig 1, A) and a multiple Based on a review of the literature that includes papulonodular form3,5,6,8-10,15,17-26 (Fig 1, B). The the recent report by Ratzinger et al,4 15 patients former is usually characterized by a single, soft red presenting with solitary lesions and showing a asymptomatic nodule about 1 cm in diameter; the benign clinical course exist11-14,16; among these, latter presents with a widespread eruption of multi- two patients presented at birth with a solitary nodule ple, firm asymptomatic lesions ranging in size from a that spontaneously regressed12 or was removed by few millimeters to 1 cm, varying in color from dark shave excision13 without relapse, respectively. red to brownish and covered by intact skin. On the other hand, 24 cases with widespread The multiple nodular form has also been docu- cutaneous lesions have been described,3,5,6,8-10,15,17-26 mented as part of nodular scabies, a persistent the majority of which having an indolent or self- reaction after acute scabies infestation, possibly limited course; indeed, in a number of reported cases representing a prolonged response of IC and treatment and follow-up were not stated.3,6,8,18,20,21 JAM ACAD DERMATOL Caputo et al 1033 VOLUME 57, NUMBER 6

Table III. Cutaneous findings, associated abnormalities, course, and treatment of unusual variants of non-Langerhans cell histiocytosis

ICH PNH HPMH ECD SBHS Age/sex Adults [ Children [ Heredity; Middle-aged and Sometimes familial; children adults beginning in older adults beginning in adolescence adolescents or or childhood; young adults mainly women Type of lesion Dark-red to Yellow-brown or Skin-colored, Red-brown Nodules and waxy brownish yellow-pink red, or yellowish papules merg- plaques; macular papules or papules or papules or ing into brownish nodules nodules nodules plaques; hyperpigmentation the lesions may become slack and atrophic Pattern Solitary Generalized, Multiple lesions; Multiple lesions; Multiple lesions nodular form; with random symmetric symmetric multiple pap- distribution distribution distribution ulonodular form Localization No Sometimes, Face, hands, Eyelids, axillae, Prominent facial preferentially prominent facial forearms, legs groin, neck, involvement; trunk, involved sites involvement trunk, face hands, feet Mucous No Yes (oral, laryngeal, No Yes (laryngeal, No membrane conjunctival) oral, involvement conjunctival) Systemic Usually none; Usually none; None Fever, weakness, Liver, spleen, symptoms/ possible few reports of weight loss/ bone marrow, involvements association association with bone (patchy lung, lymph node, with various osteosclerosis), retinal or nervous hematologic systemic neurological, involvement disorders disorders and pulmonary involvement; diabetes insipidus Clinical course Usually benign; Progressive course Slowly spreading Usually Usually benign in few cases, of the skin to other regions progressive, for the idiopathic evolution in lesions without of the body; with a high form; related to hematologic spontaneous slowly increas- mortality that of the primary disorders, involution, but ing number of disorder for notably benign clinical the lesions; no secondary leukemia behavior spontaneous forms resolution Management Usually none; Intralesional and Usually none; Systemic None in few cases, systemic cortico- in few cases, corticosteroids; various che- steroids; cyclo- surgery radiation; vari- motherapy phosphamide--all ous chemother- regimens with unsatisfac- apy regimens; tory response; surgery--all usu- surgery ally with poor response

ECD, Erdheim-Chester disease; HPMH, hereditary progressive mucinous histiocytosis; ICH, indeterminate cell histiocytosis; PNH, progressive nodular histiocytosis; SBHS, sea-blue histiocytic syndrome.

Three cases with fatal outcome have, however, been acute monocytic leukemia,25 and an infant with described: one adult patient who died of mast cell a malignant histiocytic nonleukemic behavior.15 leukemia,24 another one with non-Hodgkin’s lym- A case of systemic ICH with ocular involvement, phoma converted to ICH who developed terminal treated with polychemotherapy and corneal 1034 Caputo et al JAM ACAD DERMATOL DECEMBER 2007

Table IV. Laboratory investigations, histopathologic, immunohistochemical, and ultrastructural findings of unusual variants of non-Langerhans cell histiocytosis

ICH PNH HPMH ECD SBHS Laboratory NS NS (notably, NS (notably, " ESR; " ALP Leukopenia; findings normal lipid normal lipid thrombocytope- metabolism metabolism nia; anemia Histopathology Dermal Dermal Dermal nodular Dermal Dermal infiltration infiltration of aggregates of infiltration of micronodular of HC with eosino- HC with vacuo- epithelioid or foamy HC; infiltrate of HC philic cytoplasm lated clear spindle- presence of containing and folded nuclei; cytoplasm; shaped HC; Touton giant granules staining presence of multi- presence of deposition of cells blue-green with nucleated giant Touton-like mucinous Giemsa cells and giant cells and material lymphocytes aspects of ‘‘collagen trapping’’ Immuno- KP1(CD68)111, KP1(CD68)111, KP1(CD68)111, KP1(CD68)111, KP1(CD68)111, histochemistry S-10011, CD1a1, factor XIIIa111, factor factor S-100 factor XIIIa CD1a, S-100 XIIIa111, XIIIa11, CD1a, S-100 CD1a, S-100 Electron LC-like HC HC with HC with HC with Granules present microscopy but lacking indented bizarre-shaped cytoplasm as round dense BG nucleus and nucleus and filled with bodies, and cytoplasm rich cytoplasm rich lipid vacu- rodlike bodies in ER, Golgi C, in myelin and oles, choles- mitoch, lys, zebra bodies terol crystals, comma-shaped myeloid bodies bodies, lys, phagos

ALP, Alkaline phosphatase; BG, Birbeck granules; C, complexes; ECD, Erdheim-Chester disease; ER, endoplasmic reticulum; ESR, erythrocyte sedimentation rate; HC, histiocytic cells; HPMH, hereditary progressive mucinous histiocytosis; ICH, indeterminate cell histiocytosis; LC, Langerhans cell; lys, lysosomes; mitoch, mitochondria; NS, not significant; phagos, phagosomes; PNH, progressive nodular histiocytosis; SBHS, sea-blue histiocytic syndrome.

Table V. Panel of antibodies used

Marker Dilution Source Main reactivity S-100 protein* 1:400 Novocastra Laboratories Ltd, Dendritic cells, including Langerhans cells, nerves, United Kingdom and melanocytes CD1a Ready to use DAKO, Cytomation, Denmark Dendritic cells, including Langerhans cells KP1(CD68) 1:50 DAKO, Cytomation, Denmark Monocytes and macrophages Factor XIIIa* 1:400 DAKO, Cytomation, Denmark Dermal dendrocytes, monocytes, and macrophages

A standard alkaline phosphatase anti-alkaline phosphatase complex method has been used for immunohistochemical studies. *Polyclonal, others monoclonal. transplantation, has recently been observed but a evidence of systemic disease at onset.29 In these long-lasting follow-up was lacking.26 In addition to patients, oral cyclophosphamide gave a good clinical the cases mentioned above, chemotherapy regimens, response. However, during a 6- and a 4-year follow- including vinblastine and 2-chlorodeoxyadenosine, up period, respectively, several recurrences occurred. respectively, were necessary in two other cases with These were characterized by more resistant cutaneous extensive and disfiguring cutaneous disease despite manifestations, and required repeated cycles with the absence of visceral involvement.5,17,22 different intravenous antineoplastic regimens, includ- We observed two adult male patients with ICH ing first etoposide and subsequently a combination having widespread cutaneous eruptions without of vinblastine and metylprednisolone. During the JAM ACAD DERMATOL Caputo et al 1035 VOLUME 57, NUMBER 6

Fig 2. Indeterminate cell histiocytosis. Histology showing dermal inﬁltration of histiocytic cells, with scattered lymphocytes. (Hematoxylin-eosin stain; original magniﬁca- tion: 3100.)

including our two,9 required chemotherapy regimens.5,15,17,22,24-26

Comment Fig 1. Indeterminate cell histiocytosis. Solitary nodular 3 (A) and multiple papulonodular (B) forms. Sidoroff et al stated that, clinically, the multiple papulonodular form of ICH is indistinguishable from GEH, a rare non-LCH characterized by an indolent, usually self-healing clinical course. As a conse- last relapse, the first patient responded favorably to a quence, they speculated that GEH seems to be an course of treatment with 2-chlorodeoxyadenosine, early, indeterminate stage of various non-LC histio- after the above chemotherapeutic regimens had cytic syndromes, most notably including ICH, benign 29 failed to induce a satisfactory clinical remission. cephalic histiocytosis (BCH), JXG, PNH, xanthoma The other one developed acute myelogenous disseminatum (XD), and MR. leukemia 5 years after ICH onset and died during This view on noneLCH has recently been over- high-dose chemotherapy, consisting of cytosine- emphasized by some of the above authors, who arabinoside plus idarubicin (unpublished data). proposed that the prototype of this group is xantho- Thus, based on our experience, it seems suitable to granuloma, all other non-LCH being only variants on reconsider the prognosis of ICH, its clinical course xanthogranuloma.4 Based on this unifying concept, being not always so benign as thought in the past, ICH is regarded as representing various macrophage and to strictly monitor the possible onset of an disorders identified at various time points in the aggressive hematologic disorder. inflammatory response. On the contrary, we defend the view on ICH as a separate entity; however, we Differential diagnosis suggest lumping it into a clinicopathologic spectrum The cutaneous lesions observed in ICH are not where GEH, BCH, and JXG are the benign counter- characteristic. Solitary lesions are very similar to part, whereas PNH, XD, and MR represent more those observed in congenital self-healing reticulo- aggressive forms or forms that can be associated with histiocytosis of Hashimoto-Pritzker and in juvenile extracutaneous involvement. xanthogranuloma (JXG), and multiple lesions may look like those present in generalized eruptive his- PROGRESSIVE NODULAR HISTIOCYTOSIS tiocytosis (GEH) or in multicentric reticulohistiocy- Deﬁnition tosis (MR).30 A definite diagnosis of ICH is based on PNH is a normolipemic non-LCH affecting the the histologic, immunohistochemical, and ultrastruc- skin and mucous membranes with no signs of tural features of the cells constituting the infiltrate. spontaneous regression of the lesions. ‘‘Progressive nodular histiocytosis’’ is the name suggested in 1985 Management by one of us30 to encompass several cases reported As mentioned above, in the majority of cases the in the literature with similar clinical and histopatho- condition does not need any treatment, because its logic features,31-34 including the first one described course is usually benign. However, several cases, as ‘‘progressive nodular histiocytoma’’ by Taunton 1036 Caputo et al JAM ACAD DERMATOL DECEMBER 2007

present in the oral, laryngeal, and conjunctival mu- cosae. The second type of lesion is a large dermal nodule, with overlying telangiectasia, which gives it a red-brown color. The nodules range in size from 10 to 50 mm and are more common on the trunk. Several large nodules over pressure points may show necrosis. Neither type of lesion is prominent around the joints, but both are often seen around the genitalia.34 Sometimes, there is a tendency for lesions to coalesce on the face, producing intense ectropion and a leonine appearance30,32,36,38 (Fig 3, B). Cafe´ au lait spots and arthritis are absent.

Laboratory ﬁndings Laboratory ﬁndings, including cholesterol and triglyceride levels and lipoprotein values, are generally within normal limits.

Histopathologic, immunohistochemical, and ultrastructural findings Histology shows a dermal infiltrate composed of histiocytes with abundant, vacuolated clear cytoplasm and a variable number of multinucleated, notably Touton-like, giant cells (Fig 4). Among these histiocytes, many lymphocytes and some plasma cells are observed. In some areas, a storiform pattern is seen and an appearance of ‘‘collagen trapping’’ as a result of splaying of collagen bundles is prominent at the infiltrate edge. In biopsy specimens taken from an older lesion, fibrosis is evident and Touton-like giant cells are nearly absent.34,35 Immunohistochemically, infiltrating histiocytes are strongly positive for CD68 and factor XIIIa but negative for CD1a and S-100. However, lack of factor XIIIa expression has also been found.37 Under the electron microscope, the histiocytes have a large indented nucleus and a scanty cyto- Fig 3. Progressive nodular histiocytosis. A, Multiple plasm. The latter is rich in endoplasmic reticulum, papulonodular lesions over upper extremities and trunk. Golgi complexes, and mitochondria, but also con- B, Leonine appearance for coalescing of lesions on face. tains numerous membrane-bound, electron-dense lysosomes. In addition, there are irregularly shaped, et al35 in 1978. Up until now, very few universally electron-dense granules, some with a comma shape accepted reports of PNH existed, and these have and others with a central electronlucent area. Rare received diverse nomenclature.31-43 lipid droplets are also seen. Birbeck granules are typically absent. One of us33 observed intracytoplas- Clinical findings mic granules having a unique and highly complex Clinically, the disease is characterized by the ultrastructure in a patient with papular histiocytosis progressive appearance of hundreds of lesions of closely resembling PNH. They had a wall consisting two different types, namely superficial papules and of two parallel unit membranes separated by a light deep nodules31-43 (Fig 3, A). space of approximately 150 A8 and a portion formed The most common lesions are yellow-brown or as a result of the enlargement of the space between yellow-pink papules varying in size from 2 to 10 mm, the two unit membranes and containing vesicles. widely and randomly distributed on the body, the However, these structures have not been found in flexural areas being spared. These lesions may be PNH by other investigators.34,37 JAM ACAD DERMATOL Caputo et al 1037 VOLUME 57, NUMBER 6

histiocytes. Many intracytoplasmic lipid droplets are seen on electron microscopy. HPMH is an inherited disease. Typically, the lesions are smaller and histologic studies demonstrate the presence of mucin. Lepromatous leprosy may be ruled out because of the absence of intracellular bacilli. Finally, lipogranulomatosis of Farber is an inborn error of lipid metabolism with deposition of free ceramide and ganglioside in the brain, liver, lymph nodes, kidneys, and lungs. The disease, marked by onset in Fig 4. Progressive nodular histiocytosis. Histology reveal- early infancy, usually follows a rapidly progressive ing dermal inﬁltrate of histiocytes with abundant, vacuo- course with lipideladen histiocytic granulomas that lated clear cytoplasm and several multinucleated, notably involve the skin and mucous membranes. Large Touton-like, giant cells. (Hematoxylin-eosin stain; original papules become confluent into deep nodules on magniﬁcation: 3400.) the mucous membranes and around joints.44,45

Course and prognosis Management 34 Despite the progressive and deforming nature of Treatments, including intralesional and sys- 36 the lesions with no signs of spontaneous involution, temic corticosteroids and cyclophosphamide, patients remain in good general health. Spontaneous were unable to modify the progressive course of regression of lesions has only occasionally been the disease. Surgical procedures were performed to reported.31,33,36 PNH has been reported in associa- remove enlarging lesions from the membrane mu- tion with systemic disorders in two patients only: cous sites or the largest nodules of the face, with no 32,34,35 one38 had chronic myeloid leukemia, hypothyroid- evidence of recurrence. Carbon-dioxide laser ism, and purine and lipoprotein metabolic changes, produced cosmetically acceptable results in one 37 the other42 was a child with precocious puberty, patient, whereas it was followed by recurrence of 38 growth hormone deficiency, and a hypothalamic the lesions over the scar tissue in another one. tumor. Comment Differential diagnosis In our view, PNH may be considered the last stage As stated above, PNH may be included within a of particular forms of other non-LCH such as GEH, clinicopathologic spectrum also comprising several PX, XD, and MR, according to the concept of clini- entities from which PNH should be distinguished. copathologic spectrum mentioned above. The histologic and immunohistochemical findings in HEREDITARY PROGRESSIVE MUCINOUS PNH are similar to those in JXG, GEH, and BCH. HISTIOCYTOSIS However, in typical JXG, one or several papules and Definition nodules of 0.5 to 1.0 cm in diameter are present at HPMH was first described in 1988 by Bork and birth or appear during the first 6 months of life and Hoede46 as a new non-LCH resembling PNH in its almost always undergo spontaneous resolution by 2 clinical course, but differing from it by several clinical or 3 years of age. JXG can occur in adults, but also in and histopathologic characteristics, notably an adults the lesions regress spontaneously. Also in autosomal-dominant inheritance and mucinous GEH, the lesions, which appear rapidly, usually clear degeneration. spontaneously leaving brown macules or normale appearing skin. Giant cells are not seen on histology. Age of onset and incidence BCH can be excluded by the distribution of lesions, The disease is very rare and affects almost exclu- early onset, and lack of Touton giant cells. XD, where sively women; only 11 patients from 6 different lesions occur in flexures and tend to coalesce, and families,46-51 in addition to two sporadic cases,52,53 where respiratory involvement is common, can also have been reported. Indeed, we observed a male be excluded on clinical grounds. In MR, there is patient and his daughter both affected by HPMH involvement of the hands and mucosal and visceral (unpublished data). In HPMH, the cutaneous man- lesions and destructive arthritis. Papular xanthoma ifestations begin in adolescence or childhood. (PX) involves the skin and occasionally the mucosa. It generally resolves spontaneously after a few Clinical findings years.30 Histologically, the lesions consist mainly of The skin lesions consist of a few to numerous foamy cells, with essentially no nonlipidized skin-colored to red-brown, pinhead to pea-sized 1038 Caputo et al JAM ACAD DERMATOL DECEMBER 2007

Fig 6. Hereditary progressive mucinous histiocytosis. Histologic pattern consisting of aggregates of tightly packed histiocytes in whole dermis. (Hematoxylin-eosin stain; original magniﬁcation: 325.)

Fig 5. Hereditary progressive mucinous histiocytosis. Skin-colored to red-brown, dome-shaped nodules on enlarged and dilated rough endoplasmatic reticulum. forearms of father and daughter. Typical pleomorphic granules, as described by one of us,33 wormlike bodies, or Birbeck granules are absent.46-53 papules and dome-shaped nodules with a predilection to localize on the face, hands, forearms, and legs Course and prognosis (Fig 5). The distribution is symmetric. There are no The disease shows a progressive course marked overlying telangiectases. The lesions do not tend by a slowly increasing number of lesions, slowly to ulcerate or to merge into plaques. The mucous spreading to other regions of the body and with no membranes are always spared. No visceral involve- spontaneous regression; however, there is no evi- ment has been reported. dence of extracutaneous illness, the general health remaining good with age. Laboratory findings General investigations do not show any patho- Differential diagnosis logic changes. Results of extensive laboratory exam- The main differential diagnoses of HPMH include inations reveal normal findings; particularly, there the majority of non-LCH in addition to some non- are no abnormalities in lipid metabolism. histiocytic disorders. In PNH, lesional cells may lipidize, contain pleomorphic inclusion bodies, and Histopathologic, immunohistochemical, do not produce mucin. and ultrastructural findings GEH can be differentiated by onset late in life, Histologically, the lesions consist of nodular tendency of the lesions to resolve spontaneously, aggregates of tightly packed epithelioid or spindle- predominance of epithelioid histiocytes in the le- shaped histiocytes with large nuclei and abundant sions, and lack of mucin production. HPMH differs cytoplasm in the papillary and mid dermis (Fig 6). from MR in nearly all clinical aspects, especially the Neither involvement of the epidermis nor inflamma- localization of cutaneous nodules and clinical tory cells are seen, but a relatively high number of course; moreover, there are no associated articular mast cells has been observed by some authors.47 symptoms, and, histologically, the typical ground- Moderate to extensive dermal deposition of muci- glass appearance of the histiocytes is not observed. nous material is demonstrated in long-standing tu- Among nonhistiocytic disorders, acral persistent mors. Staining with toluidine blue reveals a marked papular mucinosis differs from HPMH in that it is metachromasia of the histiocytic cells. In accordance not hereditary, children are not affected, and the with some authors,53 immunohistochemical studies lesions show mucinous degeneration with a scant performed by us showed positive labeling of the histiocytic infiltrate.54 histiocytic cells with KP1 (CD68), and factor XIIIa, Multiple dermatofibromas are larger clinically, but S-100 protein and CD1a were negative. In con- and multiple lesions are uncommon over the upper trast, other investigators50 found that the histiocytes limbs or hands, but inheritance and mucin produc- were negative for both KP1 (CD68) and factor XIII. tion in HPMH are essential diagnostic features. Ultrastructurally, the histiocytes have large, convoluted, often bizarre-shaped nuclei and one or two Management prominent nucleoli; the abundant cytoplasm con- Considering its benign clinical behavior, most of the tains numerous myelin bodies and zebra bodies, patients with this disease received no therapy46,47,51; suggesting lysosomal storage phenomena, and an in two cases, some of the tumors were surgically JAM ACAD DERMATOL Caputo et al 1039 VOLUME 57, NUMBER 6 removed for cosmetic reasons.47,53 Indeed, in several abscesses with cutaneous perforation have all been reports the treatments were not stated.49,50,52 proposed as potential mechanisms involved in the manifestation of bone pain in ECD.57 Second in Comment frequency to bone involvement, diabetes insipidus, The nature of the disease is poorly elucidated. Its as a result of hypothalamic/posterior pituitary dis- progressive spreading with age, with no tendency to ease, has been reported in up to one third of patients, spontaneous regression and its electron microscopy often preceding the diagnosis of ECD by several aspects, led to the assumption that HPMH might be a years.57,59 Other neurologic involvement is rare but new lysosomal storage disease affecting solely the is often the source of significant morbidity.57,59-61 skin.46,47 It has been hypothesized that the stored It may manifest clinically with cerebellar signs, typ- material was a new phospholipid, eg, a sphingomye- ically lower extremity ataxia, upper motor neuron lin that could not be detected by the methods avail- deficits, and focal neurologic deficits. able at that time.46,47 On the other hand, the same Bilateral painless exophthalmos as a result of authors stated that a proliferation and accumulation retro-orbital histiocytic infiltration is also common, of macrophages as a result of an up to that time serious cases often progressing to visual impairment. unknown stimulus could not be ruled out. Currently, Although retroperitoneal and renal involvement oc- the storage nature of HPMH cannot yet be confirmed. curs in one third of patients and may manifest clinically as abdominal pain, dysuria, and hydrone- ERDHEIM—CHESTER DISEASE phrosis, the majority of cases are asymptomatic.57,58 Definition Pulmonary involvement is uncommon, occurring ECD is a rare, multisystem non-LC histiocytoxan- in approximately 20% of reported patients, and is thomatosis first described by William Chester55 and characterized by a progressive course commonly Jakob Erdheim in 1930. manifesting with dyspnea.62 Radiographic changes consist of diffuse interstitial infiltrates and pleural Age of onset and incidence and/or interlobular septal thickening.62-64 Although ECD primarily affects middle-aged and older uncommon, lung disease contributes disproportion- adults.55 The term ‘‘Erdheim-Chester disease’’ was ately to morbidity and mortality associated with ECD, first coined by Jaffe56 in 1972 and, since reporting respiratory failure and cardiac failure representing began in the literature, there have been approxi- the most common causes of death.57,62 The skin mately 180 cases recorded. involvement is present in one fourth of the cases and consists of xanthomatous lesions clinically identical Clinical findings to those observed in XD or PX. The cutaneous The disease can involve almost any organ system; manifestations resembling XD are papules red- thus, the clinical presentation of patients with ECD brown in color (Fig 7) at first and then becoming differs on a case-to-case basis, mostly because of the yellowish. These lesions, initially isolated, gradually variety of organ systems that may be involved and tend to coalesce and merge into plaques, mostly on the level of disease activity present in each case. the main folds. The hard-elastic texture of the Radiographically documentable skeletal involve- initial lesions tends to slowly diminish with time, ment is always present and focal bone pain, partic- and the skin may become slack and atrophic, espe- ularly involving the lower extremities, is the most cially on the folds and face. The distribution of the common presenting symptom in patients with ECD, lesions is typically symmetric and the preferentially with an incidence of approximately 50%.57 Indeed, involved regions are, in order of frequency, the many patients in whom radiographics findings are eyelids, the axillae, the groin, the neck, the trunk, typical of ECD may be asymptomatic. Pathogno- and the face. monic radiographic changes in the long bones con- Skin manifestations resembling PX are more rare sist of bilateral and symmetric patchy osteosclerosis and consist of 2 to 15 mm, rounded, yellow to pink- involving the metaphysis and diaphysis with epi- yellow, asymptomatic papulonodular lesions most physial sparing and loss of a clear definition between frequently involving the back and the head. cortex and medulla. Distal femur and proximal tibia and fibula are the most frequently affected sites, Laboratory findings whereas the disease usually spares the axial skeleton Laboratory findings are typically nonspecific and and flat bones.57,58 In addition to the sclerotic inconsistently include mild elevations of both eryth- changes, lytic lesions can be seen in up to 30% of rocyte sedimentation rate and C-reactive protein. An cases.59 Pathologic bone fracture, compression of elevation in alkaline phosphatase has been reported the femoral neck, and the development of bone in up to 19% of cases.57 1040 Caputo et al JAM ACAD DERMATOL DECEMBER 2007

Fig 8. Erdheim-Chester disease. Histologically, skin lesions are characterized by dermal inﬁltration almost entirely composed of foamy histiocytes. (Hematoxylin-eosin stain; original magniﬁcation: 3400.)

macrophages. Birbeck granules are absent and comma-shaped bodies are seen only occasionally.

Course and prognosis The course of ECD is usually progressive with a high mortality. The prognosis depends mainly on the extent and distribution of the extracutaneous disease. In a review of 59 patients, Veyssier-Belot et al57 reported that 22 (59%) of 37 patients with follow-up Fig 7. Erdheim-Chester disease. Red-brown papules re- had died of the disease, 8 (36%) in less than 6 sembling those of xanthoma disseminatum. months, the mean survival duration having been just less than 3 years. General symptoms of fever, weakness, and weight loss are common. Differential diagnosis ECD is often misdiagnosed because of its rarity and variety of endeorgan involvement. The differ- Histologic, immunohistochemical, ential diagnosis is extensive and includes the dis- and ultrastructural findings eases listed in Table VI. Among the differential Histologically, the skin lesions are characterized diagnoses of particular interest for dermatologists, by a dermal infiltration that is almost entirely com- LCH may be distinguished histologically based on posed of foamy histiocytes (Fig 8) in association with the characteristics of the infiltrate. This includes small numbers of lymphocytes, plasma cells, and diagnostic LC with typical convoluted, often reni- neutrophils. Touton giant cells are constantly pre- form, nucleus and abundant, slightly eosinophilic sent, but vary in number. Immunohistochemically, cytoplasm. Immunohistochemically, LC are positive foamy histiocytes express the following immuno- not only for S-100 protein but also for CD1a, e phenotype: KP1(CD68)1, factor XIIIa1, CD1a , and whereas, under the electron microscope, they con- e S-100 . tain Birbeck granules. The absence of well-formed Under the electron microscope, foamy cells are granulomas on histology is helpful in excluding characterized by an abundant cytoplasm completely the diagnosis of sarcoidosis. Sinus histiocytosis with filled with lipid vacuoles and sometimes containing massive lymphadenopathy, also referred to as Rosai- cholesterol crystals and myeloid bodies. The major- Dorfman disease,65 is a rare form of histiocytic ity of the histiocytes show the typical features of proliferation that classically appears in childhood the macrophages, namely indented nuclei, abundant as massive, painless bilateral enlargement of cervical cytoplasm containing dilated rough endoplasmic lymph nodes. Affected lymph nodes show a sinus- reticulum, coated vesicles, and numerous lysosomes oidal infiltrate of lymphocytes, plasma cells, and and phagosomes. These cells also display slender characteristic histiocytes with abundant vacuolated cytoplasm processes at the periphery. Multinucle- cytoplasm; the histiocytes are similar to those seen in ated giant cells are produced by aggregation of these ECD, differing mainly in that they frequently contain JAM ACAD DERMATOL Caputo et al 1041 VOLUME 57, NUMBER 6 intact lymphocytes within their cytoplasm (ie, em- Table VI. Differential diagnosis of peripolesis). Moreover, in all the 3 disorders men- Erdheim-Chester disease tioned above, bilateral and symmetric osteosclerosis Xanthoma disseminatum in long bones is lacking. Juvenile xanthogranuloma Langerhans cell histiocytosis Management Sinus histiocytosis with massive lymphadenopathy Treatment regimens for ECD have included ste- Sarcoidosis roids, radiation, chemotherapy, and surgery, al- Amyloidosis though no therapeutic clinical trials have been Gaucher’s disease performed because of the rarity of the disease. Niemann-Pick disease Steroids are the most commonly used treatment Mastocytosis modality, usually with poor response, although cases Paget disease of remission of localized disease have been re- Fluoride intoxication ported.66 Radiation therapy has been used to shrink Adult progressive diaphysial dysplasia Whipple’s disease lesions of ECD, the rationale being based largely on Mucopolysaccharidoses its use in a similar disease such as LCH. Chemother- Hermansky-Pudlak syndrome apy, including vinca alkaloids, anthracyclines, and Malakoplakia cyclophosphamide, and surgical debulking of tumors have also been used but with discouraging Modified by Tashjian et al.61 results.57 Effectiveness of interferon alfa in ECD has recently been reported.67 rate by the reticuloendothelial system. The latter Comment 68 group encompasses a variety of inherited metabolic The origin of ECD is unknown. It is undeter- defects including sphingomyelinase deficiency, most mined whether ECD is a monoclonal proliferative notably Niemann-Pick disease.76-78 Moreover, long- disorder or whether it is a polyclonal reactive dis- 79 68,69 term parenteral alimentation with fat emulsion and ease. Although ECD has been known to occur in 80 70 severe hypertriglyceridemia have rarely been re- patients who also have LCH, the two diseases are ported to produce the accumulation of SBH within generally regarded as representing distinct entities. the marrow. Finally, SBH have exceptionally been From a dermatologic perspective, ECD may be found in the infiltrate of mycosis fungoides.81,82 considered as a variant of XD with bone and visceral involvement and, thus, having an aggressive clinical behavior. Clinical findings In the primary form of SBHS, the most common SEA-BLUE HISTIOCYTIC SYNDROME symptoms are hepatosplenomegaly and bone mar- Definition row involvement resulting in hemorrhagic diathesis, 71 then lung infiltrates, lymphadenopathies, and, less In 1970, Silverstein et al coined the term ‘‘sea- 83,84 blue histiocyte syndrome’’ to describe a primitive frequently, retinal or nervous involvement. Cutaneous changes are very rare, having been ob- idiopathic storage disease in which many organs 85-89 were infiltrated by the so-called SBH. SBH are large served in a few patients only. They include facial macular brownish hyperpigmentation87 and nodular macrophages whose cytoplasm is filled with gran- 85,86,88,89 ules staining blue or blueegreen with Giemsa. Up lesions. Nodular lesions have been observed until now, approximately 60 cases of SBHS have on the face, trunk, hands, and feet. Eyelid infiltrative been published. In addition to the primary form of swelling and facial waxy plaques are the most prominent cutaneous features, resulting in a puffy SBHS, it is now clear that there are secondary forms 86 85 related to a wide variety of conditions, including appearance (Fig 9). The disease may be familial. diseases with a high rate of intramedullary cell death and storage diseases. The common feature is the Histopathologic, immunohistochemic, accumulation of unsaturated lipids within histiocytes and ultrastructural findings as a result of increased production or to a failure of Histologically, cutaneous nodular lesions show an catabolism. The former group includes various edematous dermis with a sparse micronodular infil- blood disorders such as chronic myeloid leukemia,72 trate composed of large, pale, monomorphous his- idiopathic thrombocytopenic purpura,73 severe au- tiocytes containing vacuoles and granules (Fig 10, A). toimmune neutropenia,74 and myelodysplastic syn- These granules become clearly visible as inclusion dromes75 in which cells are cleared at an increased bodies of varying size and shape after staining 1042 Caputo et al JAM ACAD DERMATOL DECEMBER 2007

Fig 10. A, Histology of sea-blue histiocytic syndrome. Fig 9. Sea-blue histiocytic syndrome. Facial waxy plaques Sparse infiltrate composed of large, monomorphous his- resulting in puffy appearance. Courtesy of Prof M. tiocytes within edematous dermis. (Hematoxylin-eosin Pippione. stain; original magnification: 3200.) B, Granules within cytoplasm of infiltrating cells appear clearly visible (blue- green) after staining with Giemsa. (Original magnification: with Giemsa (blue-green) (Fig 10, B) and toluidine 3400.) Courtesy of Prof M. Pippione. (dark-blue without metachromasia), and are highly birefringent under polarized light.86 Immunohisto- chemically, the histiocytes are KP1 (CD68)1 and Moreover, a leonine appearance is sometimes seen e S-100 ; in the literature, they have not been tested for in PNH.30,32,36,38 Finally, lepromatous leprosy should CD1a or for factor XIIIa. be considered and ruled out based on the absence Ultrastructurally, the granules present as round of intracellular bacilli. dense bodies, membranous or lamellated structures, occasionally showing a fingerprint appearance, and Management bodies containing dense rodlike formations.85,86 The No treatment capable of stopping the progression presence of the rodlike bodies appears to be a of the cutaneous disease has so far been reported. striking feature in SBHS, although their significance and origin remain obscure. Comment The pathogenesis of the material stored within Course and prognosis SBH is still unclear, but phospholipids, glycosphin- The idiopathic form of SBHS pursues a relatively golipids, and ceroids have been identified. Although benign clinical course, usually with no progression no consistent enzymatic defect has been identified in apart from the skin lesions. In secondary forms, the these patients, a biochemical derangement in lipid course is related to that of the primary disorder. metabolism has been hypothesized.71,90,91 Some authors have proposed that a partial sphingo- Differential diagnosis myelinase deficiency is a possible cause of SBHS.92,93 The main differential diagnoses of primary SBHS include the secondary forms of SBHS. This requires CONCLUSIONS conditions associated with presence of SBH, notably The clinical, histologic, and ultrastructural find- lymphoproliferative disorders and storage diseases, ings and the course, prognosis, and management of 5 to be ruled out. Because of the puffy appearance of unusual histiocytic disorders have been reviewed. the face observed in primary SBHS, leonine facies as Although their classification still remains controver- a feature of mycosis fungoides should be excluded, sial, we suggest lumping all these entities into the also taking into account that SBH has exceptionally wide group of non-LCH. In ICH, the proliferating been reported in association with this disease.81,82 cells express both macrophage markers, such as KP1 JAM ACAD DERMATOL Caputo et al 1043 VOLUME 57, NUMBER 6

(CD68), and LC markers, such as S-100 and CD1a. 10. Rodriguez-Jurado R, Vidaurri-de la Cruz H, Dura`n-Mckinster C, Thus, ICH was proposed to be a separate entity Ruı`z-Maldonado R. Indeterminate cell histiocytosis: clinical and showing an overlap between LCH and noneLCH. pathologic study in a pediatric patient. Arch Pathol Lab Med 2003;127:748-51. We defend the view of ICH as a distinctive entity, but 11. Miracco C, Raffaelli M, de Santi MM, Figiani M, Tosi P. Solitary we suggest including it into a spectrum comprising cutaneous reticulum cell tumor: enzyme-immunohistochemi- several classic non-LCH on the basis of the strict cal and electron-microscopic analogies with IDRC sarcoma. clinicopathologic and ultrastructural similarities be- Am J Dermatopathol 1988;10:47-53. tween the latter and ICH. 12. Levisohn D, Seidel D, Phelps A, Burgdorf W. Solitary congenital indeterminate cell histiocytoma. Arch Dermatol 1993;129:81-5. According to this concept, PNH may be classified 13. Jang KA, Ahn SJ, Choi JH, Sung KJ, Moon KC, Koh JK. into the group of non-LCH, possibly representing the Histiocytic disorders with spontaneous regression in infancy. last stage of other non-LCH. Pediatr Dermatol 2000;17:364-8. HPMH was proposed to be a storage disease, but 14. Amo J, Kawano N, Takasu H, Katsuoka K. A case of solitary this hypothesis cannot yet be confirmed. On the indeterminate cell histiocytosis. J Dermatol 2003;30:751-4. 15. Flores-Stadler EM, Gonzales-Crussi F, Greene M, Thangavelu M, other hand, the dermal deposits of mucin could Kletzel M, Chou PM. Indeterminate cell histiocytosis: immu- justify including it in the group of cutaneous muci- nophenotypic and cytogenetic findings in an infant. Med noses. However, this form sometimes resembling Pediatr Oncol 1999;32:250-4. PNH in its clinical course better fits the diagnostic 16. Berti E, Gianotti R, Alessi E. Unusual cutaneous histiocytosis criteria for non-LCH. 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