Histiocytosis Background Histiocytosis encompasses a group of diverse disorders with a common primary event: the accumulation and infiltration

of monocytes, macrophages, and dendritic cells in the affected tissues. Such a description excludes diseases in which infiltration of these cells occurs in response to a primary pathology. The clinical presentations vary greatly, ranging from mild to life threatening. Although nearly a century has passed since histiocytic disorders were recognized,[ ! their pathophysiology remains an enigma, and treatment is nonspecific. These pro"lems underscore the need for an improved understanding of the etiology and pathogenesis of histiocytosis. #ver the past $% years, the nomenclature used to descri"e histiocytic disorders has su"stantially changed to reflect the wide range of clinical manifestations and the varia"le clinical severities of some disorders that have the same pathologic findings. &or example, the entity now referred to as 'angerhans cell histiocytosis (')H* was initially divided into eosinophilic granuloma, Hand+Sch,ller+)hristian disease, and 'etterer+Siwe disease, depending on the sites and severity. 'ater, these were found to "e manifestations of a single entity and were unified under the term histiocytosis -. [.! /ost recently, this designation was changed to 'angerhans cell histiocytosis to reflect the recognition of the primary cell involved and the pathophysiology of the disease.[0, 1! Although several histiocytic disorders are "riefly discussed in this article (see History*, the primary focus is on 'angerhans cell histiocytosis. Pathophysiology 2mproved understanding of the pathology of histiocytic disorders re3uires 4nowledge of the origins, "iology, and physiology of the cells involved. 5ormal histiocytes originate from pluripotent stem cells, which can "e found in "one marrow. [$! 6nder the influence of various cyto4ines (eg, granulocyte+ macrophage colony+stimulating factor [7/+)S&!, tumor necrosis factor+alpha [T5&+alpha!, interleu4in [2'!+ 0, 2'+1*, these precursor cells can "ecome committed and differentiate to "ecome a specific group of specialized cells. )ommitted stem cells can mature to "ecome antigen+processing cells, with some possessing phagocytic capa"ilities. These cells include tissue macrophages, monocytes, dendritic cells, interdigitating reticulum cells, and 'angerhans cells. 8luripotent stem cells can also "e committed to produce dendritic cells. 9ach category of histiocytosis can "e traced to reactive or neoplastic proliferation and disorder of cells in one of these groups.[:! The importance of dendritic cells in presenting antigens to T and ; lymphocytes is increasingly recognized. <endritic cells appear to develop in several pathways. 2mmature dendritic cells respond to 7/+)S& (not to macrophage colony+stimulating factor [/+)S&!* and "ecome committed to generating dendritic cells, which are =professional> antigen+presenting cells (A8)s*. [?! These cells can capture antigen and migrate to lymphoid organs, where they present the antigens to naive T cells. [@! <endritic cells are also efficient stimulators of ;+cell lymphocytes.[A! 9ffective induction of antigen+specific T+cell responses re3uires interaction "etween the dendritic cells and T lymphocytes to prime the latter cells for expansion and appropriate function. The surface of the A8) contains . peptide+"inding proteins (ie, maBor histocompata"ility complex [/H)! classes 2 and 22*, which can stimulate cytotoxic T (T)* cells, regulatory T (Treg* cells, and helper T (T H* cells.[ %! Although circulating T+cell lymphocytes can independently recognize antigens, their num"er is small. <endritic cells display a large amount of /H)+peptide complexes at their surface and can increase the expression of costimulatory receptors and migrate to the lymph nodes, spleen, and other lymphoid tissues, where they activate specific T cells.

The first signal may involve interaction "etween an /H) 2C"ound andDor /H) 22C"ound peptide on an A8) with the T+cell receptor (T)Es* on the effector lymphocytes. T)Es can recognize fragments of antigen attached to /H) on the surface of an A8). )ostimulatory interaction (ie, second signal* is "etween )<@%(;?. *D)<@:(;?..* on the dendritic cell, with )<.@ on the T cells. [ , ., 0! A com"ination of the . signals activates the T cell, resulting in upregulation of the expression of )<1%', which, in turn, can interact with the dendritic cellCexpressed )<1% receptor. [ %! 2n perforin+deficient mice, a"normally heightened cyto4ine production "y T cells is due to overstimulation "y A8)s after a viral infection. [ 1! This cell+to+cell interaction "etween dendritic cells and T cells generates an antigen+specific T+cell response. The effective function of antigen presentation "y dendritic cells is presumed to reflect that these cells, in addition to /H) molecules, express a high density of other costimulatory factors. <endritic cells can produce several cyto4ines, including 2'+ ., which is critical for the development of T H cells from naive )<1F T cells.[ , .! 'igation of )<1% on dendritic cells triggers the production of large amounts of 2'+ ., which enhances T+ cell stimulatory capacity. This o"servation suggests that feed"ac4 to dendritic cells results in signals that are critical for induction of immune responses. The nature of the latter interaction and re3uirement for optimal dendritic cell activation is not fully understood. <endritic cells in culture derived from human "lood monocytes exposed to 7/+)S& and 2'+1 followed "y maturation in a monocyte+conditioned medium have heightened antigen+presenting activity. [ $, :! /onocyte+conditioned media contain critical maturation factors to catalyze this process. <endritic cells are present in tissues in a resting state and cannot stimulate T cells. Their role is to capture and phagocytize antigens, which, in turn, induce their maturation and mo"ilization. [ ?, @, A, .%! 2mmature dendritic cells reside in "lood, lungs, spleen, heart, 4idneys, and tonsils, among other tissues. Their function is to capture antigen and migrate to the draining lymphoid organs to prime )<1 F and )<@F T cells. 2n the process of their function, these cells mature and increase their capacity to express costimulatory receptors and decrease their capacity to process antigen. These cells can phagocytize, forming pinocytic vesicles for sampling and concentrating their surrounding medium, which is called macropinocytosis.[. ! 2mmature dendritic cells express receptors that mediate endocytosis, including )+type lectin receptors, such as the macrophage mannose receptor and <9).%$, &)+gamma, and &)+epsilon receptors. [?! /icro"ial components, as well as 2'+ , 7/+)S&, and T5&+alpha, have an important role in cellular response[.., .0, .1! and can stimulate maturation of dendritic cells, whereas 2'+ % opposes it. [.$! /ature dendritic cells possess numerous fine processes (veils, dendrites* and have considera"le mo"ility. These cells, rich in /H) classes 2 and 22, have a"undant molecules for T+cell "inding and co+stimulation, which involves )<1%, )<$1, )<$@, )<@%D;?+ , and )<@:D;?+ . /ature dendritic cells express high levels of 2'+ .. High levels of )<@0 (a mem"er of the immunoglo"ulin [2g! superfamily*, and p$$ or fascin (an actin+"undling protein* are present in these cells, as opposed to the low levels that are present in the immature cells.[?! 2'+ enhances dendritic cell function. This effect appears to "e indirect and due to activation of T5& receptorCassociated factors (TEA&s*. /ature dendritic cells also express high levels of the 5&+4appa; family of transcriptional control proteins. These proteins regulate the expression of several genes encoding inflammatory and immune proteins. Signaling "y means of the T5&+receptor family (eg, T5&+E, )<1%, T5&+related activation+induced cyto4ine [TEA5)9!, receptor activator of 5&+4appa; [EA5G!* activates 5&+4appa;. 2mmunologic response of dendritic cells to a given antigen partly involves the triggering of signal+transduction pathways involving the T5&+E family and TEA&s. 2nformation regarding the fate of dendritic cells after these events is sparse. <endritic cells disappear from the lymph nodes +. days after antigen presentation, possi"ly "ecause of apoptosis. [.:! )<A$ (&as* is

suggested to have a role in the death of the dendritic cell. [.?, .@! Although dendritic cells express )<A$, )<A$ ligation does not induce apoptosis.[.A! 9xperiments indicate that immature dendritic cells are partially suscepti"le to death receptorCmediated apoptosis.[0%! T5&+related apoptosis+inducing ligand (TEA2'* may "ind to $ separate receptors. &unctional cytoplasmic death domains characterize TEA2'+E receptors, TEA2'+E. receptors, and )<A$ receptors. 2n contrast, TEA2'+E0 is a mem"rane+anchored truncated receptor, and TEA2'+E1 does not have a functional death domain. <endritic cells express )<A$, TEA2'+E., and TEA2'+E0 in comparative levels. Similar to the role of )<A$', that of TEA2'+mediated apoptosis of mature dendritic cells has "een controversial. <ata regarding in vitro TEA2'+mediated apoptosis in these cells has "een reported [0 ! and disputed.[0%! /ature dendritic cells are resistant to TEA2'+ and )<A$'+mediated apoptosis. [0%! )+&'28, which is the caspase+@ inhi"itory protein capa"le of inhi"iting death receptorCmediated apoptosis, is highly expressed in mature dendritic cells, whereas only low levels are found in immature cells. [0%! #verexpression of )+&'28 inhi"its signals of death receptor. [0.! )+&'28 expression on dendritic cells is upregulated during maturation.[.A! 5ote that engagement of )<A$ on immature dendritic cells "y )<A$' induces phenotypic and functional maturation of these cells. 2n addition, a )<A$+activated dendritic cell upregulates the expression of /H) class 22 and costimulatory receptors, which is essential for the function of these cells. &urthermore, such engagement upregulates the expression of dendritic+cell lysosome+associated mem"rane protein (<)+'A/8* and causes the secretion of proinflammatory cyto4ines, including 2'+ "eta and T5&+alpha. [00! The function of normal 'angerhans cells is cutaneous immunosurveillance. These cells can migrate to the regional lymph nodes and potentially present antigen to paracortical T cells and cause their transformation to interdigitating dendritic cells. Some cancer cells disrupt dendritic+cell function, "loc4ing the development of tumor+specific immune responses and allowing tumors to evade recognition. [01, 0$! To counteract this effect, dendritic cells may produce the antiapoptotic protein ;cl+x'. [0$! Stimulation of dendritic cells "y )< $1, 2'+ ., or 2'+ $ increases expression of this protein. The information gained from normal physiology of dendritic cells may potentially lead to treatment modalities for histiocytic disorders. Epidemiology Frequency International The incidence of 'angerhans cell histiocytosis is 1+$.1 per million population. However, "ecause many "one and s4in lesions may not "e diagnosed as 'angerhans cell histiocytosis, this rate may "e an underestimate.[0:! The estimated incidence of neonatal 'angerhans cell histiocytosis, determined "y using the population+"ased 7erman )hildhood )ancer Eegistry, is +. per million neonates. [0?! Mortality/Morbidity See History. Sex The overall male+to+female ratio is .$: . The male+to+female ratio in individuals who have a single organ system involvement is .0: , and the male+to+female ratio in individuals with multisystem disease .A: .[0@!

Age The disease can occur in individuals of any age. 'angerhans cell histiocytosis can "e congenital [0A, 1%! or may occur in adults.[1 ! The disease is seen in all age groups, ranging from neonates to adults. [1., 10, 11, 0?! The incidence pea4s in children aged +0 years.[1$! 2n one study, the age at diagnosis was %.%A+ $. years. 8atients with single system involvement were older (%. + $. y* than those with multisystem involvement (%.%A+ 1.@ y*.[0@! History 'angerhans cell histiocytosis (')H* can "e local and asymptomatic, as in isolated "one lesions, or can involve multiple organs and systems, with clinically significant symptoms and conse3uences. [1:! The clinical manifestations depend on the site of the lesions and on the organs and systems involved and their functions (see 8hysical*. Classi ication )lassification of diseases involving histiocytic and dendritic cells is difficult, and classification systems must include a "road range of diseases. Therefore, most systems have "een incomplete and ar"itrary. The location of lesions and the extent of the disease su"stantially affect the course of the disease and the patientHs prognosis. <ecisions regarding treatment are "ased on the extent of the disease. Classi ication!o !the!"orld!Health!#rgani$ation Ta"le shows the classification of histiocytic and dendritic cell disorders the Iorld Health #rganization (IH#* proposed.[1?! Ta"le . )lassification of Histiocytosis Syndromes in )hildren (#pen Ta"le in a new window* Clas s! 2 22 'angerhans cell histiocytosis Histiocytosis of mononuclear phagocytes other than 'angerhans cells &amilial and reactive hemophagocytic lymphohistiocytosis (H'H* Sinus histiocytosis with massive lymphadenopathy (SH/'*, Eosai+<orfman disease Juvenile xanthogranuloma (J-7* Eeticulohistiocytoma /alignant histiocytic disorders Acute monocytic leu4emia (&A; /$* /alignant histiocytosis True histiocytic lymphoma Syndromes!

222

The IH# classification of neoplastic disorders of histiocytes and dendritic cells is as follows: /acrophage or histiocyte related o Histiocytic sarcoma, mainly localized o 7eneralized malignant histiocytosis (may "e related to acute monocytic leu4emia*

<endritic+cell related o o o o .A + 'ocalized or generalized 'angerhans cell histiocytosis .; + 'angerhans cell sarcoma .) + 2nterdigitating dendritic cell sarcoma .< + &ollicular dendritic cell sarcoma or tumor

Classi ication!o !the!Histiocyte!Society Ta"le . shows the wor4ing classification of histiocytosis syndromes from the Histiocyte Society. Ta"le .. Histiocyte Society )lassification of Histiocytosis Syndromes (#pen Ta"le in a new window* Class! <endritic+cell related /acrophage related /alignant disorders Syndromes! 'angerhans cell histiocytosis -anthogranuloma H'H, genetic or sporadic SH/' /onocyte related, monocytic leu4emia <endritic+cell related 'ocalized or macrophage related <isseminated (malignant histiocytosis*

The following, adapted from the Iriting 7roup of the Histiocyte Society, descri"es confidence levels for the diagnosis of class 2 'angerhans cell histiocytosis: [0! 8resumptive diagnosis + 'ight morphologic characteristics <esignated diagnosis + 'ight morphologic features plus . or more supplemental positive stains for the following: o o o Adenosinetriphosphatase S+ %% protein Alpha+<+mannosidase

8eanut lectin

<efinitive diagnosis + 'ight morphologic characteristics plus ;ir"ec4 granules in the lesional cell on electron microscopy andDor positive staining for )< a antigen (T:* on the lesional cell

Pre%ious!and!other!classi ications 'angerhans cell histiocytosis formerly was divided into 0 disease categories: eosinophilic granuloma, Hand+Sch,ller+)hristian disease, and 'etterer+Siwe disease, depending on the severity and extent of involvement. This classification and its related ris4 groups no longer are used. Systems "ased on these categories were meant to reflect the extent of involvement and its relationship to the patientHs prognosis.[
1!

Some classifications simply divide histiocytic disorders into class 2 'angerhans cell disease, class 22 non'angerhans cell histiocytic disease without features of malignant disorders, and class 222 malignant histiocytic disorders. A clinical+grouping system for 'angerhans cell histiocytosis "ased on age, extent of the disease, and organ dysfunction, as once constructed,[1@! can provide a means to compare patient data and prognoses. Karious categories, such as restricted and extensive multiorgan involvement, have also "een proposed. <ata regarding treatment results are needed to validate any classification system. The Histiocyte Society developed a classification "ased on ris4 groups that arose from the first and second international ('angerhans cell histiocytosis 2 and 22, respectively* trials of chemotherapy. [1A! At+ris4 organs and systems identified in those trials included the liver, lung, spleen, and hematopoietic system. This ris4 classification is used in the treatment protocol of the third international study for 'angerhans cell histiocytosis ('angerhans cell histiocytosis 222*. 8atients are stratified into 0 groups: ( * at+ris4 patients, or those with multisystemic involvement including or more at+ris4 organsL (.* low+ris4 patients, or those with multisystem involvement not including at+ris4 organsL and (0* other patients, or those with single+system multifocal "one disease or localized involvement of special sites (intraspinal extension or involvement of the paranasal, parameningeal, perior"ital, or mastoid region* that can lead to persistent soft+tissue swelling. 2n the trial, at+ris4 patients are randomly assigned to of . treatment arms. 'ow+ris4 patients receive standard therapy for :+ . months, and those with multifocal "one or special+site involvement receive the standard therapy for : months. #ther!Histiocytoses Although this article focuses mainly on 'angerhans cell histiocytosis, other histiocytoses are as follows: <endritic+cell disorders o /ultiple yellow+to+pin4 cutaneous nodules, which usually appear in the head and nec4 region, clinically characterize J-7. The nodules are often %.$+ cm in diameter, "ut a macronodular variant with lesions that measure several centimeters can also "e seen. 'esions have "een o"served in the deep soft tissues or organs. [$%, $ ! The condition usually presents at "irth "ut can "e o"served during infancy. Similar lesions may "e seen in adults. o 2n histologic evaluation, the lesions are well circumscri"ed and consist of an accumulation of histiocytic cells with giant cells and spindle cells. 2mmunohistochemical

studies usually reveal positivity for factor -222a, fascin )<:@, and peanut agglutinin lectin. Eesults for S+ %% protein is often, "ut not exclusively, negative. o The course of J-7 is usually mar4ed "y spontaneous resolution of the lesion. Systemic forms of J-7 that involve the )5S can "e devastating. Although no treatment is usually necessary, chemotherapy may "e re3uired to manage systemic forms of the disease.

Histiocytic disorders o Sinus hyperplasia: This disorder is a generally "enign condition o"served in lymph nodes, draining extremities, mesenteric regions, sites of malignant disorders, or foreign "odies. 9rythrophagocytosis may "e present in the involved lymph nodes. Sinuses are dilated and contain histiocytes. SH/' Also called Eosai+<orfman disease,[$.! this is persistent, massive enlargement of the nodes with an inflammatory process. The disease is rarely familial. [$0! A rare familial variation termed &aisala"ad histiocytosis has "een descri"ed in . families. These individuals have multiple congenital a"normalities including fractures, short stature, hearing impairment, Boint contractures, and massive enlarged lymph nodes resem"ling Eosai+<orfman disease. The disorder appears to "e transmitted as an autosomal recessive syndrome. [$1! The male+to+female ratio is 1:0, with a higher prevalence in "lac4s than in whites. Systemic symptoms, such as fever, weight loss, malaise, Boint pain, and night sweats, may "e present. )ervical lymph nodes are most characteristically involved, "ut other areas, including extranodal regions, can "e affected. These disorders can manifest with only rash or "one involvement. [$0, $$, :! 2mmunologic a"normalities can "e o"served.[$:! 'eu4ocytosisL mild normochromic, normocytic, or microcytic anemiaL increased 2g levelsL a"normal rheumatoid factorL and positive results for lupus erythematosus are also reported. The disease is "enign and has a high rate of spontaneous remission, "ut persistent cases re3uiring therapy have occurred.[$:, $0, $?! 2n exceptional cases with o"structive complications, surgery, radiation therapy, and chemotherapy have "een used to treat the disease.[$0!

H'H reactive hemophagocytic syndrome This is a reversi"le proliferation of histiocytes in response to viral, "acterial, fungal, and parasitic infections, as well as to various cancers. This syndrome is most prevalent in individuals of Asian descent.[$@! The disease may "e a manifestation of impaired immune response to an infection or to secondary immunodeficiency, with many of the patients having defects in cellular cytotoxicity and immune deficiencies. Symptoms are often systemic and include fever and a viral+li4e illness. 8atients fre3uently have a rash and an enlarged liver, spleen, and lymph nodes. 8ancytopenia, increased liver enzyme levels, and an a"normal coagulation profile are common. 9pstein+;arr virus may "e a triggering organism. 8athologically enlarged lymph nodes may have intact architecture with increased histiocytes in the sinusoids and paracortical areas. Histiocytes may exhi"it

platelet phagocytosis. Histiocytic hyperplasia may also "e evident in the liver and spleen. The disease is usually self+limiting, "ut treatment with chemotherapy may "e re3uired when the disease is severe. o H'H malignant T+cell lymphoma with erythrophagocytosis: 2nstances of a com"ination of T+cell lymphoma with "enign infiltration of histiocyte+simulating histiocytosis are reported. [$A, :%, : ! 6pon histologic analysis, the process involves various types of malignant lymphomas, which are often of T+cell origin. 8roduction of cyto4ines "y lymphoma cells is suspected to cause phagocytosis. 6pregulation of the T5&+alpha gene "y 9pstein+;arr virus and activation of macrophages "y T cells infected with this virus, with interferon (25&* and other cyto4ine production, have "een found.[:.! #ccurrence of 'angerhans cell histiocytosis with various leu4emias and solid tumors has "een reported. [:0! &amilial H'H (&H'H* This is a rare disorder with multiorgan involvement that manifests as fever and enlargement of the liver (A0M* and spleen (A1M*, rash (0%M*, and )5S disease (0%M*.[:1! 'a"oratory findings include throm"ocytopenia (A@M*, increased serum ferritin (A0M*, anemia (@AM*, hypofi"rinogenemia (?:M*, neutropenia (?$M*, and )S& pleocytosis ($.M*.[:1! 2mmune dysregulation is one of the hallmar4s of the disease, characterized "y reduced or a"sent activity of the natural 4iller cells (5G cells* in most cases. Karious mutations, deletions, or insertions that cause frameshift or missense mutation in perforin genes (PRF1 and PRF2*,[:$! MUNC 13-4, and syntaxin have "een reported. These findings often appear during the first year of life and almost always appear "efore age ? years. 8rimary H'H is lin4ed to chromosomes A and %. 7enetic mutations in the perforin gene on chromosome % cause the disease in a"out .$+1%M of genetically related patients. 8erforin gene mutation is reported in approximately one third of H'H cases. /utation in MUNC13-4, a gene involved in cellular cytotoxicity that encodes for a protein that controls the fusion of the lytic granules to the plasma mem"ranes, is associated with some &H'H cases (&H'0*. The mutations can "e scattered over different exons "ut, in most cases, fall within the protein functional domain. [::! A male predominance has "een reported.[:?, :@! 2n approximately $%+?$M of patients, the disease is hereditary, with an autosomal recessive trait pattern. 8arental consanguinity is common. [:A! The disease is fatal if untreated. Allogeneic "one marrow transplantation is the treatment of choice. However, the H'H+A1 international protocol of K8 :, steroids, and cyclosporine has excellent activity in achieving remission in most patients. Ihen this protocol is com"ined with allogeneic "one marrow transplantation, more than $%M of patients can "e cured.[?%! 2n patients with H'H, )5S disease is fre3uently seen. Almost ?%M of patients have nonspecific a"normalities detecta"le with )T scan and /E2 of the "rain. The most common a"normalities include periventricular white matter

involvement, with enlarged ventricular system, gray matter disorders, and "rainstem and corpus callosum disease. 2nvolvement of meninges is uncommon.
[? !

&amilial cases appear to "e clustered in certain geographic areas of the world. PRF1 gene mutations are seen in whites, "lac4s, Japanese, Hispanics, and mixed races. )lusters of the disease have "een reported in Asian, Tur4ish, Gurdish, Ara"ic, and 5ordic populations. Associations with genes on other chromosomes have also "een demonstrated. 2n a series of Japanese patients with H'H, .$M had mutations in the MUNC 13-4 gene (FHL2*, a regulator of exocytosis in perforin+containing vesicles. [?.! A small su"group, du""ed &H'1, has "een descri"ed in patients of Gurdish descent. A large consanguineous Gurdish 4indred with $ affected children had deletions in the syntaxin gene on chromosome : (&'H1*. Syntaxin is a regulator of endocytosis. [?0! This mutation is seen in approximately . M of cases.[?1! &urther genetic mutations are under investigation. 7riscelli syndrome type 22 generally has the same symptoms as H'H "ecause of associated immunodeficiency.

Hepatosplenic T+cell lymphoma: /alignant T cells that express T+cell receptor gammaDdelta have "een found in adult and (rare* pediatric patients with fever and hepatosplenomegaly. The red pulp of spleen and sinusoids of the liver contain large lymphoid cells with erythrophagocytosis.[?$, ?:, ??, ?@! Histiocytic necrotizing lymphadenitis This is a disease of un4nown etiology and is usually o"served in adolescents and adults. A female predilection is reported. The disease occurs in the cervical regionL however, other locations, multiple sites, and rare extranodal involvement are reported. )onstitutional symptoms, such as fever, weight loss, nausea, vomiting, myalgia, arthralgia, and upper respiratory infection, may "e present. [?A! 6pon histologic study, necrosis of the nodes is o"served in the paracortical area and, to a lesser extent, in the cortical area, with fi"rin deposits, 4aryorrhectic de"ris, and macrophage infiltration. Areas adBacent to the foci of necrosis exhi"it a reactive immuno"lastic proliferation. 'a"oratory findings are not diagnostic. The hematologic changes are nonspecific. Anti"odies to Yersinia enterocolitica have "een reported. The disease spontaneously resolves and rarely recurs. Systemic lupus erythematosus has "een reported.[?A! Almost ?%M of all patients with H'H have )5S a"normalities that can "e seen using )T scanning or /E2. These findings are often nonspecific. [? ! 6sing flow cytometry, )< %?a expression can "e diagnostic for MUNC 13-4 defect and can potentially discriminate "etween genetic su"types of &H'H. [@%!

<endritic lymphadenitis: This is a "enign condition in which draining lymph nodes react to a s4in lesion with paracortical expansion, dendritic cell infiltrates, and various degrees of follicular hyperplasia. /elanin pigment may "e present.

&ollicular lymphadenitis: 2nterdigitating dendritic cell sarcoma, indeterminate cell neoplasm, and fi"ro"lastic reticular cell neoplasm are rare and nearly always affect adults. )ongenital solitary histiocytoma: This is a variant of self+healing solitary lesion of Hashimoto+8ritz4er histiocytosis. This rare entity is seen in otherwise normal infants in form of a solitary $+mm to $+mm nodule or papule at "irth. 8athologically the s4in lesion consists of predominantly histiocytes with admixture of lymphocyte and eosinophiles. 8rotein S %% and )< a are positive and ;ir"ec4 granules may "e present. S4in is the only site. #ther organs and systems are not affected. The lesion is self+healing, apparently with no incidence of recurrence. Eegular follow+up physical examination has "een recommended.[@ !

Physical Ihen the disease is focal, esta"lishing the diagnosis of 'angerhans cell histiocytosis depends on a high level of suspicion. Ihen advanced multisystem involvement is o"served, diagnosis is often easy. Ade3uate wor4up to determine the extent of the disease and possi"le complications is essential. ;iopsy and pathologic evaluation are needed to esta"lish the diagnosis. ;one involvement is o"served in ?@M of patients with 'angerhans cell histiocytosis and often includes the s4ull (1AM*, innominate "one (.0M*, femur ( ?M*, or"it ( M*, andDor ri"s (@M*. 'esions of other "ones are less common. See the image "elow.

)linically detecta"le s4ull lesions in a child with advanced 'angerhans cell histiocytosis (')H*. o 6pon clinical evaluation, the lesions can "e singular or multiple. Asymptomatic or painful involvement of verte"rae can occur and can result in collapse. o 'ong+"one involvement can induce fractures. The lesions sometime cause a clinically significant periosteal reaction. 9xtension to the adBacent tissues can produce symptoms that may "e unrelated to the "one involvement. 'i4ewise, extraosteal involvement can occur in virtually any anatomic location, causing severe symptoms. [@.! 2n patients with advanced 'angerhans cell histiocytosis, lesions may "e clinically detecta"le in the s4ull (see 2maging Studies and the image a"ove*. #cular and perior"ital involvement have "een reported. /anifestation of the disease often includes perior"ital edema. 2maging studies may reveal destructive osteolytic lesions. The disease is usually unilateral, "ut "ilateral involvement can occur. ;iopsy is needed for confirmation. Treatment often includes partial resection and chemotherapy. [1%!

o o

8urulent otitis media may occur and may "e difficult to distinguish from infectious etiologies. 'ong+term se3uelae, including deafness, are reported. #r"ital involvement may cause proptosis. 2nvolvement of the eyes in the form of uveitis and iris nodules are reported. [@0! <ia"etes insipidus and delayed pu"erty are o"served in as many as $%M of patients (usual range is $+.$M*.[@1, @$, @:, @?, @@! Hypothalamic disease may also result in growth+hormone deficiency and short stature.[@?, @A! /axillary, mandi"ular, and gingival disease may cause loss of teeth, hemorrhagic gum, and mucosal ulceration and "leeding.[A%! 9rosion of the gingiva (see the image "elow* may give the appearance of premature eruption of the teeth in young children. [A , A%!

9rosion of the gingiva that creates the appearance of premature eruption of the teeth in a young child. )utaneous 'angerhans cell histiocytosis is o"served in as many as $%M of patients with 'angerhans cell histiocytosis.[A., A0, A1, A$! Eash is a common presentation, and s4in lesions may "e the only evidence of the disease or may "e part of systemic involvement (see the image "elow*. S4in infiltrates have a predilection for the midline of the trun4 and the peripheral and flexural areas of s4in. S4in infiltrates can "e maculoerythematous, petechial xanthomatous, nodular papular, or nodular in appearance. ;ronzing of the s4in can occur.

)utaneous 'angerhans cell histiocytosis (')H* in a child. S4in infiltrates are seen on the face, and the chest has maculoerythematous, petechial, and xanthomatous appearance. Scalp disease fre3uently presents as scaly, erythematous patches, which may "ecome petechial and eroded with serous crust (see the image "elow*. The lesions often are not pruritic, "ut tenderness and alopecia can occur. 2n infants, a nodular form of the disease mar4ed "y eruption of lesions that mimic varicella has "een reported.[A:, A?, A@! This variety of the disease may spontaneously remitL this feature led to the name self+healing 'angerhans cell histiocytosis.

Severe scalp disease in a patient with scaly erythematous patches. 8atches of alopecia are present. The lesions were not pruritic. 8ulmonary involvement is o"served in .%+1%M of patients and may result in respiratory symptoms, such as cough, tachypnea, dyspnea, and pneumothorax. A male predominance is o"served. 8ulmonary function test results may "e a"normal. [AA, 0 ! <iffuse cystic changes, nodular infiltrate, pleural effusion, and pneumothorax are 4nown to occur. [ %%! 2maging studies may reveal cysts and micronodular infiltrates. 8ulmonary function tests may reveal restrictive lung disease with decreased pulmonary volume.[AA, 0 ! 72 "leeding may "e the presenting sign of patients with 72 involvement. Appropriate imaging studies, endoscopy, and "iopsy may "e helpful to confirm the diagnosis. 'iver involvement is characterized "y elevated transaminase levels and, less commonly, increased "iliru"in levels. /arrow involvement or enlargement of the spleen may cause hematologic changes. 'ymph node enlargement is o"served in approximately 0%M of patients. 2n rare cases, the nodes are symptomatic. 2f the volume is massive, it may o"struct or damage the surrounding organs and tissues.[ % , %.! Suppuration and chronic drainage may occur. 'ymph node enlargement surrounding the respiratory tract may result in pulmonary+related symptoms, such as cough, dyspnea, or cyanosis. 2nvolvement of the thymus is relatively uncommon "ut does occur. [0%! 2nfiltration of various areas of the "rain gives rise to corresponding signs and symptoms, including cere"ellar dysfunction and loss of coordination.[ %0! <isruption of hypothalamic and pituitary function is most common. This includes symptoms secondary to dia"etes insipidus and, to a lesser extent, growth+hormone deficiency and hypopituitarism. [ %0, @A, %1! #ther symptoms, such as seizures and those related to increased intracranial pressure, depend on the site and volume of the space+occupying lesion. Anemia, leu4openia, throm"ocytopenia, and their related symptoms are uncommon.

Causes The causes of most histiocytoses are not 4nown. &actors implicated in the etiology and pathophysiology of these disorders include infections, especially viral infectionsL [ %$! )ellular and immune dysfunction,[ %:, %?! including dysfunction of lymphocytes and cyto4inesL[ %@, %A, %! neoplastic mechanismsL genetic factorsL[ , $, ., 0, 1, $, :, ?! cellular adhesion moleculesL[ @, A, .%! and their com"inations. Although human herpes virus : has "een found in lesions of 'angerhans cell histiocytosis, its etiologic significance has "een 3uestioned.[ @, . , ..! 9xtensive searches for evidence of viral infection have "een unrevealing. [0?! #ne report from Sweden suggests an increased rate of diagnosed histiocytosis in children conceived using in vitro fertilization.[ .0! 2n &'H, distinct genetic mutations have "een clearly demonstrated (see #ther histiocytoses*. )yto4ines play an important role in the physiology and "iology of dendritic cells and macrophages. ')H lesions contain various cyto4ines.[ %@, %A, %! 'arge amounts of cyto4ines are produced "y )< aF ')H and "y )<0F T cells, including 2'+., 2'+1, 2'+$, and T5&+alpha, which are exclusively generated "y T cells. 2'+ a is derived from 'angerhans cells. T cells and macrophages can produce 7/+)S& and 25&+alpha, whereas ')Hs and macrophages produce

2'+ %, and T cells and macrophages produce 2'+0. /acrophages produce 2'+?. 9osinophils are partly responsi"le for the production of 2'+$, 25&+gamma, 7/+)S&, 2'+ %, 2'+0, and 2'+1. [ %A, %! 9xpression of a"normal leu4ocyte cellular adhesion molecules in 'angerhans cell histiocytosis has "een reported.[ A, .%! These molecules mediate cell+to+cell and cell+to+matrix adhesion. 6sing the -+lin4ed human androgen receptor (humara* polymerase chain reaction (8)E*+"ased assay to assess clonality, researchers demonstrated that all forms of 'angerhans cell histiocytosis are clonalL therefore, 'angerhans cell histiocytosis is a clonal neoplastic disorder. #rigination from a single cell is postulated to indicate neoplasia, although it does not mean that the process is histologically malignant.[ .1! 6sing this standard, 'angerhans cell histiocytosis is considered to "e a neoplastic disease rather than a reactive disorder, as was previously proposed.[ .$! The role of genetics is not well defined. The occurrence of several cases in one family is rare "ut has "een reported.[ .:! 'angerhans cell histiocytosis has "een reported in several monozygotic and dizygotic twins.[ $, $, :, 1, ?, .?, 0! Some consanguinity and involvement in close relatives (cousins* has "een reported.[ .?! 5evertheless, the relative rarity of the familial occurrence does not indicate a nota"le hereditary influence. )onversely, &H'H, which is transmitted as autosomal recessive trait a"normalities of genes localized to "ands A3. ..+.. and %3. +.. (perforin*, is reported in some families.[ %A, %! As expected, numerous familial cases of erythrophagocytic lymphohistiocytosis have "een reported.[0$! The fusion of nucleaphosmin (NPM* and anaplastic lymphoma 4inase (ALK* genes that results in 58/+A'G fusion protein, which can "e immunohistochemically demonstrated, is reported in malignant histiocytosis. Eecently, 0 cases of histiocytosis in early infancy with enlarged liver and spleen, anemia, and throm"ocytopenia are reported. 2n one case, analysis had revealed T8/+0+ A'G fusion.[ .@! Spontaneous cytotoxicity of circulating lymphocytes is o"served in patients with 'angerhans cell histiocytosis. Anti"ody formation to autologous erythrocyte has also "een reported. [ .A! 7iven these findings, treatment with crude calf+thymus extract, although not su"stantially successful, was clinically devised and used.[ .A, 0%! A prominent feature of patients with H'H is deficiency in 5G+cell function against /H)+negative G:$. target cells. 8atients with &H'H usually exhi"it this defect at diagnosis. 8atients with infection+associated hemophagocytic syndrome may have normal function, they may never have completely negative function, or they may develop negative 5G+cell activity during the course of the disease.[$@! The etiologic role of impaired effector function of perforin with su"se3uent ina"ility to release perforin+containing granules is demonstrated in H'H. 2t is similar to the mononuclear cell infiltration associated with )hedia4+Higashi Syndrome and 7riscelli Syndrome. [ 0 , 0., 00!

&i erential!&iagnoses Acute 'ympho"lastic 'eu4emia Acute /yelocytic 'eu4emia Anemia, )hronic Atopic <ermatitis )raniopharyngioma

<ia"etes 2nsipidus <iaper <ermatitis 'ymphadenopathy 'ymphohistiocytosis 'ymphoproliferative <isorders /astoiditis 5on+Hodg4in 'ymphoma #steomyelitis #titis /edia Splenomegaly 'aboratory!Studies 'a"oratory investigations and diagnostic tests should partly "e tailored to the extent of disease suspected on the "asis of the patientHs history and physical findings. Ta"le 0 shows minimal fre3uencies of follow+up. Testing more fre3uent than that shown might "e necessary. Ta"le 0. 'a"oratory and 2maging Studies in 8atients Iith 'angerhans )ell Histiocytosis (')H*N (#pen Ta"le in a new window* Study! Hemoglo"in andDor hematocrit 'eu4ocyte count and differential cell count 'iver function testsN )oagulation studies )n%ol%ement! /onthly /onthly /onthly /onthly 9very : mo /onthly 9very : mo 9very : mo 9very : mo 9very : mo 9very : mo 9very : mo 5one "ith!Monostotic! 'esion! 5one 5one 5one 5one 5one 5one

(ype!o ! Study! 'a"oratory

6rine osmolality test after overnight water fast Eadiography )hest, posteroanterior and lateral S4eletal survey

9very : #nce at : mo mo N /easurements of alanine transaminase (A'T*, aspartate transaminase (AST*, and al4aline phosphatase. Ta"le 1 lists the indications for various la"oratory evaluations, with the minimal fre3uencies of follow+up. Testing more fre3uent than that shown might "e necessary. Ta"le 1. 2ndication for 'a"oratory 9valuations ;ased on &indings in 'angerhans cell histiocytosis (#pen Ta"le in a new window*

E%aluation! )ndication! ;one+marrow aspiration "iopsy Anemia, leu4openia, or throm"ocytopenia 8ulmonary function tests A"normal chest radiographic findings, tachypnea, intercostal retractions 'ung "iopsy after A"normal findings on pretreatment chest "ronchoalveolar lavage, if radiography to rule out infection availa"leN Small+"owel series and "iopsy 6nexplained chronic diarrhea, failure to thrive, mala"sorption Hepatic 9E)8, angiography, or High liver enzyme levels and hypoproteinemia "iopsy not caused "y protein+losing enteropathy to rule out active ')H vs liver cirrhosis

Follo*+,p!)nter%al! : mo : mo 5one 5one Ihen all evidence of disease resolves "ut hepatic dysfunction persists : mo

2K gadolinium+enhanced /E2 of Kisual, neurologic, hormonal a"normalities "rain and hypothalamic+pituitary 8anoramic radiography of the #ral involvement : mo teeth, mandi"le, and maxillaL consultation with an oral surgeon 9ndocrine investigation 7rowth failure, dia"etes insipidus, hypothalamic 5one syndromes, galactorrhea, precocious or delayed pu"ertyL hypothalamic andDor pituitary a"normality on )T or /E2 )onsultation with an audiologist Aural discharge, impaired hearing : mo and an otolaryngologist 5ote.O9E)8 P endoscopic retrograde cholangiopancreatographyL 2K P intravenous.

<iagnostic findings on "ronchoalveolar lavage o"viate lung "iopsy.

)maging!Studies See Ta"le 0+1 for appropriate imaging studies when 'angerhans cell histiocytosis is suspected. Eadiographic imaging of lytic lesions of the s4ull reveals a punched+out pattern without evidence of periosteal reaction or marginal sclerosis, shown "elow.

Eadiograph of lytic lesions of the s4ull reveals a punched+out pattern without evidence of periosteal reaction or marginal sclerosis.

Eadionuclide "one scanning with technetium+AAm polyphosphate may reveal a localized increased upta4e. This study is complementary to plain radiography. /E2 sometimes helps in identifying lesions that cannot "e detected with other modalities. &or example, in one study, .@M of children with 'angerhans cell histiocytosis had /E2 findings suggestive of neurodegenerative disease.[? ! 5eurologic findings may not always "e correlated with the /E2 results and may lag "ehind findings on /E2.[ 11! )T and /E2 can show the detailed anatomic pattern of involvement and can help in staging the disease.
[ 1$!

8ositron emission tomography (89T* with @&+fluoro+deoxyglucose (&<7* may "e an effective tool for evaluating ')H and may provide additional information regarding the activity of the lesions. [ 1:! However, this a"ility has not "een definitively studied. Iith pulmonary involvement, )T scanning is the "est modality to reveal cysts and micronodular infiltrates. #ther!(ests Ihen pulmonary involvement occurs, pulmonary function may "e a"normal. [AA, 0
!

<iffuse cystic changes, nodular infiltrate, pleural effusion, and pneumothorax are 4nown to occur. 8ulmonary function tests may reveal restrictive lung disease with decreased pulmonary volume.
[AA, 0 !

8ulmonary function tests are critical components of follow+up in patients with pulmonary involvement. Procedures ;iopsy is needed to esta"lish the diagnosis of 'angerhans cell histiocytosis. Histologic!Findings Eegardless of the clinical severity, the histopathology of 'angerhans cell histiocytosis is generally uniform. To some extent, the location and age of the lesion may influence the histopathology of the disease.[ 1?! 9arly in the course of the disease, lesions tend to "e cellular and contain aggregates of pathologic 'angerhans cells (8')s*, intermediate cells, interdigitating cells, macrophages, T cells, and giant histiocytes. /itotic figures num"er %+.0 per % high+power fields. [ $! /ultinucleated giant cells are common, and some may exhi"it phagocytosis. 'esions may also include eosinophils, necrotic cells, and 'angerhans cell histiocytosis cells. Iith time, the cellularity and num"er of 'angerhans cell histiocytosis cells are reduced, and macrophages and fi"rosis "ecome eminent. The infiltrates tend to destroy epithelial cells. Ta"le $ shows the phenotypes and cell+mar4er characteristics of 'angerhans cell histiocytosis. Ta"le $. )ell /ar4ers and 8henotypes of Histiocytic and Eelated <isorders (#pen Ta"le in a new window* Cell! Marker 'C SHM Follicular! H ' &endritic!(umor Histiocytic! Sarcoma Acute!Monocytic! 'eukemia Anaplastic!'arge+Cell! 'ymphoma

)< a )<1 )<. )<.$ )<0% )<0$ )<1$ )<:@ A'G+ S+ %% 'ysozyme

F F + + + + + + + F +

+ F FD+ F + F F F + F F

+ + F + + F + + + + +

+ F + F + + FD+ F + FD F

+ F + F + + F F + + F

+ F + FF FF + FD+ FD+ F + +

Ta"le : shows specialized stains for diagnosing these disorders, and Ta"le ? shows la"eling pattern of histiocytes and dendritic cells. Ta"le :. Stains for <iagnosing Histiocytosis (#pen Ta"le in a new window* Stain! (ype!o !(est! &rozen+section enzyme histochemistry Mononuclear! Phagocytic! System! + 'angerhan )nterdigitating! s!Cells! &endritic!Cells! &endritic! -eticulum! Cells! +

5onspecific + + esterase Acid F + + + phosphatase AT8ase + F F + 'am"da+ + F + + mannosidase $H + + + F nucleotidase 2mmunohistochemistry )< 1 ('eu F F F F /0D/Q1* )< ) ('eu F F F F /$* )<:@ (9;/ F + + + * )< a + F F + 8araffin+section H'A+<E F F F F immunohistochemistry )<:@ F + + + /ac 0@? F + + + 'ysozyme F + + + Alpha+ F + + + antitrypsin S+ %% + F F + 8eanut <iffuse Halo and Halo and dot + agglutinin dot 5ote.OAT8ase P adenosine triphosphataseL H'A P human leu4ocyte antigen.Ta"le ?. 'a"eling 8attern of Histiocytes and <endritic )ells Ta"le ?. 'a"eling 8attern of Histiocytes and <endritic )ells (#pen Ta"le in a new window* Marker Histiocyt 'angerhans! )nterdigitating! Follicular!&endritic!

es Cells Cells )< a % S % S+ %% protein % S S H'A+<E S S S )<1$ S I I Alpha+naphthyl acetate S I I esterase AT8ase I S S &ascin % % S E1D.0 % % % 5ote.O% P no stainingL S P strong and constantL I P wea4 or inconstant.

Cells % I I % I S S S

'angerhans cells express )< a antigen, H'A+<E, and a su"unit S+ %% protein. See the image "elow.

8hotomicrograph shows sample of 'angerhans cell histiocytosis (')H* that immunocytochemically stains positive for S+ %% protein. 6pon morphologic evaluation, cells are . Rm in diameter with moderately a"undant cytoplasm and a medium+sized folded, indented, or lo"ulated nucleus that has vesicular chromatin with +0 nucleoli and an elongated central groove producing a coffee+"ean appearance. [ 1@, 1A, $%! The histopathology of the 'angerhans cell histiocytosis does not appear to "e prognostic of the outcome of the disease.[ $! The aggregation of 'angerhans cells is o"served in various disorders, such as lymphomas (eg, Hodg4in disease*, lung cancer, and thyroid cancer. However, these disorders are secondary and resolve with control of the primary disorder. [1, $ ! 2n 'angerhans cell histiocytosis, the cytoplasm and, rarely, the nucleus contain the characteristic structures termed ;ir"ec4 granules, shown "elow.

Transmission electron micrograph shows a diagnostic rod+shaped 'angerhans ;ir"ec4 granule. These trilaminar organelles are A%+0:% nm long and approximately 00 nm wide, with a central striated line. These are derived from cytoplasmic mem"rane and are involved in receptor (T:*+mediated and nonC receptor+mediated endocytosis. An electron microscopic finding of rac3uet+shaped granules in the cells can "e helpful in confirming the pathologic diagnosis.

Eelatively nonspecific findings include cytoplasmic, trilaminar, mem"ranous loops and laminated su"structures of lysosomes.[ $.! 'angerin is a type 22 transmem"rane )+type lectin associated with formation of ;ir"ec4 granules. This can "e used as a selective mar4er for 'angerhans cells and cells involved in 'angerhans cell histiocytosis. 'angerin expression is present in most cases of 'angerhans cell histiocytosis.[ $0! 2mmunohistochemical determination of 'angerin and )< a may "e used to separate 'angerhans cell histiocytosis from other histiocyte proliferations. ;ir"ec4 granules are the products of internalization of complexes originating from cell+mem"rane antigens and corresponding anti"odies. )< a antigen can "e detected in paraffin+em"edded tissues to provide for relia"le diagnostic testing.[ $1, $$! AT8ase peanut lectin and alpha+<+mannoside can "e positive in the dendritic reticulum. An electron microscopic finding of rac3uet+shaped granules in the cells can "e helpful to confirm the pathologic diagnosis.[ $:! 9nzyme histochemistry and immunocytochemistry can also aid in the diagnosis of histiocytosis.[1 ! The organs and tissues most commonly involved are the "ones, s4in, lymph nodes, "one marrow, lungs, hypothalamic+pituitary axis, spleen, liver, 72 tract, and or"its. /ultisystemic involvement is common. [.%! ;ones can "e involved in isolation or as a part of multisystemic disease. The s4ull or large "ones are often involved. ;one lesions may contain an accumulation of eosinophils, multinucleated giant histiocytes, necrosis, and hemorrhage. The term eosinophilic granuloma was previously used to descri"e single "one lesions of 'angerhans cell histiocytosis. )utaneous involvement can also "e singular or can "e a part of generalized involvement. [A., A0, A1, A$! A spontaneously regressing nodular form of cutaneous 'angerhans cell histiocytosis is reported in infantsL it involves deep dermis with a nodular aggregate of histiocyte and is called congenital self+healing reticulohistiocytosis.[A:, A?, A@! 2n general, s4in lesions have a pattern of diffuse or multifocal nodular aggregation of 8')s deep in the papillary dermisL destruction of epidermal+dermal interfaceL and infiltration of histiocytes, T+cell lymphocytes, and eosinophils. The lymph nodes and thymus can "e involved as a primary site or as a part of multiorgan and systemic involvement. The most common sites are the cervical, inguinal, axillary mediastinal, and retroperitoneal areas. [ % , $?! &ive histologic motifs have "een recognized. These include sinusoidal, limited sinusoidal, epithelioid granulomatous, partial effacement, and total effacement. However, the prognostic significance of these appearances is not proven. The cellular composition includes 'angerhans cells, macrophages, multinucleated giant histiocytes, T lymphocytes, and eosinophils. [ 1@, 1A! Histologic involvement may have different appearances in lesions from separate sites. 2n some instances, lymph nodes are massive and cause airway o"structions. Suppuration resem"ling infection has "een reported.[ %.! The "one marrow may "e normal or heavily involved. ;one marrow lesions may "e focal with pathologic infiltration of 'angerhans cells or may contain neutrophils, eosinophils, lymphocytes, multinucleated cells, fi"rosis, and (in rare cases* eosinophilic accumulation. 8ulmonary involvement is more common in adults than in children (especially adults with a history of smo4ing*, "ut it occurs in .%+1%M of all patients. [AA, 0 ! Small cysts can coalesce and rupture into the pleural cavity, leading to pneumothorax. [ %%! )5S involvement, including pituitary involvement, is often part of systemic disease. [ $@, $A, :%! The )5S is rarely a primary site of 'angerhans cell histiocytosis involvement. [ : , :., :0, :1, :$, ::, :?, :@! The most common site of )5S involvement in persons with 'angerhans cell histiocytosis is the hypothalamic+ pituitary axis, which results in dia"etes insipidus in %+$%M of patients. [ :A! Histiocytosis can "e associated with cere"ellar white matter a"normalities.[ ::! 8athologic changes in the cere"ellum, "asal ganglia, and pons have "een reported.[ 1.! 'ocal involvement of the temporal lo"e has also "een o"served and represents a neurodegenerative disorder that is thought to "e similar to a paraneoplastic syndrome. [ ::! The neurodegenerative changes may occur well "efore, during, or long after diagnosis of histiocytosis. /anifestation may include

cere"ellar and pyramidal dysfunction, hormonal a"normalities, ataxia, spasticity, and cognitive pro"lems. [ 10, ::! /E2 a"normalities in cere"ellar white matter, "rain stem, "asal ganglia and cere"ral white matter are found.[ ::! 2nvolvement of the anterior pituitary is relatively uncommon. However, it can result in growth+hormone deficiency or, in rare cases, panhypopituitarism.[@A! )ere"ellar dysfunction with incoordination and white matter changes has "een reported.[ %0! 'angerhans cell histiocytosis may affect the spleen and liver. 8rimary involvement of the liver is uncommon.[ ?%, ?! 2nvolvement of the liver is often part of multiorgan disease. 9ven when 8')s are not present, sclerosing cholangitis can "e o"served. [ ?%! 'iver infiltration may result in tissue damage and increased enzyme levels, Baundice, coagulation disorders, and hypoal"uminemia. 2nvolvement of the 72 tract is pro"a"ly more common than is clinically recognized. [ ? ! 'esions in the stomach, small "owel, colon, and rectum have "een reported. [ ?., ?, ? , %A, %! The usual pathology of 72 involvement with 'angerhans cell histiocytosis includes infiltration of lamina propria and su"mucosa with glandular, mucosal, and, possi"ly, villus atrophy. <iarrhea and 72 "leeding can "e the presenting features of the disease. 2nvolvement of the pancreas is rare. [ ?0, ?1! 'angerhans cell histiocytosis rarely involves the intraocular structures. 2solated eye disease has "een reported.[ 0@! 'ytic lesions of the or"it and resulting soft+tissue extension may cause proptosis. 8tosis and optic atrophy rarely occur. 8atients with ear involvement often present with chronic otorrhea, lesions of the external auditory meatus, middle+ear involvement, and mastoid involvement. Although rare, involvement of the genital tract has "een reported. [ ?$, ?:, ??! 2n patients with 'angerhans cell histiocytosis and hematopoietic involvement, 'angerhans cell infiltration is often not evidentL however, other a"normalities are common. These include a"normal /:9 ratioL hyperplasia and dysplasia of mega4aryocytes, including mononucleated and "ilo"ed micromega4aryocytes and paratra"ecular and grouped mega4aryocytesL existence of neutrophil remnants in mega4aryocytes (emperipolesis*L increased num"ers of macrophagesL hemophagocytosisL and myelofi"rosis.[ ?@! Medical!Care #ptimal treatment of 'angerhans cell histiocytosis (')H* has not "een esta"lished. 2n ideal cases, the differences "etween normal cells and pathologic 'angerhans cells (8')s* should "e used to guide treatment of the disease. However, a lac4 of sufficient information has hampered specific therapy. Su"stantial variation of the disease and the fact that %+.%M of patients achieve spontaneous regression complicate comparisons of current nonspecific therapies.[ ?A, @%, @ ! Several agents, including drugs for cancer chemotherapy, have "een effective in the treatment. Some suggest that treatment of 'angerhans cell histiocytosis should "e conservative and limited to individuals with constitutional symptoms, such as pain, fever, failure to thrive, and vital organ disorder.[ Treatment of these disorders must often "e tailored to the patientSs prognostic factors, such as the patientSs age, extent of the disease, sites of involvement, and complications. &or example, the general agreement is that simple "iopsy and curettage are ade3uate treatment for a solitary "one lesion. [ @0, @1! See the /edication section for a discussion of agents used in the treatment of 'angerhans cell histiocytosis. Consultations

@.!

/ultidisciplinary care is essential for all patients. )onsultation with an oral surgeon and an otolaryngologist, among others, may "e re3uired. Medication!Summary The aim of therapy in histiocytosis is to relieve clinical symptoms and prevent complications of the disease. &or single+system disease (eg, of the s4in or "one*, no therapy or only local therapy may "e necessary, although further treatment may "e needed in certain circumstances.[1A! (opical!therapy 'ocalized s4in lesions, especially in infants, can spontaneously regress. 2f treatment is re3uired, topical corticosteroids may "e tried. 6se of extemporaneously prepared topical %.%.M nitrogen mustard has also "een advocated.[ @$, @:, @?! This agent, initially used systemically, appears to provide rapid response within % days[ @:! with minimal adverse effects, such as contact allergy. Scarring at the site of the lesion is thought to "e due to the disease and not therapy. [ @?! 2n one study, s4in lesions promptly healed in 1 of .. children, and . had partial responses.[ @:! 'ow+dose radiation therapy to the local lesions is often effective "ut is rarely needed. &or unresponsive s4in lesions, low+dose mild systemic therapy can "e used. )hemotherapy for multisystemic disease with local or constitutional symptoms is used.[ @1! Single agents or adBuvant use of several chemotherapeutic agents andDor "iologic+response modifiers may "e effective. 8u"lished therapies include corticosteroids, vinca al4aloids, antimeta"olites+nucleoside analogs, immune modulators such as cyclosporine,[ @@! antithymocyte glo"ulin,[0A! "iologic+response modifiers such as interleu4in (2'*+. and interferons (25&s*, [ @A! cellular treatment, and exchange transfusion.[ A%, A ! /ost reports of treatment modalities lac4 controls, with most authors citing the rarity of the disease as Bustification for the lac4.[$?, A.! Single+agent!therapy 8urine analogs with activity for treatment of 'angerhans cell histiocytosis (')H* include .+ chlorodeoxyadenosine (.)dAL cladri"ine ['eustatin!* and .+deoxycoformycin (.)<&L pentostatin [5ipent!*L [ A0, A1, ., A$, A:, .1, A?! .)dA has "een found to "e particularly toxic to monocytes. [ A@! Justification for the use of .)dA is that some histiocytes are derived from monocytes. [ A1! 2n a review of $ patients with multiorgan involvement receiving .)dA and . receiving .)<&, : had complete responses, 0 had partial responses, $ had no response, and died early. &ourteen had previously received significant treatments. [ A0! As a single agent, cyclosporine has "een used in pretreated patients with advanced 'angerhans cell histiocytosis. )yclosporine, a cyclic endecapeptide immunosuppressant of fungal origin, inhi"its immune responses. The proposed mechanism of action is "loc4age of the transmission and synthesis of lympho4ines, such as 2'+. and 25& (ie, 25&+alpha inhi"ition of the accessory cell function of 'angerhans cells and reduced capacity of dendritic cells to enhance mitogenic stimulation of lymphocytes*. )yclosporine is postulated to disrupt a"normal cyto4ine+dependent activation of lymphocytes and histiocytes in the liver, spleen, lymph nodes, and "one marrow. The activation of lymphocytes is presumed to "e secondary to uncontrolled proliferation of 'angerhans cells. &urthermore, cyclosporine can inhi"it cyto4ine+mediated cellular activation that potentially contri"utes to phagocytosis and disease progression.[ @@! 8artial and complete responses have "een recorded in a small num"er of patients. 8atients with partial response had achieved a complete response with prednisone and vin"lastine chemotherapy. )yclosporine A has also "een used in familial erythrophagocytic lymphohistiocytosis (&9'*. 2n one report of . children whose disease was resistant to steroids and etoposide, dura"le remission was o"tained with this agent.[ AA!

25&+alpha had some effect in anecdotal cases of 'angerhans cell histiocytosis. [.%%,

@A!

Treatment of multifocal relapsing and resistant "one lesions in 'angerhans cell histiocytosis is challenging. 'angerhans cells are capa"le of releasing cyto4ines, which are potent activators of osteoclasts and can result in the lytic lesions seen in the disease. 8amidronate, a "isphosphonate agent, has "een reported to induce response or result in disease sta"ility in a very small group of patients. [.% ! Multiagent!therapy /ost chemotherapy agents for the treatment of 'angerhans cell histiocytosis are used in com"ination. The length of therapy is ar"itrarily chosen. 2n some studies, patients were stratified "y ris4 factor. [.%.! 6se of a com"ination of cytara"ine ara"inoside (Ara+)*, vincristine, and prednisolone to treat disseminated 'angerhans cell histiocytosis with organ dysfunction has "een reported. 2n a study of @ pediatric patients with 'angerhans cell histiocytosis and multiorgan involvement, @ had additional organ dysfunctionL @ of % patients with organ involvement achieved complete remission. [ $ ! &ive of @ patients with additional dysfunction achieved complete remission. &our (..M* of @ patients developed dia"etes insipidus. Two with organ dysfunction died at the time of the report. The regimen was descri"ed as "eing mildly toxic and relatively well tolerated. 2n this regimen, cytara"ine ( %% mgDm .Dd for 1 consecutive days*, vincristine ( .$ mgDm. on day *, and prednisone (1% mgDm.Dd for 1 w4 followed "y .% mgDm. for .% d* were administered. The com"ination of vincristine and cytara"ine was repeated every other wee4 for 1 wee4s. Thereafter, the interval was extended "y wee4 until this com"ination was administered every : wee4s, until complete remission was achieved (1+ : w4*. 2n a multicenter study in A@0+ A@@, 2talian investigators assigned ?% patients with "iopsy+proven 'angerhans cell histiocytosis into good+prognosis or poor+prognosis groups, depending on their organ dysfunction.[.%0! Sixteen patients with limited disease were treated with surgery alone, $ received immunotherapy with thymus extract then chemotherapy, and 1A patients received chemotherapy with vin"lastine ($.$ mgDm.Dw4 for 0 mo*. 8oor responders in this group were then treated with doxoru"icin (.% mgDm . intravenously for . d every 0 w4 for 0 mo*. 8atients who did not improve with this regimen were administered etoposide (.%% mgDm . intravenously* for 0 consecutive days every 0 wee4s for at least 0 months or until their disease progressed. The poor+prognosis group ( patients* received doxoru"icin (.% mgDm . on days and .*, prednisone (1% mgDm. "y mouth on days +.A*, vincristine ( .$ mgDm . intravenously once a wee4 for 1 w4 starting on day @*, and cyclophosphamide(1%%mgDm. on days $ and .A for A courses*. #nly of % patients with good prognosis had a favora"le response during therapy with thymus extract. #f $1 patients receiving chemotherapy (1A as first+line treatment*, 01 achieved complete remission with vin"lastine, and @ had a recurrence after 1+.. months. #f $ patients achieving remission with etoposide, had a relapse % months after therapy. 2n patients with poor prognoses, ? had progressive disease, and : died within A months of diagnosis. #rgan dysfunction appeared to significantly affect survival, with only 1:M of patients surviving for . months. The main complication was dia"etes insipidus, which occurred in .%M of patients. The overall incidence of disease+related disa"ilities was 1@M. 2n the Austrian and 7erman <A'+H- @0DA% study, patients were stratified into 0 groups: those with multifocal "one disease (group A*, those with soft+tissue involvement "ut without organ dysfunction (group ;*, and those with organ dysfunction (group )*. [.%.! 2nduction therapy consisted of etoposide (:% mgDm.Dd for $ d on days +$, followed "y wee4ly dosing of $% mgDm .*, prednisone (1% mgDm. on days + .@*, and vin"lastine (: mgDm. starting at wee4 0 of therapy*. /aintenance therapy was ris4 related and consisted of vin"lastine, :+mercaptopurine, and prednisone in all patients, with etoposide added in group

; and methotrexate and etoposide added in group ). /ortality rates for groups A, ;, and ) were @M, AM, and 0@M, respectively. An organized international approach to ')H has "een successful. [ @1! 6sing the Histiocyte SocietySs 'angerhans cell histiocytosis 2 protocol,[ @0! investigators prospectively and randomly assigned patients with multisystemic 'angerhans cell histiocytosis who met criteria "ased on standard diagnostic evaluation.[1A! 8atients received vin"lastine (: mgDm. intravenously wee4ly for .1 w4* or etoposide ( $% mgDm. intravenously on 0 consecutive days every 0 w4 for .1 w4*. All patients received methylprednisolone (0% mgD4g intravenously for 0 consecutive days [maximum daily dose of g!*. #f the 11? patients who were registered from various countries, A. had multisystemic disease, and 0: were randomly assigned (?. to the vin"lastine arm and :1 to the etoposide arm*. 8atients were evaluated at predetermined intervals. Eesponses at : wee4s appeared to differentiate responders from nonresponders, who had poor outcomes. 5either the patientsS ages nor the num"er, type, or dysfunction of the organs differentiated the groups. At : wee4s, $ ($%M* of %0 patients achieved a complete response or su"stantial disease regression, whereas 0. (0 M* had sta"le disease or partial or mixed responses. <isease progression was reported in A patients. At .: months, the mortality rate was @M. Among the patients who died, 1 had an initial response, $ had intermediate responses, and A had initial nonresponses. The protocol allowed nonresponders to switch to another treatment arm. #nly 01M of patients who had switched had favora"le results. <isease recurrence was o"served in patients who received vin"lastine and in @ who received etoposide. The . arms were statistically similar in terms of initial responses, recurrences, and mortality rates. The overall pro"a"ility of dia"etes insipidus was 1.M. The randomized 'angerhans cell histiocytosis 22 study of the Histiocyte Society was performed to compare the effects of oral prednisone with vin"lastine (with or without etoposide* in patients with multisystemic disease. 8atients were divided into low+ or high+ris4 groups. All patients received prednisone (1% mgDm.Dd for .@ d with wee4ly reduction afterward* and vin"lastine (: mgDm . intravenously wee4ly for : w4*. The low+ris4 group received continuation therapy with vin"lastine (: mgDm . during wee4s A, ., $, @, . , and .1*, as well as $+day pulses of prednisone during the same wee4s. 8atients in the low+ris4 group were excluded from randomization. 8atients in the high+ris4 group were randomly assigned to treatment A or ;. Treatment consisted of an initial : wee4s of therapy with prednisolone and wee4ly vin"lastine and continuation therapy, pulses of vin"lastine andDor oral prednisone as in the low+ris4 group, and daily doses of :+mercaptopurine ($% mgDm. during wee4s :+.1*. Treatment ; was the same as treatment A, with the addition of etoposide ( $% mgDm. administered on day of wee4s A, ., $, @, . , and .1*. Eesults of this protocol have not yet "een pu"lished. The 'angerhans cell histiocytosis 222 of the Histiocyte Society study is designed to determine if methotrexate administered during the initial . courses of treatment affects outcomes. 2n addition, investigators will determine whether maintenance therapy reduces the ris4 of recurrent disease and improves overall outcomes. -adiation!therapy Eadiation therapy is effective in 'angerhans cell histiocytosis. <oses ranging from ?$%+ $%% c7y are usually administered, resulting in good local control of single lesions or metastasis, which can occur in critical areas or cause permanent damage. &ractionated doses of radiotherapy have also "een used. [.%1!

(reatment! or!recurrent!or!re ractory!disease The severity of the recurrent disease often dictates the type of therapy that is most li4ely to "e helpful. &or example, recurrence of an isolated "one lesion can often "e treated with nonsteroidal anti+inflammatory drugs (5SA2<s* or intralesional steroid inBections. Ihen "one lesions are multiple and cause clinically significant mor"idity, systemic therapy can "e helpful. 2n such circumstances, patients often respond to the same drugs that they previously received, such as vin"lastine andDor corticosteroids. 9xtensive recurrence of s4in disease, including refractory perianal or vulvar involvement, often re3uires systemic chemotherapy. Ihen patients do not have an early (ie, "y : w4 of therapy* response to vin"lastine, corticosteroids, methotrexate, :+mercaptopurine, or even etoposide, alternate therapies should "e administered. Although several immunomodulatory agents, such as cyclosporine, have "een used in patients with refractory disease, the results have "een inconsistent. )ytotoxic chemotherapy often needs to "e administered as well. Several studies, including an international phase 22 trial, demonstrated nota"le activity of .)dA. This agent was originally used to treat patients with refractory hairy+cell leu4emia and chronic lymphocytic leu4emia. Eesponse rates were more than $%M. .)dA is "oth lympholytic and monolytic, ma4ing it a potentially ideal drug to use in 'angerhans cell histiocytosis, which is characterized "y reactive lymphocytic and dendritic and macrophage components. Eesponse rates to .)dA have "een particularly good in patients with extensive s4in and "one disease, and in some patients with pulmonary involvement. #verall response rates have "een a"out 0%+1%M in children. 2n a study with a small num"er of adults, the response rate was less than ?%M. 2n . reports, a com"ination of .)dA and Ara+) seemed to have maBor effects in a small group of children with refractory disease, "ut clinically significant grade 1 toxicities and a sepsis+related death were reported.[.%$, .%:! &or some patients whose disease does not respond to .)dA alone, the com"ination of .)dA and high+ dose cytara"ine has "een effective. A similar regimen has also "een effective in patients with relapses of acute myelogenous leu4emia. 6ntil additional information is o"tained with this drug com"ination, the true response rate and the duration of response are difficult to determine. #ther approaches to the treatment of patients with refractory 'angerhans cell histiocytosis that are "eing tested or developed and include agents such as thalidomide, which is used to inhi"it tumor necrosis factor (T5&*+alpha and 25&+gamma production.[.%?! 2n some studies, only patients with low+ris4 disease were li4ely to respond to thalidomide, whereas high+ris4 patients with organ involvement were not. [.%@, . ! . &urther recognition of 5&+4appa; pathway may improve the success of targeted therapy for 'angerhans cell histiocytosis.[ 01, 0$! Targeting humanized anti"odies against lineage+specific antigens, such as )< a antigens on 'angerhans cell histiocytosis cells, is another treatment "eing developed. The application of inhi"itors of activated cyto4ine receptors and their downstream signal+transduction pathways is also an important area of future therapeutic trials. Although hematopoietic stem+cell transplantation has "een successful in some patients with refractory 'angerhans cell histiocytosis, identifying patients who might "enefit from such high+ris4 therapy is difficult, and this treatment is associated with significant acute and chronic complications. Specific therapies, including monoclonal anti"odies against the )< a or )<$. epitopes found on 'angerhans cells, are emerging.[ 1:, .%A! 'ocal therapy with various agents has "een reported. 2ntralesional infiltration of corticosteroids for treatment of localized 'angerhans cell histiocytosis has "een advocated. [. %!

/yeloa"lative therapy followed "y "one+marrow or stem+cell transplantation in disease refractory to the conventional therapy has "een reported.[. ! However, reporting of positive results are li4ely to "ias such reports. 2ntravenous immunoglo"ulin has "een used to treat neurodegenerative 'angerhans cell histiocytosis. However, to the authorsS 4nowledge, no formal study has "een done to conclusively affirm the "enefit of such a treatment. The need to develop effective treatments and, ultimately, strategies to prevention progressive fi"rosis of the lung, sclerosing cholangitis, and fi"rosis of the liver, and the neurodegenerative pattern of )5S involvement is immense. Additional clinical trials are needed to determine whether agents such as .)dA or specific inhi"itors of fi"rosis can improve the outcomes of patients with these complications. Further!#utpatient!Care 'ong+term follow+up care "y a multidisciplinary team with 4nowledge of 'angerhans cell histiocytosis (')H* is critical for all patients, not Bust those with extensive multisystem disease or those treated with systemic chemotherapy. Complications 8atients with 'angerhans cell histiocytosis, especially those with multisystemic disease or multifocal s4eletal involvement with a relapsing course, have a significant ris4 of developing adverse late se3uelae from their disease or therapy. Some estimate that more than one half of patients have at least clinically significant late effect. Therefore, long+term follow+up is of utmost importance. 2n a study of a su"set of 1% patients followed up for a median of : years, $ M had pronounced late se3uelae.[. .! Those with multisystemic involvement had the greatest ris4 of late effects. They had AM rate of )5S se3uelae. Some of the most important late effects involve the )5S and include dia"etes insipidus and other deficiencies of hypothalamic+pituitary axis. These effects lead to stunted growth and failure to achieve sexual maturity. #ther late effects include orthopedic pro"lems (particularly of the verte"ral column*, dental issues surrounding the loss of teeth and Baw"one mass, hearing loss due to mastoid and inner+ear involvement (for which patients re3uire cochlear implantation*, [. 0! and scarring of involved areas of s4in. 2n patients who develop pulmonary or hepatic fi"rosis, progression of disease may result in a need for organ transplantation. 8atients with 'angerhans cell histiocytosis may have a lifelong suscepti"ility to pulmonary disease associated with cigarette smo4ing. 8ulmonary involvement of the young child may "e extensive and characterized "y micronodular involvement and cystic formation. However, ade3uate treatment can resolve the disease and normalize lung findings and function.

5eurocognitive and psychological pro"lems are more fre3uently recognized li4ely "ecause of intensified patient follow+up.

8atients with neurodegenerative )5S involvement often present with ataxia and decreased coordination. 8athologic examination of "iopsy material usually reveals gliosis, some neuronal cell death, and, sometimes, areas of active 'angerhans cell histiocytosis. Although the condition of neurodegenerative involvement of the )5S can remain sta"le for years, clinical progression may occur in the a"sence of /E2 findings. 5o definitive treatment has "een developed for this manifestation of 'angerhans cell histiocytosis. Eadiation therapy does not appear to provide any "enefits. 5europsychological se3uelae of 'angerhans cell histiocytosis can "e su"stantial. 2n one study of % children with 'angerhans cell histiocytosis (aged $+ ? y*, 0 scored one standard deviation or more "elow the reference range on perceptual tas4s, and 1 of % children had deficiency in performance on perceptual tas4s. <ecreases in attention, speed of performance, ver"al wor4ing memory, and visual recall were noted.[. 1!

8roliferation of Gupffer cells may accompany the initial hepatic involvement with 'angerhans cell histiocytosis and su"se3uently develop into sclerosing cholangitis. This, in turn, may lead to fi"rosis and liver failure. 'ung and liver transplantation have "een successful in patients who develop organ failure due to progressive fi"rosis. Secondary malignancies are reported in patients with 'angerhans cell histiocytosis. /alignancies include secondary leu4emias (usually acute myelogenous leu4emias* caused "y exposures to al4ylating agents and, in recent reports, to etoposide. #ther cancers include thyroid carcinoma, lymphomas, and )5S tumors. Prognosis The location of the lesions and the extent of the disease su"stantially affect the course of the disease and the patientSs prognosis. 2nvolvement of ris4 organs (hemopoietic system, liver, spleen, and lungs* at diagnosis and failure of response to the initial therapy are poor prognostic signs. Eeactivation of ris4 organs is relatively rare. 2n one study, this reactivation occurred in .M of patients. [ @! 2nvolvement of the ris4 organs at reactivation had relatively low impact on survival. The degree of organ involvement is correlated with the patientSs prognosis. Although 'angerhans cell histiocytosis involvement of the spine causes lesions and, sometimes, asymmetric collapse, it is not usually associated with long+term se3uelae and deformity. Therefore, aggressive surgical management of this involvement is generally not indicated. [. $! Eapidity of the response to chemotherapy may also have prognostic value.

Patient!Education Gnown genetic factors, when applica"le, must "e explained to the patients and their families.