Histiocytoses

Sunil K. Kothiwala, Piyush Kumar, and Rajesh Kumar Mandal

Contents1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

2 Histiocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

3 Classification of Histiocytoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23.1 Langerhans Cell Histiocytosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23.2 Non-Langerhans Cell Histocytosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93.3 Malignant Histiocytosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

AbstractThe histiocytoses are a group of disorders characterized byaccumulation of variable number of monocytes, macro-phages, and dendritic cells in affected tissues of childrenand adults. Many different subtypes have been describedwith a wide range of clinical features and histopathologi-cal changes.

Langerhans cell histiocytoses include spectrum of clin-ical manifestation ranging from self-healing lesions to life-threatening disseminated disease. Juvenilexanthogranuloma is the most common type ofnon-Langerhans cells histiocytoses, and some other sub-types may show overlapping features. Necrobioticxanthogranuloma, Rosai-Dorfman disease, Erdheim-Chester disease, and multicentric reticulohistiocytosis arecharacterized by systemic involvement. Infiltrating cellsof malignant histiocytoses show cancerous changes. Thediagnosis of histiocytoses is based on clinical findings in

combination with histopathological analysis identifyingtissue infiltration by histiocytes with ultrastructural andimmunophenotypic characteristics of cells. Various differ-ent chemotherapeutic agents, lasers, cryotherapy, andradiofrequency ablation have shown variable success inthe treatment of histiocytoses.

KeywordsHistiocyte · Birbeck granule · CD1a · S100 · Langerin ·CD68 · Factor · Fascin · Histiocytosis · Classification ·Langerhans cell histiocytosis · Coffee-bean shape ·Reniform pattern · Hashimoto-Pritzker disease ·Eosinophilic granuloma · Letterer-Siwe disease · Hand-Schüller-Christian disease · Congenital self-healingreticulohistiocytosis · Histiocytosis X · Langerhans cell ·Non-Langerhans cell histiocytosis · Juvenilexanthogranuloma · Xanthogranulomatous reaction ·Benign cephalic histiocytosis · Generalized eruptivehistiocytosis · Popular xanthoma · Progressive nodularhistiocytosis · Factor XIIIa positive histiocytosis · Planexanthoma · Diffuse normolipemic plane xanthomatosis ·Paraproteinemia · Hereditary progressive mucinoushistiocytosis · Xanthoma disseminatum ·Xanthogranuloma · Multicentric reticulohistiocytosis ·Polyarthritis · Rosai-Dorfman · Emperipolesis · Erdheim-

S. K. Kothiwala (*)Consultant Dermatologist, SkinEva Clinic, Jaipur, Indiae-mail: drsunilkothiwala.aiims@gmail.com

P. Kumar (*)Department of Dermatology, Katihar Medical College, Katihar, Indiae-mail: docpiyush099@gmail.com

R. K. Mandal (*)North Bengal Medical College, Darjeeling, Indiae-mail: drrajeshkumar.mandal07@gmail.com

# Springer Nature Switzerland AG 2019B. Smoller, N. Bagherani (eds.), Atlas of Dermatology, Dermatopathology and Venereology,https://doi.org/10.1007/978-3-319-45134-3_84-2

1

Chester · Familial sea blue histiocytosis · May-Grunwaldstain · Neimann-Pick disease · Malignant histiocytoses ·True histiocytic lymphoma · Histiocytic sarcoma ·Monocytic leukemia · Malignant histiocytosis ·Histiocytic lymphoma · Lymphoma · Malignanthistiocyte · Sarcoma

1 Introduction

The histiocytic disorders are defined as abnormal prolifera-tion and accumulation of cells of the mononuclear phagocyticsystem consisting of Langerhans cells, macrophages, anddendritic cells. Dysfunction of these reactive histiocytes hasled to a group of disorder which represents a spectrum ofdisease involving skin as well as other organs. These closelyrelated entities can be broadly divided into Langerhans cellhistiocytosis (LCH) and non-Langerhans cell histiocytosis(non-LCH) (Vaiselbuh et al. 2014). This chapter covers themost common histiocytic disorders with cutaneous involve-ment and several of the rarer histiocytic disorders with cuta-neous as well as systemic involvement.

2 Histiocytes

Histiocytes derivation shares a common bone marrow pro-genitor cell, the neutrophil/macrophage colony-forming unit(NM-CFU). The maturation of monocyte precursor isinfluenced by various factors including cytokines,chemokines, glycoprotein, and stimulating factors (Kimberet al. 2000). The derived monocytes migrate from the bonemarrow to the blood and circulate to various organs, wherethey undergo differentiation into histiocytes.

Histiocytes play major role as antigen presenting cells(APC) and phagocytes. Three “histiocytes” of cutaneousimportance are: (1) the Langerhans cell, which representsimmigrant population in the epidermis and functions as apotent APC; (2) the mononuclear cell/macrophage (some-times called the “true” histiocyte), which migrates to andfrom the dermis and has both phagocytic and APC properties;and (3) the dermal dendrocyte/dendritic cell, of which thereare two subtypes. Type 1 dermal dendrocytes are factorXIIIa-positive and generally reside within the papillary der-mis, whereas type 2 dermal dendrocytes are CD34-positiveand are generally found within the reticular dermis. Type1 dermal dendrocytes may be involved in phagocytosis,antigen presentation, inflammation, collagen production,and wound healing, while the function of type 2 dermaldendrocytes is less certain (Goodman and Barett 2012).

Langerhans cells express an immunophenotype positivefor CD1a, S100, and langerin (CD207). The unique

phenotypic feature of Langerhans cells is the trilaminatecytoplasmic organelle, the Birbeck granule. The granulesoften have terminal vesicular dilations, giving rise to thecharacteristic “tennis racket” appearance (Chu and Jaffe1994). Dermal dendritic cells express CD68, factor XIIIa,and fascin. These cells are always negative for CD1a,which differentiates them from Langerhans cells (Table 1)(Hoyo et al. 1993).

3 Classification of Histiocytoses

The histiocytic disorders are generally defined by their con-stitutive cell, on the basis of well-established pathologic andimmunohistochemical criteria. The classification ofhistiocytoses is provided in Table 2. LCH is the commonestof all histiocytoses. The histiocytoses involving cells otherthan Langerhans cells have been classified on the basis ofprimarily cutaneous or systemic involvement.

3.1 Langerhans Cell Histiocytosis

LCH comprises a wide spectrum of clinical disorders rangingfrom isolated skin or bone lesions to a disseminated diseaseinvolving multiple organs and results from clonal prolifera-tion of functionally immature Langerhans cells (Figs. 1, 2,and 3). The etiology is unknown and is highly debated. Someauthors consider it a true malignancy, while others think LCHas reactive immune condition caused by unknown stimulus(Grana 2014). Initially, Langerhans cells were supposed tooriginate from epidermal Langerhans cells, but now it isbelieved that potential cellular origins include myeloid-derived dermal langerin+ dendritic cells, lymphoid tissue-resident langerin+ dendritic cells, and monocytes that can beinduced to acquire a Langerhans cell phenotype. Irrespective

Table 1 Characteristics of histiocytes

Langerhanscell

Dendriticcell

Monocyte/macrophage

HLA-DR + + � +

CD1a + + � �CD14 � ++ ++

CD68 +/� ++ ++

CD163 � � ++

Factor XIIIa � ++ �Langerin ++ � �Fascin � ++ +/�S100 + � +/�Lysozyme � � ++

Birbeckgranules

+ � �

2 S. K. Kothiwala et al.

of origin, Langerhans cells show characteristic morphologic,immunophenotypic, and ultrastructural features. These cellsare recognized as cells that are large, ovoid mononuclear cellswith abundant eosinophilic cytoplasm and lacks dendrites(Fig. 4). Their nuclei are irregular with prominent folds andgrooves, fine chromatin, and indistinct nucleoli. When thefold of the nucleus affects its center, it acquires a reniformpattern; however, if it is peripheral, the nucleus has a coffee-bean shape (Fig. 5). The Birbeck granule is cellular hallmarkof Langerhans cells and its identification by electron micros-copy was considered gold standard of diagnosis for LCH.These granules consist of an intracytoplasmic membranousbody, possessing a short, rod-like shape with a dotted linedown the midline of the space between the membranes(resembling a zipper) and a terminal expansion in the formof a vesicle, giving a racquet appearance. Immunophe-notyping is now considered gold standard of diagnosis andhas obviated the need of electron microscopy. TheLangerhans cells express CD1a (Figs. 6 and 7), S100 protein(Figs. 8 and 9), and langerin (CD207) (Harmon and Brown2015).

Clinical presentations in LCH may vary based on organsinvolved (Figs. 10, 11, 12, and 13). The disease may involvea single system only such as skin (in Hashimoto-Pritzkerdisease also known as congenital self-healingreticulohistiocytosis) or bone (in eosinophilic granuloma).On the other end of spectrum is acute, fulminant, dissemi-nated disease (Letterer-Siwe disease) involving multiple

organs. An intermediate form (Hand-Schüller-Christian dis-ease) characterized by multifocal, chronic involvement alsois introduced (El Demellawy et al. 2015).

3.1.1 Hashimoto-Pritzker Disease– Definition: Hashimoto-Pritzker disease (also known as

congenital self-healing reticulohistiocytosis) is a benignform of LCH, characterized by the presence of skin lesionsat birth or in the neonatal period, absence of systemicmanifestations and spontaneous resolution (Lee et al.2014).

– Clinical feature: The usual clinical presentation is multi-ple, red-brown papules, nodules, or vesicles found on allparts of the body, including occasional involvement ofmucosa, palms, and soles. The papules and nodules may

Table 2 Classification of histiocytoses

1. Langerhans cell histiocytoses(a) Hashimoto-Pritzker disease(b) Hand- Schüller-Christian disease(c) Eosinophilic granuloma(d) Letterer-Siwe disease

2. Non-Langerhans cell histiocytoses(a) Primarily cutaneous

(i) Juvenile xanthogranuloma(ii) Benign cephalic histiocytosis(iii) Generalized eruptive histiocytosis(iv) Papular xanthoma(v) Progressive nodular histiocytosis(vi) Xanthoma disseminatum(vii) Diffuse plane xanthomatosis(viii) Hereditary progressive mucinous histiocytosis(ix) Necrobiotic xanthogranuloma

(b) Predominantly systemic(x) Erdheim-Chester disease(xi) Multicentric reticulohistiocytosis(xii) Sinus histiocytosis with massive lymphadenopathy(xiii) Familial sea blue histiocytosis

3. Malignant histiocytoses(a) Malignant histiocytosis(b) True histiocytic lymphoma(c) Histiocytic sarcoma

Fig. 1 Adult cutaneous Langerhans cell histiocytosis; slightly hyper-pigmented papules affecting the lower legs of a 64-year-old malepatient. (Taken by Prof. Dr. Uwe Wollina, Department of Dermatologyand Allergology, Municipal Hospital Dresden, Dresden, Germany)

Histiocytoses 3

Fig. 2 Langerhans cell histiocytosis. A and B: crusted and scaly erythematous patches over the scalp in 32-year-old man in 2 views. (Taken byDr. Sara Saniee, Tabriz University of Medical Sciences, Dermatology Department, Sina Hospital, Tabriz, Iran)

Fig. 3 Langerhans cell histiocytosis. A to E: generalized papules with ulceration and crust formation along with erosion and ulcers in the flexuralareas in different views. (Taken by Dr. Maryam Nasimi, Dermatology Department, Tehran University of Medical Sciences, Tehran, Iran)

4 S. K. Kothiwala et al.

be crusted, eroded, or ulcerated (Mandel et al. 2014).Rarely, a solitary moist, eroded nodule, or plaque is seen(Lee et al. 2014). Spontaneous resolution of lesions isnorm. However, in exceptional cases disease may run achronic course and may involve other systems like lymphnodes, bones, liver, and lungs, necessitating systemictherapy.

– Pathological manifestation: The diagnosis is based ondemonstrating Langerhans cells in histopathology. Pres-ence of eosinophils in significant number is associatedwith a better prognosis (Kapur et al. 2007).

– Prognosis and treatment: Prognosis is excellent. Mostcases show spontaneous resolution. Topical

corticosteroids and tacrolimus are used for nonhealinglesions. Localized lesions may be excised. Long-termfollow-up is recommended considering possibility ofrelapse, involvement of internal organs, and chroniccourse in rare cases (Lee et al. 2014).

– Differential diagnosis: Seborrheic dermatitis, diaper der-matitis, and scabies.

3.1.2 Hand-Schüller-Christian Disease– Definition: Hand-Schüller-Christian disease, classic

multifocal form of LCH, is usually seen in infants andchildren and is characterized by triad of exophthalmos,diabetes insipidus, and calvarial lytic lesions. However,

Fig. 4 Langerhans cell histiocytosis. A and B: Langerhans cell micro-abscess in the epidermis, and dermal Langerhans and polymorphousinflammatory cells’ infiltration in two views. (Taken by Dr. Sara Saniee,

Tabriz University of Medical Sciences, Dermatology Department, SinaHospital, Tabriz, Iran)

Fig. 5 Langerhans cell; large mononuclear cell with abundant cyto-plasm and reniform nucleus. (Taken by Dr. Sherina Laskar, GauhatiMedical College and Hospital, India)

Fig. 6 Langerhans cells staining with CD1a. (Taken by Dr. SherinaLaskar, Gauhati Medical College and Hospital, India)

Histiocytoses 5

Fig. 7 Langerhans cells histiocytosis; positive immunostaining forCD1a. (Taken by Dr. Sara Saniee, Tabriz University of Medical Sci-ences, Dermatology Department, Sina Hospital, Tabriz, Iran)

Fig. 8 Langerhans cells staining with S100 protein. (Taken byDr. Sherina Laskar, Gauhati Medical College and Hospital, India)

Fig. 9 Langerhans cells histiocytosis; positive immunostaining forS100 protein. (Taken by Dr. Sara Saniee, Tabriz University of MedicalSciences, Dermatology Department, Sina Hospital, Tabriz, Iran)

Fig. 10 Langerhans cell histiocytosis in 1.5 years old child (front view).(Taken by Dr. Sudhir Singh, Department of Dermatology andVenereology, Jawahar Lal Institute of Medical Sciences, Nagpur, India)

Fig. 11 Langerhans cell histiocytosis in 1.5 years old child (backview). (Taken by Dr. Sudhir Singh, Department of Dermatology andVenereology, Jawahar Lal Institute of Medical Sciences, Nagpur, India)

6 S. K. Kothiwala et al.

the triad is seen in only one third of patients as exophthal-mos is a late finding (Cugati et al. 2011).

– Clinical feature: Mucocutaneous findings include nod-ules and ulcerated plaques, especially in the mouth, axil-lae, and anogenital region and are seen in one thirdpatients. Bony involvement is the most predominant find-ing, and cranium is most commonly affected bone. Thelesions are multifocal and coalesce to give a morpholog-ical appearance of “geographic skull” on X-ray. Centralnervous system involvement may result in convulsion,increased intracranial pressure, focal neurological deficits,mental retardation, hearing disturbance, and tremor.Involvement of the pituitary and hypothalamus may resultin delay in sexual maturity and bone development (Cugati

et al. 2011). Facial bones involvement results in soft tissueswelling, tenderness, and facial asymmetry. Ribs, pelvis,scapula, and mandible are other commonly affected bones(Lalitha et al. 2015). Systemic involvement is commonand includes hepatosplenomegaly, lymphadenopathy, gas-trointestinal tract, and renal and pulmonary involvement(El Demellawy et al. 2015).

– Pathological manifestation: The histopathological find-ings in Hand-Schüller-Christian disease are similar toother LCH entities, including proliferation of Langerhanscells mixed with inflammatory cells including eosinophils,and lymphocytes. One unique finding is abundant pres-ence of lipid laden macrophages and foam cells in latestage (Bhargava et al. 2012).

– Prognosis and treatment: Prognosis depends on patient’sage at presentation, extent of the systemic involvement,and response to treatment. Bone marrow involvementcarries a poorer prognosis. Systemic chemotherapy isusually needed, and corticosteroids, vinblastine,etoposide, cytarabine, 6-mercapto purine, methotrexate,2-chlorodeoxyadenosine, cyclosporine, and thalidomideare used in different combination regimens (Lalitha et al.2015).

– Differential diagnosis: Acute leukemia, multiple mye-loma, hyperparathyroidism, and hypopituitarism (Cugatiet al. 2011).

3.1.3 Eosinophilic Granuloma (Histiocytosis X)– Definition: Eosinophilic granuloma or histiocytosis X

(chronic unifocal LCH) is a localized variant of LCHthat usually affects the bones of young adults. It can affectany bone, but involvement of skull, mandible, spine, ribs,and long bones is common (Angelini et al. 2017). Thelesion is usually solitary, but in some instances can bemultifocal (Roginić et al. 2013) (Figs. 14 and 15). Skinand mucous membrane lesions are rare.

– Clinical feature: The clinical features depend on site ofinvolvement. It usually presents as soft tissue mass andmay be asymptomatic or painful. Otitis media, proptosis,loose teeth, and pituitary dysfunction may develop fol-lowing involvement of temporal (and mastoid) bones,orbit, mandible, and sella turcica, respectively. Calvariallesions may extend to nervous system and then a variety ofneurological manifestations may be seen. Spontaneousfracture in long bones is known and spine involvementmay be associated with vertebral collapse, leading tospinal cord compression (Kaul et al. 2009).

– Pathological manifestation: Computed tomography(CT)-guided biopsy is done to confirm the diagnosiswhen clinical and radiological findings are not confirma-tory (Angelini et al. 2017). Biopsy shows pathognomonicproliferation of Langerhans cells mixed with chronic

Fig. 12 Langerhans cell histiocytosis with bone marrow involvement.(Taken by Dr. G Sethuraman, Department of Dermatology andVenereology, All India Institute of Medical Science, New Delhi, India)

Fig. 13 Langerhans cell histiocytosis with bone marrow involvement.(Taken by Dr. G Sethuraman, Department of Dermatology andVenereology, All India Institute of Medical Science, New Delhi, India)

Histiocytoses 7

inflammatory cells consisting of macrophages, eosino-phils, multinucleated giant cells, and lymphocytes(Roginić et al. 2013).

– Prognosis and treatment: The prognosis is excellent ifthere is no complication. Spontaneous resolution is knownand observation alone may suffice in asymptomatic bonelesions. Treatment options include immobilization, meth-ylprednisolone injections, radiofrequency ablation, localexcision and curettage with or without bone grafting,low-dose radiation therapy, and chemotherapy (Angeliniet al. 2017).

– Differential diagnosis: Osteomyelitis, leukemia, lym-phoma, fibrous dysplasia, and Ewing’s sarcoma.

3.1.4 Letterer-Siwe Disease– Definition: Letterer-Siwe disease (acute disseminated

LCH) is the most severe form of LCH and is predomi-nantly seen in children aged 2–3 years (Aricò 2016).

– Clinical feature: Skin lesions are present in almost 80%of patients at the time of presentation and are a valuableclue to clinical diagnosis. The eruption may be extensivebut are predominant on scalp, face, trunk, andintertriginous areas. Lesions consist of closely set pete-chiae, yellow-brown scaly papules and crust. The lesionsmay coalesce to form an erythematous, oozy, crustederuption (Fig. 16). Intertriginous areas are oozy and maydevelop secondary infection and ulceration. Systemicfindings are frequently associated and include fever, ane-mia, thrombocytopenia, pulmonary infiltrates (resulting inchest pain, hemoptysis, dyspnea, failure to thrive, cysticchanges, and pneumothorax), hepatosplenomegaly, andlymphadenopathy. Osteolytic lesions are not commonbut are known. Clinical features depend on bone involved.

Fig. 14 A and B: Histiocytosis X in an adult in two views. (Taken by Dr. Jean Luc Perrot, University Hospital of Saint-Etienne, France)

Fig. 15 Histiocytosis X in a child. (Taken by Dr. Jean Luc Perrot,University Hospital of Saint-Etienne, France)

Fig. 16 Letterer-Siwe disease. (Taken by Dr. Neena Khanna, Depart-ment of Dermatology and Venereology, All India Institute of MedicalScience, New Delhi, India)

8 S. K. Kothiwala et al.

Neurologic manifestations include seizure, vertigo, head-ache, ataxia, and cognitive defects (Grana 2014).

– Pathological manifestation: The diagnosis rests on dem-onstration of Langerhans cells on histopathology and fur-ther confirmed by immunostaining for CD1a, S100, andlangerin (Harmon and Brown 2015).

– Prognosis and treatment: Multiple internal organs arefrequently associated, and hence, Letterer-Siwe disease isassociated with a poor prognosis. Systemic chemotherapyis indicated, and a regimen consisting of cytotoxic drugsand systemic steroids is generally effective (Grana 2014).

– Differential diagnosis: Seborrheic dermatitis, systemicinfections like tuberculosis, and internal malignancy likeleukemia and lymphoma.

3.2 Non-Langerhans Cell Histocytosis

Non-LCH is reactive histiocytoses involving either cells withthe phenotype of the dermal dendrocyte (CD68+ and factorXIIIa+) (see Table 3) or cells with phenotype of other than

Langerhans cells and dermal dendrocytes. These diseases arereactive and cells accumulate in the skin and other tissuescausing tissue damage with no evidence of malignancy.Juvenile xanthogranuloma (JXG) is typical of this group ofdiseases, and some of the conditions described may not bespecific disease entities but clinical variants of a single dis-ease showing overlapping clinical features. The typical his-tological change is a xanthogranulomatous reaction, althoughthe histological changes reflect the cell type present. Thischapter has classified Non-LCH on the basis of cutaneousor systemic involvement.

3.2.1 Primarily Cutaneous

Juvenile Xanthogranuloma (JXG)– Definition: JXG is the commonest non-LCH disorder. It is

a benign proliferative disorder of histiocytes that sponta-neously regresses. It most commonly affects infants andyoung children, though lesions have been reported in theadult and elderly (Zvulunov et al. 1995).

– Clinical feature: Cutaneous lesions are the commonestpresentation of JXG. The most common site for JXG ishead and neck followed by the upper torso and the extrem-ities. It has two clinical variants: The more common, largenodular form is characterized by one or a few firm rubberyyellow brown nodules 1–2 cm in diameter, whereaspatients with micronodular form can present with manypink to red-brown, dome-shaped papules, 2–5 mm indiameter (Fig. 17). Oral JXG is uncommon and usuallypresents as a solitary yellow nodule on the lateral aspect ofthe tongue or midline of the hard palate. Unusual morpho-logic presentations include keratotic, pedunculated, sub-cutaneous, clustered, plaque-like, and giant lesions(Newman et al. 2007).

Table 3 Immunohistochemistry markers of non-Langerhans cellhistiocytes

S-100 CD1a Langerin CD68

FactorXIIIa

Langerhans cellhistiocytoses

+ + + � �

Non-Langerhans cell histiocytoses

Juvenilexanthogranuloma

� � � + +

Benign cephalichistiocytosis

� � � + +

Generalizederuptivehistiocytoma

� � � + +

Papular xanthoma � � � + +

Progressive nodularhistiocytosis

� � � + +

Diffuse planexanthomatosis

� � � + +

Hereditaryprogressivemucinoushistiocytosis

� � � + +

Xanthomadisseminatum

� � � + +

Necrobioticxanthogranuloma

� � � + �

Multicentricreticulohistiocytosis

� � � + _

Rosai-Dorfmandisease

+ � � + _

Erdheim-Chesterdisease

� � � +

Familial sea bluehistiocytosis

� � � + Fig. 17 Juvenile xanthograuloma. (Taken by Dr. Neena Khanna,Department of Dermatology and Venereology, All India Institute ofMedical Science, New Delhi, India)

Histiocytoses 9

Extracutaneous lesions have been reported most com-monly in eye followed by lungs, central nervous system,and bone. Ocular involvement usually occurs before2 years of age and often affects the iris. Hyphema (hem-orrhage into the anterior chamber) and glaucoma are seri-ous complications which can result in blindness (Changet al. 1996).

– Pathological manifestation: JXG is characterized by awell-demarcated dense dermal histiocytic infiltrate andTouton giant cells which are multinucleated, with homo-geneous eosinophilic cytoplasmic center and xanthoma-tization in the periphery (Fig. 18). Stain for factor XIIIa,CD68, CD163, CD14, and fascin are positive. In extra-cutaneous JXG lesions, Touton cells are absent or reducedin numbers (Hernandez-Martin et al. 1997).

– Prognosis and treatment: Because of the self-limitingnature of the eruption, usually no treatment is required.Ocular lesions often require intervention (e.g., topicalcorticosteroids for iris lesions, excision for limbal lesions).The sites of systemic involvement can be followed with-out treatment unless their location interferes with normalfunction. Various chemotherapeutic regimens, radiother-apy, high-dose systemic corticosteroids, and cyclosporinehave been attempted in isolated case reports.

– Differential diagnosis: Spitz nevi, molluscumcontagiosum, mastocytomas, and dermatofibromas.

Benign Cephalic Histiocytosis– Definition: Benign cephalic histiocytosis (BCH) is a rare,

self-limiting histiocytic proliferative disorder of infantsand young children, affecting the head and neck primarily.Many consider BCH as a clinical variant or a milder form

of juvenile xanthogranuloma without systemicinvolvement.

– Clinical feature: BCH typically presents as 2–5 mm,yellow to red-brown macules and papules on the cheeks,forehead, ears, and neck which flatten, become hyper-pigmented, and often vanish completely over months oryears (Jih et al. 2002). Systemic involvement in the formof diabetes insipidus has been reported, but is extremelyuncommon (Weston et al. 2000).

– Pathological manifestation:Histologic patterns include apapillary dermal pattern, a diffuse pattern, and a lichenoidpattern. The early lesions show papillary dermal patternwhich is characterized by a circumscribed infiltrate com-posed of pleomorphic histiocytes, scattered lymphocytes,and eosinophils (Fig. 19). In diffuse pattern, pleomorphichistiocytes are rare and infiltrate is dispersed throughoutthe dermis. In lichenoid pattern, perivascular small regularhistiocytes and occasional lymphocytes are seen in thesuperficial dermis. In all forms, Touton cells are absent(Gianotti et al. 1993). The histiocytes in BCH expressCD11b, CD14b, and HAM56 in additional to classicalNon-LCH markers. Infiltrated cells may show commashape bodies on electron microscopy.

– Prognosis and treatment: BCH is generally a self-limiting disorder and usually no treatment is usuallyneeded. Regular follow-up is recommended, consideringrare association of diabetes insipidus.

– Differential diagnosis: Langerhans cell histiocytosis,non-Langerhans cell histiocytosis, in particular juvenilexanthogranuloma and generalized eruptive histiocytoma.

Fig. 18 Juvenile xanthograuloma; diffuse pan dermal infiltrate ofxanthomatized cells and spindled histiocytes with few giant cells x10H&E. (Taken by Dr. Asha Kubba, Delhi Dermpathology Laboratory,New Delhi, India)

Fig. 19 Benign cephalic histiocytosis; dermal infiltrate of histiocytes,eosinophilic cytoplasm admixed with occasional giant cell x10 H&E.(Taken by Dr. Asha Kubba, Delhi Dermpathology Laboratory, NewDelhi, India)

10 S. K. Kothiwala et al.

Generalized Eruptive Histiocytosis– Definition: Generalized eruptive histiocytosis (GEH) is a

rare form of cutaneous histiocytosis, mainly affectingadults and may have male predilection. Occasionally ithas also been described in children (Jang et al. 1999).

– Clinical feature: The eruption is characterized by recur-rent crops of red to brown papules, less than 1 cm

distributed symmetrically on the trunk, proximal extrem-ities, and occasionally the face and mucosa. Flexures areusually spared (Figs. 20 and 21). The lesions either resolvecompletely within months or leave behind hyper-pigmented macules or small scars. Mucosal surfaces areoccasionally involved, and systemic involvement has notbeen observed (Seward et al. 2004).

– Pathological manifestation: The superficial and mid der-mis typically contain a nearly uniform infiltrate of histio-cytes with a few lymphocytes. No giant cells or foam cellsare present.

– Prognosis and treatment: The disease is generally self-limiting and often does not require treatment. The efficacyof PUVA therapy, chloroquine, thalidomide, and gluco-corticoid therapy has been reported (Repiso et al. 1995).

– Differential diagnosis: Langerhans cell histiocytosis,urticarial pigmentosa, eruptive syringomas, widespreadpapular granuloma annulare, and other non- Langerhanscell histiocytosis.

Papular Xanthoma– Definition: Papular xanthoma is a rare histiocytic disorder

characterized by normolipemic xanthomatosis that affectsadults more frequently than children.

– Clinical feature: It is characterized by asymptomaticyellow or reddish yellow papulonodular lesions mostlyinvolving back and head with no tendency to merge intoplaques (Winkelmann 1981). The back and head are themost common locations. Mucosal involvement and riskfor disease progression are features of adult presentation.Most of cases are normolipemic but abnormal lipid profilehas also been reported (Burgdorf 2010). Involution takesweeks to months and lesions may heal with anetodermalike scarring (Sanchez et al. 1985).

Fig. 21 Generalized eruptive histiocytosis. (Taken by Dr. Sudhir Singh, Department of Dermatology and Venereology, Jawahar Lal Institute ofMedical Sciences, Nagpur, India)

Fig. 20 Generalized eruptive histiocytosis. (Taken by Dr. SudhirSingh, Department of Dermatology and Venereology, Jawahar Lal Insti-tute of Medical Sciences, Nagpur, India)

Histiocytoses 11

– Pathological feature: Histologically, there is an upperand mid dermal infiltrate of foamy histiocytes and giantcells and few inflammatory cells.

– Prognosis and treatment: No treatment is needed inchildren, while none has been shown to be effective inadults.

– Differential diagnosis: Micronodular form of juvenilexanthogranuloma, xanthoma disseminatum andxanthomatous lesions of chronic progressive form ofLangerhans cell histiocytosis.

Progressive Nodular Histiocytosis– Definition: Progressive nodular histiocytosis (PNH) is a

rare benign variant of non-LCH disorders that more com-monly occurs in adults than children which characterizedby progressive involvement of skin as well as mucosa.

– Clinical feature: The skin manifestations consist of twotypes of lesions: superficial yellow-orange papules rang-ing 2–10 mm in diameter and deeper subcutaneous nod-ules which are 1–5 cm in size and may be skin colored orreddish orange due to overlying telangiectasia. Distribu-tion is random with no predilection for the flexures(Fig. 22). Extracutaneous lesions have been observed inthe oral cavity, larynx, and conjunctival mucosa (Tauntonet al. 1978). Except for one patient with an associationwith leukemia (Gonzalez et al. 2000), there seems to be noassociation with malignancies or visceral involvement.

– Pathological manifestation: Histologically, early lesionsshow an accumulation of xanthomatized and scallopedhistiocytes with some infiltrating lymphocytes. In olderlesions, the histiocytes are spindle shaped and arranged ina storiform pattern. Occasional giant cells may be present(Glavin et al. 2009).

– Prognosis and treatment: PNH does not have tendencyto spontaneous involution and can result in severe disfig-urement with time (Torres et al. 1993; Robinson et al.1963). No treatment has yet been demonstrated to beeffective in inducing remission. Large or painful lesionsare usually excised.

– Differential diagnosis: Other factor XIIIa-positive non-Langerhans cell histiocytoses like multifocal juvenilexanthogranuloma and generalized eruptive histiocytosis.

Diffuse Plane Xanthomatosis– Definition: Diffuse plane xanthomatosis (DPX) is a rare,

non-inherited form is which generally seen in adults, butrare pediatric cases have been reported. It has been recog-nized to be associated with hematological diseases, espe-cially with multiple myeloma and monoclonalgammopathy.

– Clinical feature: Patients present with large, flat, plaque-like xanthomatous skin lesions involving the head, neck,periorbital area, upper trunk, buttocks, and flexures (Alt-man and Winkelmann 1962). Serum lipids are usuallynormal. Multiple myeloma and monoclonal gammopathyare the two most frequently associated diseases with DPX(Lynch and Winkelmann 1966). However, associationwith many other lymphoproliferative disorders has beenreported.

– Pathological manifestation: The histological featuresinclude accumulations of foamy macrophages infiltratethe dermis, with a distinct perivascular accentuation, andare associated with a variable degree with a mixed inflam-matory cell reaction (Tran et al. 2016).

– Prognosis and treatment: Treatment of this condition isthat of the underlying myeloproliferative disease or para-proteinemia. In patients with limited involvement, theindividual lesions can be excised. Other options includechemoabrasion, dermabrasion, and ablative laser therapy(Lorenz et al. 2001).

– Differential diagnosis:Non-Langerhans cell histiocytosislike juvenile xanthogranuloma, Erdheim-Chester disease,and other eruptive xanthomas.

Hereditary Progressive Mucinous Histiocytosis– Definition: Hereditary progressive mucinous histiocytosis

(HPMH) is a rare autosomal dominant genodermatosis. Ithad been described exclusively in female till year 2010.Three cases have been reported in males (Nguyen et al.2015; Schlegel et al. 2010).

– Clinical feature: Skin lesions appear in the first decade oflife and gradually increase throughout life. The lesionsconsist of 1–3 mm skin colored to red brown, smooth,shiny papules lacking epidermal changes. Areas of predi-lection include nose, hands, forearms, and thighs. Lesions

Fig. 22 Progressive nodular histiocytosis. (Taken by Dr. NeenaKhanna, Department of Dermatology and Venereology, All India Insti-tute of Medical Science, New Delhi, India)

12 S. K. Kothiwala et al.

are usually asymptomatic, although mild pruritus has beendescribed. Lesions may be prone to bleeding with minimaltrauma. Systemic involvement has not been reported(Nguyen et al. 2015).

– Pathological manifestation: Histopathologically, withinthe dermis there are small collections of epithelioid his-tiocytes with telangiectatic vessels in the upper dermis inearly lesions. As lesion increases in size, the infiltratechanges to nodular mid dermal aggregates of tightlypacked, spindle-shaped cells. There is moderate to exten-sive mucin in upper and mid dermis. On electron micros-copy, the spindle-shaped cells are shown to be dendritichistiocytes with abundant lysosomal storage organelles,myelin bodies, and zebra bodies. Immunohistochemically,these cells stain with MS1 (Bork 1994).

– Prognosis and treatment: The condition is progressive,with failure of individual lesions to involute spontane-ously. With thalidomide, no new lesions were reported,although there was no change in existing lesions, whileintralesional triamcinolone showed some efficacy(Narvaez-Rosales et al. 2013).

– Differential diagnosis: Benign non-Langerhans cellhistiocytosis, molluscum contagiosum, papular granulomaannulare, acral popular mucinosis, and scleromyxedema.

Xanthoma Disseminatum– Definition: Xanthoma disseminatum (XD) is a rare,

benign, mucocutaneous non-Langerhans cell histocytosischaracterized by orange to yellow-brown papules,plaques, and nodules distributed mainly on flexures. It isoften associated with diabetes insipidus.

– Clinical feature: XD is usually seen in young age groupbut rarely can occur in elderly people also. Its lesions areround to oval, orange to yellow-brown papules and nod-ules occurring over flexures mainly. Neck, axilla, ante-cubital fossa, perianal area, and groins are the mostcommonly affected sites. Mucosal involvement is alsonot uncommon and is present in around 50% cases(Figs. 23 and 24). Mouth, conjunctiva, larynx, pharynx,and trachea are commonly affected (Caputo et al. 1995).The lesions are usually widespread but may be localized insmall number of cases. Meningeal involvement is notuncommon and leads to diabetes insipidus (Mahajanet al. 2013). XD may persist or regress spontaneously.The persistent form may progress to involve internalorgans.

– Pathological manifestation: Histiocyte proliferationleading to lipid deposition is the basic pathology. Diagno-sis is made by presence of scalloped macrophages, foamycells, Touton and foreign body giant cells. Immunohisto-chemical markers for XD are CD68, CD11b, CD14,

CD11c, and factor XIIIa. XD histiocytes also stain forlysozyme and αI-antitrypsin (Zelger et al. 1992).

– Prognosis and treatment: XD may regress spontane-ously or remain persistent. Various treatment modalitiesare used like corticosteroids, chemotherapy, radiotherapy,cryotherapy, CO2 laser therapy, and surgical excisioneither alone or in combination. No single therapy iseffective.

Fig. 23 Xanthoma disseminatum. (Taken by Dr. Sudhir Singh, Depart-ment of Dermatology & Venereology, Jawahar Lal Institute of MedicalSciences, Nagpur, India)

Fig. 24 Xanthoma disseminatum. (Taken by Dr. Sudhir Singh, Depart-ment of Dermatology & Venereology, Jawahar Lal Institute of MedicalSciences, Nagpur, India)

Histiocytoses 13

– Differential diagnosis: Generalized eruptivehistiocytosis, progressive nodular histiocytosis, andnecrobiotic xanthogranuloma.

Necrobiotic Xanthogranuloma– Definition: Necrobiotic xanthogranuloma (NXG) is a

rare, progressive, locally destructive non-Langerhanshistiocytosis and is strongly associated with hematologicmalignancies.

– Clinical feature: NXG usually occurs in elderly peoplewith equal sex distribution. The lesions are asymptomatic,yellow, and brown to orange color, soft papules, nodules,or plaques around the eyes (Mehregan and Winkelmann1992) (Figs. 25 and 26). Ocular involvement may causeblurring of vision, diplopia, and transient loss of vision.Restricted ocular motility, proptosis, and blepharotosismay also occur (Ugurlu et al. 2000). NXG may also affectinternal organs like spleen, liver, lymph nodes, heart, lung,kidney, pharynx, larynx, and central nervous system(Mehregan and Winkelmann 1992). Hematologic malig-nancies and lymphoproliferative malignancies are oftenassociated with NXG (Fernández-Herrera and Pedraz2007).

– Pathological manifestation: The diagnosis is based ondemonstrating histiocytes and multinucleated giant cellsspecially Touton’s giant cell which shows wreath of nucleiaround homogenous cytoplasmic center.

– Prognosis and treatment: Clinical course of NXG ischronic and progressive. There is no single effective treat-ment modality till date. Chemotherapy with chlorambuciland corticosteroid either alone or in combination is themost commonly used modality (Wood et al. 2009). Meth-otrexate, melphelan, intralesional corticosteroid, and sur-gical excision are other treatment options (Mehregan andWinkelmann 1992).

– Differential diagnosis: Necrobiosis lipoidicadiabeticorum, granuloma annulare, foreign body granu-loma, juvenile xanthogranuloma, amyloidosis, andxanthoma disseminatum.

3.2.2 Primarily Systemic

Multicentric Reticulohistiocytosis– Definition: Multicentric reticulohistiocytosis (MRH) is a

rare systemic non-NLH characterized by papulonodularskin eruptions often associated with arthritis.

– Clinical feature: MRH is a rare disease and mostlyreported in middle-aged females although childhood dis-ease is also reported (Barrow and Holubar 1969). It pre-sents as symmetric erosive polyarthritis with affection ofdistal interphalangeal joints mostly (Santilli et al. 2002)(Fig. 27). Other joints like hands, knees, shoulders, hips,

ankles, elbows, feet, and spine may also get affected. Skinlesions comprise of brown to reddish-brown asymptom-atic papules and nodules over dorsal aspects of hands, theelbows, and the head. Systemic symptoms related to car-diac, pulmonary, and muscular system involvement mayalso occur in MRH. Rheumatoid arthritis, Sjogren’s syn-drome (Ben Abdelghani et al. 2010), systemic vasculitis(Oliver et al. 1990), primary biliary cirrhosis (Dohertyet al. 1984), and even internal malignancy may be associ-ated with MRH (Han et al. 2012).

– Pathological manifestation: Diagnosis of MRH is con-firmed histologically by the presence of pleomorphicmononuclear histiocytes along with multinucleated giantcells in a PAS positive ground glass cytoplasm.

Fig. 25 Necrobiotic xanthogranuloma. (Taken by Dr. Neena Khanna,Department of Dermatology and Venereology, All India Institute ofMedical Science, New Delhi, India)

Fig. 26 Necrobiotic xanthogranuloma. (Taken by Dr. Kanya RaniVashisht, Aura Skin Institute, Chandigarh, India)

14 S. K. Kothiwala et al.

– Prognosis and treatment: MRH may remit by itself in5 years. Treatment is needed in inflammatory period toavoid the irreversible sequelae. No definite treatment pro-tocol is available for MRH due to paucity of cases. Meth-otrexate, chlorambucil, cyclophosphamide, azathioprine,and leflunomide all have shown response in MRH alongwith NSAIDs and corticosteroids (Liang and Granston1996). MRH also responded well to biologicals likeetanercept, infliximab, and adalimumab.

– Differential diagnosis: Rheumatoid nodules, sarcoidosis,B cell lymphoma, and gout.

Rosai-Dorfman Disease– Definition: Rosai-Dorfman disease (RDD) or sinus

histiocytosis with massive lymphadenopathy (SHML) isa rare disease of unknown etiology, clinically character-ized by bilateral massive cervical lymphadenopathy withor without extranodal involvement.

– Clinical feature: RDD can occur in any age group andrace but mostly present during first or second decade withmale to female ratio of 2:1. It presents as bilateral massiveswelling of the cervical lymph nodes along with fever,weight loss, leukocytosis, and raised erythrocyte sedimen-tation rate (ESR). Less commonly axillary, mediastinal,and para-aortic lymph nodes may also get involved.Sometimes extranodal involvement is noted. Extranodalsites involved are eyes and ocular adenexa, upper respira-tory tract, skin and subcutaneous tissue, bones, gastroin-testinal tract, head, neck, central nervous system, breast,

salivary glands, and cervix of uterus (Bhasker et al. 2003)(Fig. 28).

– Pathological manifestation: Diagnosis of RDD is con-firmed by demonstrating large histiocytes with vesicularnuclei, distinct nucleoli, and pale cytoplasm. Lymphopha-gocytosis (emperipolesis) is seen with intracytoplasmicred blood cells, neutrophils, and plasma cell (Figs. 29,30, 31, 32, 33, 34, and 35). Histiocytes in RDD arepositive for S-100 protein, HAM- 56 (Azoury and Reed1966), and Leu-M3 antigens (Bhasker et al. 2003).

– Prognosis and treatment: RDD runs an indolent coursewith half of the cases resolves itself without any sequelae.In few cases symptoms may persist for long. There is no

Fig. 28 Rosai-Dorfman disease. (Taken by Dr. G Sethuraman, Depart-ment of Dermatology and Venereology, All India Institute of MedicalScience, New Delhi, India)

Fig. 29 Rosai-Dorfman disease; histiocytes with abundant eosinophiliccytoplasm, few spindled, xanthomatized histiocytes; some cells showemperipolesis. (Taken by Dr. Asha Kubba, Delhi Dermpath Laboratory,New Delhi, India)

Fig. 27 Multicentric reticulohistiocytosis. (Taken by Dr. Kanya RaniVashisht, Aura Skin Institute, Chandigarh, India)

Histiocytoses 15

definitive treatment for RDD. Surgery, chemotherapy,radiotherapy, and corticosteroids are the treatment optionwith variable results (Raveenthiran et al. 2003).

– Differential diagnosis: B-cell lymphoma.

Erdheim-Chester Disease– Definition: Erdheim-Chester disease (ECH) is a very rare,

aggressive, non- Langerhans histiocytosis of unknownetiology characterized by histiocytic infiltration of viscera,bones, retroperitoneum, and skin.

– Clinical feature: ECH may affect bones, heart, lung,kidneys, liver, pituitary gland, retroperitoneum, and skin.It occurs in adulthood with an average age of onset of

53 years. Males more frequently affected than females.Most common presentation is chronic mild bone pain oflower limbs. Cutaneous involvement is seen in 20% ofcases and lesions resemble xanthoma and present mostlyon eyelids. Trunk and submammary area may also beoccasionally affected. Other extraosseous and extra-cutaneous manifestations are exophthalmos, paplliedema,diabetes insipidus, renal failure, lung diseases, cardiomy-opathy, central nervous system disorders (Abdellateefet al. 2016).

– Pathological manifestation: Histopathological examina-tion shows infiltration with histiocytes along with fibrosis(Rush et al. 2000).

Fig. 30 Rosai-Dorfman disease. A and B: storiform spindled rectal mass in a 45-year-old female (taken by Dr. Bre Ana M. David, Department ofAnatomic Pathology, University of Virginia Health System, Charlottesville, VA, USA)

Fig. 32 Rosai-Dorfman disease; rectal mass demonstrating classicemperipolesis with engulfment of lymphocytes. (Taken by Dr. BreAna M. David, Department of Anatomic Pathology, University of Vir-ginia Health System, Charlottesville, VA, USA)

Fig. 31 Rosai-Dorfman disease; rectal mass demonstrating abundantfoamy histiocytes and scattered plasma cells. (Taken by Dr. Bre AnaM. David, Department of Anatomic Pathology, University of VirginiaHealth System, Charlottesville, VA, USA)

16 S. K. Kothiwala et al.

– Treatment and prognosis: There is no specific treatmentfor ECD. Various options include IFN-α (Esmael et al.2001), corticosteroids, radiotherapy, vinblastine, cyclo-phosphamide, vincristine, and 2-chlorodeoxyadenosine.Response is variable (Veyssier-Belot et al. 1996).

– Differential diagnosis: Langerhans cell histiocytosis,Rosai-Dorfman disease, Wegener’s granulomatosis, mul-tiple sclerosis, Paget’s disease, and sarcoidosis.

Familial Sea Blue Histiocytosis– Definition: Familial sea blue histiocytosis(SBSH) is an

autosomal recessive, rare, hereditary, non-Langerhans cellhistiocytosis of unknown etiology characterized by

infiltration of lipid laden histiocytic cells in bone marrowand other tissues. The cytoplasmic granules of the histio-cytes characteristically stain deep azure blue withMay-Grunwald stain, hence the name “sea-bluehistiocytosis.”

– Clinical feature: SBSH is a multisystemic disease andmay affect lungs, gastrointestinal tract, spleen, lymphnodes, eyes, and central nervous system (Etcheverryet al. 1991). It usually manifests in young adults ashepatosplenomgaly, thrombocytopenia, and cardiac, eye,and lung diseases. Cutaneous lesions may vary frompatchy gray-brown hyperpigmentation, petechiae to nod-ular eruptions over face, chest, and shoulders (Zina et al.1987). Ataxia, epilepsy, and dementia may present asneurological symptoms (Landas et al. 1985). It sometimesmay be associated with myelodysplastic syndromes(Pongas 2013), lymphomas, chronic myelogenous leuke-mias, idiopathic thrombocytopenic purpura and Neimann-Pick disease (Dewhurst et al. 1979).

– Pathological manifestation: Diagnosis of SBSH is con-firmed by histopathological findings. There is large mono-morphic histiocytic infiltration with cytoplasmic granulescharacteristically stains deep azure blue withMay-Grunwald stain. Granules appear yellow brownwith H&E stain and dark blue with Giemsa and Toluidineblue stain. Under polarized light birefringence may alsobe seen.

– Treatment and prognosis: It is a benign disease, butdisseminated disease with multisystemic involvementmay cause death (Landas et al. 1985). There is no specifictreatment for SBSH. Bone marrow transplantation,enzyme replacement therapy, and gene therapy may helpin SBSH. Prognosis is fatal if central nervous system is

Fig. 33 Rosai-Dorfman disease; immunostaining for S100 protein.(Taken by Dr. Bre Ana M. David, Department of Anatomic Pathology,University of Virginia Health System, Charlottesville, VA, USA)

Fig. 34 Rosai-Dorfman disease; perirectal lymph node around rectalmass showing sinus histiocytic proliferation with germinal center dis-ruption. (Taken by Dr. Bre Ana M. David, Department of AnatomicPathology, University of Virginia Health System, Charlottesville, VA,USA)

Fig. 35 Rosai-Dorfman disease; perirectal lymph node around rectalmass showing the subcapsular sinus histiocytic accumulation. (Taken byDr. Bre Ana M. David, Department of Anatomic Pathology, Universityof Virginia Health System, Charlottesville, VA, USA)

Histiocytoses 17

affected and milder if other systems are affected(Etcheverry et al. 1991).

– Differential diagnosis: Neimann-Pick disease.

3.3 Malignant Histiocytosis

Malignant histiocytoses are extremely rare tumors that orig-inate from the dendritic and macrophages lineage of cells.Based on clinical features, these can be separated into mono-cytic leukemia, malignant histiocytosis, true histiocytic lym-phoma, and histiocytic sarcoma.

3.3.1 Malignant Histiocytosis– Definition: Malignant histiocytosis is widespread neo-

plastic proliferation of sinusoidal histiocytic cells thattypically involves liver, spleen, lymph nodes, and bonemarrow.

– Clinical feature: It occurs more commonly in male withmedian age of 35 years. It is characterized by acute onset,with fever, sweats, wasting, generalized painful lymph-adenopathy, and hepatosplenomegaly and with progres-sion jaundice, purpura, anemia, and leukopenia mayoccur. Most common extranodal involvement includesskin (10–15%), bone, and gastrointestinal tract. Skininvolvement presents as single or multiple skin coloredto violaceous papulonodular lesions on lower limb andbuttocks with ulceration in large lesions. In the bone, thelesions are focal, destructive, and lytic with association ofhypercalcemia (Demers et al. 2009).

– Pathological feature: The skin and lymph nodes showsimilar histopathological features and the diagnosis can beestablished in either site. Characteristically, there is aninfiltrate of histiocytic cells showing varying degrees ofatypia that are typically non-cohesive. Cells are large(up to 50 μm in diameter) with abundant cytoplasm anddistinct cytoplasmic membranes. The histiocytic cells areheterogeneous. In the skin, there is extensive perivascularand periappendageal infiltration of the dermis, with exten-sion into the subcutaneous fat with fat necrosis and epi-dermal ulceration in advanced and large lesions. Cells arenegative for chloroacetate esterase, Sudan black B, alka-line phosphatase, and β-glucuronidase. The more differ-entiated phagocytosing cells usually stain for factor XIIIaand the anti-monocyte monoclonal antibody (Low andStafford 2006).

– Treatment and prognosis: Conventional chemotherapyand radiotherapy remain the mainstay of treatment. It wasinvariably lethal in the past, with death occurring withinweeks to months of diagnosis. However, with aggressivemanagement complete remission has been reported in up

to 50% of cases, with a mean duration of complete remis-sion of over 12 months (Demers et al. 2009).

– Differential diagnosis: Large cell anaplastic lymphomas,familial hemophagocytic lymphohistiocytosis, virus-associated hemophagocytic syndrome, and Hodgkindisease.

3.3.2 True Histiocytic Lymphoma– Definition: True histiocytic lymphoma is low-incident,

poor-prognostic histiocytic malignancy that represents amore differentiated malignant proliferation of non-LCHthan malignant histiocytosis (Chaín et al. 2004).

– Clinical feature: Majority of patients presents with pain-less enlargement of one or more group of superficiallymph nodes. Extranodal involvement of bone and gas-trointestinal tract is similar to malignant histiocytosis.Skin lesions are localized red-blue tumors that mayenlarge with time.

– Pathological feature: Infiltrating cells of true histiocyticlymphoma are more differentiated and homogenous thanthose in malignant histiocytosis. Cells express positivityfor factor XIIIa and negative for macrophage markersCD11c and CD68.

– Treatment and prognosis: It is both radiosensitive andchemosensitive. Complete remission has been achieved inlocalized skin disease using electron beam therapy.

– Differential diagnosis: Malignant histiocytosis, B and Tcell lymphoma.

3.3.3 Histiocytic Sarcoma– Definition: Histiocytic sarcoma is extremely rare,

non-LCH disorder of unknown cause that most commonlypresents with extranodal tumors and most of the time it isdiagnosis of exclusion.

– Clinical feature: It most commonly occurs in adults ofany age without gender predilection. Most commonlyaffected sites are the intestinal tract, skin, and soft tissueswhich can be involved in localized or generalized pattern(Takahashi and Nakamura 2013).

– Pathological feature: Histiocytic sarcoma shows wide-spread infiltration of large, epithelioid cells with round tooval nuclei, large distinct nucleoli, finely to moderatelydispersed chromatin, and abundant cytoplasm that is aci-dophilic with H&E and grayish with Giemsa staining.Binucleated cells are also common. Tissue necrosis isnot prominent. Cells are reactive for CD45, CD68, lyso-zyme, and CD163. Langerhans cell–dendritic cell markerssuch as CD1a, CD21, and CD35 should be negative.

– Treatment and prognosis: Histiocytic sarcoma is anaggressive disease with poor prognosis. Disease withsmall, localized, low-grade tumors that are amenable to

18 S. K. Kothiwala et al.

surgical resection is having better outcome. Relapses arecommon.

– Differential diagnosis: B and T cell lymphoma.

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